JPH0330592B2 - - Google Patents

Description

Claim 1 The following general formula () [In the formula, R ₁ and R ₂ are the same or different, and are a linear or branched alkyl group having 1 to 4 carbon atoms, or a phenyl group (in some cases, a halogen atom, a straight Chain or branched chain carbon number 1~
4 alkyl groups or linear or branched alkoxy groups having 1 to 4 carbon atoms), or one of R ₁ and R ₂ may be hydrogen. Alternatively, R ₁ and R ₂ can be taken together with adjacent carbon atoms to form a cycloalkyl group having 3 to 8 carbon atoms, and one or more carbon atoms in the cycloalkyl group can be optionally replaced by a sulfur atom, an oxygen atom, an SO group, a SO ₂ group or a NR ₈ group, where R ₈ is hydrogen, linear or branched and having 1 to 4 carbon atoms. represents an alkyl group, phenyl nucleus or benzyl group; R ₃ is a hydroxyl group; OR ₉ group (here, R ₉
is a straight-chain or branched alkyl group having 1 to 12 carbon atoms);

[Formula] Group (where R ₁₀ is hydrogen or an alkyl group having 1 to 2 carbon atoms, and R ₁₁ is a linear or branched alkyl group having 1 to 12 carbon atoms. );

[Formula] group (wherein R ₁₀ and R ₁₁ have the above meanings);

[Formula] Group (wherein R ₁₂ and R ₁₃ are the same or different and are hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms); 3-phthalidyl Oxy group; or 1-(2,5-dioxopyrrolidine-1
-yl)-ethoxy group; R ₄ is a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched alkyl group having 1 to 8 carbon atoms; acyl groups, or
CONH ₂ groups; or R ₃ and R ₄ together with adjacent carbon and nitrogen atoms constitute a hydantoin ring; R ₅ and R ₆ are the same or different and hydrogen atoms; linear or Branched carbon atom number: 1~
8 alkyl groups; phenyl groups (in some cases, halogen atoms, straight-chain or branched alkyl groups having 1 to 4 carbon atoms, or straight-chain or branched carbon atoms) or a CH ₂ COOR ₁₄ group (where R ₁₄ is a hydrogen atom, or a linear or branched alkyl group having 1 to 4 carbon atoms); One of R ₇ and R ₈ is hydrogen, and the other is a linear or branched alkyl group having 1 to 4 carbon atoms, or a phenyl nucleus (as the case may be). may be substituted with a halogen atom, a linear or branched alkyl group of 1 to 4 carbon atoms, or a linear or branched alkoxy group of 1 to 4 carbon atoms. or R ₇ and R ₈ are both methyl groups; and n is a number from 0 to 2] 1,4-thiazane-3-carboxylic acid derivative; and A salt of the compound. 2. The derivative according to claim 1, wherein in the general formula (), both R ₁ and R ₂ are methyl groups, or one is hydrogen and the other is a methyl group. 3 In the general formula (), R ₃ is a hydroxyl group, an OR ₉ group (here, R ₉ represents a linear or branched alkyl group having 1 to 4 carbon atoms),

[Formula] Group, or

[Formula] (In these formulas, R ₁₀ represents hydrogen or a methyl group, and R ₁₁ represents a linear or branched alkyl group having 1 to 8 carbon atoms) The derivative according to claim 1 or 2. 4. Claims 1 to 4, characterized in that in the general formula (), R ₄ represents hydrogen or a methyl group.
The derivative according to any one of item 3. 5 In the general formula (), R ₅ and R ₆ are the same or different, hydrogen, linear or branched alkyl having 1 to 4 carbon atoms, or
CH ₂ COOR ₁₄ (herein, R ₁₄ represents hydrogen or an alkyl group having 1 to 2 carbon atoms) according to any one of claims 1 to 4. derivatives and salts thereof. 6 In the general formula (), R ₅ represents hydrogen,
and R ₆ is linear or branched and has 1 carbon atom
The derivative according to claim 5, characterized in that it represents ˜4 alkyl groups. 7 Claims 1 to 6, characterized in that in the general formula (), n has a value of 0 or 1.
The derivative according to any one of paragraphs. 8 The derivative is 1-oxo-2,2,5-trimethol-1,4-thiazane-3-carboxylic acid, 1-
Ethyl oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylate 2,2,4,5-tetramethyl-1,4-thiazane-3-carboxylic acid, 1-oxo-2,2 ,5-trimethyl-1,
1-(pivaloyloxy)ethyl 4-thiazane-3-carboxylate, 1-oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylic acid 1-
(octyloxycarbonyl)-methyl, 1-(ethoxycarbonyl)ethyl 1-oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylate, 5-butyl-2,2-dimethyl-1, 4-
Thiazane-3-carboxylic acid, 2,2-dimethyl-
5-isopropyl-1,4-thiazane-3-carboxylic acid, 5-methyl-2-phenyl-1,4-thiazane-3-carboxylic acid, and 3-carboxy-
The derivative according to claim 1, characterized in that it is selected from ethyl 2,2-dimethyl-1,4-thiazane-5-acetate. 9 The following general formula () [In the formula, R ₁ and R ₂ are the same or different, and are a linear or branched alkyl group having 1 to 4 carbon atoms, or a phenyl group (in some cases, a halogen atom, a straight Chain or branched chain carbon number 1~
4 alkyl groups or linear or branched alkoxy groups having 1 to 4 carbon atoms), or one of R ₁ and R ₂ may be hydrogen. Alternatively, R ₁ and R ₂ can be taken together with adjacent carbon atoms to form a cycloalkyl group having 3 to 8 carbon atoms, and one or more carbon atoms in the cycloalkyl group can be optionally replaced by a sulfur atom, an oxygen atom, an SO group, a SO ₂ group or a NR ₈ group, where R ₈ is hydrogen, linear or branched and having 1 to 4 carbon atoms. represents an alkyl group, phenyl nucleus or benzyl group; R ₃ is a hydroxyl group; OR ₉ group (here, R ₉
is a straight-chain or branched alkyl group having 1 to 12 carbon atoms);

[Formula] Group (where R ₁₀ is hydrogen or an alkyl group having 1 to 2 carbon atoms, and R ₁₁ is a linear or branched alkyl group having 1 to 12 carbon atoms. );

[Formula] group (wherein R ₁₀ and R ₁₁ have the above meanings);

[Formula] Group (wherein R ₁₂ and R ₁₃ are the same or different and are hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms); 3-phthalidyl Oxy group; or 1-(2,5-dioxopyrrolidinyl)-
1-ethoxy group; R ₄ is a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched alkyl group having 1 to 8 carbon atoms; acyl group, or
CONH ₂ groups; or R ₃ and R ₄ together with adjacent carbon and nitrogen atoms constitute a hydantoin ring; R ₅ and R ₆ are the same or different and hydrogen atoms; linear or Branched carbon atom number: 1~
8 alkyl groups; phenyl groups (in some cases, halogen atoms, straight-chain or branched alkyl groups having 1 to 4 carbon atoms, or straight-chain or branched carbon atoms) or a CH ₂ COOR ₁₄ group (where R ₁₄ is a hydrogen atom, or a linear or branched alkyl group having 1 to 4 carbon atoms); One of R ₇ and R ₈ is hydrogen, and the other is a linear or branched alkyl group having 1 to 4 carbon atoms, or a phenyl nucleus (as the case may be). may be substituted with a halogen atom, a linear or branched alkyl group of 1 to 4 carbon atoms, or a linear or branched alkoxy group of 1 to 4 carbon atoms. or R ₇ and R ₈ are both methyl groups; and n is a number from 0 to 2] 1,4-thiazane-3-carboxylic acid derivative; and A method for producing a salt of the compound, the method comprising:
a compound of formula (), a compound of formula (), or a compound of formula () and ();

【formula】

【formula】

(wherein R ₁ to R ₈ and n have the above meanings,
X is a halogen, a hydroxy group or a readily removable group, and Y is a halogen) to obtain a compound corresponding to formula (), and the intermediate formed by this cyclization is reduced. to obtain a derivative corresponding to formula (), the latter or an intermediate, or a derivative of formula () obtained from a compound of formula (),
and derivatives of formula () obtained from formula () and compounds of formula (), optionally oxidized, alkylated or acylated with a substituent R ₄ or this substituent R ₄ is converted into a CONH ₂ group. and then, if the latter is a hydroxyl group, the substituent
A method characterized in that a hydantoin cyclized with R ₃ is obtained. 10 The following formula () 10. The method according to claim 9, characterized in that the derivative of is cyclized in a basic medium. 11. Process according to claim 10, characterized in that a basic medium containing triethylamine, N,N-dimethylaniline, pyridine, alkali metal hydroxide or ammonium hydroxide is used. 12 The following formula () (wherein, X represents chlorine, bromine, iodine, hydroxyl group, tosyl group, or mesyl group) is cyclized in a basic medium or a dehydrating medium. The method described in Section 9. 13 The following formula () It is characterized by reducing the 5,6-dihydro-2H-thiazane derivative represented by formula () to 1,4-thiazane of formula (), and optionally then oxidizing this to obtain the corresponding sulfoxide or sulfone. The method according to claim 9. 14 Derivative () is expressed as the following formula () The cysteine derivative represented by α-halogen ketone

14. The method according to claim 13, wherein the method is purified by reacting with the formula: ##STR2## where Y represents chlorine, bromine or iodine. 15 An amine of formula () (in which R ₄ represents hydrogen) is reacted with a reactant R ₄ Z (wherein Z is a halogen atom such as chlorine, bromine or iodine, or for example tosyl) in a basic medium. R ₄
represents a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched acyl group having 1 to 4 carbon atoms). 10. The method according to claim 9, characterized in that: 16 A derivative of formula () (in which R ₄ represents hydrogen) is reacted with a reactant of formula MNCO (in which M represents sodium, potassium, lithium or ammonium ion) to obtain a derivative of formula () (formula Inside, R ₄
10. A process according to claim 9, characterized in that the derivatives of CONH ₂ (representing 2 groups) are prepared. 17 Formula () (in which R ₃ represents a hydroxyl group and R ₄ represents a CONH ₂ group) is placed in an acidic medium, with heating if appropriate, to form a compound of formula ().
10. The method according to claim 9, wherein a derivative of R ₃ and R ₄ together with adjacent carbon atoms and nitrogen atoms constitute a hydantoin ring. 18 A derivative of formula () (in which n=0) is reacted with an oxidizing agent to form a derivative of formula () (in which n=1
or 2).The method according to claim 9, characterized in that the derivative of 19. The method according to claim 18, characterized in that the oxidation is carried out at any stage of 1,4-thiazane ring formation. 20 The derivative of formula () (in the formula, R ₃ represents a hydroxyl group) is esterified so that R ₃ is an OR ₉ group,

[Formula] Group, or

The method according to claim 9, characterized in that the conversion is carried out into a derivative which is a group of the formula: 21 Formula () (wherein R ₃ is a hydroxyl group, or OR ₉ group,

[Formula] Group or

By amidation, R ₃ is

The method according to claim 9, characterized in that the method is converted into a derivative having the formula: 22 Formula () (in the formula, R ₃ is OR ₉ group,

[Formula] Group or

[Formula] represents a group) by hydrolysis or amine decomposition, R ₃ is a hydroxyl group or

10. The method according to claim 9, characterized by converting the group to a derivative having the formula: 23 Formula () (in the formula, R ₃ is

[Formula] represents a group) by hydrolysis or alcoholysis, R ³ is a hydroxyl group, or OR ₉ group,

[Formula] Group or

The method according to claim 9, characterized in that the method is converted into a derivative having the formula: 24 The following general formula () [In the formula, R ₁ and R ₂ are the same or different, and are a linear or branched alkyl group having 1 to 4 carbon atoms, or a phenyl group (in some cases, a halogen atom, a straight Chain or branched chain carbon number 1~
4 alkyl groups or linear or branched alkoxy groups having 1 to 4 carbon atoms), or one of R ₁ and R ₂ may be hydrogen. Alternatively, R ₁ and R ₂ can be taken together with adjacent carbon atoms to form a cycloalkyl group having 3 to 8 carbon atoms, and one or more carbon atoms in the cycloalkyl group can be optionally replaced by a sulfur atom, an oxygen atom, an SO group, a SO ₂ group or a NR ₈ group, where R ₈ is hydrogen, linear or branched and having 1 to 4 carbon atoms. represents an alkyl group, phenyl nucleus or benzyl group; R ₃ is a hydroxyl group; -OR ₉ group (here,
R ₉ is a linear or branched alkyl group having 1 to 12 carbon atoms);

[Formula] Group (where R ₁₀ is hydrogen or an alkyl group having 1 to 2 carbon atoms, and R ₁₁ is a linear or branched alkyl group having 1 to 12 carbon atoms) );

[Formula] group (wherein R ₁₀ and R ₁₁ have the above meanings);

[Formula] Group (wherein R ₁₂ and R ₁₃ are the same or different and are hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms); 3-phthalidyl Oxy group; or 1-(2,5-dioxopyrrolidinyl)-
1-ethoxy group; R ₄ is a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched alkyl group having 1 to 8 carbon atoms; acyl group, or
CONH ₂ groups; or R ₃ and R ₄ together with adjacent carbon and nitrogen atoms constitute a hydantoin ring; R ₅ and R ₆ are the same or different and hydrogen atoms; linear or Branched carbon atom number: 1~
8 alkyl groups; phenyl groups (in some cases, halogen atoms, straight-chain or branched alkyl groups having 1 to 4 carbon atoms, or straight-chain or branched carbon atoms) or a CH ₂ COOR ₁₄ group (where R ₁₄ is a hydrogen atom, or a linear or branched alkyl group having 1 to 4 carbon atoms); One of R ₇ and R ₈ is hydrogen, and the other is a linear or branched alkyl group having 1 to 4 carbon atoms, or a phenyl nucleus (as the case may be). may be substituted with a halogen atom, a linear or branched alkyl group of 1 to 4 carbon atoms, or a linear or branched alkoxy group of 1 to 4 carbon atoms. or R ₇ and R ₈ are both methyl groups; and n is a number from 0 to 2] A 1,4-thiazane-3-carboxylic acid derivative; or A pharmaceutical composition for the treatment or prevention of thrombosis, characterized in that it comprises at least one salt of said compound together with a suitable pharmaceutical excipient or, if appropriate, other therapeutic agents. 25 Coated tablets, granules, tablets, capsules containing additives or excipients commonly used in pharmaceutical preparations,
25. A composition according to claim 24, characterized in that it is present as a solution, syrup, emulsion or suspension. 26. Composition according to claim 24 or 25, characterized in that it consists of a solution of at least one derivative of formula (), in particular in sterile water or in peanut oil or ethyl oleate. Description: 1,4-thiazanecarboxylic acid derivative, method for producing the same, and pharmaceutical composition containing the derivative This invention relates to a 1,4-thiazanecarboxylic acid derivative, a salt of the compound, a method for producing the compound, and a pharmaceutical composition containing the derivative. It relates to pharmaceutical compositions in which at least one of the following is present, as well as methods of using the same. The derivative of this invention has the following general formula (): It is shown by. In the formula, R ₁ and R ₂ are the same or different, and are a linear or branched alkyl group having 1 to 4 carbon atoms, or a phenyl group (in some cases, a halogen atom, a linear or branched chain with 1 or more carbon atoms
4 alkyl groups or linear or branched alkoxy groups having 1 to 4 carbon atoms), or one of R ₁ and R ₂ may be hydrogen. Alternatively, R ₁ and R ₂ can be taken together with adjacent carbon atoms to form a cycloalkyl group having 3 to 8 carbon atoms, and one or more carbon atoms in the cycloalkyl group can be optionally replaced by a sulfur atom, an oxygen atom, an SO group, a SO ₂ group or a NR ₈ group, where R ₈ is hydrogen, linear or branched and having 1 to 4 carbon atoms. represents an alkyl group, phenyl nucleus or benzyl group; R ₃ is a hydroxyl group; OR ₉ group (here, R ₉
is a straight-chain or branched alkyl group having 1 to 12 carbon atoms);

[Formula] Group (where R ₁₀ is hydrogen or an alkyl group having 1 to 2 carbon atoms, and R ₁₁ is a linear or branched alkyl group having 1 to 12 carbon atoms. );

[Formula] group (wherein R ₁₀ and R ₁₁ have the above meanings);

[Formula] Group (wherein R ₁₂ and R ₁₃ are the same or different and are hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms); 3-phthalidyl Oxy group; or 1-(2,5-dioxopyrrolidinyl)-
1-ethoxy group; R ₄ is a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched alkyl group having 1 to 8 carbon atoms; acyl group, or
CONH ₂ groups; or R ₃ and R ₄ together with adjacent carbon and nitrogen atoms constitute a hydantoin ring; R ₅ and R ₆ are the same or different and hydrogen atoms; linear or Branched carbon atom number: 1~
8 alkyl groups; phenyl groups (in some cases, halogen atoms, straight-chain or branched alkyl groups having 1 to 4 carbon atoms, or straight-chain or branched carbon atoms) or a CH ₂ COOR ₁₄ group (where R ₁₄ is a hydrogen atom, or a linear or branched alkyl group having 1 to 4 carbon atoms); One of R ₇ and R ₈ is hydrogen, and the other is a linear or branched alkyl group having 1 to 4 carbon atoms, or a phenyl nucleus (as the case may be). may be substituted with a halogen atom, a linear or branched alkyl group of 1 to 4 carbon atoms, or a linear or branched alkoxy group of 1 to 4 carbon atoms. or R ₇ and R ₈ are both methyl groups; and n is a number from 0 to 2. According to a preferred form of the invention, it relates to the following compounds of formula (). That is, R ₁ and R ₂ are
are the same or different and represent hydrogen (only one of them) or a linear or branched C ₁ -C ₄ alkyl group; R ₃ is a hydroxyl group, OR ₉
group (where R ₉ is a linear or branched C ₁ to _{C 4}
(represents an alkyl group),

[Formula] group, or

[Formula] (In these formulas, R ₁₀ represents hydrogen or a methyl group, and
R ₁₁ represents a linear or branched C ₁ -C ₈ alkyl group; R ₄ represents hydrogen or a methyl group; R ₅ and R ₆ are the same or different;
represents hydrogen, linear or branched C ₁ -C ₄ alkyl, or CH ₂ COOR ₁₄ (wherein R ₁₄ represents hydrogen or a C ₁ -C ₂ alkyl group); R ₇ represents hydrogen; and n has a value of 0 or 1. A preferred class of compounds of formula () is one in which R ₁ and R ₂ represent hydrogen (only one of them) or a methyl group; R ₃ represents a hydroxyl group or an OR ₉ group (wherein R ₉ is a linear or branched _R4 represents _{hydrogen or a methyl group; R5 represents hydrogen; R6 represents a linear} or branched _C1 - _C4 alkyl group; represents a group; R ₇ represents hydrogen; and n is a compound that can take a value of 0 or 1. Examples of compounds of this invention include 1-oxo-
2,2,5-trimethyl-1,4-thiazane-3
-carboxylic acid, ethyl 1-oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylate, 2,2,4,5-tonaramethyl-1,4-thiazane-3-carboxylic acid, 1 -oxo-2,2,
1-(pivaloyloxy)ethyl 5-trimethyl-1,4-thiazane-3-carboxylate, 1-(octyloxycarbonyl) 1-oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylate -Methyl, 1-oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylic acid 1-
(ethoxycarbonyl)-ethyl, 5-butyl-
2,2-dimethyl-1,4-thiazane-3-carboxylic acid, 2,2-dimethyl-5-isopropyl-
1,4-thiazane-3-carboxylic acid, 5-methyl-2-phenyl-1,4-thiazane-3-carboxylic acid, and 3-carboxy-2,2-dimethyl-
Examples include ethyl 1,4-thiazane-5-acetate. When the derivative of formula () is an acid addition salt,
It can be converted into the free base or into salts with other acids according to conventional methods. The most commonly used salts are pharmaceutically acceptable non-toxic acid addition salts, in which case suitable inorganic acids include, for example, hydrochloric acid, sulfuric acid or phosphoric acid, and suitable organic acids include fatty acids. alicyclic, aromatic, aromatic-aliphatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid,
Ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, hydroxybenzoic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid, methanesulfonic acid, ethane Sulfonic acid, pantothenic acid, toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid,
Mention may be made of β-hydroxypropionic acid, β-hydroxybutyric acid, oxalic acid, malonic acid, galactaric acid and galactulonic acid. Salts also include lysine, glycine, arginine, ornithine, asparagine, glutamine, alanine,
It can also be derived from natural or synthetic amino acids such as valine, threonine, serine, leucine, cysteine and similar amino acids. When R ₃ represents an OH group, the compounds of this invention combine the carboxylic acid group with sodium hydroxide,
Also includes salts composed of bases such as potassium hydroxide, lithium hydroxide, ammonium hydroxide, magnesium hydroxide and calcium hydroxide, as well as internal salts (binary salts). The compounds of formula () may have one or more asymmetric centers and may take optical isomeric, racemic or diastereomeric forms, all of which form part of this invention. Optical isomers can be obtained by stereospecific synthesis or stereoselective synthesis.
Alternatively, the racemate may be prepared using a conventional method such as tartaric acid,
forming diastereomeric salts by reaction with optically active acids such as diacetyltartaric acid, tartoranilic acid, dibenzoyltartaric acid and ditoluoyltartaric acid, and separating this diastereomeric mixture by, for example, crystallization or chromatography;
It can be produced by liberating an optically active base from this salt. Optically active compounds of formula () can also be obtained from optically active starting materials. A mixture of diastereomers is
It can be separated by a method similar to the separation of diastereomeric salts described above. Arterial and venous thrombosis has become a very important cause of death and particularly morbidity in modern Western countries. The products of the invention allow access to new therapeutic methods, which differ from treatments with substances that influence the function of platelets, and which differ from treatments with fibrinolytis enzymes. Oral or parenteral administration of the products of this invention increases the synthesis and/or release of natural activators of fibrinolysis, thereby increasing fibrinolytic activity in the blood, and therefore significantly It is expected that it can be used therapeutically under safe conditions. That is, oral administration prevented deep vein thrombosis and its often fatal consequence, pulmonary embolism, which could be followed several weeks later by surgery. It is also expected that thrombosis accompanied by phlebitis of superficial primary or secondary veins, which occurs when a patient is immobilized for a long period of time, can be prevented. The products of this invention are further useful when the fibrinolytic activity of the blood is reduced, e.g. after surgical procedures, during anesthesia,
Or it can be used in cases of insulin-treated diabetes. Finally, the products of the invention can prevent arterial or venous thrombotic strokes by themselves or together with substances that inhibit platelet adhesion or aggregation. In fact, it is known that in patients with cerebral or coronary thrombosis (myocardial infarction), the application of this substance prevents dangerous recurrence. The substances of this invention are easy to use because they can be administered orally, and they do not have enzymatic activity, are not immunogenic, and act through active factors naturally present in living organisms, so they are not commonly used. can be administered over a long period of time compared to fibrinolytic substances. The use of the substances of this invention alone or in conjunction with substances that inhibit platelet aggregation allows new approaches to the treatment and prevention of arterial and venous thrombosis. The invention also relates to pharmaceutical compositions comprising as active ingredient at least one compound of the general formula () and/or one of its salts, together with pharmaceutical excipients. These compositions are prepared for oral, rectal or parenteral administration. For example, oral preparations may be either liquid or solid, and may be tablets, capsules, granules, powders, syrups, or suspensions. These compositions include additives and excipients commonly used in pharmaceutical formulations, inert diluents, disintegrants, binders, and lactose, starch, talc, gelatin, stearic acid,
Lubricants such as silicic acid, magnesium stearate, polyvinylpyrrolidone, calcium phosphate, calcium carbonate, and the like can be included. These formulations can be prepared to prolong disintegration and thus also the duration of action of the active ingredient. Aqueous suspensions, emulsions, and oily solutions may be prepared in the presence of sweetening agents, such as sucrose or glycerin, and flavoring agents, such as vanilla, and these preparations may also contain thickeners, humectants, and preservatives. It can be made to contain. Oily emulsions and solutions are prepared in the presence of vegetable or animal oils and may contain emulsifying agents, flavoring agents, dispersing agents, sweetening agents and antioxidants. Carriers for parenteral administration include sterile water, aqueous solutions of polyvinylpyrrolidone, peanut oil, ethyl oleate, or the like. These aqueous or oil-based injections can contain thickeners, wetting agents, dispersing agents, and gelling agents. The compounds of this invention are prepared by the methods forming part of this invention and described in detail below. When a novel intermediate is produced in this method, the novel intermediate and the method for producing the intermediate also form part of this invention. According to the first method, Acta Chem by AIVirtanen et al.
Scand. 1966, 20 , 1, 163-1, 185, by cyclizing the vinyl thioether of formula () according to the following formula to obtain a derivative of formula (). In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and n
is as described above. Preferably, the cyclization is carried out in a basic medium. As a base, an organic base such as triethylamine, pyridine or N,N-dimethylaniline;
Alternatively, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or an inorganic base such as ammonium hydroxide can be used. If the base used is an organic base, the solvent may be an inert organic solvent, for example a chlorinated solvent such as chloroform or methylene chloride, an aromatic or aliphatic hydrocarbon such as benzene, toluene or the various petroleum ether fractions, Alternatively, it is preferred to use solvents such as acetonitrile, N,N-dimethylformamide or dimethylsulfoxide. If the base is an inorganic base, water is preferably used as solvent, the concentration of the basic solution being between 0.01N and 10N, advantageously between 0.2N and
Suppose it is 2N. The reaction is carried out at 0°C to the reflux temperature of the solvent. However, it is preferred to carry out the reaction at temperatures close to ambient temperature, especially when the reactants or products contain large amounts of stereoisomers that are susceptible to isomerization if the conditions are too harsh. Other manufacturing methods include ZF Calson (JF
Carson et al., Crg.Chem. 29 , 2203 (1964)
The cysteine derivative of formula () obtained by the method described in 1. is cyclized according to the following reaction scheme. In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and n
is as described above, and X represents a halogen atom such as chlorine, bromine or iodine, a hydroxyl group, or an easily removable group such as a tosyl or mesyl group. If the cyclization is carried out in a basic medium, the conditions described in the first method can be applied to this method. If the cyclization is carried out in an acid medium, hydrochloric acid,
Mineral or organic acids such as hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, formic acid or acetic acid are used. Additionally, dehydrating agents such as phosphorus pentoxide, concentrated sulfuric acid, or carbodiimides such as dicyclohexylcarbodiimide can also be used. This reaction is generally carried out in an inert organic solvent, e.g.
It is carried out in a chlorinated solvent such as chloroform or methylene chloride, an aromatic or aliphatic hydrocarbon such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene or petroleum ether, or a solvent such as dimethyl sulfoxide or N,N-dimethylformamide. The reaction is carried out at a temperature between ambient temperature and the reflux temperature of the chosen solvent. If you follow another method, as shown in the reaction formula below,
The cysteine derivative () is reacted with an α-halogen ketone () to cyclize to form an unsaturated ring compound (), which is then reduced to obtain the derivative (). In the formula, R ₁ , R ₂ , R ₃ , R ₅ and R ₇ are as described above, and Y represents a halogen atom such as chlorine, bromine or iodine. The first step of the process is carried out in an inert organic solvent, for example an alcohol such as methanol, ethanol or propanol, an ether such as dioxane or tetrahydrofuran, a solvent such as dimethyl sulfoxide or N,N-dimethylformamide, or benzene or toluene. The process is carried out in aromatic hydrocarbons such as aromatic hydrocarbons. Bases that can be used are alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, or, for example, sodium or potassium methanolate, sodium or potassium ethanolate, or sodium t-butanolate or potassium t-butanolate. - Alkali metal alcoholates such as butanolate. The reaction is carried out at a temperature between -20°C and the reflux temperature of the solvent, advantageously between 0°C and ambient temperature. Dehydrating agents such as molecular sieves can advantageously be added to the reaction mixture. The reduction of the imine () is carried out in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid in the presence of hydrogen and a hydrogenation catalyst such as palladium, palladium oxide or palladium on carbon. This reaction can be carried out at normal pressure, preferably at elevated pressure, or with an alkali metal hydride such as sodium borohydride in a solvent such as methanol, or with lithium aluminum hydride in a solvent such as ether or tetrahydrofuran. . The reaction is generally carried out at ambient temperature, but depending on the reactivity of the system it may be advantageous to heat or cool the reaction mixture. For example, acids such as hydrochloric acid, sulfuric acid or acetic acid may catalyze the reaction. To obtain the sulfoxide, reagents, e.g.
iodine, bromine in water or in the presence of acetate ions or with pyridine, peracids such as peracetic acid, monoperphthalic acid or m-chloroperbenzoic acid;
N-halogen succinimides such as N-bromosuccinimide, sodium hypochlorite or hypochlorite compounds such as t-butyl or i-propyl hypochlorite, periodic acid compounds such as sodium periodate, Hydrogen peroxide in the presence of acetic anhydride or vanadium pentoxide in tert-butanol, nitric acid compounds such as acetyl nitrate or cerium ammonium nitrate, oxides such as chromium oxide () in pyridine, vanadium pentoxide in the presence of oxygen, Alternatively, acids such as nitrogen pentoxide, peroxide, ozone, single or triplet oxygen, nitric acid, chromic acid or Caro's acid can be used, as well as other reagents such as sulfuryl chloride. ,
1-chlorobenzotriazole, chloroamine,
N-chloro-nylon 6,6, iodobenzene dichloride, iodosobenzene, iodobenzene diacetate, N-chlorotriazole, 2,4,
It is also possible to use 4,6-tetrabromocyclohexadienone or chloroauric acid ( _HAuCl4 ). These oxidation reactions are carried out in a solvent such as water, acetic acid, chloroform, methylene chloride, carbon tetrachloride, methanol, t-butanol or acetone. To obtain the sulfone, a reagent such as hydrogen peroxide, preferably in the presence of a zirconium salt,
peracids such as monoperphthalic acid and m-chloroperbenzoic acid (in the case of oxidation with peracids it is advantageous to use catalysts based on transition metals), permanganic acid in acidic or basic media; Potassium, sodium dichromate or potassium dichromate,
Osmium tetroxide, selenium oxide, hypochlorous acid t-
Preference is given to using butyl, nitric acid, ozone, oxygen in the presence of preferably iridium or rhodium salts, iodobenzene dichloride or periodic acid, or electrochemical oxidation can also be carried out. These reactions are carried out in a solvent such as water, acetic acid, chloroform, methylene chloride, methanol, ethanol, isopropanol, t-butanol, ethanol, isopropanol, t-butanol dioxane or acetone. In some cases it is advantageous to carry out the above oxidation reactions on compounds with protected groups sensitive to oxidizing agents. The cyclization, reduction and oxidation steps described above can also be carried out as part of a continuous process without the need for intermediate separation of each. It is noteworthy that the conversion of the derivative () with n=0 to the derivative () with n=1 or 2 can be carried out at any stage of the 1,4-thiazane ring formation. Substituent R ₄ is linear or branched C ₁ to _{C 8}
Alkyl group, or linear or branched C ₁ ~
When a C ₈ acyl group, this group is introduced by alkylation or acylation of the amine by the following reaction. In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and n are as defined above. Z represents a halogen atom such as chlorine, bromine or iodine, or an easily removable group such as a tosyl or mesyl group. The reaction is carried out in an inert solvent, for example, chlorinated hydrocarbons such as chloroform or methylene chloride, aromatic or aliphatic hydrocarbons such as benzene, toluene or petroleum ether, alcohols such as methanol and ethanol, or acetonitrile and ethers. It is advantageous to do so. The reaction temperature is between ambient temperature and the reflux temperature of the reaction mixture. The reaction is carried out in the presence of an organic base such as pyridine, triethylamine or N,N-dimethylaniline, or in the presence of an airless base such as alkali metal or alkaline earth metal hydroxides, carbonates and bicarbonates, or finely divided lime. This can be advantageously carried out in the presence of. Alkylated derivatives can also be obtained by reducing the corresponding acylated derivatives according to conventional methods. The substituent R ₄ =CONH ₂ is introduced by reacting the derivative ( ) with an alkali metal isocyanate or ammonium isocyanate according to a conventional method as shown in the following reaction formula. In this formula, R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ and n are as described above, and M is a monovalent cation, such as sodium ion, potassium ion,
Represents lithium ion or ammonium ion. The reaction is carried out in water at a temperature between room temperature and reflux temperature according to conventional methods. Hydantoin (XI) is obtained by heating the derivative () in which R ₃ is a hydroxyl group in an aqueous solution of an acid. In the formula, R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ and n are as defined above. As acids used are mineral acids, for example halogen-containing acids such as hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid. The reaction mixture is generally heated to approximately the reflux temperature of the solution. R ₃ of the derivative where R ₃ is a hydroxyl group is OR ₉
base,

[Formula] Group, or

Conversion to a derivative of the formula is an esterification reaction. Esterification of acids is a very common reaction that can be carried out in a variety of ways. According to the usual method, acid and alcohol are mixed with hydrochloric acid,
The reaction is carried out in the presence of an acid catalyst such as sulfuric acid or p-toluenesulfonic acid. This reaction is advantageously carried out under anhydrous conditions and using a large excess of one of the reactants. As a solvent, one of the reactants may be used, or an inert solvent such as a chlorinated hydrocarbon such as chloroform or carbon tetrachloride, or an aromatic or aliphatic hydrocarbon such as benzene, toluene or petroleum ether. May be used. The reaction temperature is between room temperature and the reflux temperature of the reaction mixture. Another method is to use suitable equipment to quickly distill off the water that forms. The reaction conditions are similar to those described above, but there is no need for one of the reactants to be present in large excess. The hydrolysis of the ester is carried out under similar conditions to the esterification reaction, but in this case one reactant, water, is used in very large excess. The catalyst and temperature conditions are the same as for esterification. R ₃ is a hydroxy group, or OR ₉ group,

[Formula] Group or

R ₃ of the derivative, which is a group such as [Formula]

The conversion of the group [formula] into derivatives is a very well-described common reaction in chemistry and is carried out according to several methods described below. For example, a carboxylic acid is contacted with an amine and the salt thus formed is converted to an amide by thermal decomposition, similar to the action of a dehydrating agent such as P ₂ O ₅ . Another method consists of converting the carboxylic acid into an acid halide and reacting with an amine to form an amide. The conversion of acids to acid halides is often carried out without the use of solvents using thionyl chloride, phosphorus pentachloride or phosphorus acid chloride. The corresponding bromides can also be used. In order to complete the reaction, it is often necessary to heat the reaction mixture to a temperature in the range of 50°C and 150°C. If a solvent is required to carry out the reaction, this solvent is an inert solvent, for example a hydrocarbon such as benzene, toluene or petroleum ether, or an ether such as diethyl ether. The reaction between an acid halide and an amine is performed by cooling the reaction mixture to 0°C to -50°C and adding an excess of amine (2 or more equivalents of amine, or 1 or more equivalents of amine and 1 or more equivalents of a tertiary organic base, e.g. This is done by introducing triethylamine). The acid chloride is added to the amine solution in an inert organic solvent or water as described above in a conventional manner. Another method is to react a carboxylic acid with an amine in the presence of a coupling agent used, for example, in peptide synthesis. Nowadays there are many coupling agents such as cyclohexylcarbodiimide, N-ethyl-N'-3-dimethylaminopropyl-carbodiimide, phosphine, phosphorous compounds, silicon or titanium tetrachloride, or EEDQ. The amine decomposition of the ester is carried out in water or in an inert organic solvent according to a conventional method. Examples of solvents that can be used include aromatic hydrocarbons such as benzene or toluene, aliphatic hydrocarbons such as hexane or petroleum ether, or halogenated hydrocarbons such as methylene chloride or chloroform. The presence of a strong base is essential in reactions with amines of low basicity or sterically hindered amines. The above reaction is carried out at a temperature between ambient temperature and the reflux temperature of the solvent. Depending on the conditions employed, the amide i.e. R ₃
but

Hydrolysis of a derivative of the formula produces a carboxylic acid or ester. By all the above reactions, the 1,4-
Cyazan derivatives are easily accessible. However, the composition of the diastereomeric mixture obtained varies depending on the method employed. The separation of this mixture of diastereomers is carried out according to conventional methods of organic chemistry. The preparation of some derivatives of the invention will now be explained by detailed examples. These examples are intended to further illustrate the features of the method of the invention. Example 1 2,2-dimethyl-1,4-thiazane-3-carboxylic acid 1S-(2-hydroxyethyl)-penicillamine 17.5 g (0.14 mol) of 2 in 100 ml of ethanol
- A solution of bromoethanol, 14.9 g in 75 ml of 2N aqueous sodium hydroxide solution, with thorough stirring
(0.10 mol) of penicillamine solution and placed under an inert atmosphere (N ₂ ). After the addition is complete,
Sufficient further ethanol is added to obtain a homogeneous medium and the medium is heated at ambient temperature for 24 hours.
Stir for an hour. After neutralization with concentrated hydrochloric acid, most of the alcohol is evaporated under reduced pressure and water is added to bring the volume to 300 ml. This solution is fixed in Dowex type 50 resin prepared in acid form. Wash this resin with water and
Elute with 3N ammonia solution. Evaporate the eluate to dryness. Treat the residue with 50 ml water and 500 ml ethanol. The solid is removed and recrystallized from isopropanol. This results in 9.0g (47
%) of a white solid is obtained. Melting point 148-150℃. 2S-(2-chloroethyl)-penicillamine (hydrochloride) 9.0 g (47 mmol) of the above product and 350 ml of 38
% strength hydrochloric acid is heated in a 95° C. bath for 7 hours. The mixture was evaporated to dryness under reduced pressure,
The residue is then recrystallized from isopropanol. 8.9 g (78%) of a single product are thus obtained in silica thin layer chromatography (solvent: BuOH/AcOH/H ₂ O; 13:3:5). _Rf :
0.59. 32,2-Dimethyl-1,4-cyazane-3-carboxylic acid 6.7 g (27 mmol) of the above chloride were dissolved in 450 ml of N,N-dimethylformamide, then 50
ml of triethylamine is added and the mixture is heated for 2.5 hours with a bath maintained at 95°C. The mixture is then evaporated to dryness under reduced pressure. The residue is dissolved in 75 ml of water and this solution is infiltrated onto 250 ml of Dowex Type 50 resin. The resin is washed with water and eluted with 1.5 ammonia solution. The eluate was concentrated under reduced pressure to a volume of 400 ml and added to the acid form of Amberlite IRC50.
Treat overnight with 100 ml of mold resin. After removing the resin, the solution is concentrated to a volume of 30 ml. Take the resulting crystals and redissolve them in 10 ml of water. 40 ml of acetone is added slowly to precipitate the final product. weight
3.1g (66%). Melting point 320℃ (decomposition). IR, NMR, and mass spectra are consistent with the predicted structure. C H N Elemental analysis calculated value (%) 48.0 7.5 8.0 Measured value (%) 47.9 7.4 7.9 Example 2 2,2,5-(R,S)-trimethyl-
1,4-Thiazane-3-(S)-carboxylic acid 1 S-allylpenicillane A solution of 6.6 g (4.1 ml; 55 mmol) allyl bromide in 50 ml ethanol and 35 ml 2N aqueous sodium hydroxide solution in 50 ml 7.5g in ethanol
(50 mmol) of penicillamine suspension slowly and simultaneously while maintaining the temperature of the medium below 20°C. After the addition has ended, the mixture is further stirred for about 2 hours while testing the disappearance of the starting thiol (using a thin layer of silica; solvent; BuOH/AcOH/H ₂ O (12:3:5); ninhydrin color development). .
The solution is neutralized with concentrated hydrochloric acid and concentrated until a solid forms. Add water to make the volume 300ml.
The obtained solution is infiltrated into a column of sulfonic acid type resin (Amberlite IR120) prepared in acid form. The resin is washed with water and eluted with 1 portion of 1N ammonia solution. The eluate is evaporated to dryness and the remaining solid is recrystallized from isopropanol. 7.8 g (82%) of product are thus obtained. Melting point 182~
184℃. 2S-(2-bromopropyl)-penicillamine hydrochloride The product of the previous step (7.8 g; 41 mmol) was
With stirring, a 40% concentrated solution of hydrogen bromide in acetic acid
Add to 300ml. After stirring for 3 hours, the reaction medium is evaporated to dryness under reduced pressure. The residue is stirred in ether and taken up. The solid obtained is used in the next step. Weight: 14.2g (99%). Melting point: 106-108℃. 32,2,5-trimethyl-1,4-thiazane-
3-Carboxylic acid The above product (14.2 g; 40 mmol) is added to 500 ml of DMF containing 50 ml of triethylamine. The mixture is heated in a bath maintained at 90° C. for 2.5 hours and evaporated to dryness under reduced pressure. residue
Sulfonic acid resin (Amberlite) was dissolved in 400ml of water, and this solution was adjusted to acid form.
IR120) Penetrate onto 500g. This resin 2
Wash with 2 portions of water and elute with 2 portions of 1N ammonia solution. The eluate was evaporated to dryness under reduced pressure, and the residue was dissolved in 500 ml of water, and this solution was prepared in acid form with carboxylic acid resin (Amberlite IRC50) 50
Stir with ml. The resin is removed and the liquid phase is evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of a 2:1 mixture of acetone and water and the solution is placed in the refrigerator. After 3 days, collect the formed crystals. After washing with acetone and drying, 3.7 g (45
%) of product. Melting point: 290℃ (decomposition). Confirm the structure of the ring closure product by IR, NMR, and mass spectra. Karl-Fisher analysis showed the presence of 8.7% water. Elemental analysis: C H N Calculated value (%) 46.4 8.3 6.8 Measured value (%) 46.1 8.5 6.4 In silica thin layer chromatography developed with a mixture of butanol/acetic acid/water (12:3:5), the product was Single. However, by gas phase chromatography after silylation, 2
It was shown that two epimers exist. Example 3 1-(R,S)-oxo-2,2,5-
(S)-trimethyl-1,4-thiazane-3-
(S)-Carboxylic Acid The recrystallized mother liquor and product wash acetone from the previous example, which had been carefully preserved, are evaporated to dryness under reduced pressure. The white solid that remains is recrystallized from ethyl acetate. The solid obtained is triturated in acetone and recrystallized from a mixture of acetone and water. Thus, 0.57 g of 2,2,5-(S)-trimethyl-1,4-thiazane-3-(S)-carboxylic acid [S-(2-bromopropyl)-penicillamine hydrochloride] concentrated to 90% 7 for salt
%]. Melting point: 328℃ (decomposition). [α] ²⁰ _D = 131° (C = 0.5; water). Elemental analysis: C H N Calculated value (%) 50.8 7.8 7.4 Measured value (%) 50.5 8.0 7.7 The above sulfide was dissolved in 10 ml of acetic acid and 30
Add 0.4 ml of % hydrogen peroxide. The mixture is stirred at ambient temperature for 24 hours and concentrated under reduced pressure to a syrup. 25 ml of acetone is added and the mixture is kept at 5°C overnight. Remove the crystalline solid and redissolve in 10 ml of water.
The solution is concentrated until a syrup is obtained. Repeat the above process and obtain a white solid product consisting of a mixture of two epimer sulfoxides.
Get 0.29% (47%). Melting point: 230℃ (decomposition). I.
R., NMR, and mass spectra are consistent with the predicted structure. Karl-Fisscher analysis showed the presence of 2.2% water. Elemental analysis: C H N Calculated value (%) 45.8 7.5 6.7 Measured value (%) 45.6 7.4 6.9 Example 4 2,2,5-(R)-trimethyl-1,
4-Thiazane-3-(S)-carboxylic acid 3.25 ml (40.3 mmol) of freshly distilled chloroacetone was dissolved in 5 g in 28 ml of water with stirring.
(33.6 mmol) of D-penicillamine. After the medium becomes homogeneous, the reactor is immersed in an ice bath. Add 20% strength aqueous sodium hydroxide solution dropwise until the pH reaches 5.3, making sure that the temperature does not exceed 10°C, and add 1 g of 5 ml of base-containing water, making sure that the temperature does not exceed 30°C.
A solution of sodium borohydride (26.4 mmol) is added dropwise. After the addition is complete, the mixture is stirred for a further 1 hour at ambient temperature. And 37%
Slowly add a concentrated aqueous solution of hydrochloric acid until the pH reaches 5.0. The final medium is evaporated to dryness under reduced pressure and the residue is treated with 50 ml of absolute ethanol. The insoluble material is removed and the liquid is evaporated to dryness under reduced pressure. The remaining colorless oil is redissolved in 10 ml of water. The solution is evaporated to dryness under reduced pressure. The white solid obtained is mixed with 10 ml of water and the mixture is heated under reflux until the solid dissolves. The solution is kept at ambient temperature for 4 hours and at 5° C. overnight to allow crystallization. Remove the solids and dry. Weight: 4.3 g (20.7 mmol; 62%). Melting point: 310℃ (decomposition). [α] ²⁰ _D = +93° (C = 1; water)
. Karl-Fisscher analysis shows 8.7% water present. IR, NMR, and mass spectra are consistent with the predicted structure. High pressure liquid chromatography analysis shows the unity of the final product. Elemental analysis: C H N Calculated value (%) 46.4 8.3 6.8 Measured value (%) 46.3 8.3 6.9 Methanol/acetic acid/chloroform (6:1:
In silica thin layer chromatography analysis using the mixture of 4), the product has an R _f :0.69. Example 5 1-(R)-oxo-2,2,5-(R)
-trimethyl-1,4-thiazane-3-(S)-
Carboxylic Acid A solution of 3.5 g of the product of the previous example in 17 ml of acetic acid/water (1:1) is prepared and cooled in an ice bath. 1.94 ml of 30% strength hydrogen peroxide are added dropwise over 5 minutes with stirring. After the addition is complete, the mixture is stirred in the cooling bath for 8 hours and at ambient temperature for 10 hours. This is evaporated to dryness under reduced pressure at a temperature not exceeding 60°C. The residual oil is dissolved in 10 ml of water and the solution is evaporated to dryness under reduced pressure. This operation is repeated until a solid is obtained. Dissolve this in 6 ml of water. While stirring, slowly add 15 ml of acetone. The mixture is stirred for 1 hour at ambient temperature and filtered. In this way, the first yield of the desired sulfoxide is obtained. A second crop is obtained by cooling the mother liquor to 10° C., adding 10 ml of acetone, and filtering the mixture after a crystallization time of 15 minutes. Total weight: 2.2g (9.9 mmol; 59
%). Melting point: 246°C (decomposition). [α] ²⁰ _D = -3.5゜(C
=
1; 1NHCl). IR, NMR, and mass spectra are consistent with the predicted structure. The absolute structure can be confirmed by X-ray analysis of the corresponding hydrochloride. Karl-Fisscher analysis shows 8.2% water present. Elemental analysis: C H N Calculated value (%) 43.0 7.7 6.3 Measured value (%) 43.2 7.6 6.4 In chromatography developed on a thin layer of silica with a mixture of methanol/acetic acid/chloroform (6:1:4), The product has R _f :0.42. Analysis by high pressure liquid chromatography confirms the unity of the product. Example 6 1-(S)-oxo-2,2,5-(R)
-trimethyl-1,4-thiazane-3-(S)-
Carboxylic Acid (Hydrochloride) The carefully stored crystalline mother liquor of the second crop of the product of the previous example is evaporated to dryness under reduced pressure. The residue weighing 1.3 g is dissolved in 10 ml of water and the solution is brought to pH 1 with 37% strength aqueous hydrochloric acid. The solution is concentrated until a wet weight of 3.0 g is obtained and the residue is kept at 5° C. overnight. Take solid food. It has an optical rotation of 79° in water. The crystals are dissolved in 10 ml of water and evaporated under reduced pressure until a syrup is obtained. 1.5 ml of acetone is added and the mixture is kept at 5°C overnight. pass this. The optical rotation of the solid is 84°. Further crystallization operation is performed,
A product of suitable purity is obtained. Weight: 0.22g (0.9
mmol; 5% based on the product of Example 4 used).
Melting point: 275℃. [α] ²⁰ _D = +85° (C = 1; water), +73
゜(C=1; 1NHCl). IR, NMR, and mass spectra are consistent with the expected structure. Karl-Fisscher analysis shows 0.5% water present. Elemental analysis: C H N Calculated value (%) 39.8 6.7 5.8 Measured value (%) 39.8 6.7 5.9 99.5% by high pressure liquid chromatography analysis
purity is indicated. Example 7 1,1-oxo-2,2,5-(R)-
Trimethyl-1,4-thiazane-3-(S)-carboxylic acid 5 g (22.4 mmol) of the product of Example 5 was dissolved in 300 ml of
Dissolve in 0.5N sulfuric acid. A solution of 2.5 g of potassium permanganate in 300 ml of water is added over 2 hours. After the addition is complete, the mixture is stirred for 2 hours at ambient temperature and 12 ml of formic acid are added. Filter the mixture and until precipitation is complete
Add 0.5N barium hydroxide aqueous solution. The mixture is filtered and the liquid is transferred to a column of ion exchange resin in strong acid form prepared in H 2 form. This resin,
Wash the effluent until it is neutral and elute with 3N ammonia solution. Add the eluate to a volume of approximately 100
Concentrate under reduced pressure to ml. The ammonium salt solution thus obtained is permeated into a column of weakly acidic resin. Evaporate the liquid under reduced pressure until a syrup is obtained and add 15 ml to this syrup.
of acetone. The mixture is stirred for 2 hours and filtered. Weight: 2.7g (11.6 mmol; 52
%). Melting point: 232°C (decomposition). [α] ²⁰ _D = +2゜(C=
1; 1NHCl). IR, NMR, and mass spectra are consistent with the expected structure. Karl-Fisscher analysis shows 6.2% water present. Elemental analysis: C H N Calculated (%) 40.7 7.1 5.9 Measured (%) 40.7 7.3 5.9 Butanol/acetic acid/water (5:
In chromatography developed with a 2:3) mixture, this product has an R _f :0.38. Example 8 5-methyl-1,4-thiazane-3-
Carboxylic acid hydantoin 3.9 g (24.0 mmol) of 5-methyl-1,4
-thiazane-3-carboxylic acid and 2.3 g (28.8 mmol) of potassium isocyanate in 25 ml of
Add to the water. Heat the mixture to boiling and return to ambient temperature. The 5-methyl-4-ureido-1,4-thiazane-3-carboxylic acid thus obtained is treated with 34 ml of a 10% strength aqueous hydrochloric acid solution. The mixture is concentrated under reduced pressure to approximately 20 ml. This is stirred for 1 hour at ambient temperature and filtered.
Finally, the solid is recrystallized from water. weight:
2.5 g (13.4 mmol; 56%). Melting point: 189°C (decomposed). IR, NMR, and mass spectra are consistent with the expected structure. Elemental analysis: C H N Calculated value (%) 45.2 5.4 15.0 Measured value (%) 44.9 5.5 15.1 Example 9 1-Oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylic acid 1-ethoxy Carbonylethyl (oxalate) 3.7 g (17.4 mmol) of the product of Example 5 in 37 ml water
The solution is treated with 0.5N aqueous potassium hydroxide until the pH reaches 9. This solution is evaporated to dryness under reduced pressure. Suspend the residue in 40 ml DMF.
Then 3.2 g (17.6 mmol) of ethyl 2-bromopropionate are added dropwise. The medium is stirred for 48 hours at ambient temperature, diluted with 100 ml of water and extracted with chloroform. The organic extract is dried and evaporated to dryness under reduced pressure. residual oil
Remove to 50 ml of ethanol and add in a minimum amount of the same solvent.
Treat with 1.6 g (17.6 mmol) of oxalic acid solution. Stir the mixture for 30 minutes and filter. The solid thus obtained is recrystallized from ethanol.
Thus 4.3 g (10.5 mmol; 64%) of pure product
get. Melting point: 196°C (decomposed). IR, NMR, and mass spectra are consistent with the expected structure. Karl-Fisscher analysis shows 3.1% water present. Elemental analysis: C H N Calculated (%) 44.1 6.5 3.4 Measured (%) 44.1 6.7 3.3 Butanol/acetic acid/water (5:
In chromatography developed with a 2:3) mixture, the product has an R _f :0.52. Example 10 1-pivaloyloxyethyl 1-oxo-2,5,5-trimethyl-1,4-thiazane-3-carboxylate (oxalate) 3.7 g (16.4 mmol) of the product of Example 5 in 37 ml water
The solution is treated with 0.5N aqueous potassium hydroxide until the pH reaches 9. The solution is evaporated to dryness under reduced pressure. Suspend the residue in 40 ml DMF.
and 2.9 g (17.6 mmol) pivalic acid 1
-Chloroethyl is added dropwise with good stirring.
After the addition is complete, continue stirring at 40°C for 48 hours. This medium is diluted with 100 ml of water and extracted with chloroform. The organic extracts are dried and evaporated to dryness under reduced pressure. Dilute the residue in 50 ml of ethanol and then add 1.6 g in a minimum volume of the same solvent.
(17.6 mmol) of oxalic acid.
Stir the mixture for 30 minutes and take off the precipitate that forms. Finally, it is recrystallized from ethanol. Thus 4.2 g (9.9 mmol; 60%)
A white crystalline solid is obtained. Melting point: 214℃ (decomposition). IR, NMR, and mass spectra are consistent with the expected structure. Elemental analysis: C H N Calculated (%) 48.2 6.9 3.3 Measured (%) 48.1 7.2 3.2 Butanol/acetic acid/water (5:
In chromatography developed with a 2:3) mixture, the product has an R _f :0.65. Example 11 Methyl 2,2,5-trimethyl-1,4-thiazane-3-carboxylate (hydrochloride) A solution of 32.2 g potassium hydroxide in 640 ml methanol is cooled to 0-5°C. 47.9 g (0.24 mol) of penicillamine methyl ester hydrochloride are added and 25.0 g of chloroacetone are added dropwise. The medium is stirred for 1 hour at the initial PH and brought to PH 6.5 with hydrogen chloride solution in ethanol. and,
Add 6.2 g of sodium borohydride in small portions. After the addition is complete, the mixture is stirred for a further 1 hour at the same temperature. Destroy the excess amount of hydride by adding concentrated hydrochloric acid, and reduce the solution to 10%
Neutralize with concentrated aqueous bicarbonate solution. This aqueous solution is extracted with chloroform. The extract is dried and evaporated to dryness under reduced pressure. The residual oil is dissolved in a mixture of 50 ml methanol and 350 ml ether. Addition of a saturated solution of hydrogen chloride in ether causes precipitation of the solid hydrochloride salt. This is taken and precipitated twice by adding ether to the methanol solution. Weight: 17.2
g (30%). Melting point: 204℃ (decomposed). IR, NMR, and mass spectra are consistent with the expected structure. Elemental analysis: C H N Calculated value (%) 45.1 7.6 5.8 Measured value (%) 45.1 7.7 5.8 Example 12 2,2,4,5-tetramethyl-1,
4-thiazane-3-carboxylic acid 1.68 g (20 mmol) sodium bicarbonate and
1.5 g (0.66 ml; 10.5 mmol) of methyl iodide in turn 2.1 g (10 mmol) in 50 ml of methanol
2,2,5-trimethyl-1,4-thiazane-
3-Add to the carboxylic acid solution. The medium thus obtained is stirred at ambient temperature for 24 hours and heated to reflux temperature for the same time as above. This is evaporated to dryness under reduced pressure and the residue is taken up in 100 ml of water.
The solution thus obtained is transferred to a column of a strong acid type ion exchange resin prepared in the H type. The resin is washed with water until the eluate is neutral and eluted with 1N aqueous ammonia. The eluate is evaporated to dryness under reduced pressure. The white solid that remains is recrystallized from ethyl acetate. Thus 1.4 g (6.8 mmol; 68
%) of pure product. Melting point: 201℃ (decomposed). IR, NMR, and mass spectra are consistent with the predicted structure. Elemental analysis: C H N Calculated (%) 53.2 8.4 6.9 Measured (%) 52.8 8.5 7.0 In chromatography on a thin layer of silica developed with methanol, the product was
R _f : has 0.60. Example 13 5-n-butyl-2,2-dimethyl-
1,4-thiazane-3-carboxylic acid (hydrochloride) 7.5 g (50 mmol) of D-penicillamine was added to 0
Add to 40 ml of water maintained at a temperature between 5°C and 5°C.
Add the following simultaneously dropwise with thorough stirring.
That is, on the one hand, 9.5 g (53 mmol) of 1-
Bromohexan-2-one is added dropwise over a period of about 10 minutes, while 25 ml (50 mmol) of 2N aqueous sodium hydroxide solution are added dropwise over a period of about 30 minutes. Stirring and temperature are maintained for an additional hour after the addition is complete and the temperature is adjusted to about 15°C. 50ml
of methanol and water containing base 9
Slowly add 1.5 g (39 mmol) of sodium borohydride solution in ml. The medium is returned to ambient temperature and extracted with chloroform. The organic extracts are dried and evaporated to dryness under reduced pressure. The residual red oil is taken up in 50 ml of diisopropyl ether and enough ethanol is added to obtain a solution. A solution of hydrogen chloride in ether is then added until precipitation is complete, and enough ethanol is added to transform the reddish-brown mass into a beige solid. This is taken, washed with diisopropyl ether and dissolved in hot ethanol. Add ethyl ether until cloudy
This mixture is then left to cool. collect crystals,
And purify twice. Weight: 8.0 g (30 mmol; 60%). Melting point: 225℃ (decomposition). IR, NMR, and mass spectra are consistent with the expected substance. Elemental analysis: C H N Calculated (%) 49.3 8.3 5.2 Measured (%) 49.5 8.2 5.5 Butanol/acetic acid/water (5:
In chromatography developed with a 2:3) mixture, this product has an R _f :0.62. Example 14 5-methyl-2-phenyl-1,4-
Thiazane-3-carboxylic acid (hydrochloride) 1 g (4.3 mmol) of threo-β-phenylcysteine hydrochloride is dissolved in 12 ml of water. The solution is cooled in an ice bath and the pH is brought to 7.0 with 20% strength aqueous sodium hydroxide solution. Add 0.42 g (4.5 mmol) of freshly redistilled chloroacetone. After keeping the pH constant for 30 minutes, add 2N aqueous sodium hydroxide solution until it becomes neutral. The mixture is stirred for a further hour in the ice bath and a solution of 0.13 g (3.4 mmol) of sodium borohydride in 2 ml of water containing the base is added. In this way, PH
Obtain a colorless and transparent solution of 9.1. Stir this for 1 hour and return to ambient temperature. Adjust the pH to 6.0 with a 37% aqueous hydrochloric acid solution. The mixture is evaporated to dryness under reduced pressure. The residue is suitably dried, taken up in 10 ml of ethanol and a 22% strength hydrogen chloride solution in ethanol is added. The mixture is stirred for 15 minutes and evaporated to dryness under reduced pressure. The residue is recrystallized twice from an isopropanol/ethanol (4:1) mixture. Weight: 0.66 g (2.4 mmol; 56%). Melting point: 248°C (decomposed). IR, NMR, and mass spectra are consistent with the expected structure. Elemental analysis: C H N Calculated value (%) 52.6 5.9 5.1 Measured value (%) 52.3 5.9 5.4 Example 15 1-(R)-oxo-2,2,5-(R)
-trimethyl-1,4-thiazine-3-(S)-
Carboxylic acid (without separation of intermediates) 7.4 g (80 mmol) of freshly distilled chloroacetone are suspended in 10 g (60 mmol) of (D)-penicillamine in 56 ml of water at ambient temperature with good stirring. Add to liquid. After a reaction time of 2 hours, 20% strength aqueous sodium hydroxide solution is added (temperature 20° C.) until the pH is 5.3. A solution of 2 g (50 mmol) of sodium borohydride in 10 ml of water is added dropwise to the reaction medium (temperature 30° C.). After a reaction time of 1 hour, the solution is acidified by adding 50 ml of acetic acid. To this, the reaction medium is cooled (0° C. temperature 5° C.) and 2.4 g (0.74 mol) of 30% strength hydrogen peroxide are added dropwise. The temperature was held between 0°C and 5°C for 8 hours and then for 4 hours.
Keep at 20℃. The mixture is concentrated under reduced pressure. The residue is taken up in 40 ml of ethanol, the suspension is filtered and the ethanolic solution is added to 240 ml of ethyl acetate with good stirring. The product is allowed to crystallize at 20° C. for 1 hour. Collect the precipitate and wash with acetone. The crude amino acid is crystallized from a mixture of H ₂ O/acetone (1:4). This gives 7.4 g (33.3 mmol; 54%) of a white crystalline solid identical to the product of Example 5. Table 1 shows the derivatives of the above examples and other derivatives of the invention prepared according to the method described above.

【table】

【table】

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Table: Example 16 (Pharmacological Tests) A series of pharmacological tests are carried out on the products of this invention. The method is described below. The results of this test are listed in Table 2. In Table 2, the numbers in the first column correspond to the numbers in the first column of Table 1. LD ₅₀ is based on the method of Lichtfield and Wilcoxon (J.Pharmacol.
Exp. Ther. 96 , 99, 1949) and is expressed in mg/Kg. The product is administered orally to mice. The influence on behavior was investigated by S. Ilwin (S.
Irwin) (Gorden Res.Conf.on Medicinal)
Chem., 133 , 1959). The substance suspended in mucilage containing 1% gum tragacanth was administered orally through an intragastric probe to a group of five male mice (CD1 strain, Charles River, deprived of food for 18 hours). do. The dose tested as a factor for the observed effect is 3000-3 mg/Kg. Behavior is observed 2, 4, 6 and 24 hours after administration. If symptoms persist at this point, observation will be extended. The number of deaths will be recorded for 14 days after administration. None of the products tested caused any abnormal behavior in mice and were not toxic.

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Table: Determination of the effect on fibrinolytic activity Bleeding time and blood loss The substance to be tested, suspended in musilizi containing 1% gum tragacanth, is administered orally to rats at a dose of 30 mg/Kg. 1 hour and 3 after administration
Blood samples are taken at time. Plasma is separated by centrifugation and euglobulin is precipitated. Fibrinolytic activity was determined by Astrup and Mullertz (Arch.Biochem.Biophys.1952).
40, 346). Add 50 μl of a solution of euglobulin in veronal buffer containing 0.25% gelatin to the dish containing the fibrin suspension at a concentration of 0.08%. Measure the diameter of the degraded zone after incubating for 18 hours at 37°C. A score is given as a function of the ratio of fibrinolytic activity in treated rats and rats given a placebo.
has the following meaning: Score 4: Increase coefficient of fibrinolytic activity 0.51~
0.99 Score 5: Fibrinolytic activity increase factor 1~
1.5 Score 6: Fibrinolytic activity increase factor 1.6 ~
2 Score 7: Increase coefficient of fibrinolytic activity 2.1~
2.5 Score 8: Fibrinolytic activity increase factor 2.6 ~
3 Score 9: Fibrinolytic activity increase factor 3.1. To measure bleeding time, rat tails kept at ambient temperature for 2 hours are cleaned with ether and 2 mm from the end is cut with a dissecting knife. After processing 1
Bleeding time is measured at the second and third hours and expressed in seconds. Collect the blood on paper. Blood loss is determined by weighing the paper before and after blood is collected. The bleeding time increase factor is the ratio of the bleeding time of treated rats to the bleeding time of rats given a placebo. A score of 3 represents an increase factor of 0.79 to 0.89. A score of 4 represents an increase factor of 0.9 to 1.09. A score of 5 represents an increase factor of 1.1 to 1.11. A score of 6 represents an increase factor of 1.12 to 1.22. A score of 7 represents an increase factor of 1.23 to 1.33. A score of 8 represents an increase factor of 1.34 to 1.44. A score of 9 represents an increase factor of 1.45. The increase factor in blood loss is the ratio of blood loss in treated rats to that in control rats. A score of 3 represents an increase factor of 0.5. A score of 4 represents an increase factor of 0.51 to 0.99. A score of 5 represents an increase factor of 1.0 to 1.5. A score of 6 represents an increase factor of 1.6-2. A score of 7 represents an increase factor of 2.1-2.5. A score of 8 represents an increase factor of 2.6-3. A score of 9 represents an increase factor of 3.1. Two products of this invention were evaluated in more detail. These are derivative 7 and derivative 12 (free base of derivative 7 in hydrated form). Compound 7 was tested for rats and monkeys at 1
A toxicity test was conducted for several months. The results of this study showed that the tolerance was complete up to a dose of 300 mg/Kg/day. The toxicity of compound 12 is outstanding, with an LD ₅₀ of greater than 8 g/Kg in mice and rats. Monkeys are completely tolerant up to 800mg/Kg. When derivative 7 is orally administered to groups of four rabbits at a dose of 2.5-50 mg/Kg, a dose-proportional increase in blood fibrinolytic activity is observed. This increase is due to e.g.
3 times after 90 minutes. This effect also occurs upon repeated administration. That is, 10mg/Kg twice a day.
When administered for 21 days, blood fibrinolytic activity is three times greater than control fibrinolytic activity. When Derivative 12 is administered intravenously at 3-5 mg/Kg/10 minutes for 2 hours, the fibrinolytic activity increases 2.8-fold from 10-30 minutes after the start of administration to at least 3 hours after the end of administration. is observed. The activity of Compound 12 is also observed after oral administration to rats and monkeys. Finally, in humans, oral administration of 100-800 mg results in a dose-proportional increase in blood fibrinolytic activity. The daily dose of the novel compounds of this invention is 5 mg to 2 g for oral administration and 10 mg to 1 g for injection or intravenous administration. The products of this invention can be used in various pharmaceutical forms. The following examples are not meant to be limiting, but relate to pharmaceutical formulations containing the active products of the invention. The active product is designated "A" and is, for example, 1-oxo-2,2,5-
Trimethyl-1,4-thiazane-3-carboxylic acid, 1-oxo-2,2,5-trimethyl-1,
Ethyl 4-thiazane-3-carboxylate, 2,2,
4,5-tetramethyl-1,4-thiazane-3-
Carboxylic acid, 1-(pivaloyloxy)ethyl 1-oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylate, 1-oxo-2,2,
(octyloxycarbonyl)methyl 5-trimethyl-1,4-thiazane-3-carboxylate, 1-(ethoxycarbonyl) 1-oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylate
Ethyl, 5-butyl-2,2-dimethyl-1,4
-thiazane-3-carboxylic acid, 2,2-dimethyl-5-isopropyl-1,4-thiazane-3-carboxylic acid, 5-methyl-2-phenyl-1,4-
Thiazane-3-carboxylic acid or 3-carboxy-
Ethyl 2,2-dimethyl-1,4-thiazane-5-acetate can be used. Example 17 (Formulation example) Coated pills A 50mg StarRX-starch 100mg Microcrystalline cellulose 60mg Crystalline fine lactose 132mg Colloidal silica 2mg Hydrogenated castor oil 6mg A 100mg Dibasic calcium phosphate 95mg Sodium starch glycolate 32.5mg Colloidal Silica 2mg Magnesium stearate 0.5mg Tablet A 500mg Mannitol 95mg Polyvinylpinyridone 27mg Polyethylene glycol 6000 powder 8mg A 300mg Starch 60mg Lactose 130mg Low viscosity ethyl cellulose 20mg Talc 5mg Aerosil 5mg Suppository A 500mg α-Tocopherol 10mg Witepsol H15 (semi-glyceride) 2600mg Injection solution A 20mg Sodium chloride 2.5mg PH with citric acid/sodium citrate buffer
4.8 Add Water for Injection 1ml A 50mg Polyethylene Glycol 300mg Ethyl Alcohol 50mg Add Water for Injection 1ml Coated Pill A containing 100mg Compound A and 300mg Acetylsalicylic Acid 100mg Acetylsalicylic Acid 300mg Ethylcellulose 60mg Lactose 40mg Aerosil 8mg Magnesium Stearate 8mg Tablet A containing 300 mg Compound A and 50 mg Dipyridamole 300 mg Dipyridamol 50 mg Hypromellose 25 mg Starch 100 mg Calcium stearate 8 mg Tablet A containing 200 mg Compound A and 100 mg Suloctidil ) 100mg Tween 80 8mg Ethyl cellulose 22mg Lactose 40mg Starch 71mg Magnesium stearate 9mg