JPH0219115B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel heterocyclic derivatives with action on histamine receptors, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. In the present invention certain novel heterocyclic derivatives have been found that have potent activity as H ₂ antagonists. The gist of the present invention is as set forth in the claims, and will be explained below, including related matters. These compounds, described in more detail below, exhibit, for example, inhibition of gastric secretion when this secretion is stimulated by histamine receptors (Ash and Shild, Brit. J. Pharmacol.
Chemother1966, 27, 427). Their ability to do this was demonstrated using the method described in German Patent Application No. 2734070, using sodium pentobarbitone (50 mg/Kg) as an anesthetic instead of urethane.
in perfused rat stomachs, with some modifications by using
using the method described in 1972 236 385
It can be demonstrated in conscious dogs with Heidenhein microstomis. Furthermore, the compound antagonizes the effect of histamine on the frequency of contractions of the isolated guinea pig right atrium, but does not alter histamine-induced contractions of isolated gastrointestinal smooth muscle mediated by _H1 receptors. Compounds with histamine _H2 blocking activity are used in the treatment of conditions in which it is advantageous to reduce the acidity of gastric juices.
It can be used as a prophylactic measure in surgical procedures, especially in gastric and peptic ulcers, and in the treatment of allergic and inflammatory conditions for which histamine is a known mediating agent. They can thus be used, for example, alone or in combination with other active ingredients, in the treatment of allergic and inflammatory conditions of the skin. The present invention provides a compound represented by the following general formula () and its pharmaceutically suitable salts, hydrates and physiological precursors. In the formula, one of R ₁ and R ₂ represents hydrogen, halogen, or a C _1-4 alkyl group which may be substituted with hydroxy or C _1-4 alkoxy, and the other represents a group
R ₄ R ₅ NAlk−, where R ₄ is hydrogen, C _1-10 alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl,
represents heteroaralkyl, trifluoroalkyl or alkyl substituted with hydroxyl, alkoxy, amino, alkylamino, dialkylamino or cycloalkyl, and R ₅ represents hydrogen or C _1-4 alkyl, or R ₄ and R ₅ together with the nitrogen atom to which they are attached may be saturated or contain at least one double bond, may be unsubstituted or contain one or more C _1-3 alkyl Alk may form a 5- to 10-membered ring which may be substituted with groups, e.g. methyl, or hydroxyl groups, and/or may contain other heteroatoms, e.g. oxygen or sulfur; represents a straight or branched alkylene chain of 1 to 6 atoms, preferably 1 to 4 atoms, R ³ may be in either the 2 or 3 position;
This represents the group -( _CH2 )nXn( _CH2 )mNH-Z, where X represents _-CH2- , -O- or -S-, n represents 0.1 or 2, m represents 2, 3 or 4, and Z is a group

[Formula] or group

[Formula], where Y is S, O, CHNO ₂ or NR ₉ (in the formula,
R ₉ is nitro, cyano, alkylsulfonyl or arylsulfonyl), R ₆ is hydrogen, halogen, alkyl, alkenyl,
represents alkynyl, alkoxyalkyl or aralkyl, R ₇ represents hydrogen, alkyl, alkenyl, aralkyl or C _2-6 alkyl substituted with hydroxyl or alkoxy, R ₈ represents hydrogen, alkyl, alkenyl, aralkyl, hydroxy represents alkyl, acyloxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkyloxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyl or alkoxy, or the group NR ₁₀ R ₁₁ , where R ₁₀ is hydrogen, alkyl, represents alkyl, alkenyl, aralkyl or heteroaralkyl substituted with hydroxyl or C _1-3 alkoxy, and R ₁₁ represents one of the groups defined for R ₁₀ or COR ₁₂ (wherein R ₁₂ represents hydrogen, alkyl, aryl, aralkyl, alkoxy, heteroaryl or heteroaralkyl), or R ₁₁ represents a group SO ₂ R ₁₃ (wherein R ₁₃ represents alkyl or aryl) , or R ₁₁ is a group

(wherein E represents oxygen or sulfur and R ₁₄ represents hydrogen, alkyl, cycloalkyl, aryl or aralkyl), or R ₁₀ and R ₁₁ together represent a group. = CR ₁₅ R ₁₆ (in the formula
R ₁₅ represents aryl or heteroaryl and R ₁₆ represents hydrogen or alkyl), provided that when R ₂ represents the group R ₄ R ₅ NAlk, R ₃ represents 2
and when R ₂ represents hydrogen, R ₃ is in the 3rd position. The term "alkyl" as a group or part of a group means that the group is straight-chain or branched and, unless stated otherwise, has 1 to 6 carbon atoms, especially 1 to 4 carbon atoms; For example, methyl or ethyl, and the terms "alkenyl" and "alkynyl" mean that the group has 3 to 6 carbon atoms. The term "cycloalkyl" means that the group has 3 to 8 carbon atoms. The term "aryl" as a group or part of a group preferably means phenyl or substituted phenyl, e.g. phenyl substituted with one or more C _1-3 alkyl or C _1-3 alkoxy groups or a halogen atom, e.g. fluorine. do. The acyl part of the acylokyalkyl group means aroyl, aralkanoyl or C _1-6 alkanoyl. Examples of acyloxyalkyl groups include acetoxymethyl, formyloxymethyl, benzoyloxymethyl and phenylacetoxymethyl. _R4 and _R8
The term "heteroaryl" as a group or part of a group falling within the meaning of ``heteroaryl'' means a 5- or 6-membered monocyclic unsaturated ring which may contain one or more heteroatoms selected from oxygen, nitrogen or sulfur. , for example furyl, pyridyl, thiazolyl or thienyl. The heterocycle may be unsubstituted or substituted with C _1-3 alkyl, C _1-3 alkoxy, hydroxyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or halogen. The alkyl portion of heteroaralkyl is a straight or branched C _1-4 alkyl chain, and the heteroaryl ring is attached to the alkyl portion via either a carbon or nitrogen atom. The present invention includes compounds of formula () in the form of pharmaceutically suitable salts with inorganic and organic acids. Particularly useful salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, acetates, maleates, succinates, tartrates, citrates,
Includes benzoate and fumarate salts. The compounds of formula () and their salts also form hydrates, and these hydrates also form part of the present invention. Compounds of formula () can exhibit tautomerism, and thus the formula is intended to include all tautomers. When optical isomers exist, the formula is intended to include all diastereomers and enantiomers. As used herein, the term biological precursor refers to a compound of formula () that has a different structure but is converted into a compound of formula () in the body when administered to an animal or human. means a compound that The compounds according to the invention are preferably in salt form and can be formulated for administration in any conventional manner;
The invention thus includes within its scope pharmaceutical compositions containing at least one compound of the invention suitable for use in human or veterinary medicine.
Such compositions can be formulated in conventional manner using one or more pharmaceutically suitable carriers or excipients. Such compositions may also contain other active ingredients, such as H ₁ -antagonists, if desired. Thus, the compounds of the invention may be formulated for oral, buccal, topical, parenteral or rectal administration. Oral administration is preferred. For oral administration, the pharmaceutical compositions may take the form of tablets, capsules, powders, solutions, syrups or suspensions, and are prepared in a conventional manner using suitable excipients. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. The compounds of the invention can be formulated for parenteral administration by injection or continuous perfusion. Formulations for injection may be presented in ampoules or in multi-dose form with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulation agents such as suspending agents, stabilizing and/or dispersing agents. It's okay. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use. The compounds of the invention may also be formulated into rectal compositions such as suppositories or retention enemas, eg, those containing conventional suppository bases such as cocoa butter or other glycerides. For topical administration, the compounds of the invention can be formulated into ointments, creams, gels, lotions, etc. in the conventional manner.
It can be formulated as a powder or spray. For internal administration, a convenient daily dosing regimen for the compounds of the invention will vary depending on the patient's condition, but will be from 2 to 4 times per day for a total of about 5 mg to 2 g, preferably 5 to 500 mg. Groups R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , Y and Alk
Examples of appropriate meanings are as follows. R ₁ or R ₂ (if not the group R ₄ R ₅ NAlk): hydrogen atom, bromine atom or C _1-3 alkyl group (e.g. methyl, ethyl or isopropyl) or C _1-3
or when R ₁ or _{R 2 is} a group R ₄ R ₅ NAlk, R ₄ : alkyl ₍ e.g. methyl , ethyl, propyl, butyl, benzyl, hexyl, heptyl or decyl), C _5-7 cycloalkyl (e.g. cyclobentyl, cyclohexyl or cycloheptyl), alkenyl (e.g. allyl or 3,3-dimethylallyl), aralkyl (e.g. benzyl or phenylalkyl, such as phenethyl),
C _1-4 alkyl substituted with trifluoromethyl group (e.g. 2,2,2-trifluoroethyl), hydroxy C _2-4 alkyl (e.g. 3-hydroxypropyl), C _1-3 alkoxy C _2-4 alkyl (e.g. methoxyethyl or ethoxyethyl), di-C _1-3
alkylaminoalkyl (e.g. dimethylaminoethyl, diethylaminoethyl or dimethylaminopropyl) or heteroaralkyl (where the heterocyclic moiety is e.g. furyl, thienyl,
represents a pyrrolyl, pyridinyl, trianidyl, oxazolyl, triazolyl or thiazolyl ring;
and the alkylene moiety represents a methylene, ethylene or propylene group), and R ₅ : hydrogen or a methyl or ethyl group; or R ₄ R ₅ N may contain one double bond and/or one or a 5- to 8-membered ring which may be substituted with two C _1-3 alkyl groups (e.g. methyl) or hydroxyl groups and/or may contain an oxygen or sulfur atom [e.g.
pyrrolidino, piperidino, hexamethyleneimino, heptamethyleneimino, tetrahydropyridino, 4-hydroxypiperidino, 4-C _1-3 alkylpiperidino (e.g. 4-methylpiperidino),
morpholino, 2,6-di-C _1-3 alkylmorpholino (e.g. 2,6-dimethylmorpholino) or thiamorpholino], R ₆ : hydrogen, C _1-4 alkyl (e.g. methyl or ethyl) or C _{1- 3} alkoxy C _2-4 alkyl (e.g. methoxyethyl); Y: CHNO ₂ or NR ₉ [wherein R ₉ is nitro,
cyano, C _1-4 alkylsulfonyl (e.g. methylsulfonyl) or anylsulfonyl (e.g. phenylsulfonyl)]; R ₇ : hydrogen, C _1-4 alkyl (e.g. methyl, ethyl or propyl) or hydroxy-C _2-4 alkyl (e.g. hydroxyethyl); R ₈ : hydrogen, hydroxy, C _1-4 alkyl (e.g. methyl, ethyl or isobutyl), hydroxy C _1-4 alkyl (e.g. hydroxymethyl, 2-
hydroxyethyl or 1-hydroxy-2-methylethyl) C _1-3 alkoxy C _1-4 alkyl (e.g. methoxymethyl or methoxyethyl), phenyl C _1-3 alkyl (e.g. benzyl or phenethyl), C _2-4 alkanoyloxy C _1-4 alkyl (e.g. acetoxymethyl), amino C _1-4 alkyl (e.g. aminomethyl), amino, C _1-4 alkylamino (e.g. methylamino or ethylamino)
or di-C _1-4 alkylamino (e.g. dimethylamino, diethylamino or dipropylamino), phenyl C _1-3 alkyl (e.g. benzylamino) or heteroaryl C _1-3 alkylamino group [wherein the heteroaryl ring is 5- or 6-membered ring containing one heteroatom (e.g. 3-
or 4-pyridylmethyl); or group
NHCOR ₂ [wherein R ₁₂ is hydrogen, C _1-3 alkyl (e.g. methyl or ethyl), C _1-3 alkoxy (e.g. methoxy or ethoxy), furyl, pyridyl, thienyl, thiazolyl or C _1-3 alkyl (e.g. methyl) or phenyl optionally substituted with a C _1-3 alkoxy (e.g. methoxy) group]; or a group NHSO ₂ R ₁₃ [wherein R ₁₃ is C _1-3 alkyl (e.g. methyl) or C _{1-3 -3} alkyl (e.g. methyl) or a group NHCONHR ₁₄ [wherein R ₁₄ is C _1-3 alkyl ₍ e.g. cyclohexyl)]; or phenyl optionally substituted with C _1-3 alkyl (e.g. methyl), C _5-7 cycloalkyl (e.g. cyclohexyl) or C _1-3 alkyl (e.g. methyl) or C _1-3 alkoxy (e.g. methoxy) groups. ) or the group N=CHR ₁₅ in which R ₁₅ represents a phenyl or pyridyl (eg 3- or 4-pyridyl) group. The group Alk can be, for example, the group (CH ₂ )p, where p is 1, 2 or 3. In particular, the groups R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and Y
has the following meaning. R ₁ or R ₂ (if not the group R ₄ R ₅ NAlk): hydrogen or C _1-4 alkyl (e.g. methyl), R ₄ : C _1-7 alkyl (e.g. methyl, propyl,
butyl, isobutyl or heptyl), C _1-4 alkyl substituted with a trifluoromethyl group (e.g. 2,2,2-trifluoroethyl), C ₂ substituted with a hydroxyl or di-C _1-3 alkylamino group _-4 alkyl (e.g. 3-hydroxypropyl or dimethylaminoethyl), C _5-7 cycloalkyl (e.g. cyclohexyl), alkenyl (e.g. allyl), phenyl C _1-3 -alkyl (e.g. benzyl) or heteroaryl C _1-3 Alkyl group [wherein the heteroaryl ring is 5 or 6 members,
contains one heteroatom (e.g. furylmethyl); R ₅ : hydrogen or methyl; or R ₄ R ₅ N may contain a double bond or an alkyl (e.g. methyl) group; represents a 6-membered ring (e.g. piperidino, 4-methylpiperidino, pyrrolidino, hexamethyleneimino or tetrahydropyridino); _R6 : hydrogen or _C1-3 alkyl (e.g. methyl); Y: _CHNO2 or _NR9 (wherein R ₉ is nitro or methylsulfonyl); R ₇ : hydrogen, methyl, ethyl or 2-hydroxyethyl; R ₈ : hydroxy, phenyl C _1-3 alkyl (e.g. benzyl), hydroxy, C _1-3 alkoxy,
C _1-4 substituted with C _2-4 alkanoyl or amino
Alkyl (e.g. hydroxymethyl, 2-hydroxyethyl, acetoxymethyl or aminomethyl): amino, di-C _1-4 alkylamino (e.g. diethylamino); NHCOR ₁₂ (wherein R ₁₂ is hydrogen,
C _1-3 alkyl (e.g. methyl), C _1-3 alkoxy (e.g. ethoxy) or phenyl];
NHCONHR ₁₄ in which R ₁₄ represents phenyl; or N=CHR ₁₅ in which R ₁₅ represents phenyl or pyridyl (e.g. 4-pyridyl). Alk is in particular a methylene or ethylene group, more particularly methylene When R ₃ is in the 3-position, preferably R ₂ represents hydrogen. When R ₃ is in the 2-position, preferably R ₂ represents alkyl (e.g. methyl). When X is sulfur, n is preferably 1 and m is preferably 2. Three preferred groups of compounds are: (i) R ₃ is in the 3 position and R ₁ is a group R ₄ R ₅ NAlk,
and compounds in which R ₂ is more particularly hydrogen. (ii) R ₃ is in the 2nd position and R ₂ is the group R ₄ R ₅ NAlk
A compound that is (iii) R ₃ is in the 2-position and R ₁ is the group R ₄ R ₅ NAlk;
and R ₂ is more particularly alkyl (e.g. methyl)
A compound that is It is represented by the formula (), where Z is a group

A preferred group of compounds having the formula are those in which Y represents the group CHNO ₂ and R ₆ is more particularly alkyl (eg methyl). It is represented by the formula (), where Z is a group A preferred group of compounds in which R ₇ is hydrogen or methyl and R ₈ is amino, hydroxyalkyl, alkoxyalkyl, benzyl, formamide, alkanoylamino, aminoalkyl, alkanoyloxyalkyl, hydroxy,
It is aroylamino or phenylcarbamoylamino. A particularly preferred group of compounds represented by the formula () is the formula () [In the formula, R ₄ and R ₅ are both methyl groups,
or together with the nitrogen atom to which they are attached form a pyrrolidyl, piperidino or hexamethyleneimino group, and Z is

[Formula] (wherein R ₆ is methyl) or Formula (wherein R ₇ is hydrogen or methyl and R ₈ is amino, hydroxyalkyl, alkoxyalkyl, benzyl, formamide, alkanoylamino, aminoalkyl, alkanoyloxyalkyl, hydroxy, aroylamino or phenylcarbamoylamino) It is one of the following. Particularly preferred are the compounds listed below and their pharmaceutically suitable salts. N-Methyl-N'[2-[[5-(dimethylaminomethyl)-3-thienylmethyl]thio]ethyl]-
2-nitro-1,1-ethenediamine, N-methyl-N'-[2-[[5-(1-pyrrolidinylmethyl-3-thienylmethyl]thio]ethyl]-2-nitro-1,1 -ethenediamine, N-methyl-N'-[2-[[5-(1-piperidinylmethyl)-3-thienylmethyl]thio]ethyl]-2-nitro-1,1-ethenediamine, N- [2-[[5-(dimethylaminomethyl)-4
-Methyl-2-thienylmethyl]thio]ethyl]
-N'-methyl-2-nitro-1,1-ethenediamine, N-[3-[[5-(dimethylaminomethyl)-3
-thienylmethoxy]propyl]-N'-methyl-
2-nitro-1,1-ethenediamine, 1-methyl- ^N5- [2-[[5-[(dimethylamino)methyl]-4-methyl-2-thienylmethyl]
thio]ethyl]-1H-1,2,4-triazole-3,5-diamine, 1-methyl-5-[[2-[[5-(dimethylaminomethyl)-3-thienylmethyl]thio]ethyl]
Amino]1H-1,2,4-triazole-3-
Methanol, 5-[[2-[[[5-(dimethylaminomethyl)-
4-Methyl]-2-thienylmethyl[thio]ethyl]amino]-1-methyl-1H-1,2,4-triazole-3-methanol, 5-[[2-[[5-(dimethylaminomethyl)] -3
-thienylmethyl]thio]ethyl]amino]-3
-Phenylmethyl-1H-1,2,4-triazole, According to one aspect, the present invention is represented by the formula (), in which one of R ₁ and R ₂ represents hydrogen and the other R ₄ R ₅ indicates NAlk, and R ₃ is

Provided are compounds of the formula ##STR1## with the proviso that Y does not represent NR ₉ , where ₉ is alkylsulfonyl or arylsulfonyl. According to another aspect, the present invention is represented by the formula (), in which one of R ₁ and R ₂ is hydrogen, and the other represents R ₄ R ₅ NAlk, and R ₃ is [In the formula, R ₈ is hydrogen, alkyl, alkenyl,
represents aralkyl, hydroxyalkyl, alkoxyalkyl, hydroxy or alkoxy, or R ₈ represents the group NR ₁₀ R ₁₁ , where R ₁₀ is hydrogen, alkyl, hydroxyalkyl,
represents alkenyl or aralkyl, and
R ₁₁ represents hydrogen, alkyl, hydroxyalkyl or the group COR ₁₂ , where R ₁₂ represents hydrogen, alkyl, aryl, aralkyl or alkoxy, or R ₁₀ and R ₁₁ together represent the group =CR ₁₅ R ₁₆ (in the formula,
R ₁₅ represents aryl and R ₁₆ represents hydrogen or alkyl]. According to another aspect, the present invention is represented by the formula (), in which R ₁ is R ₄ R ₅ NAlk, and R ₂ is substituted with halogen or hydroxyl or C _1-4 alkoxy group. is a good C _1-4 alkyl group, and R ₃ is in the 2-position,

Provides a compound having the formula: where R ₄ and R ₅ do not represent alkynyl or heteroaralkyl, and R ₄ R ₅ N does not represent a 9- or 10-membered ring. According to yet another aspect, the present invention provides a compound represented by the formula (), in which R ₁ is R ₄ R ₅ NAlk, and R ₂ is substituted with halogen or hydroxyl or C _1-4 alkoxy. is a good C _1-4 alkyl group,
And R ₃ is in second place, , where R ₄ and R ₅ do not represent alkynyl or heteroaralkyl, and R ₄ R ₅ N does not represent a 9- or 10-membered ring. In the method for producing a compound represented by the formula () shown below, for a specific reaction step, various reactive substituents in the starting material may be protected for the specific reaction, and then the protecting groups may be removed. It will be understood that this may be necessary. Such protection and subsequent deprotection may occur when R ₄ and R ₅ and/or R ₆ are hydrogen, and/or R ₇ is an alkyl group bearing a hydroxyl substituent, and/or R ₈ is hydroxyl or Of particular relevance when it is an alkyl radical with primary or secondary amino substituents. Standard protection and deprotection methods can be employed, such as phthalimide formation and subsequent cleavage by treatment with hydrazine, such as hydrazine hydrate, or a primary amine, such as methylamine. In describing methods that can be used to produce compounds of formula () or intermediates useful in their production, any of R ₁ to R ₁₆ , Alk,
X, Y, Z, E, n and m have the same meanings as in formula () unless otherwise specified. It is represented by the formula (), where Z is a group

[Formula] Compounds are R ₁₇ NH ₂ () amines represented by the general formula where the group R ₁₇
and one of R ₁₈ , the other represents a group R ₆ , and P is a leaving group,
For example, halogen, thioalkyl (preferably thiomethyl) or alkoxy. A compound represented by the formula () is an amine () with the formula () (wherein P has the same meaning as in formula ()). The above reaction can be accomplished in the absence or presence of a solvent such as ethanol, dioxane, acetonitrile, water or aqueous ethanol at temperatures from ambient to reflux. In the absence of a solvent, the reaction can be carried out by heating the reactant mixture at, for example, 100-120°C. It is expressed by the formula (), where Z is (wherein R ₈ is other than an alkoxy or acyloxyalkyl group), or -N=
Compounds exhibiting CR ₁₅ R ₁₆ have the formula () (In the formula, V′ is

or NCN, and Y′ is hydrogen, where V is oxygen or sulfur, and R′ ₈ is the same group as defined in formula () for R ₈ or cyclized indicates a group convertible thereto under the reaction conditions, or indicates halogen or alkoxy, or V′ is NH and Y′ is

It can be produced by reduction of a compound represented by the following formula. In certain embodiments of the above method, the formula ()
In the formula, the group Z is (wherein R ₈ is an amino, hydroxyl or carbon-bonded group) is a compound having the formula () (In the formula, V ₁₁ is a group NON or

It can be conveniently prepared by cyclization of a compound of the formula: and Z' represents two hydrogen atoms. The reaction is carried out in a suitable solvent such as toluene, ethanol,
It can be carried out in the absence or presence of methanol, isopropanol, acetonitrile or water at temperatures from room temperature to reflux temperature. A compound represented by the formula () in which Z' represents a divalent protecting group that can be easily removed to provide two hydrogen atoms, such as a benzylidene group, is treated with an acid,
For example, by treatment with hydrochloric acid, preferably with heating and under conditions such that cyclization to give a compound of formula (
) in which Z' represents two hydrogen atoms may be conveniently produced in situ. When preparing a compound of the formula () in which R ₈ is a hydroxyalkyl group, the hydroxyl group in the intermediate () is in a protected form, for example as an acyloxy derivative such as an alkanoyloxy or an aroyloxy derivative. It is preferable to have one. Protecting groups are usually removed during the cyclization process. It is represented by the formula (), where Alk represents CH ₂ ,
And Z is the base (In the formula, R ₈ is a group other than -N=CR ₁₅ R ₁₆ ) Compounds having the formula () (In the formula, one of R ¹ ₁ and R ¹ ₂ represents a C _{1-4 alkyl group which may be substituted with hydrogen, halogen or hydroxyl or C 1-4 alkoxy} , and the other represents a group -CHO) It can be produced by reducing the intermediate produced by reacting the compound represented by with the reagent R ₄ R ₅ NH. The reaction was carried out using ammonia or the amine R ₄ R ₅ NH as a solvent.
treatment in, for example, tetrahydrofuran or an alcohol (e.g. ethanol or methanol);
Then, for example, by reduction with a hydride reducing agent, such as an alkali metal or alkaline earth metal borohydride (e.g. sodium borohydride) or aluminum hydride or lithium aluminum hydride, or with a metal catalyst, such as palladium or platinum. more achievable. Alternatively, to produce a compound represented by the formula (), in which R ₈ is other than -N=CR ₁₅ R ₁₆ , a compound represented by the formula (), in which R ₄ is hydrogen; can be reacted with the aldehyde R' ₄ -CHO under the reducing conditions described above, where the group R' ₄ is the resulting group
R′ ₄ CH ₂ has the meaning such that it represents a group R ₄ as defined above. This process is particularly applicable to the preparation of compounds of the formula () in which R ₄ is heteroaralkyl or an optionally substituted alkyl chain containing 10 or more carbon atoms. In a particular case, it is expressed by the formula (), where Z
is the basis Compounds exhibiting can be prepared by interconversion of the substituent R ₈ . Therefore, compounds in which R ₈ is an acyloxyalkyl group can be obtained by treating the corresponding hydroxyalkyl compound with a suitable acid, such as acetic acid or benzoic acid, at elevated temperature, e.g.
It can be produced by processing at 80-120°C in the absence or presence of a solvent such as toluene. It is represented by the formula (), in which R ₈ is a group -N=
Compounds exhibiting CR ₁₅ R ₁₆ are represented by the formula (), in which R ₈ is an NH ₂ group, and are combined with an aldehyde or ketone R ₁₅ R ₁₆ CO in a solvent such as benzene, ethanol or methanol. It can be produced by reaction. The reaction is preferably carried out with heating, for example under reflux. It is represented by the formula (), in which R ₈ is a group NR ₁₀ R ₁₁ (in the formula, R ₁₁ is -COR ₁₂ , -SO ₂ R ₁₃ or -C (=E)
NHR ₁₄ ) is represented by the formula () in which R ₈ represents a group -NHR ₁₀ and R ₁ ,
R ₂ , R ₇ and R ₁₀ have the same meaning as in formula () or _are groups easily convertible thereto.
It can be produced by treatment with a reagent that can be substituted for R ₁₁ (wherein R ₁₁ has the same meaning as above). Thus, for example, the reaction is the carboxylic acid R ₁₂ COOH
or reaction with any activated derivative of the sulfonic acid R ₁₃ SO ₃ H, or isocyanate or isothiocyanate R ₁₄ NCE, where R ₁₄ is of the formula ()
any of the meanings defined for R ₁₄ in
However, it contains atoms other than hydrogen, or alkali metal atoms,
for example potassium or sodium, or an alkoxycarbonyl group such as ethoxycarbonyl), in which
R ₁₁ is each group COR ₁₂ , SO ₂ R ₁₃ or C (=E)
A compound is obtained that is NHR ₁₄ : Suitable activated derivatives include acid halides, such as acid chlorides, alkyl chloroformates, acid anhydrides, including mixed anhydrides (for example acetic formate), or esters, such as alkyl chlorides. Includes esters, orthoesters and (1-alkyl-2-pyridinyl)esters. The reaction with the acid halide is preferably carried out in the presence of a base, for example an inorganic base such as sodium hydroxide or an organic base such as triethylamine or pyridine. The reaction with the alkyl chloroformate is preferably carried out in the presence of a base such as potassium carbonate or triethylamine in a solvent such as dimethylformamide. The reaction with the acid anhydride can be carried out in the absence or presence of a solvent such as pyridine. In reaction with isocyanates or isothiocyanates, compounds of formula () in which R ₁₄ is other than hydrogen are conveniently prepared by carrying out the reaction in a solvent such as acetonitrile at elevated temperatures, e.g. under reflux. Ru. A compound of formula () in which R ₁₄ is hydrogen is heated at elevated temperature with a suitable organic isocyanate or isothiocyanate, such as ethyl carbon isothiacyanatidate, and the resulting ester is then treated with a base, e.g. It can be produced by hydrolysis with an ethanolic aqueous solution of sodium hydroxide. A compound represented by formula () can also be represented by formula ()
It can also be produced by treating a compound of the formula in which the group R ₄ R ₅ N is replaced by a quaternary ammonium group (for example a trimethylammonium group) with an amine R ₄ R ₅ NH. The reaction consists of quaternary ammonium compounds in amines (e.g. at 100-120°C)
This can be carried out by heating or the reaction can be carried out under reflux in the presence of a solvent such as an alkanol (eg ethanol). This method is particularly applicable to compounds where Alk is _CH2 . Amines of formula () can be prepared in a number of ways depending on the exact structure of the compound. Therefore, the expression () (wherein n is 1 or 2 and X is oxygen or sulfur) is an amine of the formula () (wherein n is 1 or 2). For example, an amine of the formula (), where n is 1, and (eg cysteamine hydrochloride) in concentrated mineral acid (eg hydrochloric acid). An amine of the formula () in which n is 2 and X is sulfur is of the formula (),
Alcohols in which n is 2 are converted into the corresponding haloalkyl compounds using, for example, thionyl chloride or mesylate by reaction with phosphorus tribromide or methanesulfonyl chloride, and then converted with a suitable aminoalkylthiol (e.g. cysteamine). It can be prepared by treatment in the presence of a base (eg sodium ethoxide) in a solvent such as ethanol. An amine of the formula (), in which n is 1 or 2, and potassium t-butoxide) in a solvent (eg dimethylformamide) followed by addition of a suitable haloalkylamine (eg cyclopropylamine). The alcohol represented by the formula (), like the intermediates (XII) and (XI) below, can be produced by various methods based on the usual methods in thiophene chemistry (Advances in Heterocyclic
Chemistry Volume/1963, page 2-116, Ed.A.
R.Katritzky, Academic Press, London and
NewYork; and Comprehensive Chemistny
Volume 4, page 787, Ed. PGSammes,
Pergamon Press Oxford). Some representative routes and reagents are given in each case. Alcohols of formula () in which R ₁ is a group R ₄ R ₅ NCH ₂ , n is 1, and the hydroxymethyl substituent is in either the 2 or 3 position are those of formula (XI) The compound represented by formula (XII) is treated with the amine R ₄ R ₅ NH under reducing conditions as described above for the production of the compounds of the present invention to obtain thiophenemethanamine represented by formula (XII), which is then , by introducing a hydroxymethyl group at either the 2 or 3 position by reaction with paraformaldehyde in concentrated mineral acids (eg hydrochloric acid) and acetic acid. It is represented by the formula (), where R ₂ is a group R ₄ R ₅ NCH ₂
, n is 1, and an alcohol with a hydroxymethyl substituent in the 2-position has the formula () An amide of formula () can be prepared by reacting a compound of formula () with, for example, oxalyl chloride in a solvent (e.g. benzene) and preferably in the presence of a catalyst (e.g. pyridine), followed by treatment with an amine R ₄ R ₅ NH. obtained, then complex metal hydride,
For example, a compound represented by the following formula () can be obtained by reduction with lithium aluminum hydride in a solvent such as tetrahydrofuran. The 2-hydroxymethyl group then has the formula ()
It is introduced by reacting a compound of the formula with formaldehyde or a precursor of formaldehyde, such as paraformaldehyde, in a concentrated mineral acid, such as hydrochloric acid or acetic acid. It is represented by the formula (), in which R ₁ is a group R ₄ R ₅ NCH ₂
, where R ₂ is hydrogen, n is 1, and the hydroxymethyl substituent is in the 3-position, the alcohol has the formula () It can be produced from thiophene 3-carboxylate represented by the formula (wherein R ₁₉ is an alkyl group). This compound can be prepared by halomethylation, e.g. chloromethylation, using formaldehyde, or a precursor of formaldehyde such as paraformaldehyde, and gaseous hydrogen chloride in the presence of zinc chloride in a solvent such as chloroform. The represented compound is obtained. Then, an amino group R ₄ R ₅ N- is introduced into the compound represented by the formula () by reaction with an amine R ₄ R ₅ NH in a suitable solvent, such as ether, to form a compound represented by the following formula (). A compound is obtained. Introduction of the 3-hydroxymethyl group is accomplished, for example, by reducing the 3-carboxylate using lithium aluminum hydride in a suitable solvent such as an ether. Alcohols represented by the formula (), where n is 2, are represented by the formula () (where Hal is a halogen, e.g. bromine)
A halothiophene represented by is lithiated using n-butyllithium in a suitable solvent (e.g. tetrahydrofuran) at a low temperature (e.g. -78°C),
The desired hydroxyethyl compound (X, n=2) can then be produced by treating the obtained lithio derivative () with ethylene oxide in a solvent such as tetrahydrofuran. In a variant of this method, the group Hal is represented by the formula (), in which R ₁ is a group that can be converted to R ₄ R ₅ NCH ₂ - (e.g. an aldehyde group protected as an acetal), and the group Hal is in the 3-position. By lithiation of the halothiophene in the formula (XI) as described above and treatment with ethylene oxide, A hydroxyethyl compound represented by is obtained. The compound of the invention is then treated with the amine R ₄ R ₅ NH under reducing conditions as described above to prepare the compound of formula (), where R ₁ is a group R ₄ R ₅ NCH ₂ , giving an alcohol in which n is 2 and the hydroxyethyl substituent is in the 3-position. An amine represented by formula () in which X is CH ₂ is represented by formula (XII) from a suitable haloalkylthiophene of the formula (wherein Hal is halogen), which is treated with e.g. potassium phthalimide in a solvent (e.g. dimethylformamide) and then prepared with e.g. hydrazine hydrate to form the phthalimide derivative. It can be produced by deprotection. Haloalkylthiophene represented by formula (XII) is a lithio derivative represented by formula (),
α,ω-dihaloalkane (e.g. Br(CH ₂ ) _o+n+1
Br) in a solvent such as tetrahydrofuran, thus formula (XII)
An intermediate represented by is obtained. Amines represented by the formula () in which X is CH ₂ can also be produced by conventional methods involving homologation of alkyl chains. Therefore, for example, formula (XII) Treatment of a haloalkyl (e.g. chloroethyl)thiophene of the formula with e.g. sodium cyanide in e.g. dioxane gives the corresponding cyanoethyl compound, which is then reduced (e.g. using lithium aluminum hydride in tetrahydrofuran). This gives the corresponding aminopropyl compound. Alternatively, by treating the chloroethyl compound of formula (XII) with a malonic ester, the corresponding butyric acid derivative is obtained after decarboxylation. Treatment of this with eg thionyl chloride followed by ammonia gives the corresponding amine, which is then reduced with eg lithium aluminum hydride to give the corresponding aminobutyl compound. The amine represented by the formula () in which n is O and X is oxygen is a suitable alkoxythiophene (XI) [wherein w is a halogen atom (e.g. chlorine or bromine) or a leaving group (e.g. mesylate)], an amine of the formula () in which X is CH ₂ is prepared from the corresponding haloalkylthiophene. Therefore, it can be manufactured by a method similar to that described above. The alkoxythiophene represented by formula (XI) is preferably obtained by preparing a halo (e.g. bromo)thiophene represented by ( ) with a diol HO(CH ₂ ) nOH in the presence of a base (e.g. sodium hydride) and cuprous oxide. By treatment with the addition of potassium iodide, the formula () Obtain a hydroxyalkoxy compound represented by
It is produced by treating it with, for example, thionyl chloride, phosphorus tribromide or methanesulfonyl chloride, thus obtaining an alkoxythiophene of the formula (). Amines of the formula () in which n is O and ), preferably in protected form, for example as phthalimide, and then cleaving the phthalimide group using, for example, hydrazine hydrate. Compounds represented by formula () and amines represented by formula () in which AIK is an alkylene group other than CH ₂ are derived from the above-mentioned intermediates in which AIK is CH ₂ or a group convertible thereto (for example, an ester group). ,
They can be produced by conventional means of ascending the congener series. Thus, for example, a hydroxymethyl group can be converted to a chloromethyl group, which can then be converted to an aminoethyl or aminopropyl group by a method analogous to that described for amines of the formula () in which X is _CH2 . and then AIK can lead to a group R ₄ R ₅ NAIK containing 2 or 3 methylene groups. Intermediates of formula () and () are obtained from amines of formula () according to British Patent Specification No. 2023133A and European Patent Specification No. 0016565.
It can be produced by a method similar to that described in No. Intermediates of formula () in which the aldehyde group is preferably in protected form (e.g. as an acetal) can be used in suitable intermediates.
The compounds of the present invention can be prepared by the methods described above for preparing the compounds of the invention, except that R ₄ R ₅ NAIK is replaced by a protected aldehyde group (eg, an acetal group). If the product of any of the above methods is a free base and a salt is required, this salt can be formed in conventional manner. Thus, for example, a generally convenient method for forming a salt is to mix appropriate amounts of the free base and acid in a suitable solvent, such as an alcohol such as ethanol or an ester such as ethyl acetate. The present invention is illustrated by, but not limited to, the following Examples and Preparations. In these examples, temperature is expressed in °C and tlc means thin layer chromatography performed on silica using one of the solvent systems listed below, unless otherwise specified. System A: Methanol: 0.88 Ammonia (79:1) System B: Thyl acetate: Isopropanol: Water: 0.88
Ammonia (25:15:8:2) Production example 1 (a) Methyl 5-(dimethylaminomethyl)-3-thiophenecarboxylate Drying of methyl 5-(chloromethyl)-3-thiophenecarboxylate (1.9 g) A diethyl ether (100ml) solution was treated with anhydrous dimethylamine (5ml). After 6 hours, the solvent was removed under vacuum and
The residue was then dissolved in 5M hydrochloric acid (20ml). The aqueous solution was washed with diethyl ether, basified with 5M sodium hydroxide (30ml) and extracted with ether. Evaporation of the ethereal extract gave an oily residue, which was distilled to give the title compound as a colorless oil (1.6 g). Boiling point 120-130℃ 10.5mm. The picrate salt was formed in ethanol and recrystallized from it. Melting point 165℃. The following compounds were similarly prepared from methyl 5-(chloromethyl)-3-thiophenecarboxylate (A) and the corresponding amine. (b) 5- from A (7g) and pyrrolidine (10ml)
Methyl (1-pyrrolidinylmethyl)-3-thiophenecarboxylate (3.3 g) was obtained. Picrate, melting point 122-123°C. (c) A (6g) from piperidine (10ml) to 5-(1-
Methyl piperidinylmethyl)3-thiophenecarboxylate (3.6 g) was obtained. Picrate, melting point 186°C. Production Example 2 (a) 5-(dimethylaminomethyl)-3-thiophenemethanol A solution of methyl 5-(dimethylaminomethyl)-3-thiophenecarboxylate (1.5 g) in diethyl ether (50 ml) was dissolved in sodium aluminum hydride. (0.21g). After 1 hour, water (2
ml) was added and the solution was filtered through diatomaceous earth.
By evaporating the filtrate, an oily residue is obtained,
By distilling this, the title compound was obtained as an oily substance (1.2 g). Boiling point 120℃ 10.1mm. The oxalate salt was formed in ethanol and recrystallized from it. Melting point 107-108℃. The following compounds were similarly prepared from the corresponding esters. (b) From methyl 5-(1-pyrrolidinylmethyl)-3-thiophenecarboxylate (3.2 g) to 5-(1-
pyrrolidinylmethyl)-3-thiophenemethanol (2.4 g) was obtained. Oxalate, melting point 111-112
℃. (c) From methyl 5-(1-piperidinylmethyl)-3-thiophenecarboxylate (3.6 g) to 5-(1-
Piperidinylmethyl)-3-thiophenemethanol (2.9 g) was obtained. Oxalate, melting point 115-117
℃. Production Example 3 Methyl 5-(hydroxymethyl)-3-thiophenecarboxylate 50% acetone aqueous solution (60ml) of methyl 5-(chloromethyl)-3-thiophenecarboxylate (1.7g)
The solution was treated with silver nitrate (1.52g). The precipitate obtained after 2 hours was filtered and the filtrate was evaporated. The residue was extracted with diethyl ether and the ethereal extract was washed with water. An oily substance was obtained by solvent evaporation, which was diluted on silica with ethyl acetate-gas oil at 60-80°C (1:
Chromatography in step 1) gave the title compound as an oil (0.3 g). boiling point
110℃/0.1mm, melting point 38-40℃. Production example 4 5-(hydroxymethyl)-N,N-dimethyl-
3-Thiophenecarboxamide A mixture of methyl 5-(hydroxymethyl)-3-thiophenecarboxylate (3 g); sodium methoxide (0.2 g) and excess anhydrous dimethylamine in dry methanol (20 ml) was heated to ambient temperature. in
Stirred for 24 hours. The solvent was removed under vacuum, water was added and the product was extracted with ethyl acetate. Evaporation of the organic extracts and chromatography of the resulting oily residue on silica using ethyl acetate:light oil (1:1) at 40-60°C gave the title compound (1.3g). IR(CHBr)OH3.595cm, C=
O 1.620cm. Production example 5 4-(dimethylaminomethyl)-2-thiophenemethanol 5-(hydroxymethyl)-N,N-dimethyl-
A solution of 3-thiophenecarboxamide (1.7g) in dry tetrahydrofuran (150ml) was treated with a 0.5M solution of aluminum hydride in tetrahydrofuran (26ml). After 2 hours at room temperature, water (5 ml) was carefully added and the mixture was filtered through diatomaceous earth. Evaporation of the filtrate gave an oily residue, which was
Dissolved in 2M hydrochloric acid (20ml). The aqueous solution was washed with diethyl ether, basified with 5M sodium hydroxide, and extracted with ethyl acetate. Distillation of the organic extract gave the title compound as an oil (1 g). Boiling point 110℃/0.1mm
IR (CHBr ₃ )OH 3585cm ^-1 , Me ₂ NCH ₂ 2775cm
^-1 and 2820cm ^-1 Production Example 6 1-(3-Methyl-2-thienylmethyl)piperidine 3-methyl-2-thiophenecarboxaldehyde (20g), formic acid (6ml) and N-formylpiperidine (44.4ml) The mixture was heated under reflux for 12 hours. Add water (50ml) and 2M hydrochloric acid (30ml),
The aqueous solution was washed with ether. The solution was basified to PH10 with 2M sodium hydroxide (30ml) and extracted with ether. Evaporation of the organic extract gave a brown oil which was distilled to give the title compound as a colorless oil (11.8g). Boiling point 70℃/0.4mm NMR (CDCl ₃ ) 29, d, (1H); 3.27, d,
(1H); 6.48, s, (2H); 7.6, m, (4H); 7.83,
s, (3H); ca8.5, m, (>6H). Production example 7 (a) 5-(dimethylaminomethyl)-4-methyl-
2-Thiophenemethanol N,N-trimethyl-2-thiophenemethanamine (1.5g) in dry tetrahydrofuran (50ml)
The solution was treated with a solution of n-butyllithium (1.6M, 7ml) at room temperature under a nitrogen atmosphere. After 4 hours, gaseous formaldehyde (excess) was added and the mixture
Heated at 40°C for 20 hours. Addition of water (100 ml) and chloroform (100 ml) and evaporation of the organic solution under vacuum gave an oily residue, which was dissolved in ethanol (50 ml) and treated with sodium borohydride (0.1 g).
It was then treated with acetic acid (10ml). The reaction mixture was evaporated to dryness and the residue was dissolved in sodium carbonate solution (8%,
50ml) and extracted with chloroform. Distillation of the organic extract gave the title compound as a colorless oil (0.65g). The oxalate salt, boiling point 120° C./0.1 mm, was formed in a mixture of ethanol and ethyl acetate and recrystallized from it. Melting point 116-117
℃. (b) Similarly, from 1-(3-methyl-2-thienylmethyl)piperidine (3 g) to 4-methyl-5
-(1-piperidinylmethyl)-2-thiophenemethanol was obtained as an oil (2.4 g).
Boiling point 120℃/0.2mm Nmr (CDCl ₃ ) 3.32, s, (1H); 5.32, s,
(2H); 6.48, s, (2H); 7.38, brs, (1H); 7.50−7.7, m, (4H); 7.89, s, (3H); 8.30−
8.80, m, (6H). Production Example 8 (a) 4-[[2-(amino)ethyl]thio]methyl-N,N-dimethyl-2-thiophenemethanamine 5-(dimethylaminomethyl)-3-thiophenemethanol (1 g) and A mixture of 2-aminoethanethiol hydrochloride (0.67g) was stirred in concentrated hydrochloric acid (7ml) at 0°C for 2 hours and then at room temperature for 48 hours. Solid anhydrous sodium carbonate was added and the product was extracted into ethyl acetate. Distillation of the organic extract gave the title compound as a colorless oil (0.75g). boiling point 130
C/0.05 mm, oxalate was formed in ethanol and recrystallized from ethanol and water. Melting point 178-179
℃. The following compounds were similarly prepared from 2-aminoethanethiol hydrochloride (A) and the corresponding thiophene methanol. (b) A (1.5 g) and 5-(1-pyrrolidinylmethyl)-3-thiophenemethanol (2.4 g) to 2-[[4-(1-pyrrolidinylmethyl)-2-thienylmethyl] Thio]ethaneamine (1.4g)
I got it. Oxalate melting point 162-164℃. (c) A (1.6 g) and 5-(1-piperidinylmethyl)-3-thiophenemethanol (2.9 g) to 2-[[4-(1-piperidinylmethyl)-2-thienylmethyl] Thio]ethaneamine (2.2g)
I got it. Oxalate melting point 89-91℃. (d) 5-[[2-aminoethyl]thio]methyl-N, from A (0.65 g) and 4-(dimethylaminomethyl)-2-thiophenemethanol (0.9 g),
N-dimethyl-3-thiophenemethanamine (0.8 g) was obtained. Boiling point 130℃/0.1mm. Oxalate melting point 151-152℃. (e) A (0.6g) and 5-(dimethylaminomethyl)
-4-Methyl-2-thiophenemethanol (0.6 g) to 5-[[2-aminoethyl]thio]
Methyl-N,N,3-trimethylthiophenemethanamine was obtained as a colorless oil (0.69 g). Boiling point 150℃/0.1mm. Oxalate melting point 212°C (decomposed). (f) A (1.11 g) and 4-methyl-5-(1-piperidinylmethyl)-thiophene-2-methanol (2.2 g) to 2-[[4-methyl-5-(1-
piperidinylmethyl)-2-thienylmethyl]-
Thio]ethaneamine as a yellow viscous oil (1.88
g). Boiling point 170℃/0.05mm. (g) A (1.2 g) and 4-(1-pyrrolidinylmethyl)-2-thiophenemethanol (1.7 g) to 2-[[4-(1-pyrrolidinylmetal)-2-thienylmethyl] Thio]ethanamine was obtained. Melting point 165℃/0.02mm oxalate melting point 147-148℃. (h) 5-[[2-(aminoethyl)]thio] from A (1.3 g) and 5-methyl-4-(dimethylaminomethyl)-2-thiophenemethanol (2 g)
Methyl-N,N,2-trimethyl-3-thiophenemethanamine (1.9 g) was obtained. Oxalate melting point 146-147℃. Production Example 9 4-(1-pyrrolidinylmethyl)-2-thiophenemethanol 1-(3-thienylcarbonyl)pyrrolidine 3-thiophenecarboxylic acid (15g), oxalyl chloride (15ml) and pyridine (0.05ml) The mixture in toluene (100ml) was heated to reflux for 2 hours. Excess reagent was removed under vacuum and the toluene solution was added to a solution of dry pyrrolidine (25ml) in dry toluene (100ml). After 2 hours, the reaction mixture was washed with dilute hydrochloric acid, 8% aqueous sodium carbonate solution, saturated brine, and water. The organic solution was dried and evaporated to give the title compound (1.8g) as a white crystalline solid. Melting point 70-73℃. 1-(3-Thienylmethyl)pyrrolidine A solution of 1-(3-thienylcarbonyl)pyrrolidine (12g) in dry diethyl ether (200ml) was added to a slurry of lithium aluminum hydride (2.6g) in dry diethyl ether (100ml).
The mixture was stirred for 1 hour and 5M aqueous sodium hydroxide solution (20ml) was added. The mixture was filtered and the filtrate was distilled to give the title compound (9.8 g) as a colorless oil. Boiling point 120℃/15mm. 4-(1-pyrrolidinylmethyl)-2-thiophenemethanol paraformaldehyde (1.5 g) in concentrated hydrochloric acid (15
ml) and acetic acid (30ml) was treated with 1-(3-thienylmethyl)pyrrolidine (2.7g) and the mixture was stirred for 18 hours at room temperature. Pour the mixture into saturated aqueous sodium carbonate solution,
Extracted with chloroform. The chloroform solution was extracted with dilute hydrochloric acid. The aqueous extract was basified with anhydrous sodium carbonate and extracted with chloroform. The chloroform extract was dried and evaporated to give an oil, which was first diluted with ethyl acetate:ethanol:0.88 ammonia on silica (40:3:2).
The title compound (0.8 g) was obtained as a colorless oil by chromatography using the mixture as eluent and finally purification by distillation.
Boiling point 140℃/0.02mm. Production example 10 5-(dimethylaminomethyl)-3-thiophenemethanol 5-[(dimethylamino)carbonyl]-3-thiophenecarboxylate Methyl 3-thiophenecarboxylate (2.8g) and N,N,dimethyl Carbonyl chloride (2.0ml)
The mixture was treated with stannic chloride for 5 minutes, and the mixture was
Stirred for 20 hours. Chloroform and ice water were added. The organic solution was washed with 8% aqueous sodium carbonate, dried and evaporated to give a viscous oil. The oil was heated to 70°C under vacuum and the residue was then dissolved in methyl acetate. The title compound (1.1 g) was obtained by adding petroleum ether.
was obtained as a crystalline solid. Melting point 51-52℃. 5-
(dimethylaminomethyl)-3-thiophenemethanol A solution of methyl 5-[(dimethylamino)carbonyl]-3-thiophenecarboxylate (0.5 g) in dry diethyl ether (50 ml) was added to lithium aluminum hydride (0.3 g). Dry diethyl ether (100
ml) was added to the slurry. The mixture was stirred at room temperature for 3 hours. Carefully add water and filter the mixture;
The title compound (0.4 g) was obtained by evaporating the filtrate.
was obtained as a colorless oil. Boiling point 120℃/0.1mm.
The oxalate salt was formed in ethanol and then recrystallized. Melting point 107-108℃ Production example 11 5-methyl-4-(dimethylaminomethyl)-2
-thiophenemethanol N,N,3-trimethyl-3-thiophenecarboxamide 2-methyl-3-thiophenecarboxylic acid (2
A mixture of g) and oxalyl chloride (2ml) in dry toluene (20ml) was heated to reflux and treated with pyridine (0.05ml). The reaction mixture was heated to reflux for 1 hour, cooled and then partially evaporated. The residue was added to a solution of dimethylamine in toluene at 0-5°C. After 2 hours water and diethyl ether were added. The organic phase was washed with dilute hydrochloric acid, sodium hydroxide and water, dried and evaporated to give an oil which was distilled to give the title compound (1.4g) as a colorless oil.
Boiling point 100℃/0.1mm N,N,2-trimethyl-3-thiophenemethanamine A solution of N,N,3-trimethyl-3-thiophenecarboxamide (1.3g) in dry diethyl ether (50ml) was dissolved in lithium aluminum hydride. (0.3
g) in dry diethyl ether (100ml) at room temperature. Stir the mixture for 1 hour,
Water was then added. The mixture was filtered and the filtrate was evaporated to give the title compound (0.75g) as a colorless oil. Picrate was formed in ethanol. Melting point 155℃. 5-methyl-4-(dimethylaminomethyl)-2
-Thiophenemethanol N,N,2-trimethyl-3-thiophenemethanamine (6.1g), paraformaldehyde (3.0g)
A mixture of g) in concentrated hydrochloric acid (20ml) and acetic acid (45ml) was stirred at 0-5°C for 1 hour and then at 8°C for 72 hours. The mixture was added to ice-cold saturated sodium carbonate solution. 5M aqueous sodium hydroxide solution was added and the mixture was stirred for 20 hours. The solution was extracted with chloroform and the organic extracts were washed with dilute sodium hydroxide solution and saturated brine, dried and evaporated to give an oil. The residue was distilled to obtain the title compound (6 g) as a pale yellow oil. The oxalate salt, boiling point 120° C./0.1 mm, was formed in ethanol and ethyl acetate. Melting point 129-131℃. Production example 12 3-[5-(dimethylaminomethyl)-3-thiophenemethoxy]propanamine dioxalate 5-(dimethylaminomethyl)-thiophene-3
- methanol (5.2 g) and potassium t-butoxide (3.4 g) in dry dimethylformamide (100 g)
3-chloropropylamine hydrochloride (7.8 g) dissolved in dimethylformamide (10 ml)
solution was added. The mixture was stirred at 20°C for 3 hours. Further potassium t-butoxide (6.8g) was added followed by a solution of 3-chloropropylamine hydrochloride (7.8g) in dimethylformamide (10ml) and the reaction was stirred at 20°C for 18 hours. The mixture was concentrated under vacuum and added to tetrahydrofuran (100ml).
was added, potassium carbonate was added and the mixture was filtered. The filtrate was concentrated and purified by column chromatography on silica using methanol and methanol:ammonia (79:1) to give an oil (2.2 g). Addition of oxalic acid to a solution of the oil in ethanol gave the title compound as a yellowish white solid. Melting point 176-178°C (decomposition). Elemental analysis: Experimental value: C.43.6; H, 5.8; N,
6.6; Theoretical value of C ₁₅ H ₂₄ N ₂ O ₉ S: C, 44.1; H, 5.9;
N, 6.9% Production Example 13 Dimethyldithio-N-phenacylcarbonimidinothioate Potassium carbonate (14.1g) and dimethyldithiocarbonimidinothioate hydroiodide (10.2g)
g) in acetone (150ml).
The mixture was stirred at 20°C for 2 hours. Phenylacetyl chloride (6.8 g) was added dropwise and stirring continued at 20° C. for 17 hours.
The mixture was partially evaporated and diluted with water (300ml),
Extracted with ethyl acetate. Evaporation of the combined organic extracts gave the title compound as a pale green oil (7.9g). Boiling point 160-164℃/0.06mm. Tlc Ethyl Acetate Rf 0.8. Production example 14 4-[3-(amino)propoxy]-N,N-dimethyl-2-thiophenemethanamine 4-bromo-N,N-dimethyl-2-thiophenemethanamine 4-bromo-2-thiophene Carboxaldehyde (4.8g), dry dimethylformamide (4.3ml)
and 98% formic acid (1.4ml) was heated to 120°C for 30 hours. The cooled mixture was poured into water (100ml) and basified with anhydrous sodium carbonate. Dimethyl ether (2x100ml) was added and the ethereal solution was extracted with dilute hydrochloric acid (50ml). The aqueous solution was made basic with anhydrous sodium carbonate and extracted with diethyl ether (200ml). Distillation of the ethereal extract gave the title compound (2.5 g) as a colorless oil. Boiling point 70℃/0.1mm. 3-[5-(Dimethylaminomethyl)-3-thienyloxy]-1-propanol A mixture of 1,3-propanediol (20 ml) and sodium hydride (1 g) was stirred at 80°C for 1 hour. Copper oxide () (1.3g), sodium iodide (0.05g) and 4-bromo-N,N-dimethyl-
Add 2-thiophenemethanamine (5 g),
Heating was continued for 2 days. Add dilute hydrochloric acid (60ml),
The aqueous solution was washed with diethyl ether (50ml), basified with aqueous sodium hydroxide and extracted with chloroform (200ml). Distillation of the organic extract gave the title compound (1.7 g) as a yellowish white waxy substance. Melting point 32-34℃. 3-[5-dimethylaminomethyl)-3-thienyloxy]-1-propanol methanesulfonate hydrochloride 3-[5-(dimethylaminomethyl)-3-thienyloxy]-1-propanol (0.25 g) and A solution of methanesulfonyl chloride (0.1 ml) in dry dichloromethane (10 ml) was stirred at 0-5°C for 1 hour. The mixture was poured into ice-cooled 4% aqueous sodium carbonate solution (50 ml). The solution was extracted with dichloromethane (20ml). Evaporation of the organic extracts gave the title compound (0.05g) as a white solid. Ir (nujiol) 2550, 2450, 1350, 1170 and
1195cm ^-1 Nmr (CDCl ₃ ) base: 3.40, brs (1H);
3.82, d, (1H); 5.62, t, (2H); 5.98, t,
(2H); 6.50, s, (2H); 7.01, s, (3H); 7.75
-7.80,s+m,(8H) 2-[3-[[5-(dimethylaminomethyl)-3
-Thienyloxy]propyl]-(1H)-isoindole 1,3-(2H)dione 3-[5-(dimethylaminomethyl)-3-thienyloxy]-1-propanol methanesulfonate hydrochloride (6 g ) dichloromethane (200ml)
The solution was washed with dilute sodium hydroxide (50ml).
The organic solution was dried (Na ₂ SO ₄ ), filtered and evaporated to give an oil. This oil was dissolved in dry dimethylformamide (100ml) and
Potassium phthalimide (3.7g) was added. The mixture was stirred for 72 hours. Excess liquid was removed under vacuum and the residue was dissolved in diethyl ether (1) and washed with water (2). The ethereal solution was dried (Na ₂ SO ₄ ), filtered and evaporated to give the title compound (4.8g) as an amber oil. Ir(CHBr ₃ ) 2780, 2820, 1770, 1710 cm ^-1 4-[3-(amino)propoxy]-N,N-dimethyl-2-thiophenemethanamine 2-[3-[[5-(dimethylaminomethyl )-3
-Thienyloxy]propyl]-(1H)-isoindole-1,3(2H)-dione (4.6g) was dissolved in a 30% solution of methylamine in ethanol (100ml). The mixture was stirred at room temperature for 4 hours and heated on a steam bath for 2 hours. The solvent was evaporated and the residue was dissolved in dilute hydrochloric acid (20ml). The aqueous solution was basified with anhydrous sodium carbonate and diethyl ether (150 ml)
and extracted with toluene (200ml). The title compound (1.6
g) was obtained as a colorless oil. Boiling point 120℃/
0.06mm. The oxalate salt was formed in ethanol and water and then recrystallized. Melting point 150-152℃. Production example 15 5-[(3-aminopropyl)thio)]-N,N,
3-trimethyl-2-thiophenemethanamine N-[3-[[5-(dimethylamino)methyl-4
-Methyl-2-thienyl]thio]propyl-isoindole-1,3(2H)-dione A solution of N,N,3-trimethyl-2-thiophenemethanamine (6.2 g) in dry tetrahydrofuran (100 ml) was It was treated with a solution of butyllithium in hexane (1.6M, 27.5ml) at 0°C in a nitrogen atmosphere. After 1 hour, sulfur (1.4g) was added. After a further 0.5 hour a solution of N-(3-bromopropyl)-isoindole-1,3(2H)-dione (11.8g) in dry tetrahydrofuran (50ml) was added and the mixture was stirred at room temperature for 18 hours. Water (100ml) was added and the mixture was extracted with ether. Evaporation of the organic extracts gave the title compound as a yellow oil (15.3g). Ir( _CHBr3 )2820, 2775, 1770, 1705, 1392cm
^-1 5-[(3-aminopropyl)thio]-N,N,
3-trimethyl-2-thiophenemethanamine N-[3-[[5-(dimethylamino)methyl-4
-Methyl-2-thienyl]thio]propyl]isoindole-1,3(2H)-dione (15.2g) and hydrazine hydrate (8ml) were stirred in tetrahydrofuran (150ml) at room temperature for 48 hours. The mixture was filtered and the filtrate was distilled to give the title compound as an orange oil (6.9g). Boiling point 160~
170℃/0.04mm. Production example 16 5-[4-[(3-hydroxymethyl-1-methyl-1H-1,2,4-triazol-5-yl)
Amino]butyl]-3-methyl-2-thiophenecarboxaldehyde 2-(3-methyl-2-thienyl)-1,3-dioxolane 3-methyl-2-thiophenecarboxaldehyde (12g), 1, 2-Ethanediol (20 ml) and traces of p-toluenesulfonic acid were heated at reflux in toluene (250 ml) under Dean-Stark conditions for 4 hours. The reaction mixture was cooled, washed with 5% aqueous sodium carbonate solution and water. Evaporation of the toluene solution gave an oil which was distilled to give the title compound as a pale yellow oil (14.5g). Boiling point 95℃/0.1mm. 2-[5-(4-brombutyl)-3-methyl-
2-Thienyl]-1,3-dioxolane A solution of 2-(3-methyl-2-thienyl)-1,3-dioxolane (12.3 g) in dry tetrahydrofuran (150 ml) was added to a hexane solution of n-butyllithium (1.6 M). , 50 ml) at -60°C in a nitrogen atmosphere. After 1 hour, 1,4-dibrobutane (17.3 g) was added and the mixture was heated at -50°C for 3 hours.
It was then stirred at room temperature for 18 hours. Water (75ml) was added and the mixture was extracted with ether. Distillation of the orange extract gave the title compound as a light brown oil (15.1 g). Boiling point 250℃/0.15mm. [[5-(1,3-dioxolan-2-yl)-
4-Methyl-2thienyl]-4-butyl]-isoindole-1,3(2H)-dione 2-[5-(4-bromobutyl)-3-methyl-
2-thienyl]-1,3-dioxolane (13.3g)
and potassium phthalimide (8.9 g) in dry dimethylformamide (130 ml) at 50°C for 4 hours.
It was then stirred at room temperature for 18 hours. Add the mixture to water (1500
ml) and extracted with ether. Evaporation of the organic extracts gave the title compound as a pale yellow oil (16.1g). Ir( _CHBr3 ) 1770, 1710, 1395, 1070, 1033,
720cm ^-1 4-[5-(1,3-dioxolan-2-yl)
-4-Methyl-2-thienyl]-butanamine N-[[5-(1,3-dioxysolan-2-yl)-4-methyl-2-thienyl]-4-butyl]
-isoindole-1,3(2H)-dione (16.1
g) and hydrazine hydrate (8 ml) were stirred in tetrahydrofuran (150 ml) at room temperature for 24 hours.
The mixture was filtered and the filtrate was distilled to give the title compound as a reddish brown oil (5.34g).
Boiling point 230℃/0.1mm. 5-[4-[(3-hydroxymethyl-1-methyl-1H-1,2,4-triazol-5-yl)
Amino]butyl]-3-methyl-2-thiophenecarboxaldehyde 4-[5-(1,3-dioxolan-2-yl)
-4-Methyl-2-thienyl]butanamine (2.73 g) and methyl N-[2-(acetoxy)acetyl]-1-methyl-2-(phenylmethylene)
Hydrazine carboximidothioate (3.38g)
The mixture was heated to 60°C for 2 hours. Toluene (20
ml) and 5N hydrochloric acid (12ml) were added and the mixture was stirred at room temperature for 18 hours. The mixture was basified to PH8, washed with toluene, basified to PH10 and extracted with ethyl acetate. Evaporation of the extract gave an oil which was purified by column chromatography on silica using 3:1 ethyl acetate:methanol as eluent to give the title compound as a pale yellow solid (0.6 g). Obtained. Melting point: 118-121°C (softens) Example 1 (a) N-methyl-N-[2-[[5-dimethylaminomethyl)-3-thienylmethyl)thio]ethyl]-2-nitro-1,1 -ethenediamine 4-[[2-(amino)ethyl]thio]methyl-N,N-dimethyl-2-thiophenemethanamine (0.35 g) and N-methyl-1-(methylthio)-2-nitroethanamine (0.23g) in water (5ml) was stirred at room temperature for 24 hours. The obtained precipitate was collected by filtration and recrystallized from methanol and water to obtain the title compound as a yellowish white solid (0.27 g). Melting point 143℃. Elemental analysis Experimental value: C, 47.3; H, 6.7; N, 16.8
Theoretical values for % C ₁₃ H ₂₂ N ₄ O ₂ S ₂ : C, 47.3; H, 6.7; N, 17.0% From N-methyl-1-(methylthio)-2-nitroethanamine (A) and the appropriate diamine. The following compounds were similarly prepared. (b) A (0.45 g) and 2-[[4-(1-pyrrolidinylmethyl)-2-thienylmethyl]thio]ethanamine (0.75 g) to N-methyl-N'-[2
-[[5-(1-pyrrolidinylmethyl)-3-thienylmethyl]thio]ethyl]-2-nitro-1,
1-ethenediamine (0.72g) was obtained. melting point
128-130℃ Elemental analysis Experimental value: C, 50.4; H, 6.7; N, 15.15; Theoretical value of C ₁₅ H ₂₄ N ₄ O ₂ S ₂ : C, 50.5; H, 6.8; N, 15.7% (c) A (0.23 g) and 5-[[2-(amino)ethyl]thio]methyl-N,N-dimethyl-3-thiophenemethanamine (0.35 g) to N-methyl-N-[2-[[4 -(dimethylaminomethyl)
-2-Thienyl]thio]ethyl]-2-nitro-1,1-ethenediamine carbonate was obtained as a white solid (0.2g). Melting point 99-100℃ Elemental analysis Experimental value: C, 44.93; H, 64.6; N, 15.45 C ₁₃ H ₂₂ N ₄ O ₂ S ₂ 1/2 H ₂ CO ₃ theoretical value: C, 44.85; H, 6.41; N, 15,50% (d) N-methyl-N'- from A (0.28 g) and 2-[[5-(1-piperidinylmethyl)-3-thienylmethyl]thio]ethanamine (0.5 g) [2-
[[5-(1-piperidinylmethyl)-3-thienylmethyl]thio]ethyl]-2-nilo-1,1
-Ethanediamine was obtained as a white solid (0.4g). Melting point 101-103℃ Elemental analysis Experimental value: C, 51.93; H, 7.03; N, 15.09 Theoretical value of C ₁₆ H ₂₆ N ₄ O ₂ S ₂ : C, 51.87; H, 7.02; N, 15.13% (e) A (0.2 g) and 5-[[[2-(amino)ethyl]thio]methyl]-N,N,3-trimethylthiophenemethanamine (0.3 g) to N-[2
-[[5-dimethylaminomethyl)-4-methyl-2-thienylmethyl]thio]ethyl]N'methyl-2-nitro-1,1-ethanediamine (column chromatography on silica using methanol as eluent) (purified by E.) was obtained as a white solid (0.38 g). Melting point 82-83℃ Elemental analysis Experimental value: C, 48.6; H, 7.0; N, 15.9 Theoretical value of C ₁₄ H ₂₄ O ₂ S ₂ : C, 48.8; H, 7.0; N, 16.3% (f) A( 0.27 g) and 2-[[4-methyl-5-(1
-piperidinylmethyl)-2-thienylmethyl]
Thio]ethanamine (0.5 g) to N-methyl-N'-[2-[[4-methyl-5-(1-piperidinylmethyl)-2-thienylmethyl]thio]
Ethyl]-2-nitro-1,1-ethenediamine was obtained as a white solid and recrystallized from methyl acetate-gas oil, bp 60-80°C (1:3). (0.1
g) Melting point 81℃ Elemental analysis Experimental value: C, 53.11; H, 7.38; N, 14.52 Theoretical value of C ₁₇ H ₂₈ N ₄ O ₂ S ₂ : C, 53.11; H, 7.34; N, 14.58% (g) A (0.25 g) and -2-[[4-(1-pyrrolidinylmethyl)-2-thienylmethyl]thio]ethanamine (0.4 g) to N-methyl-N'-[2
-[[4-(1-pyrrolidinylmethyl)-2-thienylmethyl]thio]ethyl]-2-nitro-1,
1-ethenediamine was obtained as a white solid (0.25g). Melting point 109-111℃ Elemental analysis Experimental value: C, 50.25; H, 6.75; N, 15.4 Theoretical value of C ₁₅ H ₂₄ N ₄ O _{2 S} 2: C, 50.55; H, 6.8; N, 15.7% (h) A (0.26 g) and 5-[[2-(amino)ethyl]thio]methyl-N,N,2-trimethyl-
3-thiophenemethanamine (0.4g) to N
-Methyl-N'-2-[[4-(dimethylaminomethyl)-5-methyl-2-thienylmethyl]thio]ethyl]-2-nitro]-1,1-ethenediamine as a white solid (0.25g) obtained as. melting point
100-101℃ Elemental analysis Experimental value: C, 48.65; H, 6.85; N, 16.10 Theoretical value of C ₁₄ H ₂₄ N ₄ O _{2 S 2} : C, 48.80; H, 7.0; N, 16.25% (i) A (0.27 g) and 3-[5-(dimethylaminomethyl)-3-thiophenemethoxy]propanamine (0.4 g) to N-[2-[[-5(dimethylaminomethyl)-3-thienylmethoxy]propyl ]-N'-methyl-2-nitro-1,1-
Ethendiamine (0.42 g) was obtained as a pale orange oil. Tlc-based B Rf 0.43 NMR (CDCl ₃ ) 0.0, br, (1H); 3.9, br,
(1H); 2.88, s, (1H); 3.12, s, (1H); 3.45,
s, (1H); 5.59, s, (2H); 6.3, m, (2H);
6.43, s, (2H); 6.7, m, (2H); 7.40, d,
(3H); 7.75, S, (6H); 8.08, m, (2H). (j) A (0.35 g) and 4-[3-(amino)propoxy]-N,N-dimethyl-2-thiophenemethanamine (0.5 g) to N-[3-[5-(dimethylaminomethyl- 3-Thienyloxy]propyl]-N'-methyl-2-nitro-1,1-ethenediamine (0.35 g) was obtained, which was purified by column chromatography and crystallized from methyl acetate. Melting point: 113°C. NMR−0.0, brs, (1H); 3.40, brs (CDCl ₃ )
(3H); 3.82, d, (1H); 6.00, t, (2H); 6.50
−6.55, s+brs, (4H); 7.1, brs, (3H); 7.75
−7.9, s+m, (8H). (k) A (0.4g) and 5-[(3-aminopropyl))
thio]-N,N,3-trimethyl-2-thiophenemethanamine to N-[3-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]thio]propyl]-N'-methyl -2-Nitro-1,1-ethenediamine was obtained which was purified by column chromatography to give a light brown oil (0.353g). NMR-0.25br.s (1H); 3.18,s, ( _CDCl3 )
(1H);3.4,br,s,(1H);Overlaps the previous one
3.4, s, (1H); 6.53s, (2H); 6.55, q,
(2H); 7.1, m, (3H); 7.18, t, (2H); 7.72,
s, (6H); 7.9, s, (3H); 8.05m, (2H). Elemental analysis Experimental values: C, 48.8; H, 7.0; N, 16.2 Theoretical values of C ₁₄ H ₂₄ N ₄ O ₂ S ₂ : C, 48.8; H, 7.1; N, 15.8% Example 2 (a) N ⁵ -[2-[[5-(dimethylaminomethyl)-
3-thienylmethyl]thio]ethyl]-1-methyl-1H-1,2,4-triazole-3,5
-diamine 4-[[2-(amine)ethyl]thio]methyl-,
N,N-dimethyl-2-thiophenemethanamine (0.375 g) and methyl N-cyano-1-methyl-
A mixture of 2-(phenylmethylene)hydrazine carboxide thioate (0.35 g) was heated at 60°C under vacuum.
It was heated for 1 hour. The resulting oil was dissolved in toluene (30ml) and 2M hydrochloric acid (2ml) was added. After 3 hours at room temperature, 8% aqueous sodium bicarbonate solution (20 ml) was added and the resulting aqueous solution was washed with toluene. The aqueous solution was further basified with 5M sodium hydroxide (30ml) and the product extracted with ethyl acetate. Evaporation of the organic solution gave the title compound as an amber oil (0.3g). NMR (CDCl ₃ ) 3.0, s, (1H); 3.1, s,
(1H); 5.6, t, (1H); 6.0, brs, (2H); 6.4,
s, (2H)6.5, s, (2H); 6.6, s+q,
(5H); 7.4, t, (2H); 7.8, t (6H). Tlc System A Rf 0.5 The following compounds were similarly prepared from methyl N-cyano-1-methyl-2-(phenylmethylene)hydrazinecarboximidothioate (A) and the appropriate diamine. (b) N 5 -[2 from A (0.42 g) and ⁵ -[[2-(amino)ethyl]thio]methyl-N,N-dimethyl-3-thiophenemethanamine (0.4 g)
-[[4-(dimethylaminomethyl-2-thienylmethyl]thio]ethyl]-1-methyl-1H-
1,2,4-triazole-3,5-diamine (0.3g) was obtained. Elemental analysis Experimental value: C, 45.3; H, 7.1; N, 24.1 Theoretical value of C ₁₃ H ₂₂ N ₆ S ₂ H ₂ O: C, 45, 4; H, 7.0; N, 24.4% NMR (CDCl ₃ ) 2.98, 2s (2H); 5.4−5.9, br,
(3H); 6.13, s, (2H); 6.55, 6.61, 2s+m,
(7H); 7.28, b, (2H); 7.7, s, (6H). (c) From A (0.43 g) and 2-[[4-((1-pyrrolidinylmethyl)-2-thienylmethyl]thio]ethanamine ( ^0.45 g)
(1-pyrrolidinylmethyl)-3-thienylmethyl]thio]ethyl-1-methyl-1H-1,2,
4-triazole-3,5-diamine was obtained as an amber gum (0.4 g). Elemental analysis Experimental values: C, 49.79; H, 6.81; N, 22.83 Theoretical values of C ₁₅ H ₂₄ N ₆ S ₂ H ₂ O: C, 49.82; H, 6.97; N, 23.24% NMR (CDCl ₃ ) 3.0− 3.1, 2s, (2H); 5.6, brt,
(1H); 6.05, br, 2H); 6.23, s, (2H); 6.33,
s, (2H); 6.52, s+m, (5H); 7.31, t,
(2H); 7.4, m, 4H); 8.25, m, (4H). (d) A (0.3 g) and 5-[[2-(amino)ethyl]
thio]methyl]-N,N-3-trimethyl-2
-1- from thiophenemethanamine (0.3g)
Methyl-N ⁵ -[2-[[5-[(dimethylamine)
Methyl]-4-methyl-2-thienylmethyl]
Thio]ethyl]-1H-1,2,4-triazole-3,5-dian was obtained as an amber gum (0.15 g). Tlc-based A Rf 0.5 Nmr (CDCl ₃ ) 3,4,s, (1H); 5.7-6.1,
t+brs+s, (5H); 6.5-6.6, s+s+m,
(7H); 7.2, m, (2H); 7.8, s, (6H); 7.9,
s, (3H). Example 3 N-[[[2-[[5-(dimethylaminomethyl)-
3-Thienylmethyl [thio]ethyl]amino]
(Methylamino)methylene]methanesulfonamide 4-[[2-(amino)ethyl]thio]methyl-
N,N-dimethyl-2-thiophenemethanamine (0.4g) and S,S'-dimethyl-N-(methylsulfonyl)-dithio-carbonimide acid (0.35g)
in ethanol (10 ml) for 1 hour.
heated to ℃. A 33% solution of methylamine in methanol (10ml) was added and the mixture was stirred for 20 hours.
The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica using methanol to give the title compound (0.5g) as an amber gum. Elemental analysis Experimental values: C, 41.0; H, 6.6; N, 14.7 Theoretical values of C ₁₃ H ₂₄ N ₄ O ₂ S ₃ : C, 40.8; H, 6.9; N, 14.5% Nmr (CDCl ₃ ); 2.9, s, (1H); 3.09, s,
(1H); 3.25, brs, (1H); 4.30, brs, (1H);
6.28, s, (2H); 6.39, s, (2H); 6.61, q,
(6.61); 7.08, s, (3H); 7.16, d, (3H);
7.36, t, (2H); 7.73, s, (6H). Example 4 N ₁₁ -cyano-N-[2-[[5-[(dimethylamino)methyl]-4-methyl-2-thienylmethyl]thio]ethyl]-N ¹ -methylguanidine 5-[[2- (amine)ethyl]thio]methyl-
N,N,3-trimethylthiophenemethanamine (0.5g) and methyl N-cyano-N'-methylcarbonimidothioate (0.27g) were heated to 110-130°C under vacuum for 7 hours. The resulting mixture was purified by column chromatography using methanol on silica to obtain the title compound as a brown oil (0.35 g). Tlc system A Rf 0.52 Nmr (CDCl ₃ ) 3.57, s, (1H); 4.16, br,
q, (1H); 4.55, br, t, (1H);. 6.17,s,
(2H); 6.52; s, (2H); 6.63, q, (2H); 7.17,
s, (3H); 7, 30, t, (2H); 7.75, s,
(6H); 7.9, s, (3H). Example 5 (a) 1-Methyl-5-[[2-[[[5-(dimethylaminomethyl)-3-thienylmethyl]thio]ethyl]amino]-1H-1,2,4-triazole-3- Methanol dihydrochloride 4-[[2-(amino)ethyl]thio]methyl-N,N-dimethyl-2-thiophenemethanamine (0.4 g) and methyl N-[2-(acetoxy)acetyl]-1
A mixture of -methyl-2-(phenylmethylene)-hydrazinecarboximidothioate (0.56g) was heated to 60°C for 1 hour. Toluene (25ml)
and dilute hydrochloric acid (3ml) were added and the mixture was stirred at room temperature for 3 hours and then heated on a steam bath for 30 minutes. Anhydrous sodium bicarbonate was added and the mixture was washed with toluene. The aqueous solution was basified with sodium hydroxide and extracted with ethyl acetate. The ethyl acetate extract was dried [Na ₂ SO ₄ ], filtered and evaporated to give an oil which was purified by column chromatography using methanol on silica to give a gum. . This gummy substance is mixed with methyl acetate (10
ml) and 8% ethereal hydrogen chloride (5 ml).
ml). The title compound (0.2 g) was obtained by crystallizing the resulting solid from methanol.
was obtained as white needle-like crystals. Melting point 182-184℃ Nmr (D ₂ O); 2.50, 2.66, 2xm, (2H);
5.35, s, (2H); 5.50, s, (2H); 6.19, s,
(2H);5.50,s,(2H),6.19,s,(2H);6,
38-6.42, s+t, (5H); 7, 11-7, 20, s
+t, (8H). Methyl N-[2-(acetoxy)alkyl]-
The following compounds were similarly prepared from 1-methyl-2-(phenylmethylene)hydrazinecarboximidothioate [B] and the appropriate diamine. (b) 5- from [B] (1.01 g) and 2-[[5-(dimethylaminomethyl)-4-methyl]-2-thienylmethyl]thio]ethanamine (0.8 g)
[[2-[[[5-(dimethylaminomethyl)-4-
methyl]-2-thienylmethyl]thio]ethyl]
Amino]-1-methyl-1H-1,2,4-triazole-3-methanol (0.73 g) was obtained as a pale yellow oil. Nmr (CDCl ₃ ) 3.36, s, (1H); 5.45, s+t,
(3H); 6.18, s, (2H); 6.46, s+m, (8H);
7.16, t, (2H); 7.72, s, (6H) 7.88, s,
(3H). The free base was converted to its citrate salt in dry methyl acetate. Melting point 45-50℃ (softens) Elemental analysis Experimental value: C, 44.3; H, 6.1; N, 11.5 Theoretical value of C ₁₇ H ₂₅ N ₅ OS ₂ C ₆ H ₈ O ₇ H ₂ O: C, 44.6; H, 6.2; N, 11.4% (c) 1-methyl from [B] (0.62 g) and 2-[[4-(1-pyrrolidinylmethyl]-2-thienylmethyl]thioethanamine (0.51 g) -5-
[[2-[[[4-(1-pyrrolidinylmethyl)]-2
-thienylmethyl]thio]ethyl]amino]-
1H,1,2,4-triazole-3-methanol (0.24 g) was obtained as a pale yellow gum. Elemental analysis Experimental values: C, 51.9; H, 6.9; N, 18.4 C ₁₆ H ₂₅ N ₅ OS ₂ 0.25 Theoretical values of H ₂ O: C, 51.65; H, 6.91; N, 18.83% Nmr (CDCl ₃ ) 3.05 ,br,s,(2H);5,30,
t, (1H); 5.52, s, (2H); 6.20, s, (2H);
6.55, m, (7H); 7,32,t, (2H); 7.55, m,
(4H); 8,30,m, (4H). (d) 1- from [B] (0.70 g) and 2-[[[4-(dimethylaminomethyl)-5-methyl]-2-thienylmethyl]thio]ethanamine (0.5 g)
Methyl-5-[[2-[[[[4-(dimethylaminomethyl)-5-methyl]-2-thienylmethyl]thio]ethyl]amino]-1H-1,2,4-triazole-3-methanol ( 0.22 g) as a brown gummy substance. Elemental analysis Experimental values: C, 50.3; H, 7.1; N, 20.2 Theoretical values of C ₁₅ H ₂₅ N ₅ OS ₂ : C, 50.7; H, 7.1; N, 19.7% Nmr (CDCl ₃ ) 3.13, s, ( 1H); 5.25−5.50,
br, t, s, br, s (4H); 6.23, s, (2H);
6.50−6.72, s, q,, s, (7H); 7.30, t,
(2H); 7.70−7.78, 2, xs, (9H) (e) From [B] (1.01 g) and 3-[[5(dimethylaminomethyl)]-3-thienylmethoxy]propanamine (0.75 g) 5-[[3-[[5-(dimethylaminomethyl)]-3-thienylmethoxy]
Propyl]amino]-1H-1,2,4-triazole-3-methanol (0.4 g) was obtained as a pale yellow oil. Tlc system B Rf 0.54 Elemental analysis Experimental value: C, 50.4; H, 7.3; N, 19.1 C ₁₅ H ₂₅ N ₅ O ₂ S./H ₂ O theoretical value: C, 50.4; H, 7.6; N, 19.6 % (f) [B] (492 mg) and 2-[[[5-(1-piperidinylmethyl)]-3-thienylmethyl]thio]
Ethylamine (417g) to 1-methyl-5-
[[2-[[[5-(1-piperidinylmethyl)]-3
-thienylmethyl]thio]ethyl]amino]-
1H-1,2,4-triazole-3-methanol (500 mg) was obtained as a pale yellow gum. Tlc1:1 ethyl acetate-methanol, Rf0.3N.
mr (CDCl ₃ ) 3.02, pd, (1H); 3,12d,
(1H); 5.46, s, (2H); 5.5, s, (1H); 6.0,
br, s, (1H) 6.36, s, (2H); 6.4, s,
(2H), 6.5, s, (3H); 6.5, q, (2H); 7.3,
t, (2H); 7.6, m, (4H); 8.5, m, (6H). (g) [B] (0.57 g) and 2-[[4-methyl-[5
-(1-piperidinylmethyl)]-2-thienylmethyl]thio]ethanamine (0.50g) to 1
-Methyl-5-[[2-[[[4-methyl-5-(1
-piperidinylmethyl)]-2-thienylmethyl]thio]ethyl]amino]-1H-1,2,4
-Triazole-3-methanol (0.12g) was obtained as a cream colored solid. Melting point 55℃ Nmr (CDCl ₃ ) 3.4s, (1H); 5.47−55.8, t&
s, (3H); 6.2, s, (2H); 6.48−6.8, 2xs,
q, s, (8H); 7.2, m, (2H); 7.6, m,
(4H); 7.9, s, (3H); 8.5, m, (6H). (h) [B] (0.75 g) and 4-[3-(amino)propoxy]-N,N-dimethyl-2-thiophenemethanamine (0.5 g) to 5-[3-[[5-
[(dimethylamino)methyl]-3-thienyloxy]propyl]amino]-1-methyl-1H-
1,2,4-triazole-3-methanol (0.2g) was obtained. Melting point 99-100℃. Tlc system B Rf 0.55 (i) [B] (0.9059 g) and 5-[(3-aminopropyl)thio]-N,N,3-trimethyl-2
-5- from thiophenemethanamine (0.72g)
[3-[[5-[(dimethylamino)methyl]-4-
Methyl-2-thienyl]thio]propyl]amino-1-methyl-1H-1,2,4-triazole-3-methanol (0.35 g) was obtained as a pale yellow oil. Tlc system B Rf 0.6 Nmr (CDCl ₃ ): 3.18, s, (1H); 5.45, s,
(2H); 5.60, s+brt (2H); 6.50, s, (3H);
6.52, q, (2H); 6.54, s, (2H); 7.19, t,
(2H): 7.75, s, (6H); 7.90, s, (3H); 8.10,
m, (2H). Example 6 (a) 5-[[2-[[5-(dimethylaminomethyl)
−
3-Thienyl]methyl]thio]amino-3-phenylmethyl-1H-1,2,4triazole 4-[[2] -(amino)ethyl]
A mixture of thio]methyl-N,N-dimethyl-2-thiophenemethanamine (1.13g) and tetrahydrofuran (10ml) was added and the reaction mixture was stirred at 20°C for 5 hours. Hydrazine hydrate (2.5g) was added and the mixture was stirred at 20°C overnight. After adding 2N hydrochloric acid (10ml) and stirring at 20°C for 3 hours, the acidic layer was basified with potassium carbonate and extracted with ethyl acetate. The title compound (0.2 g) was obtained by evaporating the ethyl acetate extract and purifying the residual oil by column chromatography using chloroform on silica and then chloroform:methanol (19:1) in ethyl acetate and a light oil (boiling point 60 ~80
It was obtained as a white solid with a melting point of 113°C after recrystallization from a mixture of Elemental analysis Experimental values: C, 58.6; H, 6.5; N, 17.9 Theoretical values of C ₁₉ H ₂₅ N ₅ S ₂ : C, 58.9; H, 6.5; N, 18.1% (b) Similarly, 5-[[ 2-(amino)ethyl]thio]
Methyl-N,N,3-trimethyl-2-thiophenemethanamine (1.0g), dimethyldithio-
5- from N-phenacyl carbonimidinothioate (0.98 g) and hydrazine (2.1 g)
[[2-[[[5-(dimethylaminomethyl)-4-
Methyl-2-thienyl]methyl]thio]ethyl]amino]-3-phenylmethyl-1H-1,
2,4-triazole (0.2g) was obtained as a white solid. Melting point 116-117℃ (decomposition) Elemental analysis Experimental value: C, 59.7; H, 6.9 N, 17.2 Theoretical value of C ₂₀ H ₂₇ N ₅ S ₂ : C, 59.8; H, 6.8; N, 17.4% Example 7 (a) N-[5-[[2-[[[5-[(dimethylamino)]
methyl]-4-methyl-2-thienyl]methyl
thio]ethyl]amino]-1-methyl-1H-
1,2,4-triazol-3-yl]acetamide N ₅ -[2-[[[[5-[(dimethylamino)methyl]
-4-methyl]-2-thienyl]methyl]thio]
A solution of methyl]-1-methyl-1H-1,2,4-triazole-3,5-diamine (1.56 g) and acetic anhydride (0.52 g) in pyridine (20 ml) at room temperature
Stir for hours. The solution was evaporated to dryness under vacuum and the residual yellow gum was dissolved in water (60ml). The solution was extracted with ethyl acetate and then anhydrous sodium carbonate (3g) was added to the aqueous fraction. The solution was extracted with ethyl acetate (3x50ml). The title compound (1.17g) was obtained by evaporating the organic extract under vacuum.
was obtained as a yellow gummy substance. Elemental analysis Experimental values: C, 50.0; H, 6.9; N, 21.7; S, 16.8; Theoretical values of C ₁₆ H ₂₆ N ₆ OS ₂ : C, 50.2; H, 6.9; N, 22.0; S, 16.8% Nmr (CDCl ₃ ) 1.0, br, (1H); 3.4, s,
(1H); 5.2, t, (1H); 6.2, s, (2H); 6.5,
s, 6.55, s, ca, 6.5, s, (7H); 7.27, t,
(2H); 7.75, m, 7.9, s, (12H). (b) 5-[2-[[5-[(dimethylamino)methyl]-3-thienylmethyl]
Thio]ethyl]-1-methyl-1H-1,2,4
-triazole-3,5-diamine (1.15g)
and acetic anhydride (0.35 ml) to N-[5-[[2-
[[5-[(dimethylamino)methyl]-3-thienylmethyl]thio]ethyl]amino-1-methyl-1H-1,2,4-triazol-3-yl]acetamide was dissolved in a yellow foam (1.1 g ) was obtained. Tc system A Rf 0.53 Nmr (CDCl ₃ ) 1.6, br, (1H); 2.98, d,
(1H); 3.1, d, (1H); 5.47, t, (1H); 6.3,
s, (2H); 6.42, s, (2H); 6.47, s, (3H);
6.53, q, (2H); 7.3, t, (2H); 7.7, m,
(9H). Examples of Pharmaceutical Compositions Tablet mg/tablet Active ingredient 100.00 Microcrystan Cellulose BPC 198.50 Magnesium stearate BP 1.50 Compressed weight 300.00 The active ingredient was passed through a 250 μm sieve, blended with excipients,
Compact using a 9.5mm punch. Tablets of other strengths can be made by varying the compression weight and using suitable punches. The tablets may be coated with a suitable film-forming material such as methylcellulose or hydroxypropylmethylcellulose using standard techniques. Alternatively, the tablet may be dragee-coated. Injection for intravenous administration Weight/Volume% Active Ingredient 1.00 Water for Injection, BP up to 100.00 Sodium chloride can be added to adjust the tonicity of the solution and the PH should be adjusted to the PH with maximum stability and/or the active ingredient It can be adjusted using dilute acid or alkali to promote the solution. The solution is prepared, clarified, filled into appropriately sized angles and sealed with a glass solution. Injectable solutions can be sterilized by heating in an autoclave using one of the appropriate cycles. or,
The solution may be sterilized by filtration and aseptically filled into sterile ampoules. The solution can be filled in an active atmosphere under nitrogen. Example 8 (a) 5-[[2-[[5-[[(2-furanylmethyl)
Amino]methyl]-3-thienylmethyl]thio
ethyl]amino]-1-methyl-1H-1,2,
4-triazole-3-methanol 4-[[[2
-[(3-hydroxymethyl-1-methyl-1H
-1,2,4-triazol-5-yl)amino[ethyl]thio]methyl]-N,N,N-trimethyl-2-thiophenemethanium iodide 5-[[2-[[5-(dimethylamino methyl)-3
-thienylmethyl]thio]ethyl]amino]-1
-methyl]-1H-1,2,4-triazole-3
- To a solution of methanol (3.72 g) in acetone (50 ml) was added a solution of methyl iodide (1.94 g) in acetone (10 ml). After stirring at room temperature for 3 hours, the separated oil was triturated to give the title compound (4.65 g). Melting point 146-149℃ 5-[[2-[[5-[[(2-furanylmethyl)amino]methyl]-3-thienylmethyl]thio]ethyl]amino]-1-methyl-1H-1,2,4 −
Triazole-3-methanol 4-[[[2-[(3-hydroxymethyl-1-methyl-1H-1,2,4-triazol-5-yl)amino]ethyl]thio]methyl]-N,N,
A mixture of N-trimethyl-2-thiophenemethanium iodide (1.12g) and 2-furanmethanamine (2.25g) was heated at 140-160°C for 2 hours. The oily residue was washed with diethyl ether (5x
(15 ml) and suspended in water (30 ml) containing anhydrous sodium carbonate (2 g). The suspension was extracted with ethyl acetate (3x30ml) and the combined extracts were dried and evaporated under vacuum. Chromatograph the oily residue (silica/ethyl acetate-methanol, 1:1)
The title compound (0.27 g) was obtained as an oil. Tlc ethyl acetate:methanol, 1:1f0.65 Nmr 2.60, m, (1H); 3.00, brs, (CDCl ₃ ) (1H); 3.09, brs, (1H); 3.70,
dd, (1H); 380, d, (1H); 5.50, s+t,
(3H); 6.13, s, (2H); 6.23, s, (2H), 6.36,
s, 6.52, s+q, (7H); 6.83, brs, (2H),
7,31,t, (2H). (b) By a similar method, 4-[[[2-[(3-hydroxymethyl-1-methyl-1H-1,2,4
-triazol-5-yl)amino]ethyl]
thio]methyl]-N,N,N-trimethyl-2
-Thiophenemethanium iodide (1.8g)
and benzenemethanamine (1.0 g), 4
Heat to 120°C for an hour and pour the mixture into water (3 x 20ml)
Column chromatography (silica; ethyl acetate-methanol,
3:1) by doing 5-[[2-[[5-
[[(phenylmethyl)amino]methyl]-3-thienylmethyl]thio]ethyl]amino]-1-
Methyl-1H-1,2,4-triazole-3
- Methanol (0.40 g) was obtained as an oil. Tlc ethyl acetate-methanol, 1:1 Rf0.55 Nmr (CDCl ₃ ) 2.70, m, (5H); 3.03, brs,
(1H, 313,) brs, (1H); 5.49, s, 5.50, t,
(3H); 6.10, s, (2H); 6.20, s, (2H); 6.38,
s, 6.54, s+q, (7H); 6.90, brs, (2H);
7.32, t, (2H). (c) By a similar method, 4-[[[2-[(3-hydroxymethyl-1H-1,2,4-triazol-5-yl)amino]ethyl]thio]methyl]-N,N,N - from trimethyl-2-thiophenemethanium iodide (1.8 g) and heptane amine (2.15 g) at 120°C for 1 hour.
It was then heated at 140°C for 4 hours and the residue was dissolved in water (4x
5-[[2-[[5-[(heptylamino ) methyl]-3-thienylmethyl]
thio]ethyl]amino]-1-methyl-1H-
1,2,4-triazole-3-methanol (0.3g) was obtained. Nmr: 3.03, d, (1H); 3.13, d, (1H); (CDCl ₃ ) 5.36, t, (1H); 5.5, s, (3H);
6.15, m, (2H); 6.38, s, (2H); 6.53, s,
(3H); 6.55, q, (2H); 6.75s (br), (2H);
7.3m, (4H); 8.3-9.0, m, (10H); 9.13t,
(3H). Tlc ethanol Rf 0.32 Example 9 5-[4-[[5-(dimethylamino)methyl-4
-Methyl-2-thienyl]butyl]amino]-
1-Methyl-1H-1,2,4-triazole-3-methanol 5-[4-[(3-hydroxymethyl-1-methyl-1H-1,2,4-triazol-5-yl)
Amino]butyl]-3-methyl-2-thiophenecarboxaldehyde (0.55 g) and dimethylamine were mixed with industrial denatured ethanol (33 parts by weight) (8 ml).
The mixture was heated to 50° C. for 18 hours. The mixture was cooled and sodium borohydride (0.5g) was added. The mixture was stirred at room temperature for 2 hours, acidified with 2N hydrochloric acid and washed with ethyl acetate. The aqueous phase was made basic with sodium carbonate solution and extracted with ethyl acetate. Evaporation of the organic extracts gave an oil which was subjected to column chromatography on silica using 2:1 ethyl acetate-methanol as eluent to give the title compound as a light brown oil (0.22 g). Ta. Nmr (CDCl ₃ ): 3.68, s, (1H); 5.47, s,
(2H); 5.90, t, (1H); 6.3, brs, (1H); 6.5−
6.7, m, (7H); 7.25, m, (2H); 7.78, s,
(6H); 7.90, s, (3H); 8.3, m, (4H). Ir( _CHBr3 ): 3585, 3420, 2820, 2770, 1530
cm ^-1 . The ability of the compounds of the present invention to suppress gastric acid secretion induced by histamine was demonstrated using perfused rat stomach preparations according to a modified method of the method described in the previously mentioned DE 2734070, namely:
MNGhosh and Schild's method
HOSchild, Brit.J.of Pharmacology1958, 13,
This is shown in a study on rats using a modified method of 54). Female rats weighing 150 g are fasted overnight and given an 8% sucrose solution in saline instead of drinking water. Rats were anesthetized with a single intraperitoneal injection of pentobarbitone sodium salt (50 mg/Kg).
Cannulate the trachea and jugular vein. The stomach is disconnected from the liver and spleen by making a midline incision in the abdominal wall to expose the stomach and cutting the connecting tissue. A small hole is made in the fundus of the stomach and the stomach is irrigated with 5% glucose solution. Connect a rubber tube to the esophagus, then cut the esophagus and vagus nerve above the cannula. A small hole is then made in the pyloric region of the stomach, and a large organic glass cannula is inserted through the small hole in the pyloric region so that the inlet end of the cannula exits the stomach through the small hole in the pyloric region. The cannula is shaped in such a way that it reduces the effective volume of the stomach and creates a turbulent flow of irrigation fluid over the mucosal surface. The drainage cannula is then inserted into the stoma of the gastric pylorus, and both cannulas are properly ligated around the stomach with ligatures in a position that avoids major blood vessels. A puncture wound is made in the body wall and the cannula is passed through.
through the esophageal cannula and pyloric cannula;
Irrigate the stomach with 5% glucose solution at 39°C at a flow rate of 1.5 ml/min each. The effluent is sent to a microflow PH electrode, and the PH value is recorded on a PH meter and a stationary recorder. The standard value for acid secretion from the stomach is the PH of the irrigation solution.
The increase in acid secretion is then induced by continuous intravenous infusion of submaximal doses of histamine to create a stable level of acid secretion, and when this condition is achieved, irrigation Measure the pH of the effluent. The test compound is then administered to the rats by intravenous injection, and changes in gastric acid secretion are monitored by measuring the PH of the irrigation effluent. From the PH change of the irrigation effluent, the difference in acid secretion between the reference value and the histamine-induced stable level is calculated as hydrogen ion concentration, moles/liter. The decrease in acid secretion caused by administration of the test compound is also calculated from the PH change of the irrigation effluent as a change in hydrogen ion concentration, moles/liter. The rate of decrease in acid secretion caused by administration of the test compound can then be calculated from the above two values. According to this, the effect of the compound is ED ₅₀ (mg/
Kg) is conveniently expressed in the form of a value. The results obtained for representative compounds of the present invention are shown below. The results obtained for several representative examples of the compounds of the present invention are shown below. Example No. ED ₅₀ 1(a) 0.054 1(d) 0.062 1(e) 0.022 1(i) 0.063 2(d) 0.074 5(b) 0.082 5(c) 0.18 6(a) 0.073 The compound of the present invention is They are generally of low toxicity at doses that effectively inhibit gastric acid secretion. Thus, for example, Examples 1(a), 1(d), 1(e), 1(i)
Compounds 2(d) and 2(d) did not produce any toxic effects when administered intravenously to anesthetized rats at doses exceeding 13 times their ED ₅₀ values.

Claims (1)

[Scope of Claims] 1. A compound represented by the following general formula () or a pharmaceutically suitable salt or hydrate thereof. [Formula width, one of R ₁ and R ₂ is hydrogen, halogen,
or C _1-4 alkyl group, and the other is a group
R ₄ R ₅ NAlk (where R ₄ is C _1-10 alkyl,
phenyl C _1-4 alkyl, or furyl C _1-3 alkyl, and R ₅ represents hydrogen or C _1-4 alkyl group, or R ₄ and R ₅ together with the nitrogen atom to which they are attached may form a 5- to 8-membered saturated ring), Alk is ( _CH2 )p (where p is 1 to 3). R ₃ is at either the 2nd or 3rd position, and is a group -
(CH ₂ ) _o X (CH ₂ ) _n NH-Z (where X represents -CH ₂ -, -O- or -S-, n is 0,
represents 1 or 2, m represents 2, 3 or 4,
and Z is a group [formula] or a group (where Y is CHNO ₂ or
NR ₉ (formula width R ₉ is cyano or C _1-4 alkylsulfonyl), R ₆ represents hydrogen or C _1-4 alkyl, R ₇ represents hydrogen or C _1-4 alkyl, R ₈ is phenyl C _1-3 alkyl, hydroxy
C _1-4 alkyl, amino, or the group NHCOR ₁₂ (where R ₁₂ represents C _1-3 alkyl)). ] 2 R ₃ is in the 3rd position, and R ₁ is the group R ₄ R ₅ NAlk
The compound according to claim 1, which is 3 Z is a group -C(=Y)NHR ₆ (wherein, Y is a group
CHNO ₂ )
A compound according to any one of Item 2. 4 Z is the base (wherein R ₇ is hydrogen or methyl, R ₈ is amino, hydroxy C _1-4 alkyl, benzyl, or the group NHCOR ₁₂ (wherein R ₁₂ represents C _1-3 alkyl)) Claims 1 to 1 which indicate
A compound according to any one of Item 3. 5 formula () [Here, R ₄ and R ₅ are both methyl groups,
or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or hexamethyleneimino group, and _Z is (wherein R ₇ is hydrogen or methyl and R ₈ is amino, hydroxyC _1-4 alkyl, benzyl, or the group NHCOR ₁₂ (wherein R ₁₂ represents C _1-3 alkyl)) The compound according to claim 1, which corresponds to any of the following. 6 N-Methyl-N-[2[[5-(dimethylaminomethyl)-3-thienylmethyl]thio]ethyl]-
2-nitro-1,1-ethenediamine, N-methyl-N'-[2-[[5-(1-pyrrolidinylmethyl)-3-thienylmethyl]thio]ethyl]-2-nitro-1, 1-ethenediamine, N-methyl-N'-[2-[[5-1-piperidinylmethyl)-3-thienylmethyl]thio]ethyl]
-2-nitro-1,1-ethenediamine, N-[2-[[5-(dimethylaminomethyl)-4
-Methyl-2-thienylmethyl]thio]ethyl]
-N'-methyl-2-nitro-1,1-ethenediamine, N-3-[[5-(dimethylaminomethyl)-3-
thienylmethoxy]propyl]-N'-methyl-2
-Nitro-1,1-ethenediamine, 1-methyl- ^N5- [2-[[5-[(dimethylamino)methyl]-4-methyl-2-thienylmethyl]
thio]ethyl]-1H-1,2,4-triazole-3,5-diamine, 1-methyl-5-[[2-[[5-(dimethylaminomethyl)-3-thienylmethyl]thio]ethyl]
Amino]-1H-1,2,4-triazole-3-
Methanol, 5-[[2-[[[5-(dimethylaminomethyl)-
4-Methyl]-2-thienylmethyl[thio]ethyl]amino]-1-methyl-1H-1,2,4-triazole-3-methanol, 5-[[2-[[5-(dimethylaminomethyl)] -3
-thienyl]methyl]thio]ethyl]amino-3
-phenylmethyl-1H-1,2,4-triazole and physiologically suitable salts thereof. 7 One of R ₁ and R ₂ represents hydrogen, the other represents R ₄ R ₅ NAlk, and R ₃ , with the proviso that Y does not represent NR ₉ (in the formula, R ₉ is C _1-4 alkylsulfonyl). 8 One of R ₁ and R ₂ represents hydrogen, the other represents R ₄ R ₅ NAlk, and R ₃ (wherein R ₄ , R ₅ , R ₇ , R ₈ , X, n and m are as described above), a compound represented by the formula () according to claim 1. 9 The amine represented by the formula R ₁₇ NH ₂ () can be converted to the general formula () (where the group R ₁₇
and one of R ₁₈ is a group and the other represents a radical R ₆ and P is a leaving group), optionally converting the product into a salt, in which Z is a radical A compound of the formula or a physiologically relevant method for preparing it. [In the formula, one of R ₁ and R ₂ is hydrogen, halogen,
or C _1-4 alkyl group, and the other is a group
R ₄ R ₅ NAlk (where R ₄ is C _1-10 alkyl,
phenyl C _1-4 alkyl, or furyl C _1-3 alkyl, and R ₅ represents hydrogen or C _1-4 alkyl group, or R ₄ and R ₅ together with the nitrogen atom to which they are attached may form a 5- to 8-membered saturated ring), Alk is ( _CH2 )p (where p is 1 to 3). R ₃ is at either the 2nd or 3rd position, and is a group -
(CH ₂ ) _o X (CH ₂ ) _n NH-Z (where X represents -CH ₂ -, -O- or -S-, n is 0,
represents 1 or 2, m represents 2, 3 or 4,
and Z is a group [formula] or a group (where Y is CHNO ₂ or
NR ₉ (wherein R ₉ is cyano or C _1-4 alkylsulfonyl), R ₆ represents hydrogen or C _1-4 alkyl, R ₇ represents hydrogen or C _1-4 alkyl, R ₈ is phenyl C _1-3 alkyl, hydroxy
C _1-4 alkyl, amino, or the group NHCOR ₁₂ (where R ₁₂ represents C _1-3 alkyl)). ] 10 Formula () (wherein V ¹ is [Formula] or NCN, and Y ¹ is hydrogen, where V is oxygen or sulfur, and R ¹ ₈ is the same group as defined for R ₈ , or or represents a group convertible thereto under the reaction conditions, or represents halogen or alkoxy, or V ¹ is NH, and
Y ¹ is [Formula]) A compound represented by general formula (), characterized in that the compound represented by [Formula] is cyclized and the product is converted into a salt as necessary; A process for producing a compound or a physiologically relevant salt thereof. [In the formula, one of R ₁ and R ₂ is hydrogen, halogen,
or C _1-4 alkyl group, and the other is a group
R ₄ R ₅ NAlk (where R ₄ is C _1-10 alkyl,
phenyl C _1-4 alkyl, or furyl C _1-3 alkyl, and R ₅ represents hydrogen or C _1-4 alkyl group, or R ₄ and R ₅ together with the nitrogen atom to which they are attached may form a 5- to 8-membered saturated ring), Alk is (CH ₂ ) _p (where p is 1 to 3). R ₃ is at either the 2nd or 3rd position, and is a group -
(CH ₂ ) _o X (CH ₂ ) _n NH-Z (where X represents -CH ₂ -, -O- or -S-, n is 0,
represents 1 or 2, m represents 2, 3 or 4,
and Z represents either the group [formula] or the group [formula] (wherein Y represents CHNO ₂ or NR ₉ (in the formula, R ₉ is cyano or C _1-4 alkylsulfonyl), and R ₆
represents hydrogen or C _1-4 alkyl, R ₇ represents hydrogen or C _1-4 alkyl, R ₈ represents phenyl C _1-3 alkyl, hydroxy C _1-4 alkyl, amino, or the group NHCOR ₁₂ (where , R ₁₂ represents C _1-3 alkyl)). ] 11 A compound represented by the following general formula () or a pharmaceutically suitable salt or hydrate thereof, together with at least one pharmaceutically suitable carrier or diluent and, if necessary, one or more other active ingredients. histamine, characterized by comprising
_H2 antagonist composition. [In the formula, one of R ₁ and R ₂ is hydrogen, halogen,
or C _1-4 alkyl group, and the other is a group
R ₄ R ₅ NAlk (where R ₄ is C _1-10 alkyl,
phenyl C _1-4 alkyl, or furyl C _1-3 alkyl, and R ₅ represents hydrogen or C _1-4 alkyl group, or R ₄ and R ₅ together with the nitrogen atom to which they are attached may form a 5- to 8-membered saturated ring), Alk is (CH ₂ ) _p (where p is 1 to 3). R ₃ is at either the 2nd or 3rd position, and is a group -
(CH ₂ ) _o X (CH ₂ ) _n NH-Z (where X represents -CH ₂ -, -O- or -S-, n is 0,
represents 1 or 2, m represents 2, 3 or 4,
and Z represents either the group [formula] or the group [formula] (wherein Y represents CHNO ₂ or NR ₉ (in the formula, R ₉ is cyano or C _1-4 alkylsulfonyl), and R ₆
represents hydrogen or C _1-4 alkyl, R ₇ represents hydrogen or C _1-4 alkyl, R ₈ represents phenyl C _1-3 alkyl, hydroxy C _1-4 alkyl, amino, or the group NHCOR ₁₂ (where , R ₁₂ represents C _1-3 alkyl)). ]