DE2155403A1 - 1,4-thienodiazepines and their acid addition salts, processes for their production and medicinal preparations - Google Patents

Description

DIPL-CHEM. DR. ELISABETH JUNG DIPL.-CHEM. DR. VOLKER VOSSIUS DIPL.-PHYS. DR. JÜRGEN SCHIRDEWAHN

PATENT LAWYERS

MUNICH 23, g fklV. | ^! J / |

CLEMEKSSTRASSE 30 " TcLEFO 1 3450Ö7 f ELEGHAMM ADDRESS E: IN VENT / ΜΠtiCHEN TELEX 5-29 688

u.z .: G 562 G (id / Vo / id) POS-26745

OUi.IITOI.iO CKELiICAL CCiIZ "ΛΪΓΥ, LIMITED Osaka, Japan

¹¹ 1,4-thienodiazepines and their acid addition salts, processes for their preparation and medicinal preparations "

Priority: November 16, 1970, Japan, No. 101330/70

December 15, 1970, Japan, Ur. 112773/70

March 2, 1971, Japan, No. 11494/71

March 2, 1971, Japan, No. 11495/71

The invention relates to new 1,4-thienodiazepines of the alü ^ eneinen I'ormel (I)

(D

_x

209822 / 10A9

BATH ORIGINAL

in the R. a hydrogen atom, a lower alkylrene or the cycloalkylmethyl group or the remainder

R ° Π,
- (CH ₉ LN; '' ^A , -CH ₉ CN ^ ° or - (CH ₉ KO-Rp mean-

B D

tet, where η is an integer from 1 to 4 and R., Rr ,, Rß, RQ and R "', Vasserstoi'fatome or lower alkyl radicals represent, R _? a hydrogen atom or a lower alkyl radical, R., a hydrogen or halogen atom and Z a halogen atom, the nitro or cyar group or a lower alkyl or lower alkoxy radical,

as well as their acid addition salts.

The invention also relates to a process for the preparation of the 1,4-thienodiazepines of the general Pomel (I) and their acid addition salts, which is characterized in that one

(a) a 2-aminoacetoamido-3-benzoylthiophene of the general Formula (II)

R ₁ 0
0

in which R., Rp, R., and X have the aforementioned meaning,

or subject a neck of this compound to cyclization or

209822/1049 bad

(b) for the preparation of those compounds of the general formula (I) in which R _{1 is} not a hydrogen atom, a 2- (lI-phthalimidoacetara do) -3-benzoylthiophene of the general formula (III)

R ₄ O

- CHo- NH ^

(III)

in the r _? , R, and X have the aforementioned meaning and R. has the same meaning as R., but is not a hydrogen atom,

with hydrazine hydrate and optionally those compounds of the general formula (1) in which R ^ is a hydrogen atom, halogenated to the corresponding halogen compound or those compounds of the general formula (I) in which R .. is a hydrogen atom, alkylated to the corresponding alkyl compound and where appropriate, the free bases in the Säuread dit i ons sal e ζ üb erführt.

The rules for lower alkyl radicals are 0 ... alkyl radicals, e.g. the ethyl, ethyl, propyl, iso]; ro] iyl, η-butyl, isbutyl, crude butyl or tertiary butyl group. S} eziei: ici examples of C ;. cJ (! lil / yl radicals are the cyclopropyl, gyclobutyl, cyclopentyloot.-r Glyc-j olioxyl group. oj ^ ecial examples for lower alkoxy

209822/1049

radicals are the methoxy, ethoxy or propoxy group.

The term halogen atoms includes chlorine, bromine, iodine or fluorine atoms.

Examples of acid addition salts of the 1,4-thienodiazepines of general formula (I) are the salts with pharmacologically acceptable inorganic or organic acids, such as hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, Acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, citric acid, camphorsulfonic acid, ethanesulfonic acid, Ascorbic acid or lactic acid.

The cyclization of 2-aminoacetamido-3-benzoylthiophen of the general formula (II) is preferably used in an inert solvent carried out. Suitable solvents are e.g. lower alkanols, such as methanol, ethanol, isopropanol or n-butanol, aromatic hydrocarbons such as benzene, toluene, xylene or nitrobenzene, pyridine, picoline, dimethylformamide, dimethyl sulfoxide or mixtures of the aforementioned solvents. Suitable salts for the cyclization are, for example, the salts with chlorine or Bromine / hydrochloric acid or with sulfuric acid.

The cyclization reaction is preferably carried out with heating, in particular at temperatures in the range from 50 ^° C. to the boiling point of the solvent used.

If the cyclization reaction is carried out without solvent, for example, reaction temperatures above the melting point of the compound of the general formula (II) are preferably used.

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- φ -

The 2-aminoacetamido-3-benzoylthiophenes used as the starting compound of the general formula (II) or their salts are obtained, for example, by reacting a 2-amino-3-benzoylthiophene general formula (IV)

/.Ac = ο (")

2 I.

O ~ ^x a

in which R ₁ , Rp, R ~ and X have the meaning given above,

with an oi'-haloacyl halide such as bromoacetyl bromide. This gives a 2-haloacetamido-3-benaoylthiophene of the general formula (V)

in which R ₁ , R ₀ , R- and X have the aforementioned meaning and Y represents a halogen atom.

The compound of the general formula (V) is then with Ammonia in the presence of an organic solvent tunge «=

According to the aforementioned / u ^ Tahrer: the following 1 epino er], old i

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5- (o-chlorophenyl) -7-chloro-1,3-dihydro-2H-thieno- / 2,3-e / -1,4-diazepin-2-one, P. 249 ° C (decomp.),

5- (o-Fluorophenyl) -7-chloro-1,3-dihydro-2H-tiiieno- / 2,3-e7-1,4-diazepin-2-one, P. 246 ⁰ C (dec.),

5- (o ~ Pluophenyl) -6-methyl-1,3-dihydro-2H-thieno- _> / 2,3-e / -1,4-diazepin-2-one,

5_ (o-fluorophenyl) -7-bromo-1, 3-dihydro ~ 2H-thieno- _ii / 2,3-e / -1,4-diazepin-2-one,

5- (o-fluorophenyl) -6-ethyl-1,3-dihydro-2H-thieno- / 2,3-e7-1,4-diazepin-2-one,

5- (o-bromophenyl) -1,3-dihydro-2H-thieno- / 2,3-e / -1,4-diazepine-

5- (o-iodophenyl) -1,3-dihydro-2H-tMeno- / 2,3-e7-1 _f 4-diazepine-

5- (p-chlorophenyl) -1,3-dihydro-2H-thieno- / 2,3-e / -1,4-diazepine-

5- (o-nitrophenyl) -1,3-dihydro-2H-thieno ~ ^ 5,3-e7-1 ^ -diazepine-

5- (o-methylphenyl) -1,3-dihydro-2H-thieno- / 2,3-e7-1,4-diazepine-

5- (o-cyanophenyl) -1 _f 3-dihydro-2H-thieno- / 2 _s 3-e7-1,4-dia; 3epiii ~ 2-one and

5- (o-methoxyphenyl) -1 »3-dihydro-2H» -tbie-nc »/ 2 _? ; 3-e7 "1 ί 4-ciiaaepln-

The establishment of the 2- (F-Ph th all m close st ami do) "-3-benzQy li ': i ± oph ---- in the general formula (III) is with hydrazine cyclrate

is preferably carried out in an inert solvent

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· ■? ■

Suitable solvents are, for example, lower alkanols such as methanol, Ethanol or isopropanol, ethers such as dioxane, tetrahydrofuran or bioethylene glycol dimethyl ether, tertiary amides such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide or N-methy1-2-pyrrolidone, Alkyl halides such as dichloromethane or chloroform, Water or mixtures of the aforementioned solvents.

Preferably the reaction is carried out with an excess of hydrazine hydrate at temperatures from room temperature to boiling point

of the solvent used. ™

The 2- (N-phthalimidoacetamido) -3-benzoylthiophene used as the starting material of the general formula (III) can be prepared in various "ways.

According to one process, a compound of the general formula (VI)

NH ₂

in which R "and X have the aforementioned meaning,

with a phthalimidoacetyl chloride su a compound of all common formula (VII)

H Il

* V ^ (VII)

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in the r _? and X have the meaning given above,

condensed. The compound of the general formula (VII) is then added in the presence of a base with an alkylating agent a compound of the general formula (VIII)

< ^s - "

R ₂ '° = °

in which Rp, R. and X have the aforementioned meaning, alkylated.

For example, alkyl halides of the general formula are used for the alkylation

in the R, has the aforementioned meaning and Y is a Represents halogen atom,

Alkyl sulfates, v / ie dimethyl sulfate, or alkyl hydrocarbons sulfonates, such as methyl p-toluenesulfonate, are suitable

Bases suitable for the alkylation are, for example, alkali hydrides, alkali amides or alkali alcoholates.

The reaction is preferably carried out in an inert solvent, e.g. a tertiary airid such as Ν, Κ-dimethylfornamide, N, W-dimethy 1 acetamide or N-LIothyl-2-pyrjOlidon, an ether such as di-

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ethyl ether, tetrahydrofuran or dioxane, an aromatic Hydrocarbon such as benzene or toluene, dimethyl sulfoxide or Mixtures of the aforementioned solvents at temperatures in the range from O C to the boiling point of the solvent used carried out.

The compounds of the general formula (VIII) thus obtained come under the general formula (III).

The compounds of the general formula are optionally used (VIII) converted into the corresponding halogen compounds of the general formula (III) in which H is a halogen atom.

The halogenation is preferably carried out in an inert solution

medium carried out. Suitable solvents are, for example, halogenated Hydrocarbons such as chloroform, carbon tetrachloride or dichloromethane, ethers such as diethyl ether or dioxane, organic Acids such as acetic acid or formic acid, amines such as pyridine or triethylamine, aromatic hydrocarbons such as Benzene, or mixtures of the aforementioned solvents. "

Examples of suitable halogenating agents are gaseous ones Chlorine, sulfuryl chloride, bromine, N-bromosuccinimide, N-chlorosuccinimide or mixtures of iodine and yellow mercury (II) oxide.

The halogenation is preferably carried out at temperatures in the range from ⁰ ° C. to the boiling point of the solvent used.

The compounds of the general formula (III) can also be prepared in the aforementioned manner by halogenating the compounds of the general formula (VII). Here, you get encryption

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Jb

bonds of the general formula (IX)

_8th SO-CH ₂ H

(IX)

in which R ₂ ^{un (} * ^ C ^d ^ ^{e have the} aforementioned meaning and "R, - represents a halogen atom,

by alkylation in the aforementioned manner into those compounds of the general formula (III), in which R 1 is not a Y / oxygen atom.

The compounds of the general formula (VIII) can also be prepared by reacting a compound of the general formula (X)

J. ₀

R ₂

in which Rp, R, and X have the aforementioned meaning make with phthalimidoacetyl chloride.

Those compounds of the general formula (III) in which R, does not represent a Waeserotoffatom, can also be obtained by reacting a compound of the general formula (XI)

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£ 155403

«^ C« ο

in the Rp, R <»Rc and X the aforementioned meaning to have,

be made with phthalimidoacetyl chloride.

The following 1-4-thienodiazepines are made according to the aforementioned procedure obtain:

1-methyl-5- (o-chlorophenyl) -1,3-dihydro-2H-thieno - ^, 3-e7-1,4-diazepin-2-one, P. 109.5 - 111.0 ⁰ O,

1-methyl-5- (o-fluorophenyl) -7-chloro-1,3-dihydro-2H-thieno / 2,3-e7-1,4-diasepin-2-one, F.101.5-103, O ⁰ C,

1-methyl-5- (o-chlorophenyl) -7-chloro-1,3-dihydro-2H-thieno / 2,3-e7-1,4-diazepin-2-one, m.p. 82.5-84 ⁰ C,

1-methyl-5- (o-bromophenyl) -7-chloro-1,3-dihydro-2H-thieno- ₍ / 2, 3-e / - g 1,4-diazepin-2-one,

1-Methy1-5- (o-fluorophenyl) -7-bromo-i, 3-dihydro-2H-thieno- / 2,3-e / -1,4-diazepin-2-one,

1-methyl-5- (o-bromophenyl) -1,3-dihydro-2H-thieno- / 2,3-e7-1,4-diazepin-2-one,

- Ethyl-5- (p-chlorophenyl) -1,3-dihydro-2H-thieno- / 2,3-e / -1,4-dia2epin-2-one,

1-methyl-5- (p-chlorophenyl) -7-chloro-1,3-dihydro-2H-thieno- / 2,3-e / -1,4-diazepin-2-one,

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1-Cyclopropylmethyl-5- (o-fluorophenyl) -7-chloro-1,3-dihydro-2H-thieno- / 2,3-e / -1,4-diazepin-2 ~ one,

1-I.Ietliy.l-5- (o-fluorophenyl) -7-3od-1,3-diliydro-2H-thieno- / 2,3-ey ⁷ -1,4-diazepin-2-one,

1-Lethyl-5- (o-nitrophenyl) -7-c] ilor-1,3-dihydro-2ir-tMeno- / 2,3-e7 1,4-diazepin-2-one,

1-methyl-5- (o-ethylphenyl) -7-chloro-1,3-dihydro-2H-thieno-.

/ 2,3-e / -1,4-diasepin-2-one,

1-methyl-5- (o-cyanophenyl) -7-chloro-1,3-dihydro-2H-thieno- / 2,3-e / -1,4-diazepin-2-one and

1-IvIe thy 1-5- (o-methoxyphenyl) -7-chloro-1,3- <3.ihydro-2H-thieno- / 2,3-e / -1 »4-diazepin-2-one.

Those compounds of the general formula (I) in which R _{7 represents} a halogen atom, ie, compounds of the general formula (XII)

(XII)

in which E ^, R ₂ , H _r ^un ^ X have the aforementioned meaning,

can be derived from the corresponding non-substituted compounds of the general formula (I), i.e. compounds of the general Formula (XIlI)

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(XIII)

in which H ₁ , Rp and X have the aforementioned meaning, prepared by reaction with a halogenating agent.

The halogenation is preferably carried out in an inert solvent. Suitable solvents are, for example, halogenated Hydrocarbons such as chloroform, carbon tetrachloride or Dichlorir.ethan, ethers such as Oiäthyläther or dioxane, organic Acids, Y.'ie acetic acid or formic acid, amines such as pyridine or triethylamine, aromatic hydrocarbons such as Bensol, or mixtures of the aforementioned solvents.

Suitable ilalogenating agents are a.B. gaseous chlorine, Sulfuryl chloride, bromine, N-bromosuccinimide, N-chlorosuccinimide or J. Mixtures of iodine and yellow mercury! II) oxide. l ^ ie halogenation is preferably carried out at temperatures in the range from 0 to the boiling point of the solvent used.

Do the aforementioned procedure using the following 1,4-Tnienodiazepines obtain:

1 -Kethyl-5- (o-fluorophenyl) -7-bromo-1,3-dihydro-2H-thieno- / 2, '5-qJ-

1-Cyclop'apyl. .j thyl ~ i ;-( o-fluorophenyl) ~ 7-chloro-1,3-dihydro-2H-thieno ~ / i-, 'i- \ J ~ 1,4-di-o.opi η-2- οιϊ,

BATH

209822 / i 0 40

21554Q3

1-methyl-5- (o-iodophenyl) -7-chloro-1,3-dihydro-2H-thieno- / 2 _r 3-e / -1,4-diazepine-2-cn,

1-dieth7 / laminoethyl-5- (o-fluorophenyl) -7-chloro-1,3-d.ihydro.-2H-thieno- / 2,3-e / -1, 4-diai: epin.-2-ori,

1- (2i-1.iethylcarbanoyliiethyl) -5- (o-fluorophenyl) -7-chloro-1,3-dihydro-2K-thieno- / 2,3-e / -1,4-diazepin-2-one, 1-Methy1-5- (o-methy! Phenyl) -7-chloro-1,3-clihydro-2H-thieno— / 2,3-e / -1,4-diaaepin-2-one,

1-IIethyl-5- (o-nitrophenyl) -7-chloro-1,3-dlhydro-2H-thieno- / 2,3-e / -1,4-diasepin-2-one,

1-methyl-5- (o-raethoxyphenyl) -7-chloro-1,3-dihydro-2H-bhieno- / 2,3-e / -1,4-dia2epin-2-one,

1-methyl-5- (o-cyanophenyl) -7-chloro-1,3-dihydro-2II-thieno- / 2,3- ^ 7-1,4-diazepin-2-one,

1-ethoxyethyl-5- (o-fluorophenyl) -7-chloro-1, 3-d L ^l iyciro-2H-thieuü- / 2,3-§ / -1,4-diazepin-2-one,

1 — methoxymethy1-5- (o-fluorophenyl) -7-chloro-1, 3-di} iydro-2H-thieno- / 2,3-e / -1,4-diaaepin-2-one,

5- (o-fluorophenyl) -7-bromo-1,3-dihydro-2H-thieno- / 2,3-e / -1,4-diazepin-2-one,

5- (o-Methoxyphenyl) -7-chloro-1,3-dihydrö-2H-thieno- / 2 ~, 3-e7-1,4-diazepin-2-one,

5- (o-Hitrophenyl) -7-chloro-1,3-dihydro-2ii-thieno / 2,3- & 7-1 »4-diasepin-2-one or

5- (o-Cyanophenyl) -7-chloro-1,3-dihydro-2H-thieno- / 2,3-e / -1,4-dia3opi.n-2-one.

Those Vei-binciun ^^ ä of the general formula (I) in which no ^r .? -. '. Süt; r3toffatoi; i be: luifcot, d.lu, compounds of all ~ e ~

2 0 9 8 2 2/1049 "

BAD ORlGINAt

my formula (XIV)

R ₂

(XIV)

in which R ₉ , R ,, R- and X have the aforementioned meaning

L. J H

to have,

v / ground by alkylation of the corresponding on the nitrogen atom unsubstituted compound of general formula (I), i.e., Compounds of general formula (XV)

in which R ₂ , R-2 and X have the aforementioned meaning, prepared with an alkylation agent in the presence of a base.

Examples of suitable alkylating agents are alkyl halides the general formula

R ₄ -ι

in which R and Y have the aforementioned meaning, Alkyl sulfates, such as dimethyl sulfate or alkyl carbon hydrogen sulfates, such as methyl p-soluenesulfonate.

Suitable jo;.: - en ijin-.l e.g. alkali hydrides, alkali amides or Al / .a-

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BATH

The reaction is preferably carried out in inert solvents, for example tertiary amides such as Ν, Ν-dimethylformamide, 'N, HI) imethylacetamide or N-methyl-2-pyrrolidinone, ethers such as diethyl ether, tetrahydrofuran or dioxane, aromatic hydrocarbons such as benzene or toluene , Dimethyl sulfoxide, or mixtures of the aforementioned solvents, carried out at temperatures in the range from O ⁰ C to the boiling point of the solvent.

^ The following 1,4-thienodiazepines, for example obtain:

1-methyl-5- (o-fluorophenyl) -7-chloro-1,3-dihydric-2H-thieno-

in ^ -on, m.p. 1O1.5-1O3 ° C.

1-methyl-5- (o-chlorophenyl) -7-chloro-1,3-dihydro-2H-thieno- / 2,3-e7-1,4-diazepin-2-one, 82.5-84 ° C,

1-methyl-5- (o-fluorophenyl) -7-bromo-1,3-dihydro-2H-thieno- / 2,3-e7-1,4-diazepin-2-one,

1-Cyclopropylmethyl-5- (o-fluorophenyl) -7-chloro-1,3-dihydro-2H-thieno- / 2,3-e / -1,4-diazepin-2-one,

1-methyl-5- (o-methylphenyl) -7-chloro-1,3-dihydro-2H-thieno- / 2 ", 3-e7-1,4-diazepin-2-one,

1-Hethyl-5- (o-nitrophenyl) -7-chloro-1,3-dihydro-2H-thieno- / 2, 3-ey ⁷ - !, 4-diazepin-2-one,

1-Lethyl-5- (o-methoxyphenyl) -7-chloro-1,3-dihydro-2H-thieno- / 2,3-e7-1> 4-diazepin-2-one,

1 -lviethyl-5- (o-cyanophenyl) -7-chloro-1,3-dihydro-2H-thieno- / 2, 3-e / - 1,4-diazepin-2-one,

1-Diethylaminoäth.yl-5- (of luorplionyl) -7-chloro ~ 1, 3-di ¹ .: ydro-2H-thie2io- / 2, 3-e / -1 »4-cliarjepin-2-one,

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BATH ORIGINAL

1- (N-carbamoylmethyl) -5- (o-fluorophenyl) -7-chloro-i, 3-dihydro-2H-thleno- / 2,3-e / -1,4-diazepin-2-one, i-hydroxyethyl-5- (o-fluorophenyl) -7-chloro-1,3-dihydro-2H-ΐhieno-

i-methoxyethyl-5- (o-fluorophenyl) -7-chloro-1,3-dihydro-2H-thieno- / 2,3-Q7-1 , 4-diasepin-2-one or

i-Methoxymethyl-5- (o-fluorophenyl) -7-chloro-1,3-dihydro-2H-thieno-, 3-e / -1,4-diazepin-2-one.

The 1,4-ihienodiazepines of the general formula (I) and their Salts are valuable drugs, e.g. as anticonvulsants Sedatives, relaxants, hypnotics or tranquillants are used and have hexobarbital potentiating effects.

The table shows the anticonvulsant effect of the compounds of the general formula (I), which was determined on mice after oral administration.

Table examined connection

5- (o-Chlorophenyl) -7-chloro-1,3-dihydro-2H-thieno- / 2,3-ζ / -1.4-1.5

diazepin-2-one

1 -Methyl-5- (cM3hlophenyl) -7-chloro-

1,3-dihydro-2H-thieno- / 2,3-e7-2,4

1,4-diazepin-2-one

5- (o-ITuophenyl) -7-chloro-1,3-dihydro-2H-thieno- / 2,3-e7-1,4-3,3

diazepin-2-one

Chlordiazepoxide rq

(known connection) '

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The compounds of the general formula (I) and their acid addition salts are preferably administered orally. They can be used together with solid or liquid carriers or diluents and other common additives and processing aids, e.g. for tablets, capsules, powders, aqueous or non-aqueous suspensions or solutions are made up.

^ The examples illustrate the invention.

example 1

A mixture of 2 g of 2-Aminoaeetamido-3- (o-fluorobenzoyl) -thiophene and 30 ml of dimethyl sulfoxide is stirred at 95 ° C. for 7 hours. After cooling, the reaction mixture is dissolved in 200 ml of water poured and extracted with chloroform. After extracting the chloroform layer with 100 ml of 1N aqueous hydrochloric acid the acidic layer is neutralized with aqueous ammonia (28 percent by weight) and extracted with chloroform.

The chloroform layer is washed with water, dried and concentrated under reduced pressure. After the residue has crystallized from ethanol, 5- (o -]? Luophenyl) -1,3-dihydro-2H-thieno- / 2,3-e / -1,4-diazepin-2-one from P. 200 , 5 to 202 ⁰ C, which after recrystallization from ethanol gives colorless prisms from P. 201 to 201.5 ° C.

Analysis C ₁ , H

.S ₁ I ₁ : 59 C. 3, H 10 N 12th S. ber .: 60 , 99 3, 49 10 , 76 12th , 32 found: , 08 43 , 67 , 2

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- 19 The starting connections are made as follows:

Procedure A

An ice-cold suspension of 5.0 g of 2-amino-3- (o-fluorobenzoyl) thiophene, 5.9 g of bromoacetyl bromide are added dropwise to 1.81 g of pyridine and 250 ml of diethyl ether. read the reaction mixture is stirred for 3.5 hours at room temperature and then treated with 60 ml of water while cooling.

The organic layer is separated, washed with water, dried over sodium sulfate and evaporated under reduced pressure. To yield the 2-bromoacetamido-3- (o-fluorobenzoyl) -thiophene pale yellow in the form of prisms, melting at 101-102 ⁰ C.

Procedure B

A solution of 4.15 g of 2-bromoacetamido-3- (o-fluorobenzoyl) thiophene in 108 ml of chloroform is saturated with gaseous ammonia while cooling with ice. After stirring for 40 hours at room temperature the reaction mixture is filtered and the filtrate is evaporated under reduced pressure. The residue will dissolved in dichlorine than and extracted with 60 ml of 0.4 η aqueous hydrochloric acid. The aqueous layer is separated and after Neutralize with aqueous ammonia, extracted with dichloromethane.

Evaporation of dichloromethane under reduced pressure gives the crystalline 2-aminoacetamido-3- (o-fluorbenr, oyl) -thiophene, melting at 127.5 to 129 ⁰ C.

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Example 2

A solution of 500 mg of 2 ~ aminoacetamido-3- (o-chlorobenzoyl) -thiophene in 7 _? 5 ml of dirnetyl sulfoxide is stirred at 95 ° C. for 14 hours. To. to the. After cooling, the reaction mixture is poured into 300 ml of water / water and extracted with chloroform. The chloroform layer is extracted with 60 ml of 1N aqueous hydrochloric acid, the aqueous layer is separated and, after neutralization, is extracted with chloroform using aqueous ammonia. The chloroform layer is evaporated after washing with water and drying under reduced pressure. This gives the crystalline 5- (o-chlorophenyl) -1,3-dihydro-2H-thieno- / 2,5-e / -1,4-diazepin-2-one, which when recrystallized from ethanol is colorless prisms of the P . 225 to 226 ⁰ C results.

Analysis C ₁₃ HnN ₂ Cl ₁ S ₁ O ₁ :

56 O 3, H 10 N ber .: 56 , 42 3, 28 10 , 12 found: , 68 23 , 04

Cl 80 1 1 S. 12, 86 1 1 , 59 12, , 46

The starting connections are made as follows:

Procedure C

An ice-cold suspension of 1.0 g of 2-amino-3- (o-chlorobenzoyl) thiophene, 0.34 g of pyridine and 40 ml of diethyl ether are added dropwise with 0.95 g of bromoacetyl bromide. The reluctant to act stirred for 4 hours at room temperature and then mixed with 12 ml of water. The organic layer is separated, washed with water / water, dried over sodium sulfate and then evaporated under reduced pressure. One obtains cI; il;

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2-Bromo-acetamido-3- (o-chlorobenzoyl) thiophene as an oily residue which, when crystallized from diethyl ether, gives ^{colorless prisms from P. 109 to 110 0 O.}

analysis

43 G 2 H 3 N 8th S. ber. ί 43 , 54 2 , 53 3 , 91 8th , 94 found: , 58 , 56 , 7 , 71 Method D

A solution of 1.01 g of 2-bromoacetamido-3- (o-chlorobenzoyl) thiophene in 26 ml of chloroform is saturated with gaseous ammonia while cooling with ice. The reaction mixture is stirred for 30 hours at room temperature and, after filtration, the filtrate is evaporated under reduced pressure. After the residue has been dissolved in 30 ml of dichloromethane, the solution is extracted with 13 ml of 0.4 μm aqueous hydrochloric acid. The aqueous layer is neutralized with gaseous ammonia and then extracted with dietilomethane. After evaporation of dichloromethane under reduced pressure gives the crystalline 2-aminoacetamido-3- (o-chlorobenzoyl) -thiophene, melting at 154 to 156 ⁰ C.

Analysis C ₁₅ H ₁₁ N ₂ Cl ₁ S ₁ :

52 C. H 9, N Cl 10 S. boron.: 52 , 97 3.76 9, 50 12.03 11 , 88 found: , 86 3.72 00 12.73 , 01

209822/1049

Example 3

A solution of 100 mg 2- (N-Phthalimidoacetyl-IT-methyl) -amino-3- (o-fluorophenyl) -thiophene, 2 ml of chloroform and 1 ml of ethanol are mixed with a solution of 27 mg of hydrazine hydrate and 27 mg of water added at room temperature. After stirring for 6 hours, the reaction mixture is poured into water and the resulting mixture is poured into it is extracted with diethyl ether.

The organic layer is washed with water, dried and evaporated under reduced pressure. Here one obtains

an oily residue, the 1-methyl-5- (o-fluorophenyl) -1,3-dihydro-2K-thieno- / 2,3 -e / 1,4-diazepin-2-one when crystallizing from ether in the form of colorless prisms with a temperature of 112 to 114 ° C.

The starting connections are made as follows:

Method E

A mixture of 5.8 g of phthaloylimidoglycine and 12.5 g of thionylw chloride is refluxed for 2 hours and then evaporated under reduced pressure. Here you get that Phthalimidoacetyl chloride as an oily residue.

This residue is mixed with 5 g of 2-amino-3- (o-fluorobenzoyl) thiophene and 50 ml of tetrahydrofuran are added, the reaction mixture is heated under reflux for 2.5 hours and then under concentrated under reduced pressure. The oily residue is neutralized with dilute aqueous ammonia and then with methylene chloride extracted. The organic layer is washed with water, dried and concentrated under reduced pressure.

209822/1049

Crystallization of the residue from acetone to yield the 2- (N-phthalimidoacetyl) amino-3- (o-fluorobenzoyl) -thioplien from P. 189-192 ⁰ C, which on recrystallization from acetone, a
white powder with a temperature of 193 to 194.5 ° 0 results.

Analysis O ^ IL,, N ₂ S ₁ O ₄ I ¹ .,:.

61 C. 3 H 6th I. 7th S. ber .: 61 , 76 3 , 21 6th , 86 7th , 85 found: , 66 , 13 , 57 , 83 Method P

A solution of 1.30 g of 2- (N-phthalimidoacetyl) -amino-3- (o-fluorobenzoyl) -thiophene in 13 ml of dimethylformamide is at
0.18 g (63 percent by weight) of sodium hydride dispersed in mineral oil are added at room temperature. After 30 minutes of stirring, the reaction mixture is cooled to 10 ⁰ C and treated dropwise with 0.91 g Methyl3odid in 1 ml dimethylformamide. The reaction mixture is stirred for 2 hours at room temperature and then poured into water. The resulting mixture is extracted with benzene, the benzene layer is washed with water, dried and then evaporated under reduced pressure. When the residue is crystallized from acetone, 2- (N-phthalimidoacetyl-N-methyl) -amino ~ 3- (o-fluorobenzoyl) -thiophene from P. 210 to 213 ° C, which when recrystallized from acetone turns into a white powder P. 216 to
217.5 ⁰ C results.

209822/1049

analysis

62 G. 3 H 6th , 63 7th S. ber .: 62 , 55 3 , 58 6th , 47 7th , 59 found: , 55 , 67 , 42

Example 4

A solution of 350 rag 1-I.Iethyl-5- (o-fluorophenyl) -1,3-dihydro- ™ 2H-thieno- / 2, 3-e / -1,4 ~ diazepin-2-one in 2 ml of bichloromethane dropwise with 190 mg of sulfuryl chloride in ".:. ^ 1 bichloromethane offset. The reaction mixture is left for 130 minutes at room temperature stirred and, after neutralization, extracted with bichloromethane using aqueous ammonia. The dichloromethane layer is washed with water, dried and concentrated under reduced pressure. This gives an oily one Residue which, when crystallizing from ether, results in the h-methyl-5- (o-fluorophynyl) -7-cblor-1,3-dnhydro-2H-thieno / 2,3-e7-1,4-diazepin-2-one from P. 101 to 103 ° C results. After recrystallization from isopropanol, the colorless prisms melt at Ί01.5 to. 1O3 ° C.

Analysis C ₁₄ Ii ₁ QfT ₂ Cl ₁ F ₁ O ₁ S ₁ :

C ₁

calc .: 5 ^, ^ - 5 found: 5 ^, 25

H 26th 9 K C. ι 10 §. 3, 17th 8th , 07 11 , 48 10 , 39 3, , 81 11 , 27 , 40

209822/1049

Example 5

A solution of 800 mg of 5- (o-3-fluorophenyl) -1,3 ~ dihydro-2H-thieno- / 2,5-e / "- 1,4-diazepin-2-one in 8 ml of glacial acetic acid is added dropwise with a solution of 490 mg of sulfuryl chloride in 3 ml Glacial acetic acid added. The reaction mixture is stirred for 2 hours at 50 ° C. and then for 15 hours at room temperature.

The mixture thus obtained is poured into ice water and, after neutralization, using aqueous ammonia (28 percent by weight) extracted with chloroform. The chloroform layer is washed with water, dried and under evaporated under reduced pressure. When the residue is chromatographed on silica gel using a mixed solvent 1 part by volume of ethyl acetate and 9 parts by volume of chloroform gives the crystalline 5- (o-fluorophenyl) -7-chloro ~ 1,3-dihydro-2H-thieno- / 2,3-e / -i, 4-diazepin-2-one, which when recrystallized from ethanol gives colorless needles with a temperature of 246 ° C.

analysis C ₁₅ H ₁ 3N ₂ Cl ₁ P ₁ S 1 ° 1 H '9 N 12th Cl 10 S. CJ 73 9 , 50 12th , 03 11 , 88 ber .: 52.98 2, 69 , 48 , 13 , 00 found : 52.89 2,

B e is ρ i e 1 6

A solution of 425 mg of 1-methyl-5- (o-chlorophenyl) -1,3-dihydro-2H-thienO " ₍ / 2,3-eJ ^; '-1,4-diazepin-2-or!" In 3 ml A solution of 217 ml of sulfuryl chloride in 3 ml of dichloromethane is added dropwise to dichloromethane.

209 8 2 2/1049

stirred at room temperature, then neutralized using aqueous ammonia and extracted with dichloromethai. The dichloromethane layer is washed with water, dried and evaporated under reduced pressure. After chromatography on silica gel using chloroform as the eluent, the residue gives the oily 1-methyl-5- (o-chlorophenyl) -7-chloro-1,3-dihydro-2H ~ thier'd ₁ ß.razepm-2- on, which when crystallizing from diethyl ether / hexane gives a white powder with a melting point of 81.5 to 84 ° C. When recrystallizing from diethyl ether, colorless prisms from P. 82.5 to 84- ⁰ C. are obtained.

Analysis C ₁ ^ H ₁ 0 ^N 2 ^C 70 ) ₁ : H 8th N 21st Cl 9 S. 9. 62 , 10 8th , 62 21st , 80 9 , 86 ber .: 51, 3 , 22 Λ7 , 61 47 found: 51, 3

Example 7

A solution of 350 mg of 5- (o-chlorophenyl) -1,3-Ä.ihydro-2H-thieno- / 2,3-e / -1,4-diazepin-2-one in 4 ml of glacial acetic acid is added dropwise with a solution of 222 mg of sulfuryl chloride in 4 ml of glacial acetic acid offset. The reaction mixture is stirred at 50 ° C. for 6.5 hours.

After cooling, the reaction mixture is poured into ice water, using aqueous ammonia (? £ J-go weight percentage) neutralized and then extracted with ChJoro.forin. The chloroform layer is washed with water, dried and quickly dumped under reduced pressure. The residue will using a wipe of solvent cius 1 part by volume

209822/1049

Chromatographed ethyl acetate and 1 part by volume of chloroform over silica gel. This gives the crystalline 5- (o-chlorophenyl> 7-chloro-1,3-dihydro-2H-thieno- / 2,3-e / ~ 1,4 ~ diazepin-2-one, which, when recrystallized from ethanol, gives colorless needles with a temperature of 24-9 ° C (decomp.).

analysis

H 59 9 N Cl 79 10 S. 2, 55 9 , 00 22 67 10 , 30 2, , 01 22 , 4-1

calc .: 50.18
found : 49.93

At s P ₁₁ _i _ e 1 8

A solution of 500 mg of 5- (o-KLuophenyl) -1,3-dihydro-2H-thieno- / 2,3-q.7-1, 4-diazopin-2-one in 5 ml of dimethylformainide is added in portions while stirring 81 mg of a 63% by weight JTatriui hydride dispersion in mineral oil were added. After stirring for 30 minutes , the reaction mixture is cooled to 10 ° C. and a solution of 309 mg of methyl iodide in 1 ml of methyl formide is added dropwise. The resulting mixture is stirred for 1 hour at room temperature and then poured into 100 ml of ice water. The mixture thus obtained is extracted with toluene. The ^r j? O3uolschicht is washed with water, dried -nd evaporated \ under reduced pressure. At the crime

Öli {.: ej-i_
The 1-ketyl-5- (of luophenyl) -1,3-dihydro-2H-thieno / 2,3-e_7-1,4-diascpin-2-one in form give a pale yellow Prisuen from F.115,6 to 116 ° C, colorless prisms upon recrystallization from ethanol, melting at 115.5 to 117.0 ⁰ C.

209822/1049

analysis

61 C. B e H N 11 S. ber .: 61 , 29 4.04 10.21 11 , 69 found: , 37 4.12 10.20 , 67 i s ρ i e 1 9

A solution of 500 mg of 5- (o-chlorophenyl) -1,3-dihydro-2H-thieno- / 2,3-e7-1,4-diazepin-2-one in 5 ml of dimethylformamide is added in portions with 76 mg of a 63 percent strength by weight sodium hydride dispersion in mineral oil. The reaction mixture is heated for 30 minutes 60 ⁰ G. Well db. the reaction mixture is cooled to 10 ° C., and a solution of 284 mg of methyl iodide in 1 ml of dimethylformamide is added dropwise. The resulting mixture is stirred for 1 hour at room temperature and then poured into 100 ml of ice water. The resulting mixture is extracted with toluene. The toluene layer is separated, washed with water, dried and evaporated under reduced pressure. When the oily residue crystallizes from diethyl ether, 1-methyl-5- (o-chlorophenyl) -1,3-dihydro-2H-thieno- / 2,3-e / -1,4-diazepin-2-one is obtained as a pale yellow powder colorless after recrystallization from diethyl ether gives prisms melting at 109.5 to 111.0 ⁰ C.

analysis

57 C. H 9 N 12th Cl ε I.
J 03 ber .: 57 , 83 3.81 9 , 64 12th , 19th 11 84 found : , 68 3.66 , 46 , 00 10,

209822/1049

Claims (22)

Claims C \ J 1,4-thienodiazepines of the general formula (I) (D in the R ^. a hydrogen atom, a lower alkyl radical or the cycloalkylmethyl group or the remainder E _A 0 _R - (CH ₂ ) _n -N ^, -GH ₂ CN ^ ^G or- (CH ₂ ) _n -OR _E means, where η B% is an integer from 1 to 4 · and R _A , Rq, R _n , R ₁₁ and Rg represents hydrogen atoms or lower alkyl radicals, R _{2 represents} a hydrogen atom or a lower alkyl radical, R. represents a hydrogen or halogen atom and X represents a halogen atom, the nitro or cyano group or a lower alkyl or lower alkoxy radical, and their acid addition salts. 2. Compounds according to claim 1, characterized in that that X is a halogen atom. 3. Compounds according to claim 1 and 2, characterized in that R _x . is a water atom, a lower alkyl radical or a cycloalkylmethyl group. 209822/1049 4. 5- (o-Pluophenyl) -7-chloro-1,3-dihydro-2H-thieno- / 2, 3-e? - 1, ^ - di 5. 1-methyl-5- (o-fluorophenyl) -7-chloro-1,3-dihydro-2H-thieno , 3-e7-1, ^ - diazepin ^ -on. 6. 5- (o-Chlorophenyl) -7-chloro-1,3-dihydro-2H-thieno- / 2,3-e / -1,4-diazepin-2-one. 7. 1-methyl-5- (o-chlorophenyl) -7-chloro-1,3-dihydro-2H-thieno / 2 _y 3-e / -1,4-diazepine-2-oil. 8. 1-methyl-5- (o-chlorophenyl) -1,3-dihydro-2H-thieno- / 2 ~, 3-e / Λ , ^ - diazepin ^ -one. 9. 5- (o-Fluorophenyl) -i, 3-dihydro-2H-thieno- / 2,3-e7-1,4-diazepin-2-one. 10. 5- (o-Chlorophenyl ) A , 3-dihydro-2H-thieno- ^, 3- © 7-1,4-diazepin-2-one. 11. 1-methyl-5- (of luophenyl) -1,3-dihydro-2H-thieno- / 2, 3 ~ 1 ^ - 12. Process for the preparation of the 1,4-thienodiazepines according to Claim 1 to 11 and their acid addition salts, characterized in that one (a) a 2-amino acetamido-3-henzoylthiophene of the general formula (II) 209822/1049 J V ** K * Ri O I Il R ₂ in which R, -, R ₂ , ^ x " ⁰³¹ U- - ^ have the meaning given above , or subjecting a salt of this compound to cyclization, (b) for the preparation of those compounds of the general Formula (I) in which R ^ is not a hydrogen atom 2- (N-Phthalimidoacetamido) -3-benzoylthiophene of the general Formula (III) 0 0 (Ill) O in which R ^, R, uodX have the aforementioned meaning and R ^ the same meaning as R _x . has, but is not a hydrogen atom, reacts with hydrazine hydrate and optionally those compounds of the general formula (I), in which R 1 is a hydrogen atom, to the corresponding halogen compound halogenated or those compounds of the general formula (I) in which R ^ is a hydrogen atom to the corresponding Alky! Compound is alkylated and optionally the free 209822/1049 - 32 bases converted into the acid addition salts. 13. Process according to Claim 12, characterized in that the cyclization reaction is carried out in the presence of an inert solvent makes under heating. 14 ·. Method according to claim 13? characterized in that the mixture is heated to temperatures in the range of 5O ⁰ C to the boiling point of the solvent used. 15 · The method according to claim 12, characterized in that the implementation of 2- (N-phthalimidoacetamido) -3-benzoylthiophene carried out with an excess of hydrazine hydrate in the presence of a solvent. 16. The method according to claim 12, characterized in that halogenation with gaseous chlorine, sulfuryl chloride, bromine, N-bromosuccinimide, N-chlorosuccinimide or a mixture from iodine and yellow mercury (II) oxide. 17. Process according to claim 12, characterized in that the alkylation is carried out with an alkyl halide of the general formula R ^ -Y »in E ₂ , which has the aforementioned meaning, an alkyl sulfate or alkyl hydrocarbon sulfonate. 18. The method according to claim 17 »characterized in that the alkylation is carried out in the presence of a base, preferably an alkali hydride, alkali amide or alkali alcoholate. 19. The method according to claim 12 to 14, characterized that a starting compound of the general formula (II) is 2098 2 2/1049 turns, in the B, - a hydrogen atom or a lower one Alkyl radical and X is a halogen atom. 20. The method according to claim 12 to 15 _5, characterized in that a starting compound of the general formula (III) is used in which R ~ is a hydrogen atom and 1L · is a lower alkyl radical or the cycloalkylmethyl group. 21. The method according to claim 12 to 16, characterized in that the starting compounds for the halogenation those compounds of the general formula (I) are used in which R ~ and R, denote hydrogen atoms. 22. The method according to claim 12, 1? and 18, characterized in that the starting compounds used for the alkylation are those compounds of the general formula (I) in which R _{x is} a lower alkyl radical or the cycloalkylmethyl group and Ro is a hydrogen atom. 23 · Medicinal preparations consisting of a compound of the general formula (I) or its acid addition salt according to Claim 1 and optionally customary, pharmacologically acceptable carriers and diluents. 209822/1049