DE3621112A1 - Non-racemic sulphoxides - Google Patents

Abstract

Novel non-racemic sulphoxides of the formula I <IMAGE> in which R<1> denotes H, A, OH, OA, SOnA, halogen, NH2, NHA, NA2, NO2 or CN, R<2> denotes A, -CH2CN, -CH2CONH2 or -CH2COOA, A denotes alkyl, alkenyl or alkynyl in each case having up to 4 C atoms and n denotes 0, 1 or 2, and their salts exhibit positively inotropic activity.

Description

The invention relates to new non-racemic mixtures Sulfoxides of the formula I.

wherein
R ¹ H, A, OH, OA, SO _n A, halogen, NH ₂ , NHA, NA ₂ , NO ₂ , or CN,
R ² A, -CH ₂ CN, -CH ₂ CONH ₂ or -CH ₂ COOA,
A alkyl, alkenyl or alkynyl each with up to 4 carbon atoms and
n is 0, 1 or 2,
as well as their salts.

Racemic compounds of the formula I, in particular racemic isomazole [2- (2-methoxy-4-methylsulfinylphenyl) imidazo [4,5-c] pyridine; corresponding to I, R ¹ = -OCH ₃ , SOR ² = p-SOCH ₃ ], are known from EP-A-72 926.

The synthesis of the new compounds creates for each enantiomer is only a form for which the structure the 3H-imidazo [4,5-c] pyridine (I) is adopted. The formation of the tautomeric is also possible 1H-Imidazo [4,5-c] pyridines I ′.

The compounds are therefore above and below as "Imidazopyridines", "Imidazo [4,5-c] pyridines" or "Compounds of formula I ″; these labels are said to be both the 3H tautomers (I) and the 1H tautomers Include (I ′).

The object of the invention was to create new connections with valuable properties, especially those used in the manufacture of medicines can be. This task is accomplished by providing of the non-racemic compounds of formula I and of their physiologically acceptable salts.

It has been found that these compounds are well tolerated valuable pharmacological properties have. In particular, they have an effect on the Blood pressure, heart strength (especially strong and long persistent positive inotropic efficacy) and ulcer Effect. The blood pressure and heart effects can e.g. B. on anesthetized or awake dogs, cats, monkeys or Mini pigs, which also have positive inotropic effects isolated cardiac preparations (e.g. atrium, papillary muscle or perfused whole heart) from rat, guinea pig or cat are determined, e.g. B. by methods as they in drug research, Volume 31 (I) No. 1a (1981), Pages 141 to 170.  

The compounds can therefore act as active pharmaceutical ingredients be used in human and veterinary medicine. They can also be used as intermediates for the manufacture other active pharmaceutical ingredients are used.

In the compounds of formula I, A is preferably Alkyl with 1-3 C atoms, in particular methyl, further preferred Ethyl, propyl, isopropyl, furthermore alkenyl with preferred 2 or 3 carbon atoms such as vinyl, allyl or propen-1 or -2-yl and alkynyl with preferably 2 or 3 carbon atoms such as ethynyl, propargyl or propin-1-yl Butyl, isobutyl, sec-butyl, tert-butyl, 1-butene-1-, -2-, -3- or -4-yl, 2-buten-1- or -2-yl, 2-methyl-1-propen-1- or -3-yl, 1-butyn-1-, -3- or -4-yl, 2-butin-1-yl.

Accordingly, R ^{1 is} preferably methoxy, and also H, methyl, ethyl, propyl, allyl, propargyl, OH, ethoxy, propoxy, allyloxy, propargyloxy, methylthio, ethylthio, propylthio, allylthio, propargylthio, methylsulfinyl, ethylsulfinyl, propylsulfinyl, propylsulfinyl , methylsulfonyl, ethylsulfonyl, propylsulfonyl, allylsulfonyl, propargylsulfonyl, F, Cl, Br, I, NH _2, methylamino, ethylamino, propylamino, allylamino, propargylamino, dimethylamino, diethylamino, dipropylamino, diallylamino, Dipropargylamino, NO ₂ or CN.

R ² is preferably methyl, and also ethyl, propyl, allyl, propargyl, -CH ₂ CN, -CH ₂ CONH ₂ , -CH ₂ COOCH ₃ or -CH ₂ COOC ₂ H ₅ .

R ¹ is preferably in the 2-position, SOR ² preferably in the 4-position of the phenyl ring.

Accordingly, those compounds of the formula I are particularly preferred in which at least one of the radicals R ¹ and R ^{2 has} one of the preferred meanings indicated and / or is in one of the positions indicated as preferred. Compounds of the formula I in which R ^{1 is} OCH ₃ and are in the o-position and in which the radical -SOR ^{2 is} in the p-position are particularly preferred. Of these, those in which R ^{2 is} CH ₃ are particularly preferred.

The invention further relates to a process for the preparation of non-racemic sulfoxides of the formula I and salts thereof, characterized in that a racemic mixture corresponding to the formula I is formed by salt formation with a non-racemic acid, subsequent separation of the diastereomers and release of the enantiomers or with the aid of others known methods split into the enantiomers
or that 3,4-diaminopyridine (II) with a non-racemic benzoic acid of the formula III or a non-racemic benzaldehyde of the formula IV in the presence of an oxidizing agent

wherein
R ¹ and R ^{2 have} the meanings given
or with one of their derivatives
or that a thioether corresponding to formula I is oxidized or enzymatically oxidized in the presence of a non-racemic auxiliary
or that a non-racemic ester of the formula V

wherein
R ^{3 represents} the residue of a non-racemic ester group and
R ^{1 has} the meaning given with an organometallic compound of the formula VI

R ² -M (VI)

M denotes MgCl, MgBr, MgJ or Li and
R ² has implemented the meaning given
or liberating a non-racemic compound of formula I from one of its functional derivatives
and / or that a non-racemic base of the formula I is converted into one of its salts by treatment with an acid.

The compounds of formula I are in the rest of known methods, such as those in the Literature (e.g. in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart; but in particular described in EP-A-72 926) are, and under reaction conditions that for the implementations mentioned are known and suitable. It is also possible to do this from known ones, not here make use of the variants mentioned in more detail.

If desired, the starting materials can also be in situ are formed such that they can be removed from the reaction mixture not isolated, but immediately to the Reacts compounds of formula I. On the other hand, it is possible to carry out the reaction in stages, whereby one can isolate further intermediates.

The non-racemic sulfoxides are preferably obtained of the formula I by using a formula I corresponding racemic mixture according to known methods cleaves mechanically or chemically into the enantiomers. In particular, one can from the racemate with a non-racemic Form acid diastereomeric salts. As acids are z. B. the D and L forms of tartaric acid, Dibenzoyl tartaric acid, diacetyl tartaric acid, camphorsulfonic acids, Mandelic acid, malic acid or lactic acid. The Diastereomers can in a conventional manner, for. B.  by fractional crystallization, separated, and the non-racemic compounds (enantiomers) of the formula I. can from the diastereomers in a conventional manner be set free, e.g. B. by treatment with an inorganic base and subsequent isolation the non-racemic base.

Use instead of salts with non-racemic acids other derivatives, which form diastereomers, e.g. B. N-acyl derivatives with non-racemic acyl groups. It is also possible to use racemic mixtures of the formula I. correspond to split chromatographically by using a non-racemic adsorbent used. Suitable as such z. B. aminopropyl silica gel, to which in ionic Binding (R) -N- (3,5-dinitrobenzoyl) -phenylglycine bound (method see Acta Chem. Scand. B 37, (1983), 325-28).

The compounds of formula I can also be obtained by reaction of II with a benzoic acid Formula III or one of its reactive derivatives. Suitable reactive derivatives are particularly suitable the corresponding nitriles, acid halides, esters, amides, Imidic acid esters, imidic acid thioesters, imidic acid halides, Amidines, thiocarboxylic acid esters, dithiocarboxylic acid esters or orthoester.

Some of the starting materials II and III are known. If they are not known, they can be produced by methods known per se. Many benzoic acids of the formula III can be obtained, for example, by oxidation of corresponding R ² S-benzoic acids and subsequent optical cleavage with bases or by etherification of corresponding hydroxybenzoic acids.

In detail, the implementation of II with III in Presence or absence of an inert solvent at temperatures between about -20 and about 120 °, preferably between 60 and 100 °. Suitable as a solvent hydrocarbons such as benzene, toluene, Xylene or mesitylene; tertiary bases such as triethylamine, Pyridine or picolines, glycols and glycol ethers such as ethylene glycol, Diethylene glycol, 2-methoxyethanol; Ketones like Acetone; Ethers such as tetrahydrofuran or dioxane, amides such as Dimethylformamide; Sulfoxides such as dimethyl sulfoxide. Also Mixtures of these solvents are suitable. In some In some cases, the addition of catalytic amounts is recommended an acid such as p-toluenesulfonic acid or the addition of a Dehydrating agents such as phosphorus oxychloride, polyphosphoric acid or thionyl chloride, the dehydrating agent can also serve as a solvent.

If the free benzoic acids of the formula III are used, so the reaction is convenient in the presence of one of the mentioned dehydrating agent and optionally a tertiary base such as pyridine or triethylamine performed, preferably at temperatures between -20 and 100 °.

The implementation can also be carried out in stages. So it is z. B. possible to partially acylate II with an acid chloride of the formula Ar-COCl to 3-amino-4-ArCONH-pyridine or to 4-amino-3-ArCONH-pyridine (or to a mixture of the latter two isomers), the then z. B. with POCl ₃ , is dehydrated to I (Ar means the phenyl radical substituted by R ¹ and SOR ² ).

It is also possible to use the corresponding aldehyde of the formula IV instead of III if one works simultaneously in the presence of an oxidizing agent. Sulfur in a hydrocarbon such as benzene, toluene, xylene or mesitylene or sodium disulfite in solvents such as dimethylacetamide are preferably used as the oxidizing agent, in each case at temperatures between about 0 and about 120 °. This reaction variant is particularly suitable for the preparation of compounds of the formula I which contain groups (for example alkoxycarbonyl groups) which are not completely inert to certain dehydrating agents (for example POCl ₃ ). The aldehydes of formula IV can, for. B. by esterification etherification of corresponding hydroxy aldehydes or by reduction of acids of the formula III, the sulfoxide group also being able to be protected as an intermediate.

Furthermore, a thioether corresponding to formula I (I, -SR ² instead of -SOR ² ) can be oxidized or enzymatically oxidized in the presence of a non-racemic auxiliary.

For example, you can use (+) - or (-) - Diethyl tartrate in the presence of a titanium tetraalkoxide such as titanium tetraisopropoxide and a peroxide such as tert. Implement butyl hydroperoxide and water, appropriate in an inert solvent such as dichloromethane Temperatures between about -25 and + 30 ° (method cf. Tetrahedron Letters 1984. 1049-52; J. Amer. Chem. Soc. 106, (1984), 8188-93).

An enzymatic oxidation succeeds e.g. B. with cultures of Corneybacterium equi IFO 3730, e.g. B. in aqueous medium containing (NH ₄ ) ₂ HPO ₄ , K ₂ HPO ₄ , MgSO ₄ · 7 H ₂ O, FeSO ₄ · 7 H ₂ O, ZnSO ₄ · 7 H ₂ O, MnSO ₄ · 4 H ₂ O and yeast extract, pH 7.2, in the presence of an inert solvent such as hexadecane at about 20-35 ° (method see Chem. Lett. 1984, 205-08 and the literature cited there).

The non-racemic sulfoxides of the formula I can also be obtained by reacting non-racemic sulfinic acid esters of the formula V with organometallic compounds of the formula R ² -M (VI) (for a method see, for example, Tetrahedron Letters 1962, 93-95; J. Amer. Chem. Soc. 94 (1972), 4684-91).

In the esters V, R ³ denotes the residue of a non-racemic ester group, in particular a non-racemic hydrocarbon residue with 4-14 C atoms such as (+) - or (-) - sec-butyl, (+) - or (-) - menthyl. The esters V are e.g. B. available by esterification of corresponding sulfinic acids. The reaction of V with VI takes place under the usual conditions of reactions with organometallic compounds, advantageously in an inert solvent, for. B. an ether such as diethyl ether, at temperatures between 0 and 30 °; is then hydrolyzed, e.g. B. with aqueous NH ₄ Cl solution.

You can also use a non-racemic compound Formula I from one of its functional derivatives in freedom set, preferably by hydrolysis.

A preferred method is the liberation from corresponding non-racemic sulfoximines (corresponding to I, but -SO (= NR ⁵ ) -R ² instead of -SOR ² , in which R ⁵ denotes an amino protective group such as p-toluenesulfonyl) with the aid of H ₂ SO ₄ / NaNO ₂ in aqueous medium at temperatures between 0 and 30 °. The sulfoximines can be obtained, for example, by condensation of II with corresponding non-racemic sulfoximinobenzoic acids or benzaldehydes in the presence of an oxidizing agent.

A non-racemic base of formula I can with a Acid transferred to the associated addition salt will. Acids are suitable for this implementation deliver physiologically acceptable salts. So can inorganic acids are used, e.g. B. sulfuric acid, Nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as Orthophosphoric acid, sulfamic acid, also organic Acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic one or polybasic carboxylic, sulfonic or sulfuric acids, e.g. B. Formic acid, acetic acid, propionic acid, pivalic acid, Diethyl acetic acid, malonic acid, succinic acid, pimelic acid, Fumaric acid, maleic acid, lactic acid, tartaric acid, Malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, Citric acid, gluconic acid, ascorbic acid, Nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, Ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, Benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono- and disulfonic acids, lauryl sulfuric acid.

The invention also relates to the use of non-racemic compounds of formula I and their physiologically acceptable salts for production pharmaceutical preparations, especially non-chemical ones Ways. You can do this together with at least a solid, liquid and / or semi-liquid Carrier or auxiliary and optionally in combination with one or more other active ingredient (s) in one suitable dosage form are brought.

The invention also relates to pharmaceuticals Preparations containing at least one non-racemic Compound of formula I and / or one of its physiological harmless salts.  

These preparations can be used as medicinal products in human or veterinary medicine. As carriers organic or inorganic substances are possible, which are suitable for enteral (e.g. oral), parenteral or suitable topical application and with the new compounds do not react, e.g. water, vegetable oils, Benzyl alcohols, polyethylene glycols, glycerol triacetate, Gelatin, carbohydrates such as lactose or starch, magnesium stearate, Talk, Vaseline. For oral use of this in particular tablets, coated tablets, capsules, syrups, juices or drops, for rectal use suppositories, for parenteral application solutions, preferably oily or aqueous solutions, further suspensions, emulsions or Implants, for topical application ointments, creams or powder. The new compounds can also be lyophilized and the lyophilizates obtained e.g. B. for production used by injectables. The specified Preparations can be sterilized and / or auxiliary substances such as sliding, preserving, stabilizing and / or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, color, taste and / or flavorings. You can if desirable, also one or more other active ingredients included, e.g. B. one or more vitamins.

The invention also relates to the use of non-racemic compounds of formula I in the Fighting diseases, especially heart failure, as well as their use in therapeutic Treatment of the human or animal body.

The substances according to the invention are generally used in analogy to known positive inotropically active substances, such as sulmazole or amrinone, preferably in doses between about 10 and 500 mg, in particular between 20 and 100 mg per dosage unit. The  daily dosage is preferably between about 0.2 and 10 mg / kg body weight. The special dose for everyone However, certain patients depend on the most diverse Factors, for example on the effectiveness of the used special connection, by age, body weight, general health, gender, diet, the time and route of administration, the rate of excretion, Drug combination and severity the respective disease to which the therapy applies. Oral application is preferred. Compared to the previously used to treat heart failure Digitalis glycosides excel in the compounds of Formula I through improved therapeutic range and peripheral relief.

In the examples below, "customary workup" means:

If necessary, add water or dilute Sodium hydroxide solution added, extracted with an organic Solvents such as ethyl acetate, chloroform or dichloromethane, separates, the organic phase dries over Sodium sulfate, filtered, evaporated and cleaned through Chromatography and / or crystallization.

Above and below, all temperatures are given in degrees Celsius. [ α ] = [ α ] in methanol, c = 1.

example 1

A solution of 30.5 g of racemic 2- (2-methoxy-4-methylsulfinylphenyl) imidazo [4,5-c] pyridine (isomazole) in 1000 ml of butanone is mixed with 15.2 g (+) - mandelic acid , briefly warmed to dissolve the acid completely and left at 20 ° for 12 hours. The precipitated crude product (mp 110-152 °) is filtered off and recrystallized several times from butanone. (+) - Isomazole mandelate, mp 158-159 °; [ α ] + 119.5 °.

9.8 g of the salt are dissolved in 80 ml of water, made alkaline with sodium carbonate solution, the crude product is filtered off, dried, dissolved in methanol and precipitated by adding fumaric acid. (+) - Isomazole fumarate, mp 204-206 °; [ α ] + 46.9 °.

Analogously, (-) - mandelic acid gives the (-) - isomazole fumarate, mp 204-106 °; [ α ] -46.9 °.

Analogously you get:
(+) - 2- (2-Methylsulfinylphenyl) imidazo [4,5-c] pyridine
(-) - 2- (2-Methylsulfinylphenyl) imidazo [4,5-c] pyridine
(+) - 2- (2-methoxy-4-cyanomethylsulfinylphenyl) imidazo [4,5-c] pyridine
(-) - 2- (2-methoxy-4-cyanomethylsulfinylphenyl) imidazo [4,5-c] pyridine
(+) - 2- (2-methoxy-4-ethylsulfinylphenyl) imidazo [4,5-c] pyridine
(-) - 2- (2-methoxy-4-ethylsulfinylphenyl) imidazo [4,5-c] pyridine
(+) - 2- (2-chloro-4-methylsulfinylphenyl) imidazo [4,5-c] pyridine
(-) - 2- (2-chloro-4-methylsulfinylphenyl) imidazo [4,5-c] pyridine

Example 2

A solution of 2 g (+) - 2- (2-methoxy-4-N- (p-toluenesulfonyl) methylsulfoximino-phenyl) imidazo [4,5-c] pyridine (available from 3,4-diaminopyridine and (+) - 2-methoxy-4-N- (p-toluenesulfonyl) methylsulfoximino-benzoic acid) in 5 ml of H ₂ SO ₄ is stirred at 50 ° for 2 hours. It is diluted with water to 50 ml with cooling, 0.7 g of NaNO _{2 are} added in portions, the mixture is stirred at 20 ° for 1 hour, made alkaline with NaOH and evaporated. The residue is taken up with CH ₂ Cl ₂ / CH ₃ OH 1: 1 and filtered through silica gel. Evaporation of the filtrate gives a crude product which is chromatographed on silica gel with CH ₂ Cl ₂ / CH ₃ OH (9: 1). The free base obtained is converted into the (-) - isomazole fumarate; F. 204-206 °; [ α ] -46.9 °.

The following examples relate to pharmaceuticals Preparations, the compounds of formula I or their Acid addition salts contain:

Example A: tablets

A mixture of 1 kg (+) - isomazole fumarate, 4 kg lactose, 1.2 g potato starch, 0.2 kg talc and 0.1 kg magnesium stearate is pressed into tablets in the usual way, such that each tablet contains 100 mg of active ingredient.

Example B: coated tablets

Analogously to Example A, tablets are pressed, which are then in the usual way with a coating of sucrose, Potato starch, talc, tragacanth and color coated will.

Example C: capsules

10 kg (+) - isomazole fumarate in the usual way Hard gelatin capsules filled so that each capsule contains 50 mg Contains active ingredient.

Example D: ampoules

A solution of 1 kg (-) - isomazole fumarate in 100 l twice distilled water is sterile filtered, in ampoules filled, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 50 mg of active ingredient.

Analogs are tablets, coated tablets, capsules and ampoules, available that contain one or more of the remaining active ingredients of formula I and / or their physiologically acceptable Acid addition salts included.

Claims (7)

1. Non-racemic sulfoxides of the formula I wherein
R ¹ H, A, OH, OA, SO _n A, halogen, NH ₂ , NHA, NA ₂ , NO ₂ or CN,
R ² A, -CH ₂ CN, -CH ₂ CONH ₂ or -CH ₂ COOA,
A alkyl, alkenyl or alkynyl each with up to 4 carbon atoms and
n is 0, 1 or 2,
as well as their salts. 2. Non-racemic 2- (2-methoxy-4-methylsulfinylphenyl) - imidazole [4,5-c] pyridines and their salts. 3. A process for the preparation of non-racemic sulfoxides of the formula I and of their salts, characterized in that a racemic mixture corresponding to the formula I is formed by salt formation with a non-racemic acid, subsequent separation of the diastereomers and release of the enantiomers or using other methods known per se in cleaves the enantiomers
or that 3,4-diamione pyridine (II) with a non-racemic benzoic acid of the formula III or a non-racemic benzaldehyde of the formula IV in the presence of an oxidizing agent wherein
R ¹ and R ^{2 have} the meanings given
or with one of their derivatives
implements
or that a thioether corresponding to formula I is oxidized or enzymatically oxidized in the presence of a non-racemic auxiliary
or that a non-racemic ester of the formula V wherein
R ^{3 represents} the residue of a non-racemic ester group and
R ^{1 has} the meaning given
with an organometallic compound of the formula VIR ² -M, 6 (VI) wherein
M denotes MgCl, MgBr, MgJ or Li and
R ^{2 has} the meaning given
implements
or liberating a non-racemic compound of formula I from one of its functional derivatives
and / or that a non-racemic base of the formula I is converted into one of its salts by treatment with an acid. 4. Process for the preparation of pharmaceutical preparations, characterized in that a non-racemic Compound of formula I and / or one their physiologically acceptable salts together with at least one solid, liquid or semi-liquid Carrier or auxiliary and optionally in combination with one or more others Brings active ingredient (s) into a suitable dosage form. 5. Pharmaceutical preparation, characterized by contains at least one non-racemic Compound of formula I and / or one of their physiological harmless salts. 6. Use of non-racemic compounds of Formula I and / or its physiologically acceptable Salt in the fight against diseases. 7. Use of non-racemic compounds of Formula I and / or its physiologically acceptable Salts for the manufacture of medicinal products.