SK121494A3 - 1,2-dihydro-2-oxo-3-methylsulfonylaminomethylpiridines, method of their preparation, pharmaceutical agents on their base and method of their production - Google Patents

Abstract

Novel 1,2-dihydro-2-oxo-3-methylsulphonylaminomethylpyridines of the formula I <IMAGE> wherein R<1> is alkyl having 1-5 C atoms, R<2> is CN or 1H-tetrazol-5-yl and R<3> is alkyl having 1-5 C atoms or cyclopropylmethyl, and their salts show angiotensin II-antagonistic properties and can be used for the treatment of hypertension, aldosteronism and cardiac insufficiency.

Description

Technical field

The present invention relates to 1,2-dihydro-2-oxo-3-methylsulphonylaminomethylpyridines, a process for their preparation, pharmaceutical preparations based thereon and a process for their preparation, as well as the use of these derivatives for the manufacture of medicaments.

BACKGROUND OF THE INVENTION

Similar compounds are known from EP 0 530 702.

The general formula I is given in this publication

(I) wherein it represents a group of the general formula

R ^{@ 1} , R ^{@ 4} and R ^{@ 5} each also represent a hydrogen atom;

is also cyano or 5-tetrazolyl;

R ⁶ and R ¹⁰ are also alkyl and

R ¹¹ is also SO ₂ R ⁷ (wherein R ⁷ is also optionally alkyl) and

X may also be missing.

However, at no point in this publication are the compounds of formula (I) of the present invention otherwise indicated or otherwise understood, including individual compounds that fall within the scope of formula (I). optionally, compounds in which R and R are each C 1 -C 5 alkyl.

SUMMARY OF THE INVENTION It was an object of the present invention to provide novel compounds having valuable properties which can be used in particular in the manufacture of medicaments.

SUMMARY OF THE INVENTION

The present invention provides novel 1,2-dihydro-2-oxo-3-methylsulionylaminomethylpyridines of formula I

where

R ^J

R ⁴ is C 1 -C 5 alkyl;

is cyano or ΙΗ-5-tetrazolyl; and

R ³ is C 1 -C 5 alkyl or cyclopropylmethyl, as well as salts thereof.

It has been found that the compounds of formula I and their salts exhibit valuable pharmacological properties with good tolerability. In particular, they exhibit the properties of an angiotensin II antagonist and can thus be used as active ingredients of medicaments in human and veterinary medicine, in particular for the prophylaxis and / or treatment of cardiovascular, circulatory and vascular diseases, in particular elevated intraocular pressure as well as central nervous system disorders, as well as vascular and heart hypertrophy and hyperplasia, angina pectoris, heart attack, stroke, restenosis and post-angioplasty conditions in bypass operations, peripheral vascular ischemia, arteriosclerosis, glaucuremia, maculaucoma, macula renal function disorders such as renal failure, diabetic nephropathy, diabetic retinopathy and psoriasis; gastrointestinal diseases, bladder disorders, lung edema, chronic bronchitis, angiotensin II mediated diseases of the female reproductive organs, perceptual disorders such as dementia, amnesia, memory disorders, states of fear, depression, epilepsy, Parkinson's or / and Parkinson's syndrome.

These effects can be demonstrated by conventional in vitro or in vivo methods, as described, for example, in US 4,880,804, US 5,036,048 and WO 91/14367, in A. T. Chiu et al., J. Pharmacol. Exp. Therap. 250, 867-874 (1989) and in P. C. Wong et al., Ibid., 719-725 (1990, in vivo, in mice).

Potassium salts of 1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) -2-oxo-3-N-methyl- or -3-N-isopropyl-N-methylsulfonylaminomethyl 6-butylpyridine (Iy or Iz) thus show an IC 50 value of 1.15 and 1.9 nM.l ^-1 , ^respectively , in the adrenal gland (experimental methodology cf. AT Chiu et al., 1c), while the known 1,2- dihydrol- (2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) -2-oxo-3-methylsulfonylaminomethyl-6-butylpyridine (cf. EP 0 530 702 A1, Example 22) shows an IC 50 of 4 in the same test 0 nM.l ^-1 .

The present invention provides compounds of formula I and salts thereof, as well as a process for the preparation of these compounds and salts thereof, characterized in that the compound of formula II

E-CH

(II) wherein it represents a chlorine, bromine or iodine atom or a free or reactive functionally modified hydroxy group; and

R ² is as defined for formula I, with a compound of formula III

Where R and R are as defined in formula (I) or a reactive derivative thereof, or

(b) the compound of formula I is liberated by treatment with a solvolytic or hydrogenolytic agent from one of its functional derivatives; or

(c) a compound of formula IV

wherein R ² and R ² are as defined in formula I, or a reactive derivative thereof is reacted with a compound of formula V

ER ³ (V) wherein E and R ³ are as defined in formula II or I;

O and / or is converted into a cyano group in a compound of formula I wherein R is cyano

The ΙΗ-5-tetrazolyl group and / or the compound of formula I, wherein R ² is ΙΗ-5-tetrazolyl, is converted by base treatment into one of its salts.

'1 2

In the foregoing and following text, the residues R, R,

R ³ and E are as defined in the formulas I and II, if not expressly stated otherwise.

In the above formulas, the alkyl group contains 1 to 5, preferably 1, 2, 3 or 4 carbon atoms and is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore pentyl, 2- or 3-methylbutyl, 1,1-, 1,2,

2,2-dimethylpropyl or 1-ethylpropyl.

The radical R is preferably butyl, further preferably ethyl or propyl.

ABOUT

The radical R is preferably ΙΗ-5-yl group, a _f. The nitriles of the formula I, wherein R is cyano, are primarily important as intermediates for the production of tetrazoles of formula I, wherein R ² is ΙΗ-5-tetrazolyl, but also itself a pharmacological activity.

The radical R is preferably methyl, ethyl, isopropyl or cyclopropylmethyl.

The compounds of formula I as well as the starting materials are generally prepared by one of the known methods described in the literature (for example, in standard publications such as Houben-Weyl, Methoden: der Organischen Chemie, Georg Thieme Verlag, Stuttgart;

J.

), in particular in U.S. Pat. No. 4,880,804), under reaction conditions which are known and suitable for these known reactions, in which case? they may also use known variants not mentioned here in greater detail.

f:

s'.

j;

Alternatively, the starting materials for the claimed process can also be produced in situ, so that they are not isolated from the reaction mixture, but are directly reacted further to the compounds of formula I.

Compounds of formula I may be obtained by reacting compounds of formula II with compounds of formula III or reactive derivatives thereof, for example alkali metal salts. In the compounds of formula (II), E is preferably a chlorine, bromine or iodine atom or a reactively functionally modified hydroxy group such as, for example, a C1-6 alkylsulfonyloxy group (preferably methylsulfonyloxy group) or a 6-10 ring arylsulfonyloxy group (preferably a phenyl group) ).

The reaction of a compound of formula II with a compound of formula III is conveniently carried out by first treating the compound of formula III with a base to convert it into a salt, for example using an alkali metal alkoxide such as sodium methoxide in an alcohol such as methanol, or cesium carbonate, sodium hydride or tert-butoxide in dimethylformamide (DMF) and the salt is then reacted with a compound of formula II in an inert solvent such as an amide such as dimethylformamide or dimethylacetamide, or a sulfoxide such as dimethyl sulfoxide (DMSO), suitably at a temperature in the range of -20 to 100 ° C, preferably at a temperature of 10 to 30 ° C.

Some of the starting materials of the formulas II and III are known. If they are not known, they can be prepared by known methods, similar to known substances. Compounds of formula II are well known (cf., for example, EP-A2-400974). For example, compounds of formula III can be obtained by reducing 1,2-dihydro-2-oxo-3-cyano-6-R ¹ pyridines to 1,2-dihydro-2-oxo-3-formyl-6-R ¹ -pyridines, reductive amidation with amines R ³ RH ₂ to give 1,2-dihydro-2-oxo-3- (R ₃ NHCH ₂ ) -6-R ¹ pyridines and acylation with methanesulfonyl chloride.

Further, the compounds of formula (I) may be released from their functional derivatives by treatment with solvolytic (e.g. hydrolytic) or hydrogenolytic agents.

Thus, according to one of the above methods, it is possible to produce a compound which corresponds to the general formula I, but instead of the tetrazolyl group it contains a functionally modified (protected by a protecting group) tetrazolyl group. Suitable protecting groups are, for example, triphenylmethyl which is cleavable by treatment with formic acid or hydrochloric acid in an inert solvent or solvent mixture, for example methanol or a mixture of ether, dichloromethane and methanol; 2-cyanoethyl which is cleavable by treatment with sodium hydroxide in a mixture of water and tetrahydrofuran (THF); and a p-nitrobenzyl group which is cleavable by the action of hydrogen in the presence of Raney nickel in ethanol (cf. EP-A2-0 291 969).

In addition, the compounds of the formula I can be obtained by reacting a sulfonamide of the formula IV (cf. EP 0 530 702 A1) or one of its reactive derivatives (e.g. its alkali metal salt, preferably sodium or potassium salt) with a compound of the formula V, preferably an alkyl halide. Conveniently, the reaction is carried out under conditions analogous to those described for the reaction of a compound of formula II with a compound of formula III.

Reaction of nitriles of formula I in which R ² is cyano with nitric acid derivatives leads to tetrazoles of formula

I (R ² = ΙΗ-5-tetrazolyl). Preferably, a trialkyltin azide such as trimethyltin azide is used in an inert solvent such as an aromatic hydrocarbon such as toluene at a temperature in the range of from 20 to 150 ° C, preferably from 80 to 140 ° C or sodium azide in N-methylpyrrolidone at ranging from about 100 to about 200 ° C.

Compounds of formula I which contain tetrazolyl groups can be converted by treatment with bases (e.g. sodium or potassium hydroxide or carbonate) into the corresponding metal salts, especially the alkali or alkaline earth metals, or the corresponding ammonium salts. The potassium salts of tetrazolyl derivatives have particular preference.

The invention furthermore relates to the use of the compounds of the formula I and their physiologically acceptable salts for the production of pharmaceutical preparations. In this manufacture, these compounds can be formulated, together with at least one carrier or excipient, optionally in combination with one or more other active ingredients, into suitable dosage forms. The preparations thus obtained can be used as medicaments in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral administration (e.g. oral or rectal administration), parenteral administration or administration by inhalation spray. The compounds according to the invention must not react with these substances. Examples are water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other glycerides of fatty acids, gelatin, soy lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc and cellulose. In particular, tablets, coated tablets, capsules, syrups, juices or drops serve for oral administration. Of particular interest are lacquered tablets and capsules with coatings or casings which are resistant to gastric juices. For rectal administration, suppositories are suitable. For parenteral administration, solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants, are suitable. Sprays in which the active ingredient is either dissolved or suspended in a propellant mixture (e.g. a hydrocarbon) are suitable for administration by inhalation spray. The active ingredient is preferably used in micronized form and one or more additional physiologically acceptable solvents, such as ethanol, can be added. Inhalable solutions may be administered using conventional inhalers. The novel compounds can also be lyophilized and the resulting lyophilizates used, for example, for the production of injectables. The formulations may be sterilized and / or mixed with adjuvants such as preservatives, stabilizers and / or wetting agents, emulsifiers, salts for affecting the osmotic pressure, pH buffers, coloring agents and / or flavoring agents. The preparations may also contain one or more other active substances, for example one or more vitamins, diuretics or anti-inflammatory drugs.

As a rule, the compounds of the invention are administered in a manner similar to other known commercially available formulations (particularly as described in EP 0 530 7C2 A1), with a preferred dosage range of about 1 mg to 1 g, especially 10 to 200 mg per dosage unit. The daily dose is preferably in the range of about 0.1 to 50 mg / kg body weight, especially about 1 to about 10 mg / kg body weight. However, the particular dose for each individual patient depends on a variety of factors, such as the efficacy of the particular compound administered, the age, body weight, general health, sex and diet of the patient, the time and route of administration, elimination rate, drug combination used and severity of the disease being treated. to which treatment is directed. Oral administration takes precedence.

In the above description, all temperatures are in degrees Celsius. In the following examples, which are purely illustrative and in no way limit the scope of the invention, the term conventional work-up is as follows: If necessary, water is added to the mixture according to the composition of the final product. 2-10, the mixture is extracted with ethyl acetate or dichloromethane, the organic phase is separated, dried over sodium sulfate, filtered and evaporated and the residue is purified by silica gel chromatography and / or crystallization. Unless otherwise stated, the Rf values are obtained by chromatography on silica gel using a 1: 1 mixture of petroleum ether and methyl tert-butyl ether. FAB represents the molar ion peak (M ⁺ +1) from mass spectrometry performed by the Fast atom bombardment procedure.

Examples of the invention

Example 1

A solution of 2,72 g of 1,2-dihydro-2-oxo-3-N-methyl-N-methylsulfonylaminomethyl-6-butylpyridine (Hla; FAB 273; obtainable by reaction of 1,2-dihydro-2-oxo-6-butylpyridine3) -carboxaldehyde with methylamine and hydrogen to form

1,2-Dihydro-2-oxo-3-methylaminomethyl-6-butylpyridine followed by reaction with methanesulfonyl chloride) in 25 ml of dimethylformamide was mixed with 1.12 g of potassium tert-butoxide. The mixture is stirred at 20 ° C for 10 minutes, then a solution of 2.72 g of 4'-bromomethyl-2-cyanobiphenyl (IIa) in 15 ml of dimethylformamide is added dropwise over 30 minutes and the mixture is stirred at 20 ° C for 16 hours. The reaction mixture is then evaporated and worked up in the usual manner. There was thus obtained 1,2-dihydro-1- (2'-cyanobiphenylyl-4-methyl) -2-oxo-3-N-methyl-N-methylsulfonylaminomethyl-6-butylpyridine (1x) as an oil;

Rf 0.35 (petroleum ether / ethyl acetate, 4: 6).

Similarly, 1,2-dihydro-1- (2'-cyanobiphenylyl-4-methyl) -2-1,2-dihydro-2-oxo-3-N-isopropyl-N-methylsulfonylaminomethyl-6-butylpyridine (FAB 301; with compound IIa) was obtained. -oxo-3-N-isopropyl-N-methylsulfonylaminomethyl-6-butylpyridine, m.p. 155 ° C.

Example 2

Suspension 1,2 g 1,2-dihydro-1- (2 '- (1H (or 2H) 1 (or 2) -triphenylmethyl-5-tetrazolyl) biphenyl-4-methyl) 2-oxo-3-N-methyl N-methylsulfonylaminomethyl-6-butylpyridine (obtainable from compound IIIa and 4-bromomethyl-2 '(1H (or 2H) -1 (or 2) -triphenylmethyl-5-tetrazolyl) biphenyl) in 80 ml methanol was mixed with 20 ml formic acid and stirred at 50 ° C for 2 hours. The solution was concentrated and the residue was chromatographed on silica gel. It will be obtained

1,2-dihydro-1- (2 '- (1H-5-tetrazolyl) biphenyl-4-methyl) 2-oxo-3-N-methyl-N-methylsulfonylaminomethyl-6-butylpyridine (Iy), m.p. 104 ° C. A potassium salt of melting point 169 DEG C. is prepared from this material by treatment with potassium hydroxide in ethanol.

Similarly, the 1,2-dihydro-l- (2 ¹ - (lH (and 2H) one (or two) -trifenylmety1-5-yl) biphenyl-4-ylmethyl) -2-oxo-3-N-isopropyl-N -methylsulfonylaminomethyl-6-butylpyridine and formic acid in methanol are obtained

1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) 2-oxo-3-N-isopropyl-N-methylsulfonylaminomethyl-6-butyl13 pyridine (Iz), m.p. 106 "C. The potassium salt has a melting point of 152 C.

Example 3

A solution of 4.35 g of 1,2-dihydro-1- (2'-cyanobiphenylyl-4-methyl) -2-oxo-3-methylsulfonylaminomethyl-6-butylpyridine (m.p. 59 ° C, cf. EP 0 530 702 A1, Example 21) 10 ml of cesium carbonate was added to 16 ml of dimethylformamide and stirred for 30 minutes. 3 ml of methyl iodide are added to the reaction mixture, and then the mixture is stirred at 20 ° C for 16 hours.

The usual work up gives compound Ix, Rf 0.35.

Similarly, the following 1,2-dihydro-1- (2'-cyanobiphenylyl) -4-methyl) is obtained using ethyl iodide, propyl iodide, isopropyl iodide, butyl iodide, isobutyl iodide, sec-butyl bromide, tert-butyl bromide, N-pentyl bromide or cyclopropylmethyl bromide. 2-oxo-6-butylpyridine:

1,2-dihydro-1- (2'-cyanobiphenylyl) -4-methyl) -2-oxo-3-N-ethyl-N-methylsulfonylaminomethyl-6-butylpyridine, oil,

Rf 0.75,

1,2-dihydro-1- (2'-cyanobiphenylyl) -4-methyl) -2-oxo-3-N-propyl-N-methylsulphonylaminomethyl-6-butylpyridine, m.p. 118 ° C;

1,2-dihydro-1- (2'-cyanobiphenylyl) -4-methyl) -2-oxo-3-N-isopropyl-N-methylsulfonylaminomethyl-6-butylpyridine, m.p.

1,2-dihydro-1- (2'-cyanobiphenylyl) -4-methyl) -2-oxo-3-N-butyl-N-methylsulfonylaminomethyl-6-butylpyridine, oil,

Rf 0.71,

1,2-dihydro-1- (2'-cyanobiphenylyl) -4-methyl) -2-oxo-3-N-isobutyl-N-methylsulfonylaminomethyl-6-butylpyridine, oil, Rf 0.62,

1,2-dihydro-1- (2'-cyanobiphenylyl) -4-methyl) -2-oxo-3-N-sec. butyl-N-methylsulfonylaminomethyl-6-butylpyridine,

1,2-dihydro-1- (2'-cyanobiphenylyl) -4-methyl) -2-oxo-3-N-tert-butyl-N-methylsulfonylaminomethyl-6-butylpyridine,

1,2-dihydro-1- (2'-cyanobiphenylyl) -4-methyl) -2-oxo-3-N-pentyl-N-methylsulfonylaminomethyl-6-butylpyridine, oil Rf 0.80 and

1,2-dihydro-1- (2'-cyanobiphenylyl) -4-methyl) -2-oxo-3-N-cyclopropylmethyl-N-methylsulfonylaminomethyl-6-butylpyridine, m.p. 93 ° C.

Similarly, the 1,2-dihydro-l- (2'-cyanobiphenyl-4-methyl) -2-oxo-3-methylsulfonylaminomethyl-6-propylpyridine, and the above alkyl halides gives the following 1,2-dihydro-l- (2 -kyanobifenylyl ¹⁾ - 4-methyl) -2-oxo-6-propyl:

1,2-dihydro-l- (2'-cyanobiphenyl) -4-methyl) -2-oxo-3-N-methyl-N-methylsulfonylaminomethyl-6-propyl,

1,2-dihydro-l- (2'-cyanobiphenyl) -4-methyl) -2-oxo-3-N-ethyl-N-methylsulfonylaminomethyl-6-propyl,

1,2-dihydro-l- (2'-cyanobiphenyl) -4-methyl) -2-oxo-3-N-propyl-N-methylsulfonylaminomethyl-6-propyl,

1,2-dihydro-l- (2'-cyanobiphenyl) -4-methyl) -2-oxo-3-N-isopropyl-N-methylsulfonylaminomethyl-6-propyl,

1,2-dihydro-1- (2'-cyanobiphenylyl) -4-methyl) -2-oxo-3-N-butyl-N-methylsulfonylaminomethyl-6-propylpyridine,

1,2-dihydro-l- (2'-cyanobiphenyl) -4-methyl) -2-oxo-3-N-isobutyl-N-methylsulfonylaminomethyl-6-propyl,

1,2-dihydro-l- (2'-cyanobiphenyl) -4-methyl) -2-oxo-3-N-sec-butyl-N-methylsulfonylaminomethyl-6-propyl,

1,2-dihydro-l- (2'-cyanobiphenyl) -4-methyl) -2-oxo-3-N-t-butyl-N-methylsulfonylaminomethyl-6-propyl,

1,2-dihydro-1- (2'-cyanobiphenylyl) -4-methyl) -2-oxo-3-N-pentyl-N-methylsulfonylaminomethyl-6-propylpyridine and

1,2-dihydro-l- (2'-cyanobiphenyl) -4-methyl) -2-oxo-3-N-cyclopropylmethyl-N-methylsulfonylaminomethyl-6propylpyridín.

Example 4

A mixture of 463 mg of compound Ix, 200 mg of trimethyltin azide and 12 ml of xylene is boiled for 96 hours. After 48 hours, 200 mg of trimethyltin azide is added once more. The mixture was cooled, ethereal hydrogen chloride was added and then evaporated. The residue is chromatographed on silica gel using dichloromethane / methanol 9: 1. Compound Iy is obtained with a melting point of 104 ’C.

Similarly, the following 1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) -2-oxo-is obtained from the 2'-cyano compounds shown in Example 3 by reaction with trimethyltin azide in xylene. 6-butylpyridine:

1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenyl-4-methyl) -2-oxo-3-N-ethyl-N-methylsulfonylaminomethyl-6-butylpyridine, m.p. 109 C, potassium salt - melting point 81 ° C,

1,2-dihydro-1- (2 '- (1H-5-tetrazolyl) biphenylyl-4-methyl) -2-oxo-3-N-propyl-N-methylsulfonylaminomethyl-6-butylpyridine, ¹ m.p. above 300 ° C, potassium salt - Melting point 104 ° C ^B 1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenyl-4-methyl) -2-oxo-3-N-isopropyl-N-methylsulfonylaminomethyl-6-butylpyridine, ( Iz), mp 106 ° C,

1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) -2-oxo-3-N-butyl-N-methylsulfonylaminomethyl-6-butylpyridine, m.p. 95 ° C, potassium salt - temperature m.p. 93 ° C,

1,2- dihydro-l- (2 '- (ΙΗ-5-yl) bifenyly1-4-methyl) -2-oxo-3-N-isobutyl-N-methylsulfonylaminomethyl-6-butylpyridine, ^a melting point of 117 DEG C., the potassium salt - mp 100 ° C,

1,2-dihydro-1- (2 '- (1H-5-tetrazolyl) biphenyl-4-methyl) -2-oxo-3-N-sec-butyl-N-methylsulfonylaminomethyl-6-butylpyridine,

1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) -2-oxo-3-N-tert-butyl-N-methylsulfonylaminomethyl-6-butylpyridine,

1,2-dihydro-1- (2 '- (1H-5-tetrazolyl) biphenyl-4-methyl) -2-oxo-3-N-pentyl-N-methylsulfonylaminomethyl-6-butylpyridine, m.p. 63 ° C, potassium salt - temperature m.p. 96 ° C a

1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) -2-oxo-3-N-cyclopropylmethyl-N-methylsulfonylaminomethyl-6: butylpyridine, m.p. 96 ° C, potassium salt - temperature mp 103 ° C, as well as the following 1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) -2-oxo-6-propylpyridines:

1,2-dihydro-1- (2 '- (1H-5-tetrazolyl) biphenylyl-4-methyl) -2-oxo-3-N-methyl-N-methylsulfonylaminomethyl-6-propylpyridine;

1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenyl-4-methyl) -2-oxo-3-N-ethyl-N-methylsulfonylaminomethyl-6-propylpyridine,

1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenyl-4-methyl) -2-oxo-3-N-propyl-N-methylsulfonylaminomethyl-6-propylpyridine,

1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) -2-oxo-3-N-isopropyl-N-methylsulfonylaminomethyl-6-propylpyridine,

1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) -2-oxo-3-N-butyl-N-methylsulphonylaminomethyl-6-propylpyridine;

1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) -2-oxo # 3-N-isobutyl-N-methylsulfonylaminomethyl-6-propylpyridine,

5: 1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) -2-oxo. 3-N-sec-butyl-N-methylsulfonylaminomethyl-6-propylpyridine;

l | 1,2-dihydro-l- (2 '- (ΙΗ-5-yl) biphenyl-4-ylmethyl) -2-oxo | 3-N-t-butyl-N-methylsulfonylaminomethyl-6-propyl,

1: 1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) -2-oxo-3-N-pentyl-N-methylsulfonylaminomethyl-6-propylpyridine and

1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) -2-oxo-3-N-cyclopropylmethyl-N-methylsulfonylaminomethyl-6-propylpyridine, Rf 0.65 (dichloromethane / methanol, 9 : 1), potassium salt - mp 119 ° C.

Example 5

A mixture of 463 mg of compound Ix, 700 mg of triethylammonium chloride, 700 mg of sodium azide and 4 ml of dimethylformamide was stirred at 120 ° C for 36 hours. The reaction mixture was cooled, the sodium chloride formed was filtered off and the filtrate was evaporated. The residue was worked up in the usual manner using hydrochloric acid and dichloromethane. Compound Iy is obtained with a melting point of 104 ’C.

The following examples relate to pharmaceutical preparations which contain as active ingredient a compound of the formula I or a salt thereof.

Example A

Tablets and dragees

Tablets of the following composition are conventionally compressed and coated with a conventional sucrose-based coating if required:

active ingredient of the formula I 100 mg microcrystalline cellulose 287.8 mg lactose 110 mg maize starch 11 mg magnesium stearate 5 mg fine-grained silica 0.2 mg

I

Example B

Hard gelatine capsules

Conventional two-piece hard gelatine capsules are filled with a composition having, based on one capsule, the following composition:

active ingredient of the formula I 100 mg lactose 150 mg cellulose 50 mg magnesium stearate 6 mg

Example C

Soft gelatin capsules

Conventional soft gelatine capsules are each filled with a composition which, based on one capsule, has the following composition: 50 mg of active ingredient of the formula I and 250 mg of olive oil.

Example D

ampoules

A solution of 200 g of an active ingredient of the formula I in 2 kg of 1,2-propanediol is made up to 10 liters with water. This solution is filled into ampoules such that each ampoule contains 200 mg of active ingredient.

Claims (5)

PATENT CLAIMS CLAIMS 1. 1,2-Dihydro-2-oxo-3-methylsulphonylaminomethylpyridines of the general formula I EMI2.0 [0007] wherein: R ¹ is C 1 -C 5 alkyl; R ² is CN or ΙΗ-5-tetrazolyl and R ³ is C 1 -C 5 alkyl or cyclopropylmethyl, as well as salts thereof. The 1,2-dihydro-2-oxo-3-methylsulfonylaminomethylpyridine of claim 1, selected from the group consisting of: 1,2-dihydro-1- (2 ^1- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) -2-oxo-3-N-methyl-N-methylsulfonylaminomethyl-6-butylpyridine and its potassium salt, 1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenylyl4-methyl) -2-oxo-3-N-isopropyl-N-methylsulfonylaminomethyl-6-butylpyridine and its potassium salt; and 1,2-dihydro-1- (2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl) -2-oxo-3-N-cyclopropylmethyl-N-methylsulfonylaminomethyl-6-butylpyridine and its potassium salt. A process for the preparation of 1,2-dihydro-2-oxo-3-methylsulfonylaminomethylpyridines of the formula I and their salts according to claim 1, characterized in that (a) a compound of formula II wherein E represents a chlorine, bromine or iodine atom or a free or reactively functionally modified hydroxy group; and R ² is as defined for formula I, with a compound of formula III (III) wherein R · '· and R ² are as defined for formula I, or a. or a reactive derivative (b) the compound of formula (I) is liberated by treatment with a solvolytic or hydrogenolytic agent from one of its functional derivatives; or c) a compound of formula IV wherein R ¹ and R ² are as defined in formula I, or a reactive derivative thereof is reacted with a compound of formula V ER ³ (A) O wherein E and R are as defined in formula II or I; o and / or in a compound of formula I wherein R is cyano, is converted to ΙΗ-5-tetrazolyl and / or a compound of formula I wherein R ² is ΙΗ-5-tetrazolyl is converted to one of its salt. Process for the manufacture of a pharmaceutical composition, characterized in that the 1,2-dihydro-2-oxo-3-methylsulfonylaminomethylpyridine of the formula I and / or one of its physiologically acceptable salts according to claim 1 is treated together with at least one solid, liquid or semi-solid carrier. or an excipient for a suitable dosage form. 5. A pharmaceutical composition comprising at least one 1,2-dihydro-2-oxo-3-methylsulfonylaninomethylpyridine of formula I