CA2019811A1 - Substituted 3-aminosydnone imines, processes for their preparation and their use - Google Patents
Substituted 3-aminosydnone imines, processes for their preparation and their useInfo
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- CA2019811A1 CA2019811A1 CA002019811A CA2019811A CA2019811A1 CA 2019811 A1 CA2019811 A1 CA 2019811A1 CA 002019811 A CA002019811 A CA 002019811A CA 2019811 A CA2019811 A CA 2019811A CA 2019811 A1 CA2019811 A1 CA 2019811A1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/04—1,2,3-Oxadiazoles; Hydrogenated 1,2,3-oxadiazoles
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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Abstract
ABSTRACT
Substituted 3-aminosydnone imines of the formula I
(I) and their pharmacologically acceptable acid addition salts, in which A denotes the radical -S- or -SO2-, R1 denotes the radical -CO-R2 or hydrogen, and R2 denotes, for example, (C1 to C4)alkyl, are prepared by cyclization of a compound of the formula II
Substituted 3-aminosydnone imines of the formula I
(I) and their pharmacologically acceptable acid addition salts, in which A denotes the radical -S- or -SO2-, R1 denotes the radical -CO-R2 or hydrogen, and R2 denotes, for example, (C1 to C4)alkyl, are prepared by cyclization of a compound of the formula II
Description
2 019 Ql~ Ref. 3443/Ausl ~7 l Dr.Eu/L10807 Substituted 3-aminosydnone imines. processes for their ~repara-tion and their use The invention relates to pharmacologically active sub-stituted 3-aminosydnone imines of the general formula I
~3~CH3 2 C~
A N N - CH . (I) C H 2 C H 2 N~-~C=N--R
and their pharmacologically acceptabl~ acid addition salts, in which A denotes the radical -S- or -S2-, R1 denotes the radical -CO-R2 or hydrogen, R2 denotes (C1 to C4 ) alkyl, (C1 to C4 ) alkoxy-(C~ to C4 )alkyl, (Cl to C4 ) alkoxy, ( C5 to C7 )cycloalkyl, phenyl, or a phenyl radical which is mono-, di- or trisubstituted by 1 to 3 halogen atoms and/or 1 to 3 alkyl radicals having 1 to 4 C atoms and/or 1 to 3 alkoxy radicals having 1 to 4 C atoms.
The invention furthermore relates to processes for the preparation of the compounds according to the invention and to their use.
Alkyl radicals, alkoxyalXyl radicals and alkoxy radicals may be straight-chain or branched. This also applie~ if they occur as substituents of phenyl.
(C1 to C4)alkyl radicals may be: methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert.-butyl and sec.-butyl. Examples of (Cl to C4)alkoxy radicals may be: methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec.-butoxy and tert.-butoxy.
(C1 to C~)alkoxy-tCl to C4)alkyl radical~ may be, for example: methoxymethyl, ethoxymethyl, propoxymethyl, butoxy-methyl, i-butoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 2-ethoxyethyl, 3-propoxypropyl, 4-propoxybutyl, 2-butoxyethyl, 3-butoxypropyl, 4-butoxybutyl, 3-i-propoxypropyl, , . ~ . ~ ~. . .. . .
20198~
4-i-propoxybutyl, 2-ethoxyethyl, 2-propoxyethyl, 2-i-propoxy-ethyl, 2-butoxyethyl, 2-i-butoxyethyl, 1-methoxyethyl, l-ethoxy-ethyl, l-propoxyethyl, 2-methoxypropyl, 2-ethoxypropyl, 2-propoxypropyl, 2-i-propoxypropyl, 3-methoxybutyl, 3-ethoxybutyl, 3-propoxybutyl, 3-i-propoxybutyl, 3-butoxybutyl,,3-i-butoxybutyl, 3-tert.-butoxybutyl, 2-methoxybutyl, 2-ethoxybutyl, 2-propoxy-butyl, 2-i-propoxybutyl, 2-butoxybutyl and 2-i-butoxybutyl.
Of the ( C5 to C7 ) cycloalkyl radicals, cyclopentyl and cyclohexyl are preferred.
Possible halogen atoms for the substituted phenyl radical are fluorine, chlorine, bromine and/or iodine, of which bromine and chlorine are preferred.
R2 preferably denotes (C1 to C4)alkyl, (Cl to C4)alkoxy, phenyl, or phenyl which is monosubstituted by chlorine, methyl or lS methoxy, monosubstituted phenyl preferably being substituted in the 4- or 2-position.
Hydrogen is preferred for R1. Preferred compounds are: N-p-anisoyl-3-(3,3-dimethyltetrahydro-1,4-thiazin-4-yl)sydnone imine, and the pharmacologically acceptable addition salts of the abovementioned compound, in particular its hydrochloride, and the pharmacologically acceptable acid addition salts, in particular the hydrochlorides, of the compounds: 3-(3,3-dimethyl-1,4-tetra-- hydrothiazine~ dioxide-4-yl)sydnone imine and 3-(3,3-dimethyl-tetrahydro-1,4-thiazin-4-yl)sydnone imine.
A compound of the general formula I can be prepared by cyclizing a compound of the general formula II
~3/ 3 CH2 ~ C
A ~N N--CH2-CN ~II) in which A has the meaning already mentioned, to give a compound of the general formula Ia ~9~
~3~C H 3 C H C
A~ ~N I_CH (Ia) C H C H N~ ~ C= N H
O
and isolating the compound obtained as the acid addition salt, or in the case in which it is intended to prepare a compound of the formula I where R1 = -COR2, acylating the compound Ia or an acid addition salt thereof with an acylating agent which introduces the radical -COR2, and isolating the compound thus obtained or, if desired, cQnverting it into a pharmacologically acceptable acid addition salt, and isolating this.
~he cyclization of the compounds II to give the compounds Ia can be carried out in a suitable organic or inorganic solvent, dispersant or diluent with the addition of a cyclizing agent, ~
normally at temperatures from -10 to 40C, in particular 0 to 40C, preferably at 0 to 20C.
Suitable cyclizing agents are those which establish a pH
of less than 3 in aqueous solution, that is to say, for example, mineral acids, such as sulphuric, nitric or phosphoric acid, preferably hydrogen chloride, but also strong organic acids, such as trifluoroacetic acid. The cycIization is normally carried out with ice-cooling.
0.1 to 10 moles, preferably 1 to 5 moles, of the cycliz-ing agents are used, for example, relative to 1 mole of the compound of the formula~II. The cyclizing agent is normally employed in excess. The use of hydrogen chloride as a cyclizing agent is particularly convenient, and it is normally passed into the reaction mixture until it is saturated. The corresponding acid addition salt of the compound Ia is normally obtained in the cyclization.
Suitable solvents, dispersants or diluents are, for example: alcohols, for example those having 1 to 8 C atoms, in particular those having 1 to 6 C atoms, preferably those having 1 to 4 C atoms, such as, for example, methanol, ethanol, i- and n-propanol, i-, sec- and tert-butanol, n-, i-, sec- and . . . , ~
.
.: . ~ ,, . - , .
-.. ~ , 2 ~
tert-pentanol, n-hexanol, 2-ethylbutanol, 2-ethylhexanol, iso-ctyl alcohol, cyclopentanol, cyclohexanol, methylcyclohexanol (mixture) and benzyl alcohol; ethers, in particular those having 2 to 8 C atoms in the molecule, such as, for example, diethyl ether, methyl ethyl ether, di-n-propyl ether, di7isopropyl ether, methyl n-butyl ether, methyl tert-butyl ether, ethyl propyl ether, di-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dLmeth-oxyethane and bis-~-methoxyethyl ether; oligoethylene glycol dimethyl ethers, such as, for example, tetraglyme or pentaglyme;
alkyl carboxylates, in particular those having 2 to 10 C atoms in the molecule, such as, for example, methyl, ethyl, butyl or isobutyl formate, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl or sec-butyl, amyl, isoamyl, hexyl, cyclohexyl or benzyl acetate or methyl, ethyl or butyl propionate; ketones, in parti-lS cular those having 3 to 10 C atoms in the molecule, such as, forexample, acetone, methyl ethyl ketone, methyl n-propyl ketone,~
diethyl ketone, 2-hexanone, 3-hexanone, di-n-propyl ketone, di-iso-propyl ketone, di-iso-butyl ketone, cyclopentanone, cyclo-hexanone, methylcyclohexanone, dimethylcyclohexanone, benzophen-one and acetophenone; aliphatic hydrocarbons, such as, for ex-ample, hexane and heptane, low and high-boiling petroleum ethers, petroieum spirit and white spirt; cycloaliphatic hydrocarbons, such as, for example, cyclopentane, cyclohexane, methylcyclohex-ane, tetralin and decalin; aromatic hydrocarbons, such as, for example, benzene, toluene, o-, m- and p-xylene, and ethylbenzene;
halogenated aliphatic or aromatic hydrocarbons, such as, for example, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene and dichlorobenzene; hexa-methylphosphoramide; sulphoxides, such as, for example, dimethyl sulphoxide; tetramethylene sulphone; and water. Mixtures of different solvents or di~persants may also be used, for example water-methanol or, preferably, ethyl acetate-methanol.
The acylation of the compound of the formula Ia, which may also be present in the form of an acid addition salt, in order to introduce the radical R1 = -COR2 can be carried out in a manner known per se using a suitable acylating agent of the formula III
~3~CH3 2 C~
A N N - CH . (I) C H 2 C H 2 N~-~C=N--R
and their pharmacologically acceptabl~ acid addition salts, in which A denotes the radical -S- or -S2-, R1 denotes the radical -CO-R2 or hydrogen, R2 denotes (C1 to C4 ) alkyl, (C1 to C4 ) alkoxy-(C~ to C4 )alkyl, (Cl to C4 ) alkoxy, ( C5 to C7 )cycloalkyl, phenyl, or a phenyl radical which is mono-, di- or trisubstituted by 1 to 3 halogen atoms and/or 1 to 3 alkyl radicals having 1 to 4 C atoms and/or 1 to 3 alkoxy radicals having 1 to 4 C atoms.
The invention furthermore relates to processes for the preparation of the compounds according to the invention and to their use.
Alkyl radicals, alkoxyalXyl radicals and alkoxy radicals may be straight-chain or branched. This also applie~ if they occur as substituents of phenyl.
(C1 to C4)alkyl radicals may be: methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert.-butyl and sec.-butyl. Examples of (Cl to C4)alkoxy radicals may be: methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec.-butoxy and tert.-butoxy.
(C1 to C~)alkoxy-tCl to C4)alkyl radical~ may be, for example: methoxymethyl, ethoxymethyl, propoxymethyl, butoxy-methyl, i-butoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 2-ethoxyethyl, 3-propoxypropyl, 4-propoxybutyl, 2-butoxyethyl, 3-butoxypropyl, 4-butoxybutyl, 3-i-propoxypropyl, , . ~ . ~ ~. . .. . .
20198~
4-i-propoxybutyl, 2-ethoxyethyl, 2-propoxyethyl, 2-i-propoxy-ethyl, 2-butoxyethyl, 2-i-butoxyethyl, 1-methoxyethyl, l-ethoxy-ethyl, l-propoxyethyl, 2-methoxypropyl, 2-ethoxypropyl, 2-propoxypropyl, 2-i-propoxypropyl, 3-methoxybutyl, 3-ethoxybutyl, 3-propoxybutyl, 3-i-propoxybutyl, 3-butoxybutyl,,3-i-butoxybutyl, 3-tert.-butoxybutyl, 2-methoxybutyl, 2-ethoxybutyl, 2-propoxy-butyl, 2-i-propoxybutyl, 2-butoxybutyl and 2-i-butoxybutyl.
Of the ( C5 to C7 ) cycloalkyl radicals, cyclopentyl and cyclohexyl are preferred.
Possible halogen atoms for the substituted phenyl radical are fluorine, chlorine, bromine and/or iodine, of which bromine and chlorine are preferred.
R2 preferably denotes (C1 to C4)alkyl, (Cl to C4)alkoxy, phenyl, or phenyl which is monosubstituted by chlorine, methyl or lS methoxy, monosubstituted phenyl preferably being substituted in the 4- or 2-position.
Hydrogen is preferred for R1. Preferred compounds are: N-p-anisoyl-3-(3,3-dimethyltetrahydro-1,4-thiazin-4-yl)sydnone imine, and the pharmacologically acceptable addition salts of the abovementioned compound, in particular its hydrochloride, and the pharmacologically acceptable acid addition salts, in particular the hydrochlorides, of the compounds: 3-(3,3-dimethyl-1,4-tetra-- hydrothiazine~ dioxide-4-yl)sydnone imine and 3-(3,3-dimethyl-tetrahydro-1,4-thiazin-4-yl)sydnone imine.
A compound of the general formula I can be prepared by cyclizing a compound of the general formula II
~3/ 3 CH2 ~ C
A ~N N--CH2-CN ~II) in which A has the meaning already mentioned, to give a compound of the general formula Ia ~9~
~3~C H 3 C H C
A~ ~N I_CH (Ia) C H C H N~ ~ C= N H
O
and isolating the compound obtained as the acid addition salt, or in the case in which it is intended to prepare a compound of the formula I where R1 = -COR2, acylating the compound Ia or an acid addition salt thereof with an acylating agent which introduces the radical -COR2, and isolating the compound thus obtained or, if desired, cQnverting it into a pharmacologically acceptable acid addition salt, and isolating this.
~he cyclization of the compounds II to give the compounds Ia can be carried out in a suitable organic or inorganic solvent, dispersant or diluent with the addition of a cyclizing agent, ~
normally at temperatures from -10 to 40C, in particular 0 to 40C, preferably at 0 to 20C.
Suitable cyclizing agents are those which establish a pH
of less than 3 in aqueous solution, that is to say, for example, mineral acids, such as sulphuric, nitric or phosphoric acid, preferably hydrogen chloride, but also strong organic acids, such as trifluoroacetic acid. The cycIization is normally carried out with ice-cooling.
0.1 to 10 moles, preferably 1 to 5 moles, of the cycliz-ing agents are used, for example, relative to 1 mole of the compound of the formula~II. The cyclizing agent is normally employed in excess. The use of hydrogen chloride as a cyclizing agent is particularly convenient, and it is normally passed into the reaction mixture until it is saturated. The corresponding acid addition salt of the compound Ia is normally obtained in the cyclization.
Suitable solvents, dispersants or diluents are, for example: alcohols, for example those having 1 to 8 C atoms, in particular those having 1 to 6 C atoms, preferably those having 1 to 4 C atoms, such as, for example, methanol, ethanol, i- and n-propanol, i-, sec- and tert-butanol, n-, i-, sec- and . . . , ~
.
.: . ~ ,, . - , .
-.. ~ , 2 ~
tert-pentanol, n-hexanol, 2-ethylbutanol, 2-ethylhexanol, iso-ctyl alcohol, cyclopentanol, cyclohexanol, methylcyclohexanol (mixture) and benzyl alcohol; ethers, in particular those having 2 to 8 C atoms in the molecule, such as, for example, diethyl ether, methyl ethyl ether, di-n-propyl ether, di7isopropyl ether, methyl n-butyl ether, methyl tert-butyl ether, ethyl propyl ether, di-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dLmeth-oxyethane and bis-~-methoxyethyl ether; oligoethylene glycol dimethyl ethers, such as, for example, tetraglyme or pentaglyme;
alkyl carboxylates, in particular those having 2 to 10 C atoms in the molecule, such as, for example, methyl, ethyl, butyl or isobutyl formate, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl or sec-butyl, amyl, isoamyl, hexyl, cyclohexyl or benzyl acetate or methyl, ethyl or butyl propionate; ketones, in parti-lS cular those having 3 to 10 C atoms in the molecule, such as, forexample, acetone, methyl ethyl ketone, methyl n-propyl ketone,~
diethyl ketone, 2-hexanone, 3-hexanone, di-n-propyl ketone, di-iso-propyl ketone, di-iso-butyl ketone, cyclopentanone, cyclo-hexanone, methylcyclohexanone, dimethylcyclohexanone, benzophen-one and acetophenone; aliphatic hydrocarbons, such as, for ex-ample, hexane and heptane, low and high-boiling petroleum ethers, petroieum spirit and white spirt; cycloaliphatic hydrocarbons, such as, for example, cyclopentane, cyclohexane, methylcyclohex-ane, tetralin and decalin; aromatic hydrocarbons, such as, for example, benzene, toluene, o-, m- and p-xylene, and ethylbenzene;
halogenated aliphatic or aromatic hydrocarbons, such as, for example, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene and dichlorobenzene; hexa-methylphosphoramide; sulphoxides, such as, for example, dimethyl sulphoxide; tetramethylene sulphone; and water. Mixtures of different solvents or di~persants may also be used, for example water-methanol or, preferably, ethyl acetate-methanol.
The acylation of the compound of the formula Ia, which may also be present in the form of an acid addition salt, in order to introduce the radical R1 = -COR2 can be carried out in a manner known per se using a suitable acylating agent of the formula III
20~98~1 1l x-c-R2 (III) in which X represents a radical which can be removed nucleophili-cally.
In the formula III, X denotes, for example, in particular halogen, preferably -Cl or -Br; -OH; -O-alkyl, in particular having 1 to 5 C atoms; -O-aryl, the aryl radical in particular beLng a phenyl radical which may also be mono- or polysubstituted by alkyl, in particular methyl, and/or nitro, and is, for ex-ample, a tolyl, dinitrophenyl or nitrophenyl radical; -O-CO-R2;
-O-CO-O-alkyl, in particular having 1 to 5 C atoms in the alkyl radical, or the radical of an azole or benzazole which has at least 2 N atoms in the quasi-aromatic 5-membered ring and is bonded via an N atom.
The acylation is expediently carried out in a liquid or liquid disperse phase in the presence of an inert solvent, dis-persant or diluent or in an excess of the acylating agent, ex-pediently with stirring.
In the acylation, the molar ratio between the compound of the formula Ia and the acylating agent of the formula III is theoretically 1 : 1. However, the acylating agent can also be employed in a sub-equivalent amount or in excess. Excesses of up to 30 mol% are usually sufficient, i.e. the molar ratio between the compound of the formula Ia and the acylating agent of the formula III is normally 1 : (1 to 1.3), preferably 1 : (1 to 1.2). If an acid is eliminated in the acylation reaction, the addition of an acid scavenger, such as, for example, an alkali metal hydroxide, such as, for example, sodium hydroxide, potas-sium hydroxide or lithium hydroxide, a tertiary organic amine, such as, for example, pyridine or triethylamine, an alkali metal carbonate or alkali metal bicarbonate, ~uch as, for example, sodium carbonate or sodium bicarbonate, or an alkali metal salt of a weak organic acid, such as, for example, sodium acetate, is expedient. Suitable catalysts, such as, for example, 4-dimethyl-aminopyridine, may al o be added during the acylation reaction.
The acylation may in principle be carried out at .
^.
"' ` ~ ' ,. ~
.. . . .
. ~
2 ~
temperatures between -10C and the boiling point of the solvent, dispersant or diluent used. In many cases, the reaction is car-ried out at 0 to 50C, in particular at 0 to 30C and preferably at room temperature.
The compounds of the formula III are acylating agents and thus represent, for example: for X = halogen: acid halides or haloformic acid esters, of which acid chlorides and chloroformic acid esters are preferred; for -OH: carboxylic acids; for -O-alkyl and -O-aryl: esters, of which the tolyl, 2,4-dinitro- or 4-nitrophenyl esters are preferred; for -O-CO-R: anhydrides; for -O-CO-O-alkyl; mixed carboxylic acid/carbonic acid anhydrides; or heterocyclic amides or azolides, in particular of N,N'-carbonyl-diazoles, such as, for example, N,N'-carbonyldiimidazole, 2,2'-carbonyl-1,2,3-ditriazole, 1,1'-carbonyl-1,2,4-ditriazole, N,N'-carbonyldipyrazole and 2,2'-carbonylditriazole (compare, for example, H.A. Staab, M. LUcking and F.H. Durr, Chem. Ber. 95, ~
(1962), 1275 ff, H.A. Staab and A. Mannschreck, Chem. Ber. 95, (1962), 1284 ff.; H.A. Staab and W. Rohr, "Synthesen mit hetero-cyclischen Amiden (Azoliden)" tSyntheses with heterocyclic amides (azolides)] in "Neuere Methoden der Praparativen Organischen Chemie" [Newer methods of preparative organic chemistry], volume V, Verlag Chemie, 1967, p. 53 et seq., in particular pp. 65 to 69). The acylating agents of the formula III can be prepared by processes which are known per se.
When using a carboxylic acid as the acylating agent, the addition of an activating agent which has the object of increas-ing or of activating the acylating potential of the carboxylic acid or of converting the carboxylic acid into a reactive car-boxylic acid derivative of the formula III in situ or preferably shortly before the reaction with the compound of the formula Ia is expedient. Suitable activating agents of this type are, for example: N,N'-disubstituted carbodiimides, in particular if they contain at least one secondary or tertiary alkyl radical, such as, for example, diisopropyl, dicyclohexyl or N-methyl-N'-tert.-butylcarbodiimide (compare Methodicum Chimicum, Verlag G. Thieme, Stuttgart, Vol. 6, (1974), pp. 682/683, and Houben-Weyl, Methoden der Org. Chemie [Methods cf organic chemistry], Vol. 8, (1952), ~9~
pp ~S21/522); carbonic acid derivatives, such a~, for example, phosgene, chloroformic acid esters, in particular having 1 to 5 C
atoms in the alkyl radical (compare, for example, Tetrahedron Letters 24 (1983), 3365 to 3368); carbonic acid esters, such as for example, N,N~-disuccinimidyl carbonate, diphthal,imidyl car-bonate, l,1'-(carbonyldioxy)dibenzotriazole or di-2-pyridyl carbonate (compare, for example, Tetrahedron Letters, Vol. 25, No. 43, 4943-4946), if desired in the presence of suitable cata-lysts, such as, for example, 4-dimethylaminopyridine. In addi-tion, N,N'-carbonyldiazoles, such as, for example, N,N'-carbonyldiimidazole, 2,2'-carbonyl-1,2,3-ditriazole, l,1'-car-bonyl-1,2,4-ditriazole, N,N'-carbonyldipyrazole, 2,2'-carbonyl-ditetrazole, N,N'-carbonylbenzimidazole or N,N~-carbonylbenzotri-azole are suitable as activating agents (compare, for example, H.A. Staab, M. ~ucking and F.H. Durr, loc. cit; H.A. Staab and A.
Mannschreck loc. cit.; X.A. Staab and W. Rohr loc. cit). The N,N~-carbonyldiazole used is frequently the commercially avail-able N,N'-carbonyldiimidazole. However, the other N,N'-carbonyl-azoles are also easily accessible from the respective azole and phosgene.
In addition, suitable activating agents for carboxylic acids are: derivatives of oxalic acid, such as, for example, oxalyl chloride (compare, for example, GB Patent Specification 2,139,225) or N,N'-oxalyldiazoles, such as, for example, 1,1'-oxalyldiimidazole, 1,1'-oxalyldi-1,2,4-triazole and l,l'-oxalyl-di-1,2,3,4-tetrazole (compare, for example, Shizuaka Nurata, Bull. Chem. Soc. Jap. S7, 3S97-3598 (1984)); methylethylphos-phinic anhydride (compare~ for example, German Offenlegungs-schrift 3,101,427); diphosphorus tetraiodide (Chem. Lett. 1983, 449); dialkyl disulphite (Indian J. Chem. 21, 259 (198~)); or other reactive agents.
Suitable solvents, dispersants or diluents are, for example, those which have been mentioned for carrying out the cyclization, and moreover also, for example, pyridine and amides, such as, for example, dimethylfonmamide. In addition to water, polar organic solvents, such as dimethylformamide, dimethyl sulphoxide or pyridine, are preferred for the acylation. Solvent 2 ~
mixtures, such as, for example, a mixture of water and methylene chloride, are also suitable.
The substituted 3-aminosydnone imines of the general formula I can form acid addition salts with inorganic or organic acids. Inorganic or organic acids are suitable for the formation of acid addition salts of this type. For the formation of pharma-cologically acceptable acid addition salts, suitable acids are, for exampLe: hydrogen chloride, hydrogen bromide, naphthalene-disulphonic acids, in particular 1,5-naphthalenedisulphonic acid, phosphoric, nitric, sulphuric, oxalic, lactic, tartaric, acetic, salicylic, benzoic, formic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, malic, sulphamic, phenylpropionic, gluconic, ascorbic, isonicotinic, methane-sulphonic, p-toluenesulphonic, citric or adipic acid. The acid addition salts may be prepared in a customary manner by combining the components, expediently in a suitable solvent or diluent.
The compounds of the formula Ia are unstable in the free form, but are isolated in the form of their acid addition salts.
In the synthesis of the compounds of the formula Ia, the acid addition salts are normally obtained.
The starting compounds of the general formula II required may be prepared in a manner known per se by Strecker's amino-nitrile synthesis from compounds of the general formula IV or their acid addition salts ~3~CH3 /CH2 C\ ( IV) CH CH
in which A has the meaning already mentioned, by reaction with formaldehyde and hydrocyanic acid or sodium cyanide in a suitable solvent or diqpersant or solvent or dispersant mixture, for example in water, a compound of the general formula V
2019~
~3/ 3 2 C\ ( V ) A ~N--NH-CH2-CN
first being formed, which is converted by nitrosylation into the compound II. The nitrosylation is carried out in a known manner in`a suitable`solvent or dispersant or solvent or dispersant mix-ture, for example in water, for example at temperatures of -10 to 10C. The nitrous acid is in this case normally generated from an alkali meta~ nitrite, for example sodium nitrite, and hydro-chloric acid. It is expedient to adjust the aqueous solution of the compound V to a pH of 1 to 3 with hydrochloric acid and to add the alkali metal nitrite to the stirred and cooled solution in the form of an aqueous solution. The solution of the compound II obtained here can be subjected directly to the cyclization reaction. However, normally it is appropriate to take up the nitroso compound II in a suitable organic solvent first and to carry out the cyclization to give the compound of the formula Ia in it, if desired after addition of a further solvent.
The compounds of the general formula IV can be prepared, starting from compounds of the general formula VI
C~ 3~ C H ~
/CH2 ~\ (VI) A N--H
CH --CH
by either a) nitrosylating a compound of the formula VI to give the N-nitroso compound VII and then reducing, expedient y with lithium aluminium hydride:
_ g _ .. , :. ~ .
20~L9~
(VI~ A N-NO ~ A N-NH2 tVII ) ( IV) or, in a manner known per se b) converting a compound of the formula VI into the urea deriva-tivë VIII with potassium cyanate in acidic medium, and then converting by means of oxidation with sodium hypochlorite by the Hoffmann degradation into the compound IV:
CH3 CH3 KNCO C\3/CH3 AN-H - ~ A N-CO-NH2 (VI) (VIII) ~CH
/ 2 C\ NaOCl /CH -C
A N-CO-NH ~A\ /N-NH2 ( V I I J ) ( I V ) The compound 3,3-dimethyltetrahydro-1,4-thiazine (A = -S-in formula VI) can be prepared by reaction of 2,2-dimethylaziri-dine (which can be prepared by elimination of water from 2-amino-2-methylpropan-1-ol) with 3-mercaptoethanol, 2-hydroxyethyl 2-amino-2-methylpropyl sulphide being formed first. The hydroxyl group in this compound is replaeed by chlorine by chlorination, for example with thionyl chloride, and the compound thus obtained is then cyelized by the aetion of a base.
The eompound 4-amino-3,3-dimethyl-1,4-tetrahydrothiazine-l,1-dioxide (A = -SO2- in formula IV) is known (eompare ~01~811 Arzneimittelforschung 22, (1972), 1568). It can be prepared as -~ollows: monothioethylene glycol and 2,2-dimethyloxirane are reacted at elevated temperature in the presence of catalytic amounts of alkali metal hydroxide to give 2-hydroxy-2-methyl-propyl 2-hydroxyethyl sulphide, this is converte~ with H20z into the corresponding 2-hydroxy-2-methylpropyl 3-hydroxyethyl sul-phone and this is cyclized in the presence of a dehydrating agent, such as, for example, potassium hydrogen sulphate to give 2,2-dimethyl-1,4-oxathiane-4,4-dioxide of the formula IX:
~3~CH3 2 C~
02s\ o (IX) CH CH
This compound can be reacted with hydrazine hydrate to give the compound IV where A = -SO2-, compare Arzneimittelforschung loc.
cit. and Example la below.
Compounds of the formula I according to the invention where A = -SO2- can also be prepared by reacting a compound of the formula I according to the invention where A = -S- or a compound of the formula I where A = -SO-, or an acid addition salt of such a compound, with a substance donating oxygen and converting the compound obtained, if desired, into an acid addition salt and isolating it, or in the case in which a compound of the formula I
where A = -SO2- and R1 = H has been obtained and is intended to prepare a compound of the formula I where A = -SO2- and R2 = -COR2, acylating the compound obtained or an acid addition salt thereof with an acylating agent which introduces the radical -COR2 and isolating the compound thus obtained or, if desired, converting it into a pharmacologically acceptable acid addition salt and isolating this. Examples of suitable oxygen-donating substances which may be mentioned are: hydrogen peroxide, peroxoacids, such as, for example, performic, peracetic, perbenzoic, m-chloro-perbenzoic and perphthalic acid, and also diacyl peroxides.Mixtures of various oxygen-donating substances may also be used.
The oxygen-donating substance is employed in at least the 20~9~
stoichiometrically necessary amount. The reaction may expediently `)e carried out in a suitable solvent or dispersant or solvent or dispersant mixture at temperatures from 0C, preferably from room temperature, up to the boiling point of the solvent or dispersant or solvent or dispersant-mixture. Suitable solve~ts or disper-sants are, for example, the ethers already mentioned, aliphatic, cycloaliphatic and aromatic hydrocarbons, halogenated aliphatic and aromatic hydrocarbons, water, but in particular lower car-boxylic acids, such as formic or acetic acid.
An acylation with an acylating agent introducing the radical -COR2 to be carried out, if desired, after the reaction with the oxygen-donating agent is carried out in the manner already mentioned using an acylating agent of the formula III.
The conversion to be carried out, if desired, into the acid addition salt is carried out, as already mentioned above, in a manner known per se.
The compounds of the formula I where A = -S02- can be prepared analogously to the compounds of the formula I where A = -S- from compounds of the formula II where A = -SO2-.
The compounds of the general formula I according to ~he invention and their pharmacologically acceptable acid addition salts have useful pharmacological properties, for example haemo-dynamic, thrombocyte function-inhibiting and antithrombotic, in particular coronary antithrombotic, properties. Their action on the cardiovascular system is particularly pronounced. Compared with known sydnone imine compounds similarly substituted struc-turally in the 3-position, for example those of French Patent Specification 1,496,056 and the compounds of the older German Patent Application P 3820210.7, they unexpectedly have a surpris-ingly longer duration of action. For example, they lower the blood pressure as well as the pulmonary arte~y pressure and the left ventricular end-diastolic pressure and thus contribute to a relief of the load on the heart in the sense of an antianginal action, without provoking reflex tachycardia in this connection.
The compounds of the formula I according to the invention and their pharmacologically acceptable acid addition salts can therefore be administered to humans as medicaments per se alone, 2~
in mixtures with one another or in the form of pharmaceutical preparations which permit enterzl or parenteral use and which contain as the active component an effective dose of at least one compound of the formula I according to the invention or an acid addition salt thereof, in addition to one or more customary pharmaceutically acceptable excipients or diluents and, if de-sired, one or more additives.
The medicaments can be administered orally, for example in the form of tablets, film tablets, coated tablets, hard and soft gelatin capsules, microcapsules, granules, powders, pellets, solutions, syrups, emulsions, suspensions, aerosols, foams, pills or pastille~. Administration may, however, also be carried out rectally, for exam~le in the form of suppositories, or parenter-ally, for example in the form of in~ection solutions, or per-cutaneously, for example in the form of ointments, creams, gels,pastes, aerosols, foams, powders, tinctures, liniments or so-called transdermal therapeutic systems (TTS). -The pharmaceutical preparations can be prepared in a manner known per se using pharmaceutically inert inorganic or organic auxiliaries, excipients, fillers or diluents. For the preparation of pills, tablets, film tablets, coated tablets and the pellet or granule fillings of hard gelatin capsules, for example calcium phosphate, lactose, sorbitol, mannitol, starches, prepared starches, chemically modified starches, starch hydroly-æates, cellulose, cellulose derivatives, synthetic polymers, talcetc., can be used. Excipients or diluents for soft gelatin cap-sules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc. Suitable exci-pients or diluents for the preparation of solutions and syrups are, for example, water, polyols, solutions of sucrose, dextrose, glucose etc. Suitable excipients for the preparation of injection solutions are, for example, water, alcohols, gIycerol, polyols or vegetable oils. Suitable excipients or diluents for ointments, creams and pastes are, for example, natural petroleum ~elly, synthetic petroleum ~elly, viscous and mobile paraffins, fat-q, natural or hardened vegetable and animal oils, neutral oils, waxes, wax alcohols, polyethylene glycols, polyacrylic acid, ~. , , ~ , .....
-i silicone gels etc. 2 01~ 8 ~ ~
The pharmaceutical preparations may also contain, in a manner known per se, in addition to the active compounds and diluents, fillers or excipients, one or more additives or auxili-aries, such as, for example, disintegrants, bind,ers, glidants, lubricants, mould release agents, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colourings, flavourings, buffer substances, and in addition solvents or solubilizers, so~ution accelerators, antifoams, salt-forming agents, gelling agents, thickeners, flow regulators, absorbents, agents for achieving a depot effect or agents, in particular salts, for changing the osmotic pressure, coating agents or antioxidants, etc. They may also contain two or more compounds of the formula I
or their pharmacologically acceptable acid addition salts and also one or more other therapeutically active substances.
Examples of other therapeutically active substances of~
this type may be: ~-receptor blockers, such as, for example, propranolol, pindoloI, metoprolol; vasodilators, such as, for example,~carbochromen; tranquilizers, such as, for example, barbituric acid derivatives, 1,4-benzodiazepines and meprobamate;
diuretics, such as, for example, chlorothiazide; cardiotonic agents, such as, for example, digitalis preparations; hypotensive agents, such as, for example, hydralazine, dihydralazine, prazo-sin, clonidine, Rauwolfia alkaloids; agents which lower the fatty acid level in the blood, such as, for example, bezafibrate, fenofibrate; and agents for thrombosis prophylaxis, such as, for example, phenprocoumon.
The content of the active compound or the active com-pounds of the formula I in the pharmaceutical preparations can vary within wide limits and is, for example, 0.05 to 50% by weight, preferably 0.05 to 20% by weight. In solid administration forms, such as coated tablets, tablets etc., the content of one or more active compound~ of the formula I is in many cases 2 to 20% by weight. Liquid administration forms, such as drops, emul-sions and in~ection solutions frequently contain 0.05 to 2% by weight, preferably 0.05 to 1% by weight, of one or more active compounds of the formula I. The content of one or more active 2019~1~
compounds of the formula I in the pharmaceutical preparations may `~e partially replaced, if desired, for example up to 50% by weight, preferably up to 5 to 40% by weight, by one or more other therapeutically active substancec.
The compounds of the formula I according,to the inven-tion, their pharmacologically acceptable acid addition salts and pharmaceutical preparations which contain the compounds of the formula I according to the invention or their pharmacologically acceptable acid addition salts as active compounds can be used in humans for combating or preventing disorders of the cardio-vascular system, for example as antihypertensive medicaments in the various forms of high blood pressure, and in combating or prevention of angina pectoris etc. The dosage may vary within wide limits and is to be suited to the individual requirements in each individual case. In geheral~ a daily dose of about 0.5 to 100 mg, preferably 1 to 20 mg, per human individual is suitable for oral administration. For other administration forms, the daily dose, owing to the good absorption of the active compounds, is in similar amount ranges, i.e. in general also 0.5 to 100 mg/
human. The daily dose is normally divided into several, for example 2 to 4, part administrations.
The pharmacological action of the compounds of the for-mula I according to the invention was determined by a modified method of Godfraind and ~aba (Arch. Int. Pharmacodyn. Ther. 196, (Suppl) 35 to 49, 1972) and of Schuman et al. (Naunyn-Schmiede-berg's Arch. Pharmacol. 289, 409 to 418, 1975). In this connec-tion, spiral strips of the pulmonary artery of the guinea-pig are depolarized with 40 mmol/l of potassium after equilibration in calcium-free Tyrode solution. An addition of 0.5 mmoltl of CaCl2 then induces a contraction.
The relaxing action of the test substance is determined by cumulative addition in 1/2 log 10 stepped concentrations. From the concentration-effect curve (abscissa: -log mol/l of test substance, ordinate: % inhibition of the maximum contraction, average value of 4 to 6 vessel strips), the concentration of the test substance is determined which inhibits the contraction by 50% (= IC5~, mol/l). The duration of action of the test substance ' . ` ' 2~19~1~
is shown by the time which is needed after the addition of the :est substance until the starting value is obtained again. In the following table, the values thus obtained are indicated.
IC50 values and duration of action of sydnone imines of the formula R R
- / 2 C~
A N -- N--C H
CHz_CH N~-~C=NH HCl O
Compound A R IC50 Duration of action No. in mol/l in min . _ . .
l 02S\ CH3 6 x 10-6 240 10 2 S CH3 2 x 10 6 200 3 O\ H 1 x 10 6 80 ~ 1 X 10 6 120 Compound No. 1 of the table is the preferred compound according to the invention 3-(3,3-dimethyl-1,4-tetrahydro-thiazine-1,1-dioxide-4-yl)sydnone imine hydrochloride.
Compound No. 2 of the Table is the preferred compound from Example 5.
Compound No. 3 of the table is the compound 3-morpholino-sydnone imine hydrochloride known from Example 2 of French Patent Specification 1,406,056.
Compound No. 4 of the table i~ the compound 3-t3,3-di-methylmorpholin-4-yl)sydnone imine hydrochloride of Example No. 1 of the older German Patent Application P 3820210.7.
As can be seen from the above table, the compounds according to the invention have a substantially longer duration of action at a comparable IC5~ value than the two comparison compounds.
2~!811 If the duration of action of the compounds is determined `at the concentration of 6 x 10-6 mol/l, the values indicated below are obtained:
Compound No. Duration of action in min.
From these values, it can be seen that the compounds according to the invention also have a considerably longer dura-tion of action at an equal dose than the comparison compounds.
If not indicated otherwise in the examples which follow, percentage data are percentages by weight.
Example 1 3~ -DimethYl-1 4-tetrahydrothiazine~ dioxide-4-yl)sydnone imine hydrochloride a) 4-Amino-3,3-dlmeth~l-1 4-tetrahydrothiazine-111-dioxide hydro-aensulphate ~
A mixture of 57 g of 2,;2-dimethyl-1,4-oxathiane-4,4-20dioxide of the formula IX -;
CHz--C~ -C H 2_C H 2 ( IX ) 45.5 g of hydrazine hydrate and 650 ml of water is heated in an autoclave at 180-C for 6 h. After cooling, the mixture is con-centrated on a rotary evaporator, the residue is dissol~ed in as little water as possible, and the ~olution i8 rendered acidic with 50S strength sulphuric acid and ~tirred at O-C. The precipi-tate is filtered off with suction, washed with ethanol and dried.
Yield: 25 g ~.p. 206-C ~dec.) b) 4-Cyanomethylamino-3.3-dimethyl-1.4-tetrahydrothiazine-1,1-dioxide A solution of 26 g of 4-amino-3,3-dimethyl-1,4-tetra-hydrothiazine-l,l-dioxide hydrogensulphate (step a) in 300 ml of - }7 -.
- ~
.. - . - . , .
,...
, , - ~
.. . ..
2~19~1~
water is cooled to 5C and 7.8 g of potassium cyanide are added.
pH of 7 to 7.5 is established by addition of sodium carbonate solution and 7.7 g of a 39% strength formalin solution is added.
The mixture is then stirred at room temperature for 6 h, the pH
being kept at 7 by addition of some hydrochloric acid or sodium carbonate solution. The product is separated off by shaking twice with ethyl acetate and after drying and concentrating the solvent remains behind as an oil which solidifies after a short time.
Yield: 15 g M.p. 84 to 85 C
c) 3-(3.3-Dimethyl-1 4-tetrahydrothiazine-l,l-dioxide-4-yl)-sydnone imine hydrochloride 6.8 g of sodium nitrite are added with cooling and under nitrogen to a mixture consisting of 14 g of 4-cyanomethylamino-3,3-dimethyl-1,4-tetrahydrothiazine-1,1-dioxide (step b), 200 ml of ice-water, 10 ml of 10 N hydrochloric acid and 200 ml of ethyl acetate and the mixture is further stirred at room temperature-- for 1 h. The organic phase is separated off, dried and 30 ml of 25~ strength isopropanolic hydrochloric acid are added at 0C.
After 15 h, the mixture is concentrated in a water jet vacuum and the residue is boiled with 500 ml of ethyl acetate. After cool-ing, the solid is filtered off with suction and dried.
Yield: 5.5 g M.p. 220C dec.
Analysis: C~Hl5ClN4O3S
C H N O
Calc. 34.0 5.3 19.8 17.0 Found 33.? 5.4 20.0 16.7 The starting compound IX needed in step a can be prepared as follows (compare Arzneimittelforschung loc. cit.):
1 mol of ROH is dissolved in l mol of ethanol and 1 mol of 2-mercaptoethanol is added. 1 mol of 2,2-dimethyloxirane i8 added dropwise to this solution in the course of 60 min and with cooling. The mixture is then neutralized, the precipitate is filtered off, and the filtrate i8 concentrated and distilled in vacuo. 2-Hydroxy-2-methylpropyl 2-hydroxyethyl sulphide of boil-ing point 93C at 0.199 mbar is obtained.
0.5% by weight of phosphoric acid is added to the sul-phide obtained and the sulphide is then oxidized by dropwise 2~81~
addition of 3096 strength by weight H2O2 to give 2-hydroxy-2-methyl-propyl 2-hydroxyethyl sulphone. This sulphone is obtained after concentration as a non-distillable oil.
A mixture of 32 g of 2-hydroxy-2-methylpropyl 2-hydroxy-5 ethyl sulphone and 5 g of KHS04 are heated to 12qC, after thecyclization is complete the mixture is cooled, the precipitate is filtered off, the filtrate is neutralized with potassium car-bonate, the precipitate is again filtered off, and the filtrate is~concentrated and distilled in vacuo at 0.532 mbar. The com-pound 2,2-dimethyl-1,4-oxathiane-4,4-dioxide has a boiling point of 100-102 C at this pressure. M.p.: 83C
Example 2 N-Ethoxycarbonyl-3-(3 3-dimethyl-1 4-tetrahydrothiazine-1 1-dioxide-4-yl)sydnone imine 1.11 g of NaHCO3 and a solution of 0.65 g of ethyl chloro-formate in 20 ml of methylene chloride are added to a solution~of 1.5 g of 3-(3,3-dimethyl-1,4-tetrahydrothiazine-1,1-dioxide-4-yl)sydnone imine hydrochloride (Example 1) in 20 ml of water cooled to 0 to 5C and the mixture is stirred at a temperature 20 increas-ng to room temperature until evolution of gas is com-plete. The organic phase is separated off, dried and concentrated in a water jet vacuum, and the residue is recrystallized from ethyl acetate.
Yield: 0.82 g M.p. 188--190C
Analysis: Cl1Hl8N4O5S
C H _ N O
Calc. 41.5 5.7 17.6 25.2 Found 41.5 5.6 17.8 24.9 Examole 3 N-p-Anisoyl-3-(3,3-dimethyl-1,4-tetrahydrothiazine-1,1-dioxide-4-yl)sydnone imine The compound is obtained analogously to Example 2 using p-anisoyl chloride instead of ethyl chloroformate.
M.p.: 178 to 180C
Analysis: Cl6H20N4O5S
2 0 ~
C __ H N o _ `Calc. 50.5 5.3 14.7 21.1 Found 50.2 5.4 15.0 20.8 Example 4 N-Cyclohexylcarbonyl-3-t3~3-dimethyl-1~4-tetrahydrothiazine-1,1-dioxide-4-yl~sydnone imine The compound is obtained analogously to Example 2 using cyclohexanecarbonyl chloride instead of ethyl chlorofc~mate.
M.p~: 150 to 151C
Analysis: C15H24N4O4S
C H N O
Calc. 50.6 6.7 15.7 18.0 Found 50.5 6.5 15.8 18.0 Example S
3-(3,3-Dimethvltetrahydro-1,4-thiazin-4-yl)sydnone imine hydro-chloride a) 2,2-Dimethylaziridine 100 g of 2-amino-2-methylpropan-1-ol are dissolved in 200 ml of water. A cold solution of 110 g of conc. sulphuric acid in 200 ml of water is then added dropwise with stirring and the water is then removed by distillation at normal pressure until an internal temperature of 115C is obtained. The mixture is then further distilled in a water jet vacuum up to a bath temperature of 180C and the contents of the flask are kept under these conditions until they are solid. The mixture is then heated further in a water jet vacuum and at 180C for 1 more hour.
A solution of 100 g of NaOH in 200 ml of water is added to the product, and it is comminuted and allowed to stand over-night. Water is removed from the suspension by distillation under normal pressure. 50 g of KOH are added with stirring to the residue and the mixture i~ stirred for 3 hours. After allowing to stand, the upper layer is separated off, 20 g of KOH are added and the mixture is allowed to stand overnight. The oil is poured off, 10 g of KOH are added and the mixture is distilled under normal pressure.
Yield: 60.3 g b) 2-Hydroxvethyl 2-amino-2-methy~e~g~y~ 9 ~1~
~ 234 g of 2-mercaptoethanol are dissolved in 90 ml of dimethoxyethane. 63.3 g of 2,2-dimethylaziridine are added drop-wise to this solution and the mixture is stirred at 70C for 4 hours and concentrated, and the residue is disti~led in a water jet vacuum.
B.p.: 141-142 C (at 20 mbar) M.p.: 49-51 c~ 3 3-Dimethyltetrahydro-1,4-thiazine Hydrogen chloride is passed into a solution of 14.9 g of 2-hydroxyethyl 2-amino-2-methylpropyl sulphide (step b) in 100 ml of dimethoxyethane with stirring until it is saturated and 17.9 g of thionyl chloride are then added dropwise, and the mixture is stirred at room temperature for another hour an~ then heated at reflux for 1 hour. The solution is then concentrated in a water jet vacuum. The residue of 2-chloroethyl 2-amino-2-methylpropyl sulphide hydrochloride crystallizes out.
The hydrochloride obtained is dissolved in water, the solution is rendered strongly alkaline with potassium carbonate, the precipitate is taken up in 100 ml of toluene and the aqueous phase is again extracted by shaking with 2 x 30 ml of toluene.
The organic phases are combined, dried over potassium carbonate and concentrated, and the residue is distilled in a water jet vacuum.
Yield: 8.1 g B.p.: 73-75C (at 20 mbar) d) 4-Nitroso-3 3-dimethyltetrahydro-1,4-thiazine 12 ml of 10 N HCl are added with cooling to a mixture of 15.7 g of 3,3-dimethyltetrahydro-1,4-thiazine (step c) and 60 ml of ice-water. A solution of 12.4 g of sodium nitrite in 40 ml of water is then added dropwise at 4 to 6C. The mixture is subse-quently stirred at room temperature for 4 hours, rendered alka-line with potassium carbonate and extracted by shaking with ethyl acetate. The organic phase is dried and concentrated in a water jet vacuum.
Yield: 17.5 g - M.p.: yellow oil e) 4-Amino-3 3-dimethyltetrahydro-1,4-thiazine hydrochloride 4.4 g of lithium aluminium hydride are added in portions at 60-65C to a solution of 17.2 g of 4-nitroso-3,3-dimethyl-2~9~11 tetrahydro-1,4-thiazine ~step d) in 150 ml of tetrahydrofuran and -the mixture is then heated to reflux for 2 hours. The suspension is cooled and a solution of 5 ml of water in 50 ml of tetrahydro-furan is added dropwise. After 20 minutes, 10 ml of 27% strength by weight sodium hydroxide solution are added dropwise and the mixture is allowed to stand for a few hours. The precipitate is then filtered off and the hydrochloride is precipitated in the ice-cooled filtrate.
Yie,ld: lZ.2 g f) 4-(2-Cyanoethylami,no)-3,3-dime,thyltetrahydro-1,4-thiazine A solution of 6.1 g of KCN in 30 ml of water is added dr~pwise to a solution of 12.1 g of 4-amino-3,3-dimethyltetrahydro-1,4-thia-zine hydrochloride (step e) cooled to -3 to -5C. The pH of the solution is then adjusted to 7.2 with hydrochloric acid and 16.3 g of 39% strength by weight aqueous formaldehyde are then added, the pH being kept at 6 to 7. The mixture is subsequently stirred overnight at a temperature increasing to room temperature. The suspension is extracted by shaking with ethyl acetate, and the organic phase is dried and concentrated.
Yield: 9.4 g M.p.: oil g) 3-(3,3-Dimethyltetrahvdro-1,,~4-thiazin-4-yl)sydnone_imine hydrochloride 9.4 g of 4-(2-cyanoethylamino)-3,3-dimethyltetrahydro-1,4-thiazine (step f), 40 ml of ethyl acetate, 40 g of ice-water and 5 ml of lO N hydrochloric acid are cooled to -5C. 5.3 g of sodium nitrite are introduced into this mixture and it is subse-quently stirred at room temperature for 3 hours. The organic phase is separated off, dried and filtered off, and 20 ml of a saturated solution of HCl in isopropanol are added dropwise with cooling. The mixture is subsequently stirred overnight at room temperature. ~he precipitate is separated off and recrystallized from isopropanol.
Yield: 5.9 g M.p.: 172C (decomposition) Exam~le 6 N-p-Anisoyl-3-(3,3-dimethyltetrahydro-1~4-thiazin-4-yl~sydnone imine 2 g of 3-(3,3-dimethyltetrahydro-1,4-thiazin-4-yl)sydnone 2~9~
imine hydrochloride (Example 5 g) are dissolved in 20 ml of ice-water and 1.7 g of NaHCO3 are added. 1.7 g of p-anisoyl chloride, dissolved in 20 ml of ethyl acetate, are then added dropwise.
After subsequently stirring overnight at room temperature, the phases are separated, the aqueous phase is extracted by shaking with ethyl acetate, and the organic phases are combined, dried and concentrated. The crystalline product obtained is recrystal-lized from isopropanol.
Yield: 1,9 g M.p.: 131 to 133C
Example 7 N-EthoxycarbonYl-3-(3.3-dimethyltetrahYdro-1 4-thiazin-4-yl ! -sydnone imine The compound is obtained analogously to Example 6 using ethyl chloroformate (1 g) instead of p-anisoyl chloride and is purified by stirring with petroleum ether.
Yield: 1.8 g N.p.: 110 to 112C
Example 8 N-Methoxycarbonyl-3-L3,3-dimethyl-1,4-tetrahydrothiazine-1~1_ dioxo-4-yl)sydnone imine The compound is obtained analogously to Example 7 using methyl chloroformate (0.6 g) instead of the ethyl ester and is recrystallized from ethyl acetate.
Yield: 2.0 g M.p.: 233 to 235C (dec.) Example 9 N-Butoxycarbonyl-3-~3~3-dimethyl-1.4-tetrahydrothiazine-1 1-dioxo-4-yl~sydnone imine hydrochloride The compound is obtained analogously to Example 7 using butyl chloroformate (0.8 g) instead of the ethyl ester and is precipitated from ethyl acetate as the hydrochloride using iso-propanolic hydrochloric acid.
Yield: 1.3 g M.p.: 153 to 154C (dec.) Example 10 N-Butoxyacetyl-3-(3 3-dimethyl-1.4-tetrahydrothiazine-1 1-dioxo-4-yl)sydnone imine hydrochloride The compound is obtained analogously to Example 7 using 0.9 g of butoxyacetyl chloride instead of ethyl chloroformate and is precipitated from ethyl acetate as the hydrochloride using isopropanolic hydrochloric acid.
Yield: 1.9 g M.p.: 165C (dec.) Example 11 3-(3 ~3-Dimeth ~ 4-tetrahydrothiazine-l~l-dioxide-4-yl)sydnone imine hydrochloride 3 g of a 35% strength hydrogen peroxide solution are added at room temperature to a solution of 3 g of 3-(3,3-dimethyl-tetrahydro-1,4-thiazin-4-yl)sydnone imine (prepared according to Example 5) in-40 ml of glacial acetic acid. The temperature increases to 30 to 40C. The mixture is stirred for 2 h and then concentrated in a water jet vacuum. The residue is stirred in isopropanol and recrystallized from methanol.
Yield: 1.8 g M.p.: 219C (dec.) Pharmaceutical preparations are described in Examples A
to H below.
Example A
Soft gelatin capsules, containing 5 mg of active compound per capsule:
` er capsule Active compound 5 mg - Triglyceride mixture fractionated from coconut oil 150 mg Capsule contents 155 mg Example B
25 Injection solution, containing 1 mg of active compound per ml:
per ml Active compound 1.0 mg Polyethylene glycol, 400 0.3 ml Sodium chloride 2.7 mg Water for in~ection purposes to 1 ml Example C
Emulsion, containing 3 mg of active compound per 5 ml per 100 ml of emulsion Active compound 0.06 g Neutral oil q.s.
Sodium carboxymethylcellulose 0.6 g Polyoxyethylene stearate q.s.
Glycerol, pure 0.2 to 2200g~ 9 8 1 Flavouring q.s.
~ater (demineralized or distilled) to 100 ml Example D
5 Rectal medicament form, containing 4 mg of active compound per suppository per suppository Active compound 4 mg Suppository base . to 2 g Example E
Tablets, containing 2 mg of active compound per tablet er tablet Active compound 2 mg Lactose 60 mg Cornflour 30 mg Soluble starch 4 mg Magnesium stearate 4 mg 100 mg ExamDle F
20 Coated tablets, containing 1 mg of active compound per coated tablet ~er coated tablet Active compound 1 mg Cornflour 100 mg Lactose 60 mg sec Calcium phosphate 30 mg Soluble starch 3 mg Magnesium stearate 2 mg Colloidal silicic acid 4 mg 200 mg Example G
The following recipes are suitable for the preparation of the contents of hard gelatin capsules:
a) Active compound 10 mg Cornflour l90 mg 200 mg .~ . , .
. ' , ,' ~ :
~ -. . .
, b) Active compound 40 mg 2 019 ~11 Lactose 80 mg Cornflour 80 mg 200 mg Example H
Drops can be prepared according to the following recipe (20 mg of active compound in 1 ml = 20 drops):
Active compound 2.00 g Methyl benzoate 0.07 g Ethyl benzoate 0.03 g Ethanol, 96% strength 4 ml Demineralized water to 100 ml
In the formula III, X denotes, for example, in particular halogen, preferably -Cl or -Br; -OH; -O-alkyl, in particular having 1 to 5 C atoms; -O-aryl, the aryl radical in particular beLng a phenyl radical which may also be mono- or polysubstituted by alkyl, in particular methyl, and/or nitro, and is, for ex-ample, a tolyl, dinitrophenyl or nitrophenyl radical; -O-CO-R2;
-O-CO-O-alkyl, in particular having 1 to 5 C atoms in the alkyl radical, or the radical of an azole or benzazole which has at least 2 N atoms in the quasi-aromatic 5-membered ring and is bonded via an N atom.
The acylation is expediently carried out in a liquid or liquid disperse phase in the presence of an inert solvent, dis-persant or diluent or in an excess of the acylating agent, ex-pediently with stirring.
In the acylation, the molar ratio between the compound of the formula Ia and the acylating agent of the formula III is theoretically 1 : 1. However, the acylating agent can also be employed in a sub-equivalent amount or in excess. Excesses of up to 30 mol% are usually sufficient, i.e. the molar ratio between the compound of the formula Ia and the acylating agent of the formula III is normally 1 : (1 to 1.3), preferably 1 : (1 to 1.2). If an acid is eliminated in the acylation reaction, the addition of an acid scavenger, such as, for example, an alkali metal hydroxide, such as, for example, sodium hydroxide, potas-sium hydroxide or lithium hydroxide, a tertiary organic amine, such as, for example, pyridine or triethylamine, an alkali metal carbonate or alkali metal bicarbonate, ~uch as, for example, sodium carbonate or sodium bicarbonate, or an alkali metal salt of a weak organic acid, such as, for example, sodium acetate, is expedient. Suitable catalysts, such as, for example, 4-dimethyl-aminopyridine, may al o be added during the acylation reaction.
The acylation may in principle be carried out at .
^.
"' ` ~ ' ,. ~
.. . . .
. ~
2 ~
temperatures between -10C and the boiling point of the solvent, dispersant or diluent used. In many cases, the reaction is car-ried out at 0 to 50C, in particular at 0 to 30C and preferably at room temperature.
The compounds of the formula III are acylating agents and thus represent, for example: for X = halogen: acid halides or haloformic acid esters, of which acid chlorides and chloroformic acid esters are preferred; for -OH: carboxylic acids; for -O-alkyl and -O-aryl: esters, of which the tolyl, 2,4-dinitro- or 4-nitrophenyl esters are preferred; for -O-CO-R: anhydrides; for -O-CO-O-alkyl; mixed carboxylic acid/carbonic acid anhydrides; or heterocyclic amides or azolides, in particular of N,N'-carbonyl-diazoles, such as, for example, N,N'-carbonyldiimidazole, 2,2'-carbonyl-1,2,3-ditriazole, 1,1'-carbonyl-1,2,4-ditriazole, N,N'-carbonyldipyrazole and 2,2'-carbonylditriazole (compare, for example, H.A. Staab, M. LUcking and F.H. Durr, Chem. Ber. 95, ~
(1962), 1275 ff, H.A. Staab and A. Mannschreck, Chem. Ber. 95, (1962), 1284 ff.; H.A. Staab and W. Rohr, "Synthesen mit hetero-cyclischen Amiden (Azoliden)" tSyntheses with heterocyclic amides (azolides)] in "Neuere Methoden der Praparativen Organischen Chemie" [Newer methods of preparative organic chemistry], volume V, Verlag Chemie, 1967, p. 53 et seq., in particular pp. 65 to 69). The acylating agents of the formula III can be prepared by processes which are known per se.
When using a carboxylic acid as the acylating agent, the addition of an activating agent which has the object of increas-ing or of activating the acylating potential of the carboxylic acid or of converting the carboxylic acid into a reactive car-boxylic acid derivative of the formula III in situ or preferably shortly before the reaction with the compound of the formula Ia is expedient. Suitable activating agents of this type are, for example: N,N'-disubstituted carbodiimides, in particular if they contain at least one secondary or tertiary alkyl radical, such as, for example, diisopropyl, dicyclohexyl or N-methyl-N'-tert.-butylcarbodiimide (compare Methodicum Chimicum, Verlag G. Thieme, Stuttgart, Vol. 6, (1974), pp. 682/683, and Houben-Weyl, Methoden der Org. Chemie [Methods cf organic chemistry], Vol. 8, (1952), ~9~
pp ~S21/522); carbonic acid derivatives, such a~, for example, phosgene, chloroformic acid esters, in particular having 1 to 5 C
atoms in the alkyl radical (compare, for example, Tetrahedron Letters 24 (1983), 3365 to 3368); carbonic acid esters, such as for example, N,N~-disuccinimidyl carbonate, diphthal,imidyl car-bonate, l,1'-(carbonyldioxy)dibenzotriazole or di-2-pyridyl carbonate (compare, for example, Tetrahedron Letters, Vol. 25, No. 43, 4943-4946), if desired in the presence of suitable cata-lysts, such as, for example, 4-dimethylaminopyridine. In addi-tion, N,N'-carbonyldiazoles, such as, for example, N,N'-carbonyldiimidazole, 2,2'-carbonyl-1,2,3-ditriazole, l,1'-car-bonyl-1,2,4-ditriazole, N,N'-carbonyldipyrazole, 2,2'-carbonyl-ditetrazole, N,N'-carbonylbenzimidazole or N,N~-carbonylbenzotri-azole are suitable as activating agents (compare, for example, H.A. Staab, M. ~ucking and F.H. Durr, loc. cit; H.A. Staab and A.
Mannschreck loc. cit.; X.A. Staab and W. Rohr loc. cit). The N,N~-carbonyldiazole used is frequently the commercially avail-able N,N'-carbonyldiimidazole. However, the other N,N'-carbonyl-azoles are also easily accessible from the respective azole and phosgene.
In addition, suitable activating agents for carboxylic acids are: derivatives of oxalic acid, such as, for example, oxalyl chloride (compare, for example, GB Patent Specification 2,139,225) or N,N'-oxalyldiazoles, such as, for example, 1,1'-oxalyldiimidazole, 1,1'-oxalyldi-1,2,4-triazole and l,l'-oxalyl-di-1,2,3,4-tetrazole (compare, for example, Shizuaka Nurata, Bull. Chem. Soc. Jap. S7, 3S97-3598 (1984)); methylethylphos-phinic anhydride (compare~ for example, German Offenlegungs-schrift 3,101,427); diphosphorus tetraiodide (Chem. Lett. 1983, 449); dialkyl disulphite (Indian J. Chem. 21, 259 (198~)); or other reactive agents.
Suitable solvents, dispersants or diluents are, for example, those which have been mentioned for carrying out the cyclization, and moreover also, for example, pyridine and amides, such as, for example, dimethylfonmamide. In addition to water, polar organic solvents, such as dimethylformamide, dimethyl sulphoxide or pyridine, are preferred for the acylation. Solvent 2 ~
mixtures, such as, for example, a mixture of water and methylene chloride, are also suitable.
The substituted 3-aminosydnone imines of the general formula I can form acid addition salts with inorganic or organic acids. Inorganic or organic acids are suitable for the formation of acid addition salts of this type. For the formation of pharma-cologically acceptable acid addition salts, suitable acids are, for exampLe: hydrogen chloride, hydrogen bromide, naphthalene-disulphonic acids, in particular 1,5-naphthalenedisulphonic acid, phosphoric, nitric, sulphuric, oxalic, lactic, tartaric, acetic, salicylic, benzoic, formic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, malic, sulphamic, phenylpropionic, gluconic, ascorbic, isonicotinic, methane-sulphonic, p-toluenesulphonic, citric or adipic acid. The acid addition salts may be prepared in a customary manner by combining the components, expediently in a suitable solvent or diluent.
The compounds of the formula Ia are unstable in the free form, but are isolated in the form of their acid addition salts.
In the synthesis of the compounds of the formula Ia, the acid addition salts are normally obtained.
The starting compounds of the general formula II required may be prepared in a manner known per se by Strecker's amino-nitrile synthesis from compounds of the general formula IV or their acid addition salts ~3~CH3 /CH2 C\ ( IV) CH CH
in which A has the meaning already mentioned, by reaction with formaldehyde and hydrocyanic acid or sodium cyanide in a suitable solvent or diqpersant or solvent or dispersant mixture, for example in water, a compound of the general formula V
2019~
~3/ 3 2 C\ ( V ) A ~N--NH-CH2-CN
first being formed, which is converted by nitrosylation into the compound II. The nitrosylation is carried out in a known manner in`a suitable`solvent or dispersant or solvent or dispersant mix-ture, for example in water, for example at temperatures of -10 to 10C. The nitrous acid is in this case normally generated from an alkali meta~ nitrite, for example sodium nitrite, and hydro-chloric acid. It is expedient to adjust the aqueous solution of the compound V to a pH of 1 to 3 with hydrochloric acid and to add the alkali metal nitrite to the stirred and cooled solution in the form of an aqueous solution. The solution of the compound II obtained here can be subjected directly to the cyclization reaction. However, normally it is appropriate to take up the nitroso compound II in a suitable organic solvent first and to carry out the cyclization to give the compound of the formula Ia in it, if desired after addition of a further solvent.
The compounds of the general formula IV can be prepared, starting from compounds of the general formula VI
C~ 3~ C H ~
/CH2 ~\ (VI) A N--H
CH --CH
by either a) nitrosylating a compound of the formula VI to give the N-nitroso compound VII and then reducing, expedient y with lithium aluminium hydride:
_ g _ .. , :. ~ .
20~L9~
(VI~ A N-NO ~ A N-NH2 tVII ) ( IV) or, in a manner known per se b) converting a compound of the formula VI into the urea deriva-tivë VIII with potassium cyanate in acidic medium, and then converting by means of oxidation with sodium hypochlorite by the Hoffmann degradation into the compound IV:
CH3 CH3 KNCO C\3/CH3 AN-H - ~ A N-CO-NH2 (VI) (VIII) ~CH
/ 2 C\ NaOCl /CH -C
A N-CO-NH ~A\ /N-NH2 ( V I I J ) ( I V ) The compound 3,3-dimethyltetrahydro-1,4-thiazine (A = -S-in formula VI) can be prepared by reaction of 2,2-dimethylaziri-dine (which can be prepared by elimination of water from 2-amino-2-methylpropan-1-ol) with 3-mercaptoethanol, 2-hydroxyethyl 2-amino-2-methylpropyl sulphide being formed first. The hydroxyl group in this compound is replaeed by chlorine by chlorination, for example with thionyl chloride, and the compound thus obtained is then cyelized by the aetion of a base.
The eompound 4-amino-3,3-dimethyl-1,4-tetrahydrothiazine-l,1-dioxide (A = -SO2- in formula IV) is known (eompare ~01~811 Arzneimittelforschung 22, (1972), 1568). It can be prepared as -~ollows: monothioethylene glycol and 2,2-dimethyloxirane are reacted at elevated temperature in the presence of catalytic amounts of alkali metal hydroxide to give 2-hydroxy-2-methyl-propyl 2-hydroxyethyl sulphide, this is converte~ with H20z into the corresponding 2-hydroxy-2-methylpropyl 3-hydroxyethyl sul-phone and this is cyclized in the presence of a dehydrating agent, such as, for example, potassium hydrogen sulphate to give 2,2-dimethyl-1,4-oxathiane-4,4-dioxide of the formula IX:
~3~CH3 2 C~
02s\ o (IX) CH CH
This compound can be reacted with hydrazine hydrate to give the compound IV where A = -SO2-, compare Arzneimittelforschung loc.
cit. and Example la below.
Compounds of the formula I according to the invention where A = -SO2- can also be prepared by reacting a compound of the formula I according to the invention where A = -S- or a compound of the formula I where A = -SO-, or an acid addition salt of such a compound, with a substance donating oxygen and converting the compound obtained, if desired, into an acid addition salt and isolating it, or in the case in which a compound of the formula I
where A = -SO2- and R1 = H has been obtained and is intended to prepare a compound of the formula I where A = -SO2- and R2 = -COR2, acylating the compound obtained or an acid addition salt thereof with an acylating agent which introduces the radical -COR2 and isolating the compound thus obtained or, if desired, converting it into a pharmacologically acceptable acid addition salt and isolating this. Examples of suitable oxygen-donating substances which may be mentioned are: hydrogen peroxide, peroxoacids, such as, for example, performic, peracetic, perbenzoic, m-chloro-perbenzoic and perphthalic acid, and also diacyl peroxides.Mixtures of various oxygen-donating substances may also be used.
The oxygen-donating substance is employed in at least the 20~9~
stoichiometrically necessary amount. The reaction may expediently `)e carried out in a suitable solvent or dispersant or solvent or dispersant mixture at temperatures from 0C, preferably from room temperature, up to the boiling point of the solvent or dispersant or solvent or dispersant-mixture. Suitable solve~ts or disper-sants are, for example, the ethers already mentioned, aliphatic, cycloaliphatic and aromatic hydrocarbons, halogenated aliphatic and aromatic hydrocarbons, water, but in particular lower car-boxylic acids, such as formic or acetic acid.
An acylation with an acylating agent introducing the radical -COR2 to be carried out, if desired, after the reaction with the oxygen-donating agent is carried out in the manner already mentioned using an acylating agent of the formula III.
The conversion to be carried out, if desired, into the acid addition salt is carried out, as already mentioned above, in a manner known per se.
The compounds of the formula I where A = -S02- can be prepared analogously to the compounds of the formula I where A = -S- from compounds of the formula II where A = -SO2-.
The compounds of the general formula I according to ~he invention and their pharmacologically acceptable acid addition salts have useful pharmacological properties, for example haemo-dynamic, thrombocyte function-inhibiting and antithrombotic, in particular coronary antithrombotic, properties. Their action on the cardiovascular system is particularly pronounced. Compared with known sydnone imine compounds similarly substituted struc-turally in the 3-position, for example those of French Patent Specification 1,496,056 and the compounds of the older German Patent Application P 3820210.7, they unexpectedly have a surpris-ingly longer duration of action. For example, they lower the blood pressure as well as the pulmonary arte~y pressure and the left ventricular end-diastolic pressure and thus contribute to a relief of the load on the heart in the sense of an antianginal action, without provoking reflex tachycardia in this connection.
The compounds of the formula I according to the invention and their pharmacologically acceptable acid addition salts can therefore be administered to humans as medicaments per se alone, 2~
in mixtures with one another or in the form of pharmaceutical preparations which permit enterzl or parenteral use and which contain as the active component an effective dose of at least one compound of the formula I according to the invention or an acid addition salt thereof, in addition to one or more customary pharmaceutically acceptable excipients or diluents and, if de-sired, one or more additives.
The medicaments can be administered orally, for example in the form of tablets, film tablets, coated tablets, hard and soft gelatin capsules, microcapsules, granules, powders, pellets, solutions, syrups, emulsions, suspensions, aerosols, foams, pills or pastille~. Administration may, however, also be carried out rectally, for exam~le in the form of suppositories, or parenter-ally, for example in the form of in~ection solutions, or per-cutaneously, for example in the form of ointments, creams, gels,pastes, aerosols, foams, powders, tinctures, liniments or so-called transdermal therapeutic systems (TTS). -The pharmaceutical preparations can be prepared in a manner known per se using pharmaceutically inert inorganic or organic auxiliaries, excipients, fillers or diluents. For the preparation of pills, tablets, film tablets, coated tablets and the pellet or granule fillings of hard gelatin capsules, for example calcium phosphate, lactose, sorbitol, mannitol, starches, prepared starches, chemically modified starches, starch hydroly-æates, cellulose, cellulose derivatives, synthetic polymers, talcetc., can be used. Excipients or diluents for soft gelatin cap-sules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc. Suitable exci-pients or diluents for the preparation of solutions and syrups are, for example, water, polyols, solutions of sucrose, dextrose, glucose etc. Suitable excipients for the preparation of injection solutions are, for example, water, alcohols, gIycerol, polyols or vegetable oils. Suitable excipients or diluents for ointments, creams and pastes are, for example, natural petroleum ~elly, synthetic petroleum ~elly, viscous and mobile paraffins, fat-q, natural or hardened vegetable and animal oils, neutral oils, waxes, wax alcohols, polyethylene glycols, polyacrylic acid, ~. , , ~ , .....
-i silicone gels etc. 2 01~ 8 ~ ~
The pharmaceutical preparations may also contain, in a manner known per se, in addition to the active compounds and diluents, fillers or excipients, one or more additives or auxili-aries, such as, for example, disintegrants, bind,ers, glidants, lubricants, mould release agents, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colourings, flavourings, buffer substances, and in addition solvents or solubilizers, so~ution accelerators, antifoams, salt-forming agents, gelling agents, thickeners, flow regulators, absorbents, agents for achieving a depot effect or agents, in particular salts, for changing the osmotic pressure, coating agents or antioxidants, etc. They may also contain two or more compounds of the formula I
or their pharmacologically acceptable acid addition salts and also one or more other therapeutically active substances.
Examples of other therapeutically active substances of~
this type may be: ~-receptor blockers, such as, for example, propranolol, pindoloI, metoprolol; vasodilators, such as, for example,~carbochromen; tranquilizers, such as, for example, barbituric acid derivatives, 1,4-benzodiazepines and meprobamate;
diuretics, such as, for example, chlorothiazide; cardiotonic agents, such as, for example, digitalis preparations; hypotensive agents, such as, for example, hydralazine, dihydralazine, prazo-sin, clonidine, Rauwolfia alkaloids; agents which lower the fatty acid level in the blood, such as, for example, bezafibrate, fenofibrate; and agents for thrombosis prophylaxis, such as, for example, phenprocoumon.
The content of the active compound or the active com-pounds of the formula I in the pharmaceutical preparations can vary within wide limits and is, for example, 0.05 to 50% by weight, preferably 0.05 to 20% by weight. In solid administration forms, such as coated tablets, tablets etc., the content of one or more active compound~ of the formula I is in many cases 2 to 20% by weight. Liquid administration forms, such as drops, emul-sions and in~ection solutions frequently contain 0.05 to 2% by weight, preferably 0.05 to 1% by weight, of one or more active compounds of the formula I. The content of one or more active 2019~1~
compounds of the formula I in the pharmaceutical preparations may `~e partially replaced, if desired, for example up to 50% by weight, preferably up to 5 to 40% by weight, by one or more other therapeutically active substancec.
The compounds of the formula I according,to the inven-tion, their pharmacologically acceptable acid addition salts and pharmaceutical preparations which contain the compounds of the formula I according to the invention or their pharmacologically acceptable acid addition salts as active compounds can be used in humans for combating or preventing disorders of the cardio-vascular system, for example as antihypertensive medicaments in the various forms of high blood pressure, and in combating or prevention of angina pectoris etc. The dosage may vary within wide limits and is to be suited to the individual requirements in each individual case. In geheral~ a daily dose of about 0.5 to 100 mg, preferably 1 to 20 mg, per human individual is suitable for oral administration. For other administration forms, the daily dose, owing to the good absorption of the active compounds, is in similar amount ranges, i.e. in general also 0.5 to 100 mg/
human. The daily dose is normally divided into several, for example 2 to 4, part administrations.
The pharmacological action of the compounds of the for-mula I according to the invention was determined by a modified method of Godfraind and ~aba (Arch. Int. Pharmacodyn. Ther. 196, (Suppl) 35 to 49, 1972) and of Schuman et al. (Naunyn-Schmiede-berg's Arch. Pharmacol. 289, 409 to 418, 1975). In this connec-tion, spiral strips of the pulmonary artery of the guinea-pig are depolarized with 40 mmol/l of potassium after equilibration in calcium-free Tyrode solution. An addition of 0.5 mmoltl of CaCl2 then induces a contraction.
The relaxing action of the test substance is determined by cumulative addition in 1/2 log 10 stepped concentrations. From the concentration-effect curve (abscissa: -log mol/l of test substance, ordinate: % inhibition of the maximum contraction, average value of 4 to 6 vessel strips), the concentration of the test substance is determined which inhibits the contraction by 50% (= IC5~, mol/l). The duration of action of the test substance ' . ` ' 2~19~1~
is shown by the time which is needed after the addition of the :est substance until the starting value is obtained again. In the following table, the values thus obtained are indicated.
IC50 values and duration of action of sydnone imines of the formula R R
- / 2 C~
A N -- N--C H
CHz_CH N~-~C=NH HCl O
Compound A R IC50 Duration of action No. in mol/l in min . _ . .
l 02S\ CH3 6 x 10-6 240 10 2 S CH3 2 x 10 6 200 3 O\ H 1 x 10 6 80 ~ 1 X 10 6 120 Compound No. 1 of the table is the preferred compound according to the invention 3-(3,3-dimethyl-1,4-tetrahydro-thiazine-1,1-dioxide-4-yl)sydnone imine hydrochloride.
Compound No. 2 of the Table is the preferred compound from Example 5.
Compound No. 3 of the table is the compound 3-morpholino-sydnone imine hydrochloride known from Example 2 of French Patent Specification 1,406,056.
Compound No. 4 of the table i~ the compound 3-t3,3-di-methylmorpholin-4-yl)sydnone imine hydrochloride of Example No. 1 of the older German Patent Application P 3820210.7.
As can be seen from the above table, the compounds according to the invention have a substantially longer duration of action at a comparable IC5~ value than the two comparison compounds.
2~!811 If the duration of action of the compounds is determined `at the concentration of 6 x 10-6 mol/l, the values indicated below are obtained:
Compound No. Duration of action in min.
From these values, it can be seen that the compounds according to the invention also have a considerably longer dura-tion of action at an equal dose than the comparison compounds.
If not indicated otherwise in the examples which follow, percentage data are percentages by weight.
Example 1 3~ -DimethYl-1 4-tetrahydrothiazine~ dioxide-4-yl)sydnone imine hydrochloride a) 4-Amino-3,3-dlmeth~l-1 4-tetrahydrothiazine-111-dioxide hydro-aensulphate ~
A mixture of 57 g of 2,;2-dimethyl-1,4-oxathiane-4,4-20dioxide of the formula IX -;
CHz--C~ -C H 2_C H 2 ( IX ) 45.5 g of hydrazine hydrate and 650 ml of water is heated in an autoclave at 180-C for 6 h. After cooling, the mixture is con-centrated on a rotary evaporator, the residue is dissol~ed in as little water as possible, and the ~olution i8 rendered acidic with 50S strength sulphuric acid and ~tirred at O-C. The precipi-tate is filtered off with suction, washed with ethanol and dried.
Yield: 25 g ~.p. 206-C ~dec.) b) 4-Cyanomethylamino-3.3-dimethyl-1.4-tetrahydrothiazine-1,1-dioxide A solution of 26 g of 4-amino-3,3-dimethyl-1,4-tetra-hydrothiazine-l,l-dioxide hydrogensulphate (step a) in 300 ml of - }7 -.
- ~
.. - . - . , .
,...
, , - ~
.. . ..
2~19~1~
water is cooled to 5C and 7.8 g of potassium cyanide are added.
pH of 7 to 7.5 is established by addition of sodium carbonate solution and 7.7 g of a 39% strength formalin solution is added.
The mixture is then stirred at room temperature for 6 h, the pH
being kept at 7 by addition of some hydrochloric acid or sodium carbonate solution. The product is separated off by shaking twice with ethyl acetate and after drying and concentrating the solvent remains behind as an oil which solidifies after a short time.
Yield: 15 g M.p. 84 to 85 C
c) 3-(3.3-Dimethyl-1 4-tetrahydrothiazine-l,l-dioxide-4-yl)-sydnone imine hydrochloride 6.8 g of sodium nitrite are added with cooling and under nitrogen to a mixture consisting of 14 g of 4-cyanomethylamino-3,3-dimethyl-1,4-tetrahydrothiazine-1,1-dioxide (step b), 200 ml of ice-water, 10 ml of 10 N hydrochloric acid and 200 ml of ethyl acetate and the mixture is further stirred at room temperature-- for 1 h. The organic phase is separated off, dried and 30 ml of 25~ strength isopropanolic hydrochloric acid are added at 0C.
After 15 h, the mixture is concentrated in a water jet vacuum and the residue is boiled with 500 ml of ethyl acetate. After cool-ing, the solid is filtered off with suction and dried.
Yield: 5.5 g M.p. 220C dec.
Analysis: C~Hl5ClN4O3S
C H N O
Calc. 34.0 5.3 19.8 17.0 Found 33.? 5.4 20.0 16.7 The starting compound IX needed in step a can be prepared as follows (compare Arzneimittelforschung loc. cit.):
1 mol of ROH is dissolved in l mol of ethanol and 1 mol of 2-mercaptoethanol is added. 1 mol of 2,2-dimethyloxirane i8 added dropwise to this solution in the course of 60 min and with cooling. The mixture is then neutralized, the precipitate is filtered off, and the filtrate i8 concentrated and distilled in vacuo. 2-Hydroxy-2-methylpropyl 2-hydroxyethyl sulphide of boil-ing point 93C at 0.199 mbar is obtained.
0.5% by weight of phosphoric acid is added to the sul-phide obtained and the sulphide is then oxidized by dropwise 2~81~
addition of 3096 strength by weight H2O2 to give 2-hydroxy-2-methyl-propyl 2-hydroxyethyl sulphone. This sulphone is obtained after concentration as a non-distillable oil.
A mixture of 32 g of 2-hydroxy-2-methylpropyl 2-hydroxy-5 ethyl sulphone and 5 g of KHS04 are heated to 12qC, after thecyclization is complete the mixture is cooled, the precipitate is filtered off, the filtrate is neutralized with potassium car-bonate, the precipitate is again filtered off, and the filtrate is~concentrated and distilled in vacuo at 0.532 mbar. The com-pound 2,2-dimethyl-1,4-oxathiane-4,4-dioxide has a boiling point of 100-102 C at this pressure. M.p.: 83C
Example 2 N-Ethoxycarbonyl-3-(3 3-dimethyl-1 4-tetrahydrothiazine-1 1-dioxide-4-yl)sydnone imine 1.11 g of NaHCO3 and a solution of 0.65 g of ethyl chloro-formate in 20 ml of methylene chloride are added to a solution~of 1.5 g of 3-(3,3-dimethyl-1,4-tetrahydrothiazine-1,1-dioxide-4-yl)sydnone imine hydrochloride (Example 1) in 20 ml of water cooled to 0 to 5C and the mixture is stirred at a temperature 20 increas-ng to room temperature until evolution of gas is com-plete. The organic phase is separated off, dried and concentrated in a water jet vacuum, and the residue is recrystallized from ethyl acetate.
Yield: 0.82 g M.p. 188--190C
Analysis: Cl1Hl8N4O5S
C H _ N O
Calc. 41.5 5.7 17.6 25.2 Found 41.5 5.6 17.8 24.9 Examole 3 N-p-Anisoyl-3-(3,3-dimethyl-1,4-tetrahydrothiazine-1,1-dioxide-4-yl)sydnone imine The compound is obtained analogously to Example 2 using p-anisoyl chloride instead of ethyl chloroformate.
M.p.: 178 to 180C
Analysis: Cl6H20N4O5S
2 0 ~
C __ H N o _ `Calc. 50.5 5.3 14.7 21.1 Found 50.2 5.4 15.0 20.8 Example 4 N-Cyclohexylcarbonyl-3-t3~3-dimethyl-1~4-tetrahydrothiazine-1,1-dioxide-4-yl~sydnone imine The compound is obtained analogously to Example 2 using cyclohexanecarbonyl chloride instead of ethyl chlorofc~mate.
M.p~: 150 to 151C
Analysis: C15H24N4O4S
C H N O
Calc. 50.6 6.7 15.7 18.0 Found 50.5 6.5 15.8 18.0 Example S
3-(3,3-Dimethvltetrahydro-1,4-thiazin-4-yl)sydnone imine hydro-chloride a) 2,2-Dimethylaziridine 100 g of 2-amino-2-methylpropan-1-ol are dissolved in 200 ml of water. A cold solution of 110 g of conc. sulphuric acid in 200 ml of water is then added dropwise with stirring and the water is then removed by distillation at normal pressure until an internal temperature of 115C is obtained. The mixture is then further distilled in a water jet vacuum up to a bath temperature of 180C and the contents of the flask are kept under these conditions until they are solid. The mixture is then heated further in a water jet vacuum and at 180C for 1 more hour.
A solution of 100 g of NaOH in 200 ml of water is added to the product, and it is comminuted and allowed to stand over-night. Water is removed from the suspension by distillation under normal pressure. 50 g of KOH are added with stirring to the residue and the mixture i~ stirred for 3 hours. After allowing to stand, the upper layer is separated off, 20 g of KOH are added and the mixture is allowed to stand overnight. The oil is poured off, 10 g of KOH are added and the mixture is distilled under normal pressure.
Yield: 60.3 g b) 2-Hydroxvethyl 2-amino-2-methy~e~g~y~ 9 ~1~
~ 234 g of 2-mercaptoethanol are dissolved in 90 ml of dimethoxyethane. 63.3 g of 2,2-dimethylaziridine are added drop-wise to this solution and the mixture is stirred at 70C for 4 hours and concentrated, and the residue is disti~led in a water jet vacuum.
B.p.: 141-142 C (at 20 mbar) M.p.: 49-51 c~ 3 3-Dimethyltetrahydro-1,4-thiazine Hydrogen chloride is passed into a solution of 14.9 g of 2-hydroxyethyl 2-amino-2-methylpropyl sulphide (step b) in 100 ml of dimethoxyethane with stirring until it is saturated and 17.9 g of thionyl chloride are then added dropwise, and the mixture is stirred at room temperature for another hour an~ then heated at reflux for 1 hour. The solution is then concentrated in a water jet vacuum. The residue of 2-chloroethyl 2-amino-2-methylpropyl sulphide hydrochloride crystallizes out.
The hydrochloride obtained is dissolved in water, the solution is rendered strongly alkaline with potassium carbonate, the precipitate is taken up in 100 ml of toluene and the aqueous phase is again extracted by shaking with 2 x 30 ml of toluene.
The organic phases are combined, dried over potassium carbonate and concentrated, and the residue is distilled in a water jet vacuum.
Yield: 8.1 g B.p.: 73-75C (at 20 mbar) d) 4-Nitroso-3 3-dimethyltetrahydro-1,4-thiazine 12 ml of 10 N HCl are added with cooling to a mixture of 15.7 g of 3,3-dimethyltetrahydro-1,4-thiazine (step c) and 60 ml of ice-water. A solution of 12.4 g of sodium nitrite in 40 ml of water is then added dropwise at 4 to 6C. The mixture is subse-quently stirred at room temperature for 4 hours, rendered alka-line with potassium carbonate and extracted by shaking with ethyl acetate. The organic phase is dried and concentrated in a water jet vacuum.
Yield: 17.5 g - M.p.: yellow oil e) 4-Amino-3 3-dimethyltetrahydro-1,4-thiazine hydrochloride 4.4 g of lithium aluminium hydride are added in portions at 60-65C to a solution of 17.2 g of 4-nitroso-3,3-dimethyl-2~9~11 tetrahydro-1,4-thiazine ~step d) in 150 ml of tetrahydrofuran and -the mixture is then heated to reflux for 2 hours. The suspension is cooled and a solution of 5 ml of water in 50 ml of tetrahydro-furan is added dropwise. After 20 minutes, 10 ml of 27% strength by weight sodium hydroxide solution are added dropwise and the mixture is allowed to stand for a few hours. The precipitate is then filtered off and the hydrochloride is precipitated in the ice-cooled filtrate.
Yie,ld: lZ.2 g f) 4-(2-Cyanoethylami,no)-3,3-dime,thyltetrahydro-1,4-thiazine A solution of 6.1 g of KCN in 30 ml of water is added dr~pwise to a solution of 12.1 g of 4-amino-3,3-dimethyltetrahydro-1,4-thia-zine hydrochloride (step e) cooled to -3 to -5C. The pH of the solution is then adjusted to 7.2 with hydrochloric acid and 16.3 g of 39% strength by weight aqueous formaldehyde are then added, the pH being kept at 6 to 7. The mixture is subsequently stirred overnight at a temperature increasing to room temperature. The suspension is extracted by shaking with ethyl acetate, and the organic phase is dried and concentrated.
Yield: 9.4 g M.p.: oil g) 3-(3,3-Dimethyltetrahvdro-1,,~4-thiazin-4-yl)sydnone_imine hydrochloride 9.4 g of 4-(2-cyanoethylamino)-3,3-dimethyltetrahydro-1,4-thiazine (step f), 40 ml of ethyl acetate, 40 g of ice-water and 5 ml of lO N hydrochloric acid are cooled to -5C. 5.3 g of sodium nitrite are introduced into this mixture and it is subse-quently stirred at room temperature for 3 hours. The organic phase is separated off, dried and filtered off, and 20 ml of a saturated solution of HCl in isopropanol are added dropwise with cooling. The mixture is subsequently stirred overnight at room temperature. ~he precipitate is separated off and recrystallized from isopropanol.
Yield: 5.9 g M.p.: 172C (decomposition) Exam~le 6 N-p-Anisoyl-3-(3,3-dimethyltetrahydro-1~4-thiazin-4-yl~sydnone imine 2 g of 3-(3,3-dimethyltetrahydro-1,4-thiazin-4-yl)sydnone 2~9~
imine hydrochloride (Example 5 g) are dissolved in 20 ml of ice-water and 1.7 g of NaHCO3 are added. 1.7 g of p-anisoyl chloride, dissolved in 20 ml of ethyl acetate, are then added dropwise.
After subsequently stirring overnight at room temperature, the phases are separated, the aqueous phase is extracted by shaking with ethyl acetate, and the organic phases are combined, dried and concentrated. The crystalline product obtained is recrystal-lized from isopropanol.
Yield: 1,9 g M.p.: 131 to 133C
Example 7 N-EthoxycarbonYl-3-(3.3-dimethyltetrahYdro-1 4-thiazin-4-yl ! -sydnone imine The compound is obtained analogously to Example 6 using ethyl chloroformate (1 g) instead of p-anisoyl chloride and is purified by stirring with petroleum ether.
Yield: 1.8 g N.p.: 110 to 112C
Example 8 N-Methoxycarbonyl-3-L3,3-dimethyl-1,4-tetrahydrothiazine-1~1_ dioxo-4-yl)sydnone imine The compound is obtained analogously to Example 7 using methyl chloroformate (0.6 g) instead of the ethyl ester and is recrystallized from ethyl acetate.
Yield: 2.0 g M.p.: 233 to 235C (dec.) Example 9 N-Butoxycarbonyl-3-~3~3-dimethyl-1.4-tetrahydrothiazine-1 1-dioxo-4-yl~sydnone imine hydrochloride The compound is obtained analogously to Example 7 using butyl chloroformate (0.8 g) instead of the ethyl ester and is precipitated from ethyl acetate as the hydrochloride using iso-propanolic hydrochloric acid.
Yield: 1.3 g M.p.: 153 to 154C (dec.) Example 10 N-Butoxyacetyl-3-(3 3-dimethyl-1.4-tetrahydrothiazine-1 1-dioxo-4-yl)sydnone imine hydrochloride The compound is obtained analogously to Example 7 using 0.9 g of butoxyacetyl chloride instead of ethyl chloroformate and is precipitated from ethyl acetate as the hydrochloride using isopropanolic hydrochloric acid.
Yield: 1.9 g M.p.: 165C (dec.) Example 11 3-(3 ~3-Dimeth ~ 4-tetrahydrothiazine-l~l-dioxide-4-yl)sydnone imine hydrochloride 3 g of a 35% strength hydrogen peroxide solution are added at room temperature to a solution of 3 g of 3-(3,3-dimethyl-tetrahydro-1,4-thiazin-4-yl)sydnone imine (prepared according to Example 5) in-40 ml of glacial acetic acid. The temperature increases to 30 to 40C. The mixture is stirred for 2 h and then concentrated in a water jet vacuum. The residue is stirred in isopropanol and recrystallized from methanol.
Yield: 1.8 g M.p.: 219C (dec.) Pharmaceutical preparations are described in Examples A
to H below.
Example A
Soft gelatin capsules, containing 5 mg of active compound per capsule:
` er capsule Active compound 5 mg - Triglyceride mixture fractionated from coconut oil 150 mg Capsule contents 155 mg Example B
25 Injection solution, containing 1 mg of active compound per ml:
per ml Active compound 1.0 mg Polyethylene glycol, 400 0.3 ml Sodium chloride 2.7 mg Water for in~ection purposes to 1 ml Example C
Emulsion, containing 3 mg of active compound per 5 ml per 100 ml of emulsion Active compound 0.06 g Neutral oil q.s.
Sodium carboxymethylcellulose 0.6 g Polyoxyethylene stearate q.s.
Glycerol, pure 0.2 to 2200g~ 9 8 1 Flavouring q.s.
~ater (demineralized or distilled) to 100 ml Example D
5 Rectal medicament form, containing 4 mg of active compound per suppository per suppository Active compound 4 mg Suppository base . to 2 g Example E
Tablets, containing 2 mg of active compound per tablet er tablet Active compound 2 mg Lactose 60 mg Cornflour 30 mg Soluble starch 4 mg Magnesium stearate 4 mg 100 mg ExamDle F
20 Coated tablets, containing 1 mg of active compound per coated tablet ~er coated tablet Active compound 1 mg Cornflour 100 mg Lactose 60 mg sec Calcium phosphate 30 mg Soluble starch 3 mg Magnesium stearate 2 mg Colloidal silicic acid 4 mg 200 mg Example G
The following recipes are suitable for the preparation of the contents of hard gelatin capsules:
a) Active compound 10 mg Cornflour l90 mg 200 mg .~ . , .
. ' , ,' ~ :
~ -. . .
, b) Active compound 40 mg 2 019 ~11 Lactose 80 mg Cornflour 80 mg 200 mg Example H
Drops can be prepared according to the following recipe (20 mg of active compound in 1 ml = 20 drops):
Active compound 2.00 g Methyl benzoate 0.07 g Ethyl benzoate 0.03 g Ethanol, 96% strength 4 ml Demineralized water to 100 ml
Claims (11)
1. A substituted 3-aminosydnone imine of the general formula I
or a pharmacologically acceptable acid addition salt thereof, wherein A denotes the radical -S- or -S02-, R1 denotes the radical -CO-R2 or hydrogen, R2 denotes (C1 to C4)alkyl, (C1 to C4)alkoxy-(C1 to C4) alkyl, (C1 to C4)alkoxy, (C5 to C7)cycloalkyl, phenyl or a phenyl radical which is mono-, di- or trisubstituted by 1 to 3 halogen atoms and/or 1 to 3 alkyl radicals having 1 to 4 C atoms and/or 1 to 3 alkoxy radicals having 1 to 4 C atoms.
or a pharmacologically acceptable acid addition salt thereof, wherein A denotes the radical -S- or -S02-, R1 denotes the radical -CO-R2 or hydrogen, R2 denotes (C1 to C4)alkyl, (C1 to C4)alkoxy-(C1 to C4) alkyl, (C1 to C4)alkoxy, (C5 to C7)cycloalkyl, phenyl or a phenyl radical which is mono-, di- or trisubstituted by 1 to 3 halogen atoms and/or 1 to 3 alkyl radicals having 1 to 4 C atoms and/or 1 to 3 alkoxy radicals having 1 to 4 C atoms.
2. A substituted 3-aminosydnone imine according to Claim 1, wherein R denotes (C1 to C4)alkyl, (C1 to C4)alkoxy, phenyl, or phenyl monosubstituted by chlorine, methyl or methoxy.
3. The compound 3-(3,3-dimethyltetrahydro-1,4-thiazin-4-yl)sydnone imine or a pharmacologically acceptable acid addition salt thereof.
4. The compound N-p-anisoyl-3-(3,3-dimethyltetrahydro-1,4-thiazin-4-yl)sydnone imine or a pharmacologically acceptable acid addition salt thereof.
5. The compound 3-(3,3-dimethyl-1,4-tetrahydrothiazine-1,1-dioxide-4-yl)sydnone imine or a pharmacologically aeceptable acid addition salt thereof.
6. A substituted 3-aminosydnone imine aceording to Claim 1, 2, 3, 4 or 5 wherein the pharmaeologieally aceeptable acid addition salt is the hydrochloride.
7. A process for the preparation of the compound of the formula I according to Claim 1 or 2, which process comprises a) when A denotes the radical -S- or -S02-, cyclizing a compound of the formula II
(II) in which A denotes the radical -S- or -S02-, to prepare a compound of the formula Ia and isolating the compound so obtained as an acid addition salt, or, in the case in which it is intended to prepare a compound of the formula I where Rl = -COR2, acylating the compound Ia or an acid addition salt thereof with an acylating agent which intro-duces the radical -COR2 and isolating the compound so obtained or, if required, converting it into a pharmacologically acceptable acid addition salt, which is isolated or b) when A denotes the radical -SO2-, reacting a compound of the general formula Ic (Ic) in which A denotes the radical -S- or -SO- and R1 has the meaning as defined in Claim 1 or 2, or an acid addition salt thereof with an oxygen-donating compound and, if required, converting the compound so obtained into an acid addition salt and isolating it, or, in the case in which a compound of the formula I where A = -SO2- and R1 = H has been obtained and it is intended to prepare a compound of the formula I where A =
-SO2- and R1 = -COR2, acylating the compound obtained or an acid addition salt thereof with an acylating agent which introduces the radical -COR2 and isolating the compound so obtained or, if required, converting it into a pharmacologically acceptable acid addition salt which is isolated.
(II) in which A denotes the radical -S- or -S02-, to prepare a compound of the formula Ia and isolating the compound so obtained as an acid addition salt, or, in the case in which it is intended to prepare a compound of the formula I where Rl = -COR2, acylating the compound Ia or an acid addition salt thereof with an acylating agent which intro-duces the radical -COR2 and isolating the compound so obtained or, if required, converting it into a pharmacologically acceptable acid addition salt, which is isolated or b) when A denotes the radical -SO2-, reacting a compound of the general formula Ic (Ic) in which A denotes the radical -S- or -SO- and R1 has the meaning as defined in Claim 1 or 2, or an acid addition salt thereof with an oxygen-donating compound and, if required, converting the compound so obtained into an acid addition salt and isolating it, or, in the case in which a compound of the formula I where A = -SO2- and R1 = H has been obtained and it is intended to prepare a compound of the formula I where A =
-SO2- and R1 = -COR2, acylating the compound obtained or an acid addition salt thereof with an acylating agent which introduces the radical -COR2 and isolating the compound so obtained or, if required, converting it into a pharmacologically acceptable acid addition salt which is isolated.
8. A process according to Claim 6a), wherein the cyclization is carried out in a solvent, dispersant or diluent at a temperature of from -10 to 40°C with the aid of a cyclizing agent which establishes a pH below 3 in aqueous solution.
9. A process according to Claim 8, wherein the cyclization is carried out at a temperature of from 0 to 20°C.
10. A substituted 3-aminosydnone imine or a pharmacological-ly acceptable acid addition salt thereof according to Claim 1, 2, 3, 4 or 5 for the use in the combating and prevention of cardio-vascular disorders.
11. A pharmaceutical composition comprising an effective amount of a substituted 3-aminosydnone imine according to Claim 1, 2, 3, 4 or 5 or pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3939550A DE3939550A1 (en) | 1989-11-30 | 1989-11-30 | New substd. 3-amino-sydnonimine derivs. |
| DEP3939515.4 | 1989-11-30 | ||
| DEP3939550.2 | 1989-11-30 | ||
| DE19893939515 DE3939515A1 (en) | 1989-11-30 | 1989-11-30 | New substd. 3-amino-sydnonimine derivs. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2019811A1 true CA2019811A1 (en) | 1991-05-31 |
Family
ID=25887500
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002019811A Abandoned CA2019811A1 (en) | 1989-11-30 | 1990-06-26 | Substituted 3-aminosydnone imines, processes for their preparation and their use |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0429751B1 (en) |
| JP (1) | JPH03178975A (en) |
| KR (1) | KR910009697A (en) |
| AT (1) | ATE90677T1 (en) |
| CA (1) | CA2019811A1 (en) |
| CZ (1) | CZ278933B6 (en) |
| DE (1) | DE59001784D1 (en) |
| DK (1) | DK0429751T3 (en) |
| ES (1) | ES2057282T3 (en) |
| HU (1) | HUT59399A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4337335A1 (en) * | 1993-11-02 | 1995-05-04 | Cassella Ag | Process for the preparation of Sydnoniminium hydrogen sulfate |
| KR100552893B1 (en) * | 2003-09-30 | 2006-02-21 | 스마트머티리얼스 테크널러지주식회사 | Fabrication Methods of Conductive Coating Solution Using Conducting Polymer |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2930736A1 (en) * | 1979-07-28 | 1981-02-12 | Cassella Ag | PHARMACOLOGICALLY ACTIVE, SUBSTITUTED 3-AMINO-SYDNONIMINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
| DE3732174A1 (en) * | 1987-09-24 | 1989-04-06 | Cassella Ag | SUBSTITUTED 3-AMINO-DYNONOMINES, PROCESS FOR THEIR PREPARATION AND THEIR USE |
| DE3800830A1 (en) * | 1988-01-14 | 1989-07-27 | Cassella Ag | SUBSTITUTED 3-SYNDNONIMINES, METHOD FOR THEIR PREPARATION AND THEIR USE |
| DE3820210A1 (en) * | 1988-06-14 | 1989-12-21 | Cassella Ag | SUBSTITUTED 3-AMINO-DYNONOMINES, PROCESS FOR THEIR PREPARATION AND THEIR USE |
-
1990
- 1990-06-25 AT AT90112002T patent/ATE90677T1/en active
- 1990-06-25 EP EP90112002A patent/EP0429751B1/en not_active Expired - Lifetime
- 1990-06-25 DK DK90112002.2T patent/DK0429751T3/en active
- 1990-06-25 ES ES90112002T patent/ES2057282T3/en not_active Expired - Lifetime
- 1990-06-25 DE DE9090112002T patent/DE59001784D1/en not_active Expired - Fee Related
- 1990-06-26 CZ CS903177A patent/CZ278933B6/en unknown
- 1990-06-26 JP JP2165852A patent/JPH03178975A/en active Pending
- 1990-06-26 CA CA002019811A patent/CA2019811A1/en not_active Abandoned
- 1990-06-27 HU HU904013A patent/HUT59399A/en unknown
- 1990-06-27 KR KR1019900009528A patent/KR910009697A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DE59001784D1 (en) | 1993-07-22 |
| ATE90677T1 (en) | 1993-07-15 |
| HUT59399A (en) | 1992-05-28 |
| EP0429751A2 (en) | 1991-06-05 |
| EP0429751B1 (en) | 1993-06-16 |
| EP0429751A3 (en) | 1991-07-24 |
| JPH03178975A (en) | 1991-08-02 |
| DK0429751T3 (en) | 1993-12-13 |
| HU904013D0 (en) | 1990-12-28 |
| ES2057282T3 (en) | 1994-10-16 |
| CZ278933B6 (en) | 1994-09-14 |
| KR910009697A (en) | 1991-06-28 |
| CZ317790A3 (en) | 1994-05-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |