3-alkoxycarbonyl-thiadiazine, the method of production thereof and pharmaceutical composition

 

(57) Abstract:

Describes new thiadiazine General formula I, in which R1denotes A; R2and R3denote H, A; R4represents benzoyl, substituted C1-C6-alkoxygroup; R5denotes NA2or a saturated five - or six-membered heterocyclic residue with at least one N-atom, which may be substituted by A; Q denotes a branched or unbranched alkylene with 1-10 C-atoms or is absent; n is 1,2, or 3; And denotes alkyl with 1-6-C-atoms, and their physiologically acceptable salts. The compounds may find use in the treatment of heart failure. Also describes the method of obtaining the compounds and pharmaceutical composition thereof. 3 S. and 1 C.p. f-crystals, 1 PL.

The invention relates to new 3-alkoxycarbonyl-thiadiazine formula (I)

< / BR>
where R1, R2and R3each, independently of one another, denote H or A;

R4denotes acyl with 1 to 15 C-atoms;

R5denotes NH2, NHA, NA2or saturated three - to eight-membered heterocyclic residue with at least one N-atom, which may be substituted with A and g is sulfur;

Q is absent or denotes a branched or unbranched alkylene with 1-10 C-atoms;

"n" represents 1, 2 or 3; and

A denotes alkyl with 1-6 C-atoms;

and their physiologically acceptable salts.

Derivatives of thiadiazine, the basic structure of which corresponds to the formula (I), which, however, in the rest we have another example of substitution is known from the patent Germany 3719031-A1.

The basis of the invention is the task of finding new compounds with valuable properties, especially those that can be used for the preparation of drugs.

It was found that the compounds of formula (I) with good compatibility possess valuable pharmacological properties. In particular, they have a strong antiarrhythmic effect and a positive inotropic effect; further, substances acting vasodilator and therefore contribute to the bloodstream. Vasodilator effect and the effect on the heart can be detected, for example, under anesthesia or awake dogs, cats, monkeys or pigs; positive inotropic action can also be set on isolated preparations of the heart (e.g., atrium, papillary muscle or Voutsa in Arzneimittelforschung, volume 31 (1) Nla (1981, S. 141-170, or Schliep and others, 9-th International Congress of Pharmacol., London., Abstracts of papers 9P (1984).

Further, there are antithrombotic, inhibit platelet aggregation and affect the shape of the erythrocytes properties. Impact on the function of platelets in the sense of suppressing aggregation can be proved on a rat ex vivo test for Born (Nature, 194, 927-929, 1962). Antithrombotic effect is manifested in prolonged bleeding time according to Stella (Thrombos, Res. 7, 709-716, 1975), in reducing the weight of the thrombus in the case of induced cold thrombosis of the jugular vein in rats according to Meng (Ther. Ber. 47, 69-79, 1975) and in raising necessary for a complete thrombosis of the laser pulse on Mensenterial-Venale rats, respectively, a change in the method according to Kovacs (Microvasc. Res., 6., 194-201, 1973).

A beneficial effect on the deformability of erythrocytes found in nucleopore filter according to Schmid-Schonbein (Pfluger''s Archiv., 338, 93-114, 1973). You can also set a favorable impact on the time fibrinolysis/lysis euglobulin according to v. Kaulla (Progr. Chem. Fibrinol Thrombol. 1, 131-149, 1975; ed. J. F. Davidson, Raven Press, N. Y.).

Further, it was found that the introduction of the basically substituted alkoxycarbonyl residues in thiadiazine ring leads to water soluble compounds, which possess good b is arctonyx tools in medicine and veterinary medicine. Further, they can serve as intermediates for other biologically active substances of medicines.

Accordingly, the subject invention are the compounds of formula (I), their salts accession acids, as well as the retrieval method, characterized in that the compound of formula (II):

< / BR>
where R1, R2, R3, R4and n have the above values, enter into interaction with the compound of the formula (III)

X-CO2-Q-R5< / BR>
where Q and R5have the specified values, and X denotes Cl, Br, OH or a reactive, esterified ester to an OH group, or a compound of the formula (IV)

< / BR>
where R1, R2, R3, R4, n, Q and X have the above values, enter into interaction with the compound of the formula (V)

R5-H (V)

where R5has a specified value;

or a compound which corresponds to formula (I), but instead of R4contains a hydrogen atom in the ordinary way, b;

or in the compound of formula (I) one residue R4turn in the remainder R4;

or the compound of formula (I) where the remainder R5contains primary or secondary amino group, in the normal way alkiline the

Above - and below, the remains of R1, R2, R3, R4, R5, Q and X, and the parameter "n" are specified in the case of formula (I), (II), (III), (IV) and (V) values, unless nothing else.

In formulas residue A is preferably of neravetla contains preferably 1, 2, 3 or 4 C-atoms and preferably denotes methyl, further preferably ethyl or propyl, further preferably isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, but also n-pentyl, isopentyl, n-hexyl or isohexyl.

Q denotes preferably ethylene, propylene, butylene, pentile, hexylen, further, for example, 1-mutilation.

Q-R5means preferably also N-methylpiperidin.

The remains of R1, R2and R3preferably denote, depending on the circumstances, H or methyl.

n preferably represents 2.

R4represents the acid residue of carboxylic or sulfonic acids, preferably alkanoyl from 1 to 10, especially 1, 2, 3, 4 or 5 C-atoms, particularly preferably acetyl, further preferably formyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl (trimethylacetyl), further preferably in the case of high q preferably one of the following groups: alkyl, alkoxyl, allylthiourea, alkylsulfonyl or alkylsulfonyl, depending on the circumstances, from 1-3, preferably 1 or 2 C-atoms, methylenedioxy, then, OH, F, Cl, Br, I, NO2, NH2alkylamino or dialkylamino 1-3, preferably 1 or 2 C atoms in each alkyl group. Individual preferred rollname residues are benzoyl; o-, m - or p-toluyl, o-, m - or p-methoxybenzoyl; 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzoyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5-trimethoxybenzoyl; o-, m-, or p-methylthiophenol; o-, m-, or p-methylsulfonylbenzoyl; o-, m-, or p-methylsulfonylbenzoyl; 2,3 - or 3,4-methylenedioxybenzyl, 1 - or 2-naphtol. Acyl, then, may refer to heteroarylboronic with 2-10 C-atoms, as a 2 - or 3-furoyl, 2 or 3-thenoyl, pikolinos, nicotinoyl, isonicotinoyl, in addition, arylalkyl as phenylacetyl, o-, m-, or p-methoxyphenylacetyl, 2 - or 3-phenylpropionyl; 2-, 3 - or 4-phenylbutyric; cycloalkylcarbonyl; as cyclohexylcarbonyl; alkylsulfonyl as methyl-, ethyl-, propyl - or butylsulfonyl; arylsulfonyl as benzazolyl, -, m - or p-toluensulfonyl, o-, m - or p-methoxy-benzazolyl, 1 - or 2-naphthalenesulfonyl.

The remainder R5preferably indicates methylamino-, Dima.

The subject invention are in particular those compounds of formula (I) in which at least one of these residues has one of the abovementioned preferred meanings. Some preferred groups of compounds can be expressed by the following partial formulas (1a) to (1h), which correspond to the formula (I) and where more is not indicated residues are specified in the case of the formula (I) value, where, however:

in 1a: R1denotes methyl and "n" denotes 2;

1b: R1denotes H and "n" denotes 2;

in 1c: R1denotes methyl, R2and R3denote H and "n" = 2;

in 1d: R1and R2denote methyl; R3denotes H and "n" = 2;

in 1e: R1, R2and R3denote methyl and "n" = 2;

in 1f: R1, R2and R3denote methyl; R4denotes acyl with 1 to 10 C-atoms and "n" denotes 2;

in 1g: R1and R2each, independently of one another, denote H or methyl; R3denotes H; R4denotes acyl with 1 to 10 C-atoms, Q denotes a branched or unbranched alkylene with 1-6 C-atoms;5denotes NH2, NHCH3, NHC2H5N(CH3)2or N(C2H5)2; and "n" = 2;

in 1h: R1, R2

The compounds of formula (I), however, get itself known in ways that are described in the literature (for example in standard works, as Houben-Weil, Methods of organic chemistry, ed. Georg-Thieme, Stuttgart), namely under reaction conditions which are known and suitable for the specified interactions. You can also apply itself known here more not mentioned options.

Source materials for the proposed method in the desirable case can be formed in situ, so that they are not isolated from the reaction mixture, and immediately injected into the interaction further, to obtain the compounds of formula (I).

Educt of formula (II) and (III) partially known. If they are unknown, they can get itself known methods. Obtaining compounds of formula (II) are known from the patent Germany 3719031.

In particular, the interaction of the compounds of the formula (II) with compounds of the formula (III) is carried out in the presence or absence of an inert solvent, at temperatures from about -20oC the birth, as benzene, toluene, xylenes or mesitylene; halogenated hydrocarbons like dichloromethane, trichloroethylene or chlorobenzene; alcohols, like methanol, ethanol or isopropanol, glycols or simple glycol ethers as ethylene glycol, diethylene glycol, 2-methoxyethanol, NITRILES like acetonitrile, ethers, like tetrahydrofuran or dioxane, amides, as dimethylformamide (DMF); sulfoxidov as dimethyl sulfoxide. Also suitable mixture of these solvents.

In the compounds of the formula (III), X preferably represents chlorine or bromine. If X is a reactive, esterified ester to OH-group, it preferably represents alkylsulfonates with 1-6 C atoms, for example, methanesulfonamido, or arylsulfonate group with 6-10 C atoms, for example, benzene-, p-toluene - or 1 - or 2-naphthalenesulfonate.

Further, the compound of formula (I) can also be obtained by the fact that the compound of formula (IV) enter into interaction with the compound of the formula (V).

The compounds of formula (IV) can be obtained by the fact that the compound of formula (II) enter into interaction with the compound of the formula Y-CO2-Q-OH, where Y denotes Cl, Br or reactive, esterified ester to O the STI then functionalitywith terminal OH-group.

The compounds of formula (V) are known or can be obtained in itself known methods.

Just one residue R4can be transformed into another residue R4. For example, in the application itself known reactions can be atrificial to simple broadcasting OH-group or, however, to split a simple aryl ether. Further, the substituents of the remainder R4as, for example, S-A - or SO-A-group, it is possible to oxidize, as the reaction proceeds selectively on the remainder R4.

The compound which corresponds to formula (I), but instead of R4contains a hydrogen atom, can be allievate using acylhomoserine formula R4-Cl or R4-Br or anhydride of formula (R4)2O, in an inert solvent, expediently in the presence of a base, such as hydroxide of alkali or alkaline earth metal, and carbonate, alcoholate or hydride of an alkaline or alkaline earth metal hydroxide, carbonate, methylate, ethylate or sodium hydride or potassium; further, secondary or tertiary amines, such as triethylamine or pyridine.

The obtained base of formula I with acids can be converted to the corresponding salt accession acid. For this inter is acid, for example sulfuric acid, halogen acids as hydrochloric acid or Hydrobromic acid, phosphoric acid, like phosphoric acid, nitric acid, sulfamic acid; further, organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic one - or polybasic carboxylic, sulfonic or sulfuric acids, as formic acid, acetic acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2 - or 3-phenyl-propionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - and econsultation, ethicalfashion, 2-hydroxy-econsultation, benzoylacetate, p-toluene-acid, naphthalene mono - and di-sulfonic acids, lauryl-sulfuric acid. Salts with physiologically unacceptable acids, for example the picrate can be used for purification of the compounds of formula (I).

The compounds of formula (I) may contain one or more assimlate, mechanically or chemically, to their enantiomers according itself known methods. Preferably the racemic mixture by introducing into interaction with optically active separating agent get diastereoisomers. As a separating agent for major compounds of formula (I) are suitable, for example, optically active acids, such as D - and L-forms of tartaric acid, diatsetilvinny acid, dibenzoyltartaric acid, almond acid, malic acid, lactic acid or the various optically active camphorsulfonic as camphorsulfonate or, however, optically active Campanula acid, respectively other optically active terpene acids.

Naturally, it is also possible to obtain optically active compounds of formula (I) according to the above-described methods that use source materials, which are already optically active.

Formula (I) encompasses all stereoisomers and their mixtures, such as racemates.

The subject of the invention, then, is the use of compounds of formula (I) and their physiologically acceptable salts for the preparation of pharmaceutical compositions, in particular by non-chemical. While their together with at least one solid, liquid skolicki other biologically active substances can be brought to a suitable dosage forms.

The subject of the invention, then, are tools, in particular pharmaceutical compositions containing at least one compound of formula (I) and/or one of its physiologically acceptable salts.

These compositions can be used as drugs in medicine or veterinary medicine. As carriers take into account organic or inorganic substances which are suitable for intestinal (for example), oral, parenteral or topical administration and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glyceryltrinitrate, gelatin, carbohydrate as lactose or starch, magnesium stearate, talc, vaseline. For oral administration are, in particular tablets, coated tablets, capsules, syrups, juices or drops; for rectal use candles; for parenteral administration are solutions, preferably oily or aqueous solutions; further, suspensions, emulsions or implants; for topical application are ointments, creams, plasters (Sticks) or powders (powder). The new compounds can also be liofilizirovanny and received lyophilizate to apply, for example, for the preparation of drugs for injection.

The compounds of formula (I) can be used in the fight against diseases, especially arrhythmias and cardiac nedostatocnosti, as well as in the treatment of the human or animal body.

This proposed according to the invention the substance is usually administered by analogy with the known positive inotrope active substances, as Amrinone, preferably at doses of about 1-100 mg, in particular 2-20 mg, dosing unit.

The daily dose is preferably about 0.2-20 mg/kg of body weight. Special dose for each particular patient depends, however, on a variety of factors, such as efficiency used a specific connection on the age, body weight, General health, sex, on cost, time and route of administration, rate of excretion, combination of drugs and the severity of the corresponding C is R used to treat heart failure Digitalis-glycosides, the compounds of formula (I) have improved therapeutic range and peripheral discharge.

In the following examples, the expression "conventional treatment" means add, if necessary, water or a diluted solution of hydroxyl sodium, extracted with an organic solvent like ethyl acetate, chloroform or dichloromethane, separated, the organic phase is dried over sodium sulfate, filtered, evaporated and purified by chromatography and/or crystallization, Rf-values are determined on silica gel.

Above and below, all temperatures are given in degrees Celsius.

Example 1

To a solution of 10 g of 3,6-dihydro-5-/1,2,3,4-tetrahydro-1-(3,4 - dimethoxybenzoyl)-6-chinolin/-6-methyl-2H-1,3,4-thiadiazin-2-it ("A") and 9.8 ml of triethylamine in 100 ml dichloromethane under stirring pin 6 g of 2-N,N-Diethylaminoethanol of ester Harborview acid, dissolved in 50 ml of dichloromethane and additionally stirred for one hour at 20oC. the Solvent is removed, is treated as usual and get 3-/2-(N,N-diethylamino)-etoxycarbonyl/-5-/1,2,3,4-tetrahydro-1-(3,4 - dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-he; hydrochloride.

Similarly, by vzaimode oxycarbonyl/-5-/1,2,3,4 - tetrahydro-1-(3,4-dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro - 2H-1,3,4-thiadiazin-2-he; hydrochloride;

6-N, N-dimethylamino-hexyl ether Harborview acid get 3-/6-(N, N-dimethylamino)-hexyloxybenzoyl/-5-/1,2,3,4 - tetrahydro-1-(3,4-dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro - 2H-1,3,4-thiadiazin-2-it, hydrochloride;

2-N,N-dimethylamino-1-methyl-ethyl ether of Harborview acid get 3-/1-methyl-2-(N, N-dimethylamino)-etoxycarbonyl/- 5-/1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-chinolin/-6-methyl - 3,6-dihydro-2H-1,3,4-thiadiazin-2-he; hydrochloride;

1-methyl-4-piperidinyl ether Harborview acid obtained 3-(1-methyl-4-piperidinylcarbonyl)-5-/1,2,3,4-tetrahydro-1-(3,4 - dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-he; profumata;

2-morpholino-ethyl ether of Harborview acid obtained 3-(2-morpholino-etoxycarbonyl)-5-/1,2,3,4-tetrahydro-1-(3,4 - dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-he;

3 morpholino-propyl ether Harborview acid obtained 3-(3-morpholino-propoxycarbonyl)-5-/1,2,3,4-tetrahydro-1-(3,4 - dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-he;

2-thiomorpholine-ethyl ether of Harborview acid obtained 3-(2-thiomorpholine-etoxycarbonyl)-5-/1,2,3,4-tetrahydro-1-(3,4 - dimethoxybenzoyl)-6-chinolin/-6-methyl-imortalize-propoxycarbonyl)-5-/1,2,3,4-tetrahydro - 1-(3,4-dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4 - thiadiazin-2-he;

2-piperazine derivatives-ethyl ether of Harborview acid obtained 3-(2-piperazine derivatives-etoxycarbonyl)-5-/1,2,3,4-tetrahydro-1-(3,4 - dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-he;

with 3-piperazine derivatives-propyl ether Harborview acid obtained 3-(3-piperazine derivatives-propoxycarbonyl)-5-/1,2,3,4-tetrahydro-1-(3,4 - dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-he;

2-pyrrolidino-ethyl ether of Harborview acid obtained 3-(2-pyrrolidino-etoxycarbonyl)-5-/1,2,3,4-tetrahydro-1-(3,4 - dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-he;

with 3-pyrrolidino-propyl ether Harborview acid obtained 3-(3-pyrrolidino-propoxycarbonyl)-5-/1,2,3,4-tetrahydro-1-(3,4 - dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-he;

Similarly, by reacting (+)-3,6-dihydro-5-/1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6 - chinolin/-6-methyl-2H-1,3,4-thiadiazin-2-it

2-N, N-diethylamino-ethyl ether of Harborview acid get(+)-3-/2-(N, N-diethylamino)-etoxycarbonyl/-5-/1,2,3,4 - tetrahydro-1-(3,4-dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro - 2H-1,3,4-thiadiazin-2-he; hydrochloride; so pl. 135oC;

with 3-N, N-diethylamino-propyl ether Harborview acid floor is ro - 2H-1,3,4-thiadiazin-2-he; hydrochloride, T. pl. 130oC;

6-N, N-diethylamino-hexyl ether Harborview acid get(+)-3-/6-(N, N-dimethylamino)-hexyloxybenzoyl/-5-/1,2,3,4 - tetrahydro-1-(3,4-dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro - 2H-1,3,4-thiadiazin-2-he; hydrochloride; so pl. 133oC;

6-N, N-diethylamino-1-methyl-ethyl ether of Harborview acid get (+)-3-/1-methyl-2-(N,N-dimethylamino)-etoxycarbonyl/- 5-/1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6 - dihydro-2H-1,3,4-thiadiazin-2-he; hydrochloride; so pl. 168oC;

1-methyl-4-piperidinyl ether Harborview acid get (+)-3-/1-methyl-4-piperidinylcarbonyl/-5-/1,2,3,4-tetrahydro-1-(3,4 - dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-he; hydrochloride; so pl. 150oC.

Similarly, by reacting 2-N,N-Diethylaminoethanol ether Harborview acid

5/1,2,3,4-tetrahydro-1-(3-ethoxy-4-methoxybenzoyl)-6 - chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one obtained 3-/2-(N, N-diethylamino)-etoxycarbonyl/-5-/1,2,3,4-tetrahydro-1-(3 - ethoxy-4-methoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4 - thiadiazin-2-he;

5/1,2,3,4-tetrahydro-1-(3-methoxy-4-ethoxybenzoyl)-6 - chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one obtained 3-/2-(N,N-di is Azin-2-he;

5/1,2,3,4-tetrahydro-1-(3-methoxy-4-hydroxybenzoyl)-6 - chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one obtained 3-/2-(N, N-diethylamino)-etoxycarbonyl/-5-/1,2,3,4-tetrahydro-1-(3 - methoxy-4-hydroxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4 - thiadiazin-2-it.

Example 2

To a solution of 10 g of 3,6-dihydro-5-/1,2,3,4-tetrahydro-1-(3,4 - dimethoxybenzoyl)-4,4-dimethyl-6-chinolin/-6-methyl-2H-1,3,4-thiadiazin-2-it ("B") and 9.8 ml of pyridine in 100 ml of dichloromethane was added dropwise with stirring 6 g of 2-N,N-diethylamino-ethyl ether of Harborview acid, dissolved in 50 ml of dichloromethane, and additionally stirred for one hour at 20oC. the Solvent is removed, is treated as usual and get 3-/2-(N,N-diethylamino)-etoxycarbonyl/-5-/1,2,3,4-tetrahydro - 1-(3,4-dimethoxybenzoyl)-4,4-dimethyl-6-chinolin/-6-methyl-3,6-dihydro-2H - 1,3,4-thiadiazin-2-he; Rf (THF) = 0,65.

Similarly, through the interaction of a "B"

with 3-N, N-diethylamino-propyl ether Harborview acid get 3-/3-(N, N-diethylamino)-propoxycarbonyl/-5-/1,2,3,4 - tetrahydro-1-(3,4-dimethoxybenzoyl)-4,4-dimethyl-6-chinolin/-6 - methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-he; Rf (THF) = 0,64;

6-N, N-dimethylamino-hexyl ether Harborview acid get 3-/6-(N, N-dimethylamino)-hexyloxybenzoic is;

2-N, N-dimethylamino-1-methyl-ethyl ether of Harborview acid get 3-/1-methyl-2-(N,N-dimethylamino)-etoxycarbonyl/-5-/1,2,3,4 - tetrahydro-1-(3,4-dimethoxybenzoyl)-4,4-dimethyl-6-chinolin/-6-methyl - 3,6-dihydro-2H-1,3,4-thiadiazin-2-he; Rf (THF) = 0,25;

1-methyl-4-piperidinyl ether Harborview acid obtained 3-(1-methyl-4-piperidinylcarbonyl)-5-/1,2,3,4-tetrahydro-1-(3,4 - dimethoxybenzoyl)-4,4-dimethyl-6-chinolin/-6-methyl-3,6-dihydro-2H - 1,3,4-thiadiazin-2-he; profumata; Rf (THF) = 0,65.

Similarly, by reacting 2-N,N-Diethylaminoethanol ether Harborview acid

5/1,2,3,4-tetrahydro-1-(3-ethoxy-4-methoxybenzoyl)-6-chinolin/- 4,4-dimethyl-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one obtained 3-/2-(N,N-diethylamino)-etoxycarbonyl/-5-/1,2,3,4-tetrahydro-1-(3 - ethoxy-4-methoxybenzoyl)-4,4-dimethyl-6-chinolin/-6-methyl-3,6 - dihydro-2H-1,3,4-thiadiazin-2-he;

5/1,2,3,4-tetrahydro-1-(3-methoxy-4-ethoxybenzoyl)-6-chinolin/- 4,4-dimethyl-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one obtained 3-/2-(N,N-diethylamino)-etoxycarbonyl/-5-/1,2,3,4-tetrahydro-1-(3 - methoxy-4-ethoxybenzoyl)-4,4-dimethyl-6-chinolin/-6-methyl-3,6-dihydro - 2H-1,3,4-thiadiazin-2-he;

5/1,2,3,4-tetrahydro-1-(3-methoxy-4-hydroxybenzoyl)-4,4 - dimethyl-6-chinolin/-6-methyl-3,6-dihydro)-2H-1,3,4-thiadiazin-2-he is alil/-6-methyl-3,6 - dihydro-2H-1,3,4-thiadiazin-2-he;

Example 3

To a solution of 10 g of 3-/2-chlorocarbons/-5-/1,2,3,4-tetrahydro - 1-(3,4-dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4 - thiadiazin-2-she and 9 ml of pyridine in 100 ml of dichloromethane was added dropwise with stirring 2.5 g of diethylamine dissolved in 30 ml of dichloromethane, and additionally stirred for one hour at 20oC. the Solvent is removed, is treated as usual and get 3-/2-(N, N-diethylamino)-etoxycarbonyl/-5-/1,2,3,4-tetrahydro-1-(3,4 - dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-he; hydrochloride.

Example 4

Analogously to example 1, by reacting 3-N,N-diethylaminopropylamine ether Harborview acid

5/1,2,3,4-tetrahydro-1-(3-ethoxy-4-methoxy-benzoyl)-6 - chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one obtained 3-/3-(N, N-diethylamino)-propoxycarbonyl/-5-/1,2,3,4-tetrahydro-1-(3 - ethoxy-4-methoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4 - thiadiazin-2-he;

5/1,2,3,4-tetrahydro-1-(3-methoxy-4-ethoxybenzoyl)-6 - chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one obtained 3-/3-(N,N-diethylamino)-propoxycarbonyl/-5-/1,2,3,4-tetrahydro-1-(3 - methoxy-4-ethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4 - thiadiazin-2-he;

5/1,2,3,4-tetrahydro-1-(3-methoxy-4-hydroxybenzoyl)-6 - hiill/-6-methyl-3,6-di is cebesoy)-6-chinolin/-6-methyl-3,6-dihydro-2H - 1,3,4-thiadiazin-2-it.

Example 5

Analogously to example 2, by reacting 3-N,N-diethylaminopropylamine ether Harborview acid

5/1,2,3,4-tetrahydro-1-(3-methoxy-4-methoxybenzoyl)-4,4 - dimethyl-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one obtained 3-/3-(N,N-diethylamino)-propoxycarbonyl/-5-/1,2,3,4 - tetrahydro-1-(3-ethoxy-4-methoxybenzoyl)-4,4-dimethyl-6-chinolin/-6 - methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-he;

5/1,2,3,4-tetrahydro-1-(3-methoxy-4-ethoxybenzoyl)-4,4 - dimethyl-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one obtained 3-/3-(N, N-diethylamino)-propoxycarbonyl/-5-/1,2,3,4 - tetrahydro-1-(3-methoxy-4-ethoxybenzoyl)-4,4-dimethyl-6-chinolin/-6 - methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-he;

5/1,2,3,4-tetrahydro-1-(3-methoxy-4-hydroxybenzoyl)-4,4 - dimethyl-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one obtained 3-/3-(N, N-diethylamino)-propoxycarbonyl/-5-/1,2,3,4 - tetrahydro-1-(3-methoxy-4-hydroxybenzoyl)-4,4-dimethyl-6-chinolin/-6 - methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-it.

Example 6

A solution of 12 g of 3-/2-(N,N-diethylamino)-etoxycarbonyl/-5-(1,2,3,4 - tetrahydro-6-chinolin)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-it (obtained analogously to example 1 by reacting 5-(1,2,3,4-tetrahydro-6-chinolin)-6-methyl-3,6-dihydro-2H-1,3,4 - thiadiazin-2-one with 2-N, N-diethylaminoethyl ether PI is 4 ml acetylchloride. Stirred for another hour at 20oC, decompose water, process as usual and get 3-/2-(N, N-diethylamino)-ethoxy-carbonyl/-5-(1-acetyl-1,2,3,4 - tetrahydro-6-chinolin)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-it.

Similarly receive the following 3-/2-(N,N-diethylamino-etoxycarbonyl/-[R]-6-methyl-3,6-dihydro-2H - 1,3,4-thiadiazin-2-ones, where[R] denotes:

5-(1-formyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-propionyl 1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-butyryl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-isobutyryl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-valeryl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-isovaleryl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-pivaloyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-benzoyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-p-methoxybenzoyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-/1-(3,4-methylenedioxybenzyl)-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-p-methyldibenzo-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-p-methylsulfonylbenzoyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-p-methylsulfonylbenzoyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-pikolinos-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-nicotinoyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-isonicotinoyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-methanesulfonyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-b the Il-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-acetyl-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-propionyl 4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-butyryl-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-isobutyryl-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-valeryl-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-isovaleryl-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-pivaloyl-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-benzoyl-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-p-methoxybenzoyl-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-/1-(3,4-methylenedioxybenzyl)-4,4-dimethyl-1,2,3,4-tetrahydro-6 - chinolin/-;

5-(1-p-methyldibenzo-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-p-methylsulfonylbenzoyl-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-p-methylsulfonylbenzoyl-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-pikolinos-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-nicotinoyl-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-isonicotinoyl-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-methanesulfonyl-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-benzazolyl-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

5-(1-p-toluensulfonyl-4,4-dimethyl-1,2,3,4-tetrahydro-6-chinolin)-;

Example 7

Analogously to example 1, by usaimage is morpholino-propyl ether Harborview acid obtained 3-(3-morpholino-propoxycarbonyl)-5-/1,2,3,4-tetrahydro-1-(3 - methoxy-4-ethoxybenzoyl)-6-chinolin/-6-methyl-2H-1,3,4-thiadiazin-2-he;

3,6-dihydro-5-/1,2,3,4-tetrahydro-1-(3-methoxy-4-ethoxybenzoyl)-6 - chinolin/-6-methyl-2H-1,3,4-thiadiazin-2-one with 3-piperidino-propyl ether Harborview acid obtained 3-(3-piperidino-propoxy-carbonyl)-5-/1,2,3,4-tetrahydro-1-(3 - methoxy-4-ethoxybenzoyl)-6-chinolin/-6-methyl-2H-1,3,4-thiadiazin-2-it.

Example 8

To a solution of 10 g of 3-(3-piperazine derivatives-propoxycarbonyl)-5-/1,2,3,4 - terravita-1-(3,4-dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro - 2H-1,3,4-thiadiazin-2-she and 1.8 g of triethylamine in 100 ml of toluene under stirring pin of 1.3 g of ethylchloride dissolved in 10 ml of toluene, and stirred under heating for one hour. The solvent is removed, is treated as usual and get 3-/3-(1-ethyl-4-piperazinil)-propoxycarbonyl/- 5-/1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-chinolin/-6 - methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-it.

Example 9

Analogously to example 1, by interaction

3,6-dihydro-5-/1,2,3,4-tetrahydro-1-(3-methoxy-4-ethoxybenzoyl)- 4,4-dimethyl-6-chinolin/-6-methyl-2H-1,3,4-thiadiazin-2-one with 3-morpholinopropan ether Harborview acid obtained 3-(3-morpholino-propoxycarbonyl)-5-/1,2,3,4-tetrahydro-1-(3-methoxy-4 - ethoxybenzoyl)-4,4-dimethyl-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4 - thiadiazin-2-he;

3,6-dihydro-5-/1,2,3,4-tetrahydro-1-(3-meth is avinou acid obtained 3-(3-piperidino-propoxycarbonyl)-5-/1,2,3,4-tetrahydro-1-(3-methoxy-4 - ethoxybenzoyl)-4,4-dimethyl-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4 - thiadiazin-2-he;

3,6-dihydro-5-/1,2,3,4-terravita-1-(3,4-dimethoxybenzoyl)-6 - chinolin/-6-methyl-2H-1,3,4-thiadiazin-2-it with Cl-C (=O)-O-C10H20-N-(CH3)2get 3-/10-(N, N-dimethylamino)-decyloxybenzoic/-5-/1,2,3,4-tetrahydro - 1-(3,4-dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4 - thiadiazin-2-it, so pl. = 87oC;

3,6-dihydro-5-/1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6 - chinolin/-6-methyl-2H-1,3,4-thiadiazin-2-one with 6-pyrrolidino-hexyl ether Harborview acid obtained 3-(6-pyrrolidino-hexyloxyphenyl)-5-/1,2,3,4-tetrahydro-1-(3,4 - dimethoxybenzoyl)-6-chinolin/-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-he; so pl. = 107oC.

The following examples relate to pharmaceutical compositions that contain biologically active substances of the formula (I) or their salts.

Example: Pills and tablets

As usual pressed tablets of the following composition, which, if necessary, cover shell for drops on the basis of sucrose:

biologically active substance of the formula (I) is 100 mg

microcrystalline cellulose - much as 278.8 mg

lactose - 110 mg

corn starch - 11 mg

magnesium stearate 5 mg

highly dispersed silicon dioxide - 0.2 mg

Example B: Hard gelatin capsules

Abusage composition:

biologically active substance of the formula (I) is 100 mg

lactose 150 mg

cellulose 50 mg

magnesium stearate 6 mg

Example: Soft gelatin capsules

Conventional soft gelatin capsules filled with a mixture of 50 mg of biologically active substances and 250 mg of olive oil.

Example D: Capsules

A solution of 200 mg of biologically active substances in 2 kg propane-1,2-diol add water to 10 ml and fill them ampoules so that each ampoule contains 20 mg of biologically active substances.

Example D: an Aqueous suspension for oral administration

Prepare as usual aqueous suspension of biologically active substances. Single (single) dose (5 ml) contains 100 mg of biologically active substances, 100 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate and 100 mg of sorbitol.

Example E: Candles

Melt a mixture of 20 g of biologically active substances with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and leave to cool. Each suppository contains 20 mg of biologically active substances.

Pharmacological data

Was determined in vivo positive inotropic activity of some typical compounds of General formula (I) according to met the ti increase the left vertical pressure (dP/dt) are given in the table below.

< / BR>
R4= 3,4-dimethoxybenzoic

1. 3-Alkoxycarbonyl-thiadiazine formula I

< / BR>
where R1means AND;

R2and R3denote H, A;

R4represents benzoyl, substituted C1- C6-alkoxygroup;

R5denotes NA2or a saturated five - or six-membered heterocyclic residue with at least one N-atom, which may be substituted by A;

Q is absent or denotes a branched or unbranched alkylene with 1 to 10 C-atoms;

n denotes 1, 2 or 3;

And denotes alkyl with 1 to 6 C-atoms,

and their physiologically acceptable salts.

2. 3-Alkoxycarbonyl-thiadiazine under item 1, representing

(a) 3-[2-(N, N-diethylamino)-etoxycarbonyl] -5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxy-benzoyl)-6-chinolin] -6-methyl-2H-3,6-dihydro-1,3,4-thiadiazin-2-he;

(b) 3-[3-(N, N-diethylamino)-propoxycarbonyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxy-benzoyl)-6-chinolin] -6-methyl-2H-3,6-dihydro-1,3,4-thiadiazin-2-he;

(b) 3-[6-(N,N-dimethylamino)-hexyloxyphenyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxy-benzoyl)-6-chinolin] -6-methyl-2H-3,6-dihydro-1,3,4-thiadiazin-2-he;

(g) 3-[1-methyl-2-(N, N-dimethylamino)-etoxycarbonyl] -5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxy-benzoyl)-(3,4-dimethoxy-benzoyl)-6-chinolin]-6-methyl-2H-3,6-dihydro-1,3,4-thiadiazin-2-he;

(e) 3-[2-(N, N-diethylamino)-etoxycarbonyl] -5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxy-benzoyl)-4,4-dimethyl-6-chinolin] -6-methyl-2H-3,6-dihydro-1,3,4-thiadiazin-2-he;

(W) 3-[6-(N,N-dimethylamino)-hexyloxyphenyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxy-benzoyl)-4,4-dimethyl-6-chinolin] -6-methyl-2H-3,6-dihydro-1,3,4-thiadiazin-2-he;

(C) 3-[1-methyl-4-piperidinylcarbonyl] -5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxy-benzoyl)-4,4-dimethyl-6-chinolin] -6-methyl-2H-3,6-dihydro-1,3,4-thiadiazin-2-he;

(and) 3-[1-methyl-2-(N, N-dimethylamino)-etoxycarbonyl] -5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxy-benzoyl)-4,4-dimethyl-6-chinolin] -6-methyl-2H-3,6-dihydro-1,3,4-thiadiazin-2-it.

3. The method of obtaining compounds of formula I on p. 1 or their salts, which consists in the fact that the compound of formula II

(II)

where R1, R2, R3, R4and n are specified in paragraph 1 values

enter into interaction with the compound of the formula III

X-CO2-Q-R5,

where R5and Q are specified in paragraph 1 values;

X denotes Cl, Br, OH or a reactive, esterified ester to OH-group,

followed if necessary transformations: a compound which corresponds to formula (I) instead of R5contains primary or secondary amino group, normal Nim way acelerou; in the compound of formula I one residue R4turn in the remainder R4; and/or the base of the formula I by treatment with acid is converted into one of its salts.

4. Pharmaceutical composition with a positive inotropic effect, characterized in that the active substance it contains at least one compound of formula I under item 1 and/or one of its physiologically acceptable salt in an effective amount.

 

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< / BR>
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< / BR>
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< / BR>
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