Substituted benzodiazepines and process for preparing thereof

The invention also relates to substituted benzodiazepine compounds and acid addition salts thereof. The invention also relates to a method of preparation. of these alou's.

The compounds of the present invention can be prepared by the following reaction scheme, which involves the process of converting lactam to amidine in one or more steps, using readily cleavable groups that are replaced in situ or by subsequent reaction with an amine.

<img file="CS197449B1_D0001.tif" />

AND

197 449

<img file="CS197449B1_D0002.tif" />

In the reaction scheme, a is hydrogen, lower alkyl, lower alkoxy, halogen, nitro, trifluoromethyl, methylthio, methylsulfonyl or hydroxy,

(B)₃ is hydrogen or nickel alkyl,

(B)₇ Yeah

<img file="CS197449B1_D0003.tif" />

or Ц

-l- / CH₂/_n-M- / a₅/₂ wherein B * is hydrogen, alkyl, 2-hydroxyethyl, phenyl or nitro phenylalkyl, n is 2 or 3, and

R5 is destroying alkyl ·

197 449

The leaving group X comprises the following groups: S, (halogen) Cl, -OR, in which R is a lower alkyl group, -SR in which R is a lower alkyl group,

<img file="CS197449B1_D0004.tif" />

wherein R is a lower alkyl, fepyl or substituted phenyl, or -ZZ group wherein Z comprises elements such as titanium, silicon, phosphorus, zirconium or aluminum. This group may occur at different stages of oxidation and the substitution may be carried out by a lower alkyl group, a lower alkoxy group, a phenyl group, a substituted phenyl group, a halogen or a phenoxy group.

The present invention provides benzodiazepine compounds of the general formula:

<img file="CS197449B1_D0005.tif" />

wherein R R and Rg are hydrogen, an alkyl group having a total of 1 to 2 carbon atoms; 4 carbon atoms. an alkoxy group having a total of 1 to carbon atoms, a halogen atom, a nitro group, a trifluoroethyl group, a methylthio group, a methylsulfonyl group, and a hydroxy group,

R 1 is a hydrogen atom or an alkyl group containing up to 4 carbon atoms in total,

<td> «7</td><td>is a group</td>

<td></td><td>O ··· Ό • or H -L / CHg / n-Nr / Rj / g</td>

<td>where B₄</td><td>represents a hydrogen atom, an alkyl group having a total of 1 to 4 carbon atoms, a 2-hydroxy ethyl group, a phenylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety;</td>

<td>n</td><td>is 2 or 3, and</td>

<td> «5</td><td>is a (1-4C) alkyl group,</td>

and acid addition salts thereof.

In a preferred embodiment, the above substituted benzodiazepine derivatives are as follows:

10-Z1-piperazinyl / 4H-thieno * / 3,4, b7,5,5-benzodiazepine,

10- (4-methyl-1-piperazinyl) -4H-thieno [3,4] b7- (1,57) benzodiazepine,

4-Methyl-10- (4'-methyl-1-pipereziinyl) -4H-thieno-Γ 3,4, b7 / 1,57 'benzodiazepine,

7-chloro-1⁰~^/4-me^thy^l-l-^piperaz^andJn^{yl /}-4^H~ t^hieno- Z3.4, b⁷ OF^-1,57 ^benzodiaze^pin, 6 * chloro-10- (4-methyl-1-piperazinyl) -4H-thieno- [3,4, b], ξ benzodiazepine, 7-chloro-4-methyl-10- (44-methyl-1'-ppJ) * trans-4H-thieno- [1,4] b / 1, 57 benzodiazepine, and.

101piptridinO14H1thisnO1. (73.4, 17.77, 57) benzodiazepine.

The present invention also provides several processes for the preparation of the benzodiazepine derivatives of general formula (I) which will be described in the following.

j '187 448 «I · *.

According to the first embodiment of the process for the preparation of the bonsodissopine derivatives of general formula (1) mentioned above, in which my R 6, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8 and R 8. In the above reaction, a compound of the general formula is reacted:

<img file="CS197449B1_D0006.tif" />

in which Rj_, Rg and Rj and the amine of general formula:

the same substituents as mentioned above,

<img file="CS197449B1_D0007.tif" />

or

H

HN- / CH₂/_n-H / R₅(g) wherein R ^ denotes a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an S-hydrosyethyl group, a phenyl group or a phenylalkyl group having 1 to 4 carbon atoms in the alkyl moiety, n 'being 2' or 3, and

R 1 represents an alkyl group having a total of 1 to 4 carbon atoms, the pH at which the temperature is elevated ^poh^ybuj^andC^and and in rosmes from 100 to. 200 ° C, whereby the reaction^pIt is run for a period of from 10 to 120 hours in the presence of acetic acid.

Another embodiment of the process for the preparation of bensodiasepine derivatives in general^ého vsorce / V », in which they have^and Rj. , Rg,.^Rj , - R ?, R? R^j and the above exemplification is a process^, at tterta, the reaction is initiated at. a temperature range from - 100 to 250 ° C of a compound of the general formula:

<img file="CS197449B1_D0008.tif" />

R is hydrogen, and in which R is₂ » * ^with3 and the amine of formula:

<img file="CS197449B1_D0009.tif" />

or

H₂NvCH₂/_n-N- / Ry₂ in which R ^, Rj and n are as defined above, the resulting product has fallen.

In another embodiment of the process for the preparation of substituted benzodiazepine compounds of formula (I) in which 8, R 1, H 2, J 1 and J 1 are as defined above, the reaction comprises reacting a compound of the formula

<img file="CS197449B1_D0010.tif" />

wherein R is hydrogen, and

Rf, B₂ and R1 is as defined above,

197 449 cl-s-χ in which X represents an alkyl group having a total of 1 to 4 carbon atoms, a phenyl group or a substituted phenyl group, followed by reaction with an amine of the formula:

<img file="CS197449B1_D0011.tif" />

or

H₂N- / CH₂/_n-J- / R₅/₂ and then the product is separated ·

SUMMARY OF THE INVENTION In another embodiment of a process for the preparation of substituted benzodiazepine compounds of formula (I) wherein R 1, R 2 are₂ , R ^, R? R R, R ^ and n are as defined above, characterized in that a compound of formula (I) is reacted

<img file="CS197449B1_D0012.tif" />

wherein R is hydrogen, and

R ^, R R 'and R ^ are as defined above, with a compound of the formula:.

in which it means

<img file="CS197449B1_D0013.tif" />

^R7 amine of formula:

<img file="CS197449B1_D0014.tif" />

or

HgN-ZCHg / nN-ZRj / g, wherein Rj₍ Rj and n already have the above-mentioned meaning, while delaying the resulting product.

Another embodiment of a process for the preparation of substituted benzodiazepine compounds of formula (I) wherein R 1, R 6, R 6, R 6, R 6, R 6 and n is as hereinbefore defined is to react a compound of the formula:

<img file="CS197449B1_D0015.tif" />

wherein R is hydrogen, and

Ry, Rg, Rj are as defined above, with a compound of the formula:

187 448

CH, i³_x

CH2 - Si - Cl

CH₃ followed by reaction with an amine of formula:

<img file="CS197449B1_D0016.tif" />

or

H₂N- / CH₂/ nH- / H₅/₂ wherein R4, R3 and n are as defined above, wherein the product is separated

In another embodiment of the process for the preparation of substituted benzodiazepine compounds of formula (I), in which R R, Rg, Rj, Βγ, Rj and n are as defined above, a compound of the formula:

<img file="CS197449B1_D0017.tif" />

wherein R is hydrogen, and

R3, R8 and R3 are as defined above, with a compound of the formula:

CH₃^E Si ^β Ry

0Η₃ in which · represent · R?

amine of formula:

<img file="CS197449B1_D0018.tif" />

or

H₂N- / CH₂/ⁿ- / H₅/₂ wherein R 1, R 2 and n are as defined above, the product formed is separated.

SUMMARY OF THE INVENTION A further embodiment of a process for the preparation of substituted benzodiazepine compounds of the general formula (X), wherein R 1 is a compound of formula (X). , Rg, Rj, R? "R 1, R 1" and "R", as defined above, consists in reacting a compound of the formula:

<img file="CS197449B1_D0019.tif" />

wherein R is hydrogen, and

Rx, Rg ', Bj are as defined above, and phosphorus pentachloride, followed by reaction with an amine of the formula:

<img file="CS197449B1_D0020.tif" />

197 449

<img file="CS197449B1_D0021.tif" />

or

H₂N- / CH₂/_n-M! - / a₅/ 2, where, Rg and n already find the ehbra meaning, whereby the resulting product is separated *

The essence of another embodiment of a process for the preparation of substituted benzodiazepine compounds of the general formula (1) in which they have ®1 »Rg * ^йз ♦ * 7 · 44 ♦ R5 ^and n The above meaning is that a compound of the formula:

R 0

<img file="CS197449B1_D0022.tif" />

wherein R is hydrogen, and

R1, Rg and Rj are as defined above, the formula:

with a complex 'compound' of an amine and a 'metal' of the IVb group of a 'periodic' system, said 'amine having a general

<img file="CS197449B1_D0023.tif" />

»

<img file="CS197449B1_D0024.tif" />

or

H₂M- / CH₂/_n-On₅/₂ ,......

wherein R4, 'Rg' and n are as defined above, at a temperature ranging from 100 to 250 ° C and in the presence of a solvent such as anieol or

SUMMARY OF THE INVENTION A further embodiment of a process for the preparation of substituted benzodiazepine compounds of the general formula (1), in which Rg, Rg, Rg, R6, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8 and R8 are R8. , R4, R8 and n are as defined above, comprising reacting a compound of the formula:

toluene, the product separated *

<img file="CS197449B1_D0025.tif" />

wherein R is hydrogen, and

Rj, Rg and Rj are as defined above, and triethyloxonium fluoroborate in a solvent such as methylene chloride at ambient temperature.^pLots moving in range^and from 5 to 20 ° C^{R, at}Which then does not sweeten the reaction with an amine of the formula:

<img file="CS197449B1_D0026.tif" />

or

HgN- (CH2) nH- / R₅/ 2, wherein R1, R1 and n are as defined above, in the presence of a weak acid at ^tE^plot^E move^bin the range of ЭД0 to 250 ° C, whereby vzⁿto sell ^{se o}&lt;Monday ·

The starting compounds used in the above processes for preparing the compounds of the present invention can be prepared according to the following schemes.

<img file="CS197449B1_D0027.tif" />

197 449

<img file="CS197449B1_D0028.tif" />

/ 11 /,

Preferably substituted 1,3,4_t9-tetrah; yd ^ o-¹OH-thieno /³_t4, b7 jj^,G7benzodiazep^andn10-one of structural formula (IIIa) in which R1 is a methyl group, may be prepared by reacting N-methyl-o-phenylenediamine and methyltetrahydro-4-oxo-3-thiophenecarboxylate at reflux temperature. The compound of structural formula (IIIa) is then combined with sulfur,^exwhere the emergence: poor^dpov^andda.j^andInsulated ^4,9-dihy^dro-^10H~^thieno Z⁴,^b, bj7 ** 1,5J7-benzodiazepin-10-one, structural formula (11) is separated.

The compounds of Examples 14 - and 11 can be prepared as described above, wherein the compound of structural formula (IIIa) is substituted with an R 1 substituent converted to ethyl with N-ethyl-o-phenylenediamine. The compound of formula (IIIa) is then reacted with N-chlorosuccinimide in a suitable solvent to give a compound of formula (N) in which R 1 is ethyl.

A compound of structural formula - (IIIa) in which Rf and Rg is chloro and Rj is methyl is prepared by reacting N-methyl-4,1-dichloro-o-phenylenediamine with methyltetrahydro-4-oxo-3-thiophenecarboxylate at temperature reflux condenser. This compound of structural formula (IIIa) is then converted to the corresponding substituted compound of structural formula (11) by reaction with N-chlorosuccinimide.

Preferably, a substituted compound of structural formula (II) wherein R 1, R 2, R 8 is hydrogen can be prepared by reacting methyltetrahydro-4-oxo-3-thiophenecarboxylate and o-phenylenediamine in a suitable solvent such as toluene, the reflux temperature. The compound of formula (IIa) is then converted to the corresponding substituted compound of formula (IIe) by e-treatment with N-bromosuccinimide in dimethylformamide at ambient temperature.

Further starting compounds can be prepared according to the following reaction equations:

<img file="CS197449B1_D0029.tif" />

'WITH

197 449

15 / CH₃O / zSO₂ in

<img file="CS197449B1_D0030.tif" />

Particular compounds within the scope of the present invention are: 10-4-methyl^l-^l-^pand^perazine^yl^/-4H-^thieno ^{£ 3,4,}67 N -benzodiazepine, N-chloro-4-methyl-N, N-methyl-4-piperazin-4-yl-oxo-C 3,4,4,6^{7 £ I,}577 benzodiazepine,

6-chloro-10-Z4-methyl-1-^pO^peraz^Onyl^OF-4^H-th^andeno- (73,4,17) -S-Tbenzo-4-azein,

7-chloro-10-Z4-methyl-1-piperazinyl-4H-thieno- Z73,4, b7 Z7I »5.77benzndoazepine_t

4-ethyl-1/4/4-methyllyl-ee^perosinzl4H-ihinno- (73.4, S7)_&gt;J7benzndoazeein,

IO-pperoperdn-4H-thenoeno- / ~ 3,4-b7 £ 1,5_7benzenediazee_&gt;^AND0-^OFl-^p0peraz^Ony^lZ-4^H-th^Oenn^{/ 7з}_t⁴-^{£7 /}7^1,2⁷ “ ^- benzodium,

I0- / 7 4-Z2-h^ydroχyethyl^OF-l-^piperaz^Onyl7-4^H-th^andeno- / 73.4-17- /^{7 and}^ 7beznz^andiazepine_J

IO-Z4-phenyl-1-^p3,4-benzodiazepine, 10-Z4-benzyl-1-ee-azazinyl-4H-thienine⁷3,4-ε7 Z⁷AND_t57benzndoazep0n,

T-chloro-^10-/ 4-^of2-lhf drug^χгet^bhl^lzl-^-eoeгazioyl7^-4H-^th0enn-^{/7 3,}4-b7 Z^AND, ^ benzodOazep.in,

4-Methyl-10-Z1-piperazinyl-4H-thenoeno 73,4-b7 Z^_I, 57benzenediazeein_&gt;

10^-Z 4-^OF2-d^andmethylam⁰noethyl^OF-^l-^p0eeraz⁰nyl7 * 4H-th⁰eno-Z73^,4-J £ 7 / ~ 1^,57benzndiazepine,

5-flunr-1^O-^Z4-methy^l-^l-^piperaz⁰nyi^OF-4^H-t^h0enn^Z7з,4^нJ7-OF⁷ l, JZbβnzod^Oand that^p0n^,

6- tr^tflunrmethyl-^ANDO-^Zl-^piperaz^andny V - ^^ Weno ^ /³,^4-b ^ -_&lt;/^-1,7^OFbenznd^Oazθ^aftern, 6-fluoro-4-methyl-4- (4-methyl-1-piperazinyl) -1H-thieno-^-/“ 3^,4-£7 ^Z71,J 1 benzene-dazazone_l

7-mntox1o-Z5^Z4eщ_θtlyl-eoeipezozin-1-H-pyrimidine 3,4-6 / -71 • Ibeenoddiazepine,

6,7-dichloro-10- (4-methyl-1-piperazinyl) -1H-thieno [3,4-b] -4,4-benzodiazepine,

5-Methoxy-10- (1-piperazinyl) -4H-thieno [3,4-b] -1,7-benzodiazepine

6,7-dimethyl-10- (4-72-hydroxyethyl) -1-piporaziny-4 H -thieno [3,4- b] -1,7] benzodiazepine,

6,7-dimstoxy-10- (4-methyl-1-piperazinyl) -4H-thieno [3,4b7] -1, benzamide zepine,

8-chloro-10- (1-piperazinyl) -4H-thieno [3,4-b7] 1,57benzodiazepine,

4-Ethyl-10- (4-methyl-1-piperazinyl) -4H-thieno)^_3,4-E7 - / 1,57benzodiazepine,

7-chloro-4-propyl-10- (4-ethyl-11-piperazinyl) -4B-thieno [3,4-a] [1,7] benzo-diazepine,

7-chloro-4-methyl-10- (1-piperazinyl) -4H-thieno [3,4-b7- [1,5,5] benzodiazepine, 7-chloro-10- (1-piperazinyl) -4H-thieno] 4 ', 4-phenylethylbenzodiazepine

5-chloro-10- (4-methyl-1-piperazinyl) -4H-thieno [3,4-b] -benzodiazepine, 7-hydroxy-10- (4-methyl) -1- piperazines 1 / -4H-thieno [3,4,4] -7,5,5-benzodiazepine,

6-hydroxy-10-4-methyl-1-piperazinyl / -4H-thieno [3,4- b] - [1,5] benzodiazepine

10- [4- (3-dimethylaminopropyl) -1-piperazinyl] -4H-thieno - [3,4-b7] -1,17-benzo diazepine,

7-methylsulfonyl-10- (4-methyl-1-piperazinyl) -4H-thieno - [3,4-b7] -1,7-benzo diazepine,

10- (1-piperazinyl) -4-ethyl-4H-thieno [3,4-b7] methyl-benzodiazepine,

4-ethyl-10- [4- (2-hydroxyethyl) -1-piperazinyl] -4H-thieno- [3,4-b7] 1,1'-benzodiazepine,

7-nitro-10- (4-methyl-1-piperazinyl) -4H-thieno [3,4-b] -benzodiazepine; and

6-methylthio-10- (4-methyl-1-piperazinyl) -4H-thieno [3,4-b7-] 1,57benzodiazepine

The compounds of the present invention are potent analgesic agents, the effect of which can be ascertained by conducting a test for ** seizure syndrome to monitor analgesic activity as described by Siegmund et al., Proc. Soc. Exp. Bio.and Med., 95, 729 (1957), and various modifications. This method is based on the reduction in the number of convulsions following intraperitoneal administration of one mg per kilogram body weight of phenyl, p-quinone in white dishwashers (male) weighing 15-25 g. This syndrome is characterized by intermittent abdominal contractions, twisting and writhing of the trunk and stretching of the hind legs, which appear after 3 to 5 minutes after administration of phenyl, p-quinone. Test compounds were administered orally at the indicated dosages to groups consisting of two animals, the test compounds

187 448 were administered 30 minutes before the administration of phenyl, p-quinone. The total number of seizures exhibited by each wash group was recorded for 3 minutes starting 13 minutes after phenyl, p-quinone administration. Compounds were considered active if the total number of seizures in the two mice tested was reduced from a control value of 30 to a pair to X8 or less. Table I below shows the overall results of this test on selected compounds of the invention.

Table I

<td>Compound .....</td><td>Dose (mg - / kg)</td><td>A number of convulsions per pair of animals</td>

<td>X0- (4-methyl-1-^p(piperazinyl) -4H-thieno [3,4-67] &amp; lt; 5 &amp; gt;⁷benzod^andand that^Fri4-Methyl 1-10- (4-methyl-X-piperazinyl) -4H-thieno [ 3,4-67] -benzodiazepine 7-chloro-10- (4-methyl-X-pi)^perazinyl) -4H thieno (= 3,4-67) ”1,5_^7benzod^andand that^Frin, dichloromethane 6- c^hlsteed-¹⁰-⁽4-meth^y1-¹-^pand^peraziny¹⁾-4^Hthieno [3,4-b7] -1,5,7-benzodiazepine 7-chloro-4-methyl-X- (4-methyl-X-)^pand^peraziny1) 4^H-t^hieno / 23 »4-p⁷ OF"¹,5_7^Eenzod^andаzepine, dichloromethane</td><td> 6,25 50 1,6 6,25 1,6</td><td> 4.2 0,0 1.2 7,6 6,2</td>

The compounds of the invention are useful as agents for the alleviation of pain and inflammation in warm-blooded animals. In this case, a modification according to Randall and Selitto / Arch was used to determine the analgesic activity. Int. Pharmacotyn.i^XXX&gt; 4⁰9 / ^χ957 / ^/· The nature of this test^whoseby detecting threshold pain in rats whose paws were more susceptible to compression than normal by injecting 0.1 m of a 20% aqueous suspension of brewer's yeast under the skin of the left ^ofPaws · Swelling t^land^pku then ptaobita et^ále increasing network⁰a / ryc^hl° st^and16 g / sec. / Analgesy Meter, Ugo Basile was used for this purpose. This paw concealment was discontinued when the paw was applied at 250 g, at which point the test animal was no longer responding / in this case there was a lot of stress and loud sounds. audio speeches. Control rats given the control composition, which was a starch solution, exhibited a pressure response of about 30 g. Initial pressures of pain caused by pressure were always recorded two hours after brewing yeast administration. An estimate of analgesic efficacy was calculated and recorded as the ratio of response of the treated animal (T) to the control animal (C). Test compounds were considered to be effective if they exhibited a 100% susceptibility reduction (T / C ratio 1.37). The results of this assay, which was conducted with selected compounds of the invention, are shown in Table II.

Table II

<td>Compound</td><td>T / C ratio</td>

<td>benzodiazepine</td><td> 1,57</td>

<td>71chlor141mtthy11'10- (41methy1111piptraziny1) ^ 4Hteteno / 1M-⁶⁷ /^ll57^benzo^diazt^pin&gt; dichteristan</td><td> 1,55</td>

The compounds of the present invention are psychically active on the central nervous system and exhibit high activity as anti-psychotic or neuroleptic. ^Cinid^land. ^{V t}om^to - if Ьу¹ a test for detectable anti-peychotic activity was used^erýthe reduction in motor activity in said animals was measured.

Groups consisting of 4 rats were treated orally with compound dissolved or suspended in the starch composition at the maximum allowable dose. At the estimated time when the peak effect occurred, the animals were housed individually

187 448 into the Animax Activity Counter, and the activity of each rat was recorded at an interval of 9 minutes. Values^y akHvR b^ywere compared and predisposed. or^para^leln^andm^and tontrolním.

values ​​to detect an increase or decrease in motor activity.

The compounds of the present invention were considered active if the values ​​of these activities were 50% or lower than the control values.

In this test, the median effective dose (MDD), which is the dose at which a 50% reduction in motor activity occurs for each group of 6 rats, was determined by least squares method (DF Finney, Statietical Methods in Biological Assay, Second Edition. Hofner Publishing Co., New York ^ 45⁶-457 ^/19^{64/ /} . AT^whosefinancial lining, ' ^toter^E cause 5⁰ % reduced! The motor activities (MDDjq), expressed in mg / kg body weight, of several typical compounds of the present invention are listed in Table III.

Table III

<td>Compound 1. ..... ...... '. . '. . '. . '....</td><td>mdd ^ q (mg / kg)</td>

<td>¹0-⁽Ethyl-1β^andpe ^ az^andn = 1) -4^H-t^hienoj '3,4-b7- / ”1.57benz^andazep^andn</td><td> 6,1</td>

<td>6-chloro-10T (4-methyl-1-piperazinyl) -4H-thieno [3,4-f] -benzamide;^l_l5⁷benzod^andazep^andn.</td><td> 7,7</td>

<td>7-chloro-10- (4-methyl-1-piperazinyl) -4H-thieno [theta] 3_F4-fi7 j ”¹,and⁷benzod^andazep^andn, ^dich^lsteed^andtent</td><td> 20</td>

<td>7-chloro-4-methyl-10- (4-methyl * 1 'Plperaz: Lnyl) - 4^H-th^andenoj * 3,4-§⁷ j ”¹,5^Tbenžo^diand that^Frin^, ^ c ^ oristan</td><td> ..... 25</td>

<td>⁴-methyl-10-⁽4-methyl^y1-¹-^Friperaz^andn^yl)-4^H-th^andeno / 3,4-b⁷ /¹,and⁷benzod^andazep^andn</td><td> 12</td>

The compounds of the invention are psychologically active on the central nervous system and exhibit high activity as anti-psychotic or neuroleptic agents.

In this case, an assay for detecting anti-paychotic activity was used, which consisted of b^ywas found in said animals ^,

Ptoza is determined by closing the eye^ho lids that^E is in^heavier No⁷⁰ %. ^WITHlou^CThe compounds of the invention that were tested were administered orally to groups consisting of 10 rats. Gradually, after treatment, the rats were carefully placed on the upper surface of the rat^pwhere b^yfound in them ^pO ^dobu 9⁰ sekun^dptoza. This, ma ^ i^pulov^andn^andit excludes the apposition of ptosis. The rats were then released from a height of 55 cm / exteroceptive^withtimula^ce / on the top surface of the cage in order to achieve^and reveralbiHty ^pt ° zy. ^Reverzn^{í p}t^OZ is defined as less than 70% of revolutions^andThe eye is closed ^pO ^dobu ^del^šThis is indicative of the neuroleptic activity of the administered compositions. This test has been described by DR Tedeschi in the article Criteria for the Selection of Pharmacological Test Procedures by Neuroleptic Drugs, in the Proceesings of the VI International Congress of the Collefium Internationale Neuropaychoprahmacologicum, pp. 145-153 (1968). The results of this test with selected compounds of the present invention are shown in Table IV, which shows the dose of (EDED), which is an estimate of the occurrence of reverse^and ptozy in 50% vol^irand^t.

Table IV

<td>Compound</td><td>^ED5^{0 (}mg^/kg)</td>

<td>¹O- (4-methyl-1p.)^andperazi^nyl) -4R-thien-3,4-b⁷OF"¹,5^7benzo^diand that^Frin</td><td> 13</td>

<td>7-chloro-10- (4-methyl-1-piperazinyl) -4R-thieno- (3,4-b) [1,5] benzodiazepine dichloromethane</td><td> 10</td>

<td>6-chloro-10- (4-methyl-1-piperazinyl) -4H-thieno [3,4-d]⁷ Z ~^l,5^7benzod^andand that^Frin</td><td> 17</td>

197 449

The compounds of the present invention exhibit anti-paychotic activity which can be assured of performing a conditional reflex test.

In this test, the rats (long-Evans species) were administered the compounds of the present invention in a universal starch composition.

According to this test, it was^y rats mortified unit^ifin^E in separate Uectahs, and an alarm signal was heard every 20 seconds. Each rat had the option of squeezing the rod, and if done within 5 seconds, an electric shock was prevented from the cage floor, referred to as a conditional response.

Fifty signals were used in each rat, with almost conditional responses being recorded. The compounds were administered at various dosages. Means that proj^evueats anti-^peychotic activity are notorious in that they make it impossible to form ^podmín^En^éhabout reflex. In this test, the median effective dose (ED 50) was estimated to reduce conditional reflex formation by 50% compared to control animals. The results of this test are shown in Table V.

Table V

<td>Compound</td><td>^EDj0 ⁽"G^/kg)</td>

<td> 10-⁽4-Methyl-i-^pand^peraz^andnyl) -4H-th^andeno / “3^,4-b^andand that^Frin</td><td> 7</td>

<td>4-Methyl-10- (4-ethyl-1-^pand^perazinyl) -4H-thieno- N, 3,4-phenoxy-17-benzediazepine</td><td> 17</td>

<td>Chlorpromazine</td><td> 9</td>

The active compounds of the present invention may be used in the form of mixtures such as tablets, wherein the basic active ingredient is mixed and^andm^and with^ložkam^and like them^klwith^d ob^andln^and ěkro ^ ^andact^Esa^, sucrose, sorbitol, talc, stearic acid, magnesium stearate, calcium phosphate, resins or the like, such as a notoxic pharmaceutically acceptable diluent or carrier. These compositions in the form of tablets or pills may be coated or otherwise compounded with the active compounds of the present invention to provide a dosage form that provides the benefits of the present invention over a prolonged period or with delayed action or with a predetermined sequential effect. For example, the tablets or pills may comprise an inner component and an outer component, the outer component forming a coating of said mold. The two components can be separated by an inner layer that serves to^andb^y nedošl^O to disintegrate in the stomach and allow the vnd.tíW component of the projft to be non-ionic^Cené ^Fto the duodenum.

A variety of materials can be used for this purpose, which may serve as inner layers or coatings, including a large number of polymeric acids or mixtures thereof.^Esí ^polymern^andCh kyHin with ta^tomaterials such as Š^Ealcohol, shellac and cetyl alcohol, cellulose acetate and the like^Cen^andn^y. A particularly preferred internal component is a styrene-maleic acid copolymer, which may be mixed with known materials which contribute to the good properties of the layer.

The compounds of the present invention may also be included in a liquid composition to be administered, which may be, for example, aromatic emulsions with shortening fats such as cottonseed oil, sesame oil, coconut oil, peanut oil and the like, as well as other similar pharmaceutical compositions. For parenteral use, sterile suspensions or solutions may be prepared. Isotonic preparations containing suitable preservatives are suitable for administration by injection. '

As used herein, the term "dosage form" refers to a particular physical unit suitable as a unit dose for a warm-blooded animal, and each unit contains a predetermined amount of active ingredient, which is ascertained as desired. a therapeutic effect, and further a desired pharmaceutical diluent, carrier or other composition. The dosage amount of ee may range from 1 mg to 70 mg per kilogram of warm-blooded animal weight per day, preferably ee being administered in the form of multiple doses. The daily dose may range from 50 mg to 2000 mg. The description of the individual dosage forms of the present invention is determined by the characteristics of the individual active compounds and the particular therapeutic effect to be achieved, or by the limitations of the compounding of these active compounds for terpereutic use in warm-blooded animals as already described. Examples of suitable oral dosage forms of the invention include, for example, tablets, capsules, pills, powder granules, wafers, teaspoonfuls, drip vials, ampoules, or combinations thereof.

The following examples illustrate in more detail the preparation of the compounds of the present invention.

197 449

Example 1. *

Preparation of 1,3,4,9-tetrahydro-4-methyl-10H-thieno- [3,4,4- d] -2,27biphenyl-10-one.

In this example, an aqueous solution of 1.2 g of N-methyl-phenyenylenediamine was made alkaline with an excess of 1 M sodium hydroxide solution and this solution was extracted with toluene. 8 g of methyltetrahydro-4-oxo-3-thiophenecarboxylate. This solution was heated at reflux for 3 hours, during which time $ 0 ml of distillate was collected in DeanStark, collector. the product thus obtained ranged from 196 to 198 ° C.

Example 2

Preparation of 4,9'-dihydro-4-methyl-10H-thieno-4 ', 3,4-b7', 4 ', 7-benzodiezepin-10-one.

A mixture of 0.5 g, 3,4,9-tetrahydro-4-methyl-10H-thieno (3,4-b) (1,5) benzodiazepin-10-one and 0.5 g of sulfur was melted at 0.5 g. 160 ° C + 5 ° C for 1 hour · The fused mixture was diluted to a caustic mass with chloroform and then filtered · The filtrate was chromatographed on silica gel with 9: 1 benzene / methanol to recrystallize the resulting solid from a mixture of methanol and water »to give the final reddish-yellow product · The melting point of the product thus obtained was in the range of 224 DEG to 225 DEG C. (with decomposition).

Example 3

A similar preparation of 4,9-dihydro-4-methyl-10-thieno [3,4-b] -Z^_1,5) benzodiazepin-10-one.

3.8 g, 3,4,9-tetrahydro-4-methyl-10H-thieno] was added to the suspension.^_3,4-b7H-1,57-benzodiazepin-10-one in 15 dry pyridine was added portionwise to a total amount of 2.18 g of N-chlorosuccinimide. The resulting rost was heated on a steam bath for 15 minutes, then cooled and diluted with water. The resulting solid was collected and subjected to recryatalization with methanol to give the final reddish yellow product. The melting point of the product thus obtained was in the range of 224-225 ° C (with decomposition).

Example 4

Preparation of 4,9-dihydro-4-methyl-9- [2- (4-phenyl-1-piperazines) -ethyl] -1H-thienol]³4- [1- [1- (1,4-benzodiazepin-10-one)] dihydrochloride.

A mixture of 0.13 g of a 55% sodium hydride dispersion in mineral oil and 0.5 g of 4,9-dihydro-4-methyl-10H-thieno [3,4-b] - [1,5,5] benzodiazepine 10- in 25 ml of dry dimethylformamide was stirred at room temperature for 0.5 hour. To this mixture was added 0.8 g of N - (2-bromoethyl) - N -phenylpiperazine and stirring was continued for an additional 18 hours. The resulting reaction mixture was cooled, then quenched with water and extracted with chloroform. The dry chloroform extracts were concentrated to a brown oil which was purified by thin layer chromatography (tlc) on silica gel with eluent 2: 1 benzene / ethyl acetate. The oily product obtained was converted to the dihydrochloride and recrystallized from ethanol / swab to give a white solid. Melting point: 180-183 ° C (dec.)

197 449

Example 5

Ex^íprava 4-ethyl-^l, 3,4,9-tetrahy^dro-¹⁰H-th^andeno-1,3,4-b⁷"/" L,^Tbbenzodiazepin-10-one.

An aqueous suspension of N-ethyl-o-phenylenediamine hydrochloride (4.3 g) was basified with an excess of sodium hydroxide in the form of an aqueous solution and then this suepension was extracted with toluene. The combined toluene extract thus obtained^/ in quantity^{í /} 2⁰⁰ m^{£ / was}O ^atgiven 2^,4 ^G methyl 4-oxo-3-thiophenecarboxylate. The resulting solution was heated at reflux for 3 hours, during which time 100 ml of distillate was collected in a Dean-Stak trap. The resulting toluene solution was concentrated to dryness and the residue was recrystallized from ethyl acetate to give the final compound as yellow crystals.^ystalků. Te^pthe melting point thus obtained ^tor^ysta^lto^at se ^afterh^ybova^land within range^and from 195 to 197 ° C.

Example 6

Preparation of 4,9-dihydro-4-ethyl-10H-thienol-3,4-i1,5⁷~ benzod^andand that^Frin-1⁰-onu.

According to this example, a suspension of 0.246 g of 4-ethyl-1,3,4,9-tetrahydrol-thieno-3,44,71-l was suspended.^l,57benzo^diand that^Frinl⁰-on at 2 m^£ such^Eho wrhltau ^atgiven ^pwith parts totaling 0,133 g of N-chloro-succinimide. The resulting solution was heated on a steam bath for 15 minutes, cooled and diluted with water. The solid was collected and recrystallized from a mixture of methanol and water to give the final product as white crystals. The melting point of the product thus obtained was between 201 and 202 ° C.

Example 7

Preparation of 1,3,4,9-tetrahydro-4,6,7-trimethyl-10-H^thifemale - / ”3,4-1j7 l“¹, S7benzo^diand that^Frinl^O~ onu.

According to this example. .was water. A suspension of 4.7 g of N-methyl-4,5-dimethyl-o 26 phenylenediamine, dihydrochloride, was made alkaline with sodium hydroxide solution and then extracted with toluene. To the combined toluene extracts (400 ml) thus obtained was added 2.25 g of methyl-tetrahydro-4-oxo-3-thiophenecarboxylate. The resulting solution was heated at reflux for 3 hours during which time it was cooled^odeb^ryes 250 m^£ distillate for ^pomoci. Dean-Stark^hycovače. Odeteaný rozto^kby^lThe solid was collected and recrystallized from ethyl acetate to give yellow crystals of the final product. The melting point thus obtained^pof crystals ^pbending in the range^and from 25^{0 d}252 ° C ^/ for decomposition ^/Example 8

Preparation 4,9-d^andhydro-4,6,7-trimethyl-10H-thieno [3,4-b] [1,5] benzodiaze^pin-10-one.

To a suspension of 0.40 g, 3,4,9-tetrahydro-4,6,7-trimethyl-1H-thieno-4 ', 3,4-tert-benzebenzodiazepin-10-one in 3 N dry pyridine was added portionwise total amount of 0.21 g of N-chlorosuccinimide. The resulting solution was heated on a steam bath for 15 minutes, then cooled and diluted with water. The solid was collected and recrystallized from methanol to give the final product as yellow crystals. The melting point was 260 ° C d^O 262 ° C.

Example 9

Preparation of 6,7-dichloro-1,3,4,9-tetrahydro-4-methyl¹⁰H^-thi enoZ ”3^,4^-b⁷ Z ”1^,5^7benzod^andazepi.n-10-one *

In this example, a solution of 2.7 g of N-methyl-4,5-dichloro-o-phanylenediamine and J. 85 g of methyl tetrahydro-4-oxo-3-thiophenecarboxylate in 150 µ of toluene was heated with reflux for 3 hours, during which 100 µl of distillate was collected using a Dean-Stark trap. The resulting solution was cooled and the precipitated solid was removed and then recrystallized from ethyl acetate to give the title product as yellow crystals. The melting point of the product thus obtained was in the range^and from 281 to 283 ° C.

Example 10

Preparation of 6,7-dichloro-4,9-dihydro-4-methyl-10H-thieno-3,4,4,7,7-benzodiazepin-10-one.

197 449

In this example, 0.40 g of 6,7-dichloro-1,3,4,9-tetrahydro-4-methyl-10H-thieno was added to the suspension.^,3f4 * b7 ^ * 1,5Zbenzodiazepin-10-one in 2.7 ml dry pyridine added in portions a total amount of 0.18 g of N-chlorosuccinimide · The resulting solution was heated on a steam bath for 15 minutes, then cooled and diluted water to give a solid which was removed and recrystallized from a mixture of methanol and water to give the final product as white crystals. The melting point was 270-272 ° C (dec.).

Example 11

Preparation of 1,3,4,9-tetrahydro-10H-thienoZ-3,4-b7 H -1,37-benzodiazepin-10-one.

According to this procedure, a solution of 0.4 g of methyl tetrahydro-4-oxo-3-thiophenecarboxylate and 0.27 g of o-phenylenediamine in 35 ml of toluene was heated at reflux for a period of time.

2.5 hours during which 15 m £ of distillate was collected using a Dean-Stark trap · The resulting solution was cooled and the precipitate was removed · Recrystallized from dimethylformamide / water to give the final product as yellow crystals · The melting point of the product thus obtained was in the range of 216 to 218 ° C.

In a similar manner, 4-fluoro-phenylenediamine was condensed with methyl-tetrahydro-4-oxo-3-thiophenecarboxylate to give a mixture of 7-fluoro- and 6-fluoro-1,3,4,9-tetrahydro-10H-thieno [theta] 4.^w3,4 * b7 ^ * 1,57-benzodiazepin-10-one ·

When similar procedures are carried out, the following product mixtures can be obtained with the aid of the following starting compounds:

4-methoxy-o-phenylenediamine

4-hydroxy-O-phenylenediamine —------------- *,

4-tfifluoromethyl-f-felylene --- · diamine efiulrelefefylenediamine&gt;

4-fimrl-1-feftiefdiamif

4eoemetlthiOeOefeftlefdiaoif »

4eoethtiaulfoftielefeftlef »

7-Oethoxy-, and S-methoxyl-3,4-tetrahydro-1H-methanol (3,4-b7e).

/ 1,5/^benzldiazepine-10-of

T-hydroxy, and? -Hydroxy-1,4-tetraethyl^drl^elOHeteienl * 3, 4 ^ 7/ * lιí7benzld^andand that^Frin-¹⁰eln

7etrifiulgememeyl-, and S-triflulroemeyi1,3,4,9-te tra drl · 10Hethienl-g * 3,4-J7 g ~^and,2^7bθnzl^diazep^andF-¹⁰-ln

5-fluoro-, and 8-fluoro-1_F3_l4,9etetгae e ^^dгoe^iOHem^Eienl / 3,4eb⁷eg γ-g enzodiazepine 10-1

T-nitro-, and 6efimгo-1_F3_&gt;4.9-metaeydro « ^iOHE^meieno^G^ З, 4-] 2⁷E/"^and,5^7bθnzl^diazep^andf10-oi

T-methyl-o-, and β-oemeyiteioel_&gt;3,4,9 ^ ratytoo-ЗЮН-ЧИХепо ^ З ^ -Ь⁷ Z-gb-benzodiazepine 10-1f

7-memethylaiphenyl, and .alpha.-ethylaiphenyl 1,3,4,9-tetrahydro-OH-thienyl * 3,4-J7 (1,5)^benzldiazepineiO-ln.

Example 12

PMprava 4,9e^dietdrle^10HeteieflÁЗ, 4-b7 £ 11.5? befzodiazepif-10eone_t

According to this procedure, the solution was 1.1 gI, 3,4,9-dimethylether (&amp; gt; 10H-thieno * 3, e-6). ¹,⁵/^benz^ldiazep^andn^-10eln^at and ^0,9 g⁰ uí dioete^yIforoamidamide is stirred for 1 hour at room temperature, then diluted with water at 200 ° C and cooled. This produced a precipitate which was collected and crystallized from

197 449 from a mixture of methanol and water to give the final compound as red-yellow cr^ystalků. The melting point thus lost^pgenus^tohere ^poh^ybova^l in range^and from 2¹⁸ to 2²⁰ ° C (with decomposition).

In a similar manner, the mixture of 7-fluoro- and 6-fluoro-1,3,4,9-tetrahydro-10H-thieno [3,4-a] [eta] &amp; lt; 5 &amp; gt;^l,5^7benzo^diand that^pin^-10-onu z^pgulls^andin^andon ^Nbromsukc^andn^andm^anddem, ^přičem^oforiginated as a horse^Cný ^pro^dukt 7-^fluor- a 6-^fluor-4_l9-^dihydro-1^0H-t^hieno / ”3,4-5⁷ j ”^{1, g7}benzodiazepin-10-one.

By using the same procedures and starting materials listed below, the following product mixtures can be obtained:

7-Methoxy- and 6-methoxy-1,3,4,9-------- ► tetrahydro-10H-thienoyl-3,4-benzodiazepin-10-one

7-hydroxy- and 6-hydroxy-1,3,4,9- --------^dro^-1OH-thieno &lt;/ * 3,^4-b⁷ j "¹,1⁷benzodiazepin-10-one

7-Trifluoromethyl and 6-trifluoromethyl-1,3,4,9-tetrahydro^ydro «^10H-t^hieno-_&lt;j3,4-¾⁷j ”1, 1⁷benzo^diaze^pin-¹⁰-he

1-fluoro- and 8-fluoro-1,3,4,9-tetra- ------- hydro-10H-thieno]^-3.4-b⁷ £“1,^g7benzodiazepin-10-one

7-methoxy- and 6-methoxy-4,9-dihydro-4 H -thieno [f] -b⁷ [11] benzodiazepine-10-one

7-hydroxy- and 6-iy^droxy-4,9-dehydro-4 &amp; apos;^,4^-b⁷ N -benzo-azein-10-one

T-Trifluoromethyl- and 6-trifluoromethyl-4,9-dihydro-10H-thienol-3,4-b7 / 1,17-benzo^deaznpin-10-one

5-flr- and 8-fluoro-4_t9-dihydro-10HШппо⁷*-*^1,1^7benzo^diand that^peO-¹⁰-ln

7-methyl- and 6-methyl-1,3,4,9-tetrahydro^rl-10H-hhieno7,3^,4-⁷7-^/l^l17 benzldeazepin-10-one

7-nitro- and 6-nitro-4,9-dehydro-10H-thieno- *³,⁴^⁷ /^ll,^g7benzo^diazθp^En-1⁰-oo

7-methylthyl and 6-methylthio-1,3,4,9hehra^andУ^drl-^10H-th^Enno-j 3,4-j⁷ £ Zl »1^{7 b}enzldiazepine-10-lo

7-methylthio- and 6-methylthio-4,9^dehy (h * o-10H-t^hienol^/3,4-Ь⁷ £*¹^,1^7bnzldiazepin-10-one

7-methylsulfinyl-a

6-methylsulphonyl 17-methylsulphonyl-6-methylsulphonyl ^1.3.4.9 ^tra^hydгo-10-t^hienol^/3^,4-¾⁷ /2¹.1^7benzo^deand that^Frin-¹⁰-oo

4. ^^^^ го-КШ - ^^ по! "^3, 4-^b7 /"AND,¹⁷benzodiaznpeo-10-one

Example 13

Preparation of 4,9-dihydro-9-methyl-10H-thienoZ-3,4 - (7H, 1,27-banzodiazepin-10-one).

According to this procedure, a stirred mixture of 0.84 g of 4,9-dihydro-10-thieno [3,4-f] -7,5,5-benzodiazepin-10-one and 0.18 g of a 55Ϊ dispersion of sodium hydride and mineral oil in 25 m-dimethylformamide, 0.3 mC of methyl iodide was added. The resulting reaction mixture was stirred for 2.5 hours, cooled, diluted with water and finally filtered. The resulting solid was recrystallized from methanol / water to give the final product as pale yellow crystals. The melting point of the product thus obtained was between 195 and 198 ° C.

Example 14

Preparation of 4-benzyl-4,9-dihydro-9-methyl-10H-thieno [3,4-b] [1,5] benzodiazepin-10-one.

According to this procedure, 0.92 g of 4,9-dihydro-9-sethyl-10H-thiono [3,4-b7-] -1,2-dihydro-9-ethyl-10H-thiono was added to a stirred solution of 0.18 g of 57% aq. , 57benzodiazepin-10-one and 0.8m of benzyl bromide. The resulting mixture was stirred at room temperature for 3.5 hours, then quenched dropwise with added water, further diluted with 200 ° C water and extracted several times with chloroform. The chloroform extracts were combined with magnesium sulphate aulenes, and then the solution was concentrated under reduced pressure to give an amber oil which was triturated while crystallizing with methanol. Further, recrystallization was carried out from aqueous methanol and then from ethyl acetate to give the final product as white crystals. The melting point of the crystals thus obtained ranged from 151.5 to 153 ° C.

Example 15

Preparation of 6-chloro-4,9-dihydro-10H-thieno [3,4-d] (7,1,5) -benzodiazepin-10-one.

197 449

1.6 g of 7-chloro-6-chloro-1,3,4,9t was added to the mixture^Etr^andhydro-10H-thieno [3]^,4-f27 Zl^,5⁷e · nzodiаze^Frin ·¹⁰-onm / which ^by^land during^pby tondensation of 4-chloro-o-phenylenediamine and methyl tetrahydro-4-oxo-3-thiophenecarboxylate in toluene ^pat ref^luxu / v ¹² min pyrimidine ^při^dyes after ^Cás^tech O,^{85 G} N-chloro-succinimide. They were also for this solution^při^willny ³ mp - pyridine and ssto ^by^land warmed up ^p15 to 20 minutes. The resulting mixture was cooled and diluted with water to give gold colored crystals which were collected by filtration. This product was recrystallized from methanol to give 0.39 g of product. The melting point thus obtained for^duktu se ^poh^ybova^land from ²⁷9 ^do - ²⁸¹ Deň: 32 ° C.

The filtrate obtained from this procedure after the addition of water was treated as described in Example 16.

Example 16

Preparation of 7-chloro-4,9-dihydro-10H-thieno]^3,4-Ь⁷ OF"^l,2⁷-^benzo^diand that^Frin-^χ0-onu ·

The aqueous filtrate obtained in Example 15 was further diluted with water to give yellow solid crystals. This solid was recrystallized from aqueous methanol to give 0.4 g of the final product. The melting point is thus obtained n^EThe product is adjusted to within the range of 1: 1^and O^{d χ}97 to ¹⁹⁸ Deň: 32 ° C.

Example 17

Preparation of 7-chloro-4,9-dihydro-4-methyl-10H-thieno [theta] 3^,4-Ь7- / ”¹·5^7benzo^diand that^Frin-¹⁰-onu ·

A portion of 532 mg of 7-chloro-1,3,4,9-tetrahydro-4-methyl was obtained^X0H-thieno - / * 3⁴-b⁷ [Α] ^ a zoze zozeer. .Er ^{byl prip}raven reaction 4-c^hlor-2-amino-N-methylaniline and 3-keto-4-carbomethoxytetrahydrothiophene at reflux temperature^luenu / sus^pterminated in 4 mf pyriin. К^této sm^Ewith^{I was adding}n ^pO^part 27⁶ mg Kc^hlorsuccinimide ^pabout tricks, ^přičthat you^l p^driverán je^{ětě χ} mř ^ r ^ inu. ^Zíekan^and the mixture was heated on a steam bath for 15 to 20 minutes, cooled and finally diluted with water to give a brown solid which was recrystallized twice with methanol. 0.25 g of product was obtained, the melting point of the product being in the range of 244 to 246 ° C.

Example 18

Preparation of 4,9-dihydro-10H-thieno [3,4-b] benzodiazepin-10-one.

According to this example, a mixture of 0.76 g of 4,9-dihydro-10H-thieno-4 ', 3,4-g-7', 4'-benzodiazapin-10-one and 1.0 g of phosphorus sulphide in 10.6 dry The reaction mixture was concentrated to dryness to give an oily matter as a residue, and this residue was stirred for 18 hours with 25-30 L of 1 N sodium carbonate solution having a pH in range from 7 to 7.2 / · The solid obtained was separated, washed with water and finally recrystallized from methanol to give the final product as orange crystals. The melting point of the crystals thus obtained ranged from 210 to 212 ° C.

In a similar manner to the above process, 7-fluoro-4,9-dihydro-10H-thieno [3,4-b7] -1,57-benzodiazepin-10-one was treated with phosphorous pentoxide to give 7-fluoro-4,9- dihydro-10H-thieno [3,4- d] -benzodiazepine-10-thione.

Using a similar procedure and starting materials, the following compounds can be obtained:

6-methoxy-4,9-dihydro-10H-thieno [3,4-b] [1,5] benzodiazepin-10-one

6-methoxy-4,9-dihydro-10H-thieno [3,4-b] -1,17-benzodiazepine-10-thione

7-Hydroxy-4,9-dihydro-10H-thieno [3,4-b] z '1,5-benzodiazepin-10-one 7-hydroxy-4,9-dihydro-10H-thieno / Z3,4 .beta., 15benzodiazepine-10thion

6-Trifluoromethyl-4,9-dihydro-10H-thieno [1,3,4- {1,5,7-benzodiazepin-10-one [alpha] -trifluoromethyl-4,9-dihydro-10H-thieno]^-3,4-g-1- [1,2-benzodlazepine]

10-thione

5-? 1αθΓ-4,9- &lt;№1 ‰άΓθ-10Η-1Ηίθηο- /³₉⁴- £ 7 --- j ”^l,WITH⁷benzod^andazep^andn-¹O-he в

7-nitro-⁴l9-d^andhydro-¹OH-th^andeno-0 ”3t^4-b⁷ ►

OF¹»5⁷ben zod^andazep^andn-¹⁰-he

6-Methylthio-⁴_t9-dihydi-101-thieno [3,4-a] 3,4-a7-benzodiazepine-10-one

7- methy1au1fony1-⁴_&gt;9-dihydro-10-OH

th^andenoj * 3^,4-^b7 /^g^enzo^azepi.n10-ob

7-methyl-4,9-dihydro-10H-thieno [3,4-b] -

О “^ 2⁷benzod^andand that^Frin-¹⁰-he

187 448

5- :^017-9,9^^(1-10^1^^10110/^33-6⁷O, S, benzodiazol

7-n^itro-4,9-⁹ⁱE^ydio-¹⁰H-te^andeno ^ 3 3-6⁷/^^-benzcdi.azejdn-W-Wl.on

6-meУ1teihi4-9,9ihy9r0г1o1-Heihieno / - ^4-b⁷ OF¹, J^7benz o^d ia z ^ nU-ta ^ n

7- mθtey1au15ony1-⁴9-diey910-10H- [3,4-b7] -1,17-benzodiazepine-M-thione

7-Methyl-4'-dihydro-10-thieno [eta] &amp; lt; 3 &amp; gt; -b⁷/^1|WITH⁷Ьenzo⁹ⁱand that^Frin-¹⁰-t^hihe

Example 19

Preparation 10- (metey1teio) -⁴H-thieno / 33-b⁷ j^{T1 |}her⁷bhnzo⁹iaze^Frinu

In this example, 1.3 g of 4-9-yydi-10-O-thienoZ-33-y⁷ O*^1|5^{7hβnгo9iazβ}7^andn-^10-te^andonu v ¹5 R. ^diof oxane is added simultaneously ^při te^plot * nUe than ⁴⁰° C solution ^1,9 g ^ mHu toase ^^ ov ¹⁰ ml of methanol and 2^,2 ^G meth^y1 of sulfate. Upon completion of this addition, stirring was continued for another time

1.5 hours. The resulting mixture was diluted with methanol and filtered. The resulting filtrate was from^tocentered on o^bjem as^{i 20} mC ^{, p}otom z^Ředěn vo^dou az^filcosts^andn. ^PThis gave a sticky precipitated mass which was dissolved in chloroform, and the chloroform solution was concentrated to a solid which was recrystallized from methanol / water to give the final product as dark yellow crystals. The melting point of the product thus obtained was in the range. from 128.5 to 130 ° C.

In a similar manner, 7-fluoro-4,9-9-hydro-10H-thieno [1,4-h7] 1,57-benzodiazepine-10-thione was reacted with potassium hydroxide and methyl sulfate to give Tn-uor-10-Methyl-1 Wi. (zH-thieno) 0.4.1,7.1-benzodiazejiii.

In the case where a similar procedure to the following starting materials is used, the following products can be obtained:

6-methoxy-4,9-dihydro-10H-thieno ----- 6-methoxy-10- (methylthio) -4H-thieno [3,4- b] 7,2,2,2-benzodiazepine-10-] 3,4-b7 / l, $ 7benzodiazepine, thion

7-hydroxy-4,9-dihydro-10H-thieno [3,4-b] -1,4,7-benzodiazepine-10-thione

6-Trifluoromethyl-4,9-dihydro-1H-thieno [3,4-b] -benzodiazepine-10-thione

5-fluoro-4,9-dihydro-10H-thieno-1,1-benzodiazepine-10-thione

7-nitro-4,9-dihydro-10H-thieno- [3,4- b] -4,5,5-benzodiazepine-10-thione

6-methylthio-4,9-dihydro-10H-

[3,4-b7] -1,5S-honzodiazepine-10thion

7-Methylsulfonyl-4,9-duhydro-10H-thieno [3,4-b] [1,4] benzodiazepine-10-thione

7-methyl-4,9-dihydro-10H-thieno- ....

N, 3,4-b7-, 1,1-benzodiazopine-10-thione

7-Hydroxy-10- (methylthio) -4H-thieno-1,4,7,7-1,2,2-benzodiazepine

6-Trifluoromethyl-10- (methylthio) -4Hthieno [3,4-a] [1,1] benzodiazepine

5-fluoro-10- (methylthio) -4H-thieno [3,4-a] [1,2] benzodiazepine

7-nitro-10- (methylthio) -4H-thieno-

Z, 3,4-b7H-1,57-benzodiazepine

-me thy 1-thi-Ю- (methylthio) -4H-thienoZ-3,4-phenoxy-1,57-benzodiazepine

7-methyl-ulphonyl-10- (methylthio) -4Hthieno [3,4-b] -4,1,7-benzodiazepine

7-Methyl-10- (methylthio) -4H-thieno [3,4-b7] -1,27-benzodiazepine

Example 20

197 449

.....35................ .........

Preparation of 10- (4-methyl-1-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine.

According to this example, a solution of 1.0 g of 10- (methylthio) -4H-thieno [3,4-b] [1,5] benzodiazepine in 5 ml of N-methylpiperazine was treated with 2 to 3 drops of glacial acetic acid and then heated at reflux for 4 days. The resulting solution was concentrated to dryness and the residue was heated with dilute acetic acid solution. The resulting acidic solution was filtered, cooled and finally basified with concentrated ammonium hydroxide solution. (at 30 to 60 ° C), the melting point of the product thus obtained was in the range of 197.5 to 199 ° C;

In a similar manner, 7-fluoro-10- (methylthio) -4H-thieno [3,4-b] z, 1,7-benzodiazepine and N-methylpiperazine was reacted to give 7-fluoro-10- (4-methyl-1-piperazinyl). (4H-thieno)_t4-methyl-1,57-benzodiazepine and using 7-methoxy-10- (methylthio) -4H-thienoZ * 3,4-b7,4,5,5-benzodiazepine gave 7-methoxy-10- (4-methyl-1- piperazinyl / -4Hr-thieno-3,4,4,7,7-benzodiazepine

Example 21

Preparation of 10- (1-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine

A cylinder filled with 2.5 g of 10- (methylthio) -4H-thieno [3,4-b7] -1,57-benzodiazepine, 8.6 g piperazine and three drops of acetic acid was placed in an oil bath and heated to room temperature. range 155 to 160 ° C for 4 days · Then the cylinder was cooled and the contents were dissolved in 2 N acetic acid solution · The obtained solution was filtered and the filtrate was basified with ammonium hydroxide and finally extracted with chloroform · The extracts were combined, dried, filtered and evaporated to give a yellow solid · This was recrystallized from ethanol to give the final compound as pale red-yellow crystals · Melting point: 228-231 ° C (dec.) ·

Example 22

Preparation of 10- (piperidino) -4H-thieno [3,4-b] 1,1'-benzodiazopine.

A solution of 0.7 g of 10- (methylthio) -4H-thieno [3,4-b] Z, 7benzodiazepine in 5-piperidine was treated with one drop of glacial acetic acid, and then the beto-βαβό was heated at reflux for 4 days. Excess piperidine was then removed under reduced pressure and the resulting oily residue was heated with dilute acetic acid and filtered. Further, the filtrate was cooled and made alkaline with concentrated ammonium hydroxide solution to give a yellow solid. Finally, recrystallization from a mixture of acetone and petroleum ether (at 30 to 60 ° C) gave the final product as yellow crystals. The melting point of the product thus obtained was between 157 and 159 ° C.

Example 23

Preparation of 4,9-dihydro-4-methyl-10-thienoZ-3,4-tert-1,17-benzodiazepine-10-thione.

A mixture of 0.4 g of 4,9-dihydro-4-methyl-10H-thienoZ-3,4 * b7Z-1,2-benzodiazepin-10-one and 0.5 g of phosphorus pentasulphide in 5 dry pyridine was stirred and heated at reflux for 4 hours. The resulting reaction mixture was then concentrated to dryness and the residue was stirred with 10 ml of 1 N sodium carbonate solution and stirring was continued for an additional 18 hours. This produced a solid which was collected, washed with water and recrystallized from methanol to give the final product as gold-colored crystals. The melting point of the product thus obtained was between 203 and 204 ° C.

Example 24

Preparation of 4-methyl-10- (methylthio) -4HthienoZ3,4-7,7,17-benzodiazepine.

37....... '

To a stirred suspension of 0.7 g of 4,9-dihydro-4-methyl-10H-thieno [3,4-f] [1,5] benzodiazepine-10-thione in 10 ml of dioxane was added dropwise at the same temperature at room temperature. in the range of 30 to 40 ° C a solution of 0.95 g of potassium hydroxide in 10 ml of methanol and 0.8 ml of methyl sulfate. After the addition was complete, the emulsion was stirred for 3 hours, then diluted with methanol and filtered. The filtrate was concentrated to a volume of about 20 ml, then diluted with water and extracted with chloroform. The resulting chloroform solution was concentrated to give a solid which was recrystallized from methanol / water to give the final product as orange crystals. The melting point of the crystals thus obtained was between 113 and 115 ° C.

Example 25

Preparation of 4-methyl-10- (4-methyl-1-piperazinyl) 4H-thieno [3,4-c] -4,1-benzodiazepine.

A solution of 1.2 g of 4-methyl-10- (methylthio) 4H-thieno [3,4-b] [1,3] benzodiazepine in 6 ml of N-methylpiperezine was treated with 2 to 3 drops of glacial acetic acid. and then the solution was heated at reflux for 4 days. The resulting solution was concentrated to dryness and the residue was heated with acetic acid. The resulting acidic solution was filtered, cooled and basified with concentrated ammonium hydroxide solution. This produced a precipitate which was collected, washed with water and dissolved in chloroform. The resulting chloroform solution was dried and concentrated to an oily matter which slowly crystallized. Finally, recrystallization from ethanol was performed to afford the final product as yellow crystals. The melting point of the crystals thus obtained was between 83 and 85 ° C.

Example 26

Preparation of 6-chloro-1,3,4,9-tetrahydro-1H-thieno [3,4-b] [1,5] benzodiazepin-10-one and

7-Chloro-1,3,4,9-tetrahydro-10H-thieno-3,4-b7,4'-benzziaziazin-10-one

A solution of 0.4 g of methyl tetrahydro-4-oxo-3-thiophenecarboxylate and 0.36 g of 4-chloro-o-phenylenediamine in 20 and toluene was heated at reflux for 3 hours, then cooled and finally filtered. The solid was recrystallized from dimethylformamide to give the final product as a yellow solid. Melting point: 233-235 ° C (dec.)

Example 27

Preparation of 6-chloro-4,9-dihydro-10H-thieno [3,4-b] [1,5] benzodiazepin-10-one and 7-chloro-4,9-dihydrol-1-thieno [3,4-b7] Benzodiazepine-10-one.

A suspension of 1.5 g of 6-chloro-1,3,4,9-tetrahydro-10H-thieno [3,4-b7] -1,5-benzodiazepin-10-one and 7-chloro-1,3-dimethylamine was added to the suspension. 3,4,9-tetrahydro-10H-thieno [3,4-b7] -1,5-benzodiazepin-10-one (prepared as described in Example 26) at 15 m dry pyridine, added in portions to a total amount of 0, 8 g of N-chlorosuccinimide. The resulting solution was heated on a steam bath for 15-20 minutes, then the mixture was cooled and diluted with water. The precipitate was collected and recrystallized from methanol to give dark golden crystals having a melting point of 279-281 ° C to give pure 6-chloro-4,9-dihydro-10H thieno [3,4-b7] -1,17-benzodiazepin-10-one. The methanol filtrate was also diluted with water to give a yellow solid which had a melting point of 197-198 ° C and was 7-chloro-4,9-dihydro-1H-thieno. / ”3,4-b7 /” 1, $ 7benzodiszepin-10-one.

Example 28

EXAMPLE 7-Chloro-4,9-dihydro-10H-thieno [3,4-b] -1,7,7-benzodiazepine-1-thione.

Following the procedure of this example, a mixture of 0.88 g of 7-chloro-4,9-dihydro-1H-thieno [3,4,4,7,7] benzodiazepin-10-one and 1.0 g of phosphorus pentoxide in 10 ml of dry pyridine was stirred. and heated at reflux for 4 hours. The resulting mixture was concentrated to dryness and the residue was taken up^was mixed with 20 ml ¹ N solution of sodium carbonate ^{/ kt}black me¹ pH between 7 and 7.2 / for 18 hours. This procedure resulted in a precipitate which was collected, washed with water and recrystallized from methanol / water to give the final product as a dark yellow solid. The melting point of the product thus obtained is^poh^yin the range from 197 ^dO ¹98^,5 Deň: 32 ° C ^/ for. decay^/ ·

Example 29

Preparation of 7-chloro-10- (methylthio) -4Ht^hieno / 3,4-b⁷ / “^^ TbenzoUaze ^ nu»

By the procedure of this example, a stirred suspension was added. 0.8 g of 7-chloro-4,9-ditydro-4-carboxylic acid⁷ 1- (benzodiazol-4-one) v ¹⁰ m^{1 di}oxane is added ^po ka^pkác^h at the same time^plot^y in the range of 3^{0 d}O ⁴⁰ ° C solution ^{0.95 g} Potassium hydroxide 10 [alpha] -methanol and 0.8 g of methyl sulfate. After the addition was complete the reaction mixture was mea. The reaction mixture was diluted with methanol and finally filtered. Obtained three times^byl concentrated to volume ²⁰ m^{£ ,} with water and ^potom ex^tra^hov^andn form. The resulting chloroform solution was concentrated under reduced pressure to give a solid. mass which was recrystallized from a mixture of methanol and water to give the final product as yellow crystals. The melting point of the product thus obtained was in the range^Od 111 d^O 113 ° C.

Example 30

Preparation of 7-chloro-10 (4-methyl-1-piperazinyl) 4^H-t^hienol '3,4-b⁷ /“^1,and⁷benzo^di and that ^Frin, d^and c ^ print anu.

A solution of 0.9 g of 7-chloro-10- (methylthio) 4 was used^H-th^andeno^OF“3^,4-17 ΖΊ, 57benz^andazep^andnu ve 4^,5 ml of N-methyl-4-azaz^praced with 2 to 3 drops of glacial acetic acid and then heated at reflux for 4 days. The solution thus obtained was concentrated to dryness and the residue was heated together with a dilute acetic acid solution. The resulting acidic solution was filtered, cooled and finally basified with concentrated ammonium hydroxide solution. This gave a sticky precipitate which was collected and dissolved in chloroform. The obtained dried chloroform solution was concentrated under reduced pressure to give 7-chloro-N-methyl-4-imidazole-2-carboxylic acid.⁷ / ^ TTbanso ^ aze ^ nv ^pof both matter. The ethanolic solution of this oil was then treated with 70% chloroic acid and diluted with water. This produced a precipitate which was recrystallized from methanol to give the final product as yellow crystals. Melting point: 268-270 ° C (dec.)

Example 31

Preparation of 6-chloro-4,9-dihydro-10H-thieno [3,4-b] 1,5,5benzodiazepine-10-thione.

A mixture of 0.88 g of 6-chloro-4,9-dihydro-10H-thieno [3,4-b7] -1,7,7-benzodiazepin-10-one and 1.0 g of phosphorus pentasulphide in 10 ° C dry was pyridine stirred and heated at reflux for 4 hours. The resulting reaction mixture was concentrated to dryness and the residue was stirred with 20 µl of 1 N sodium carbonate solution (at a pH ranging from 7 to 7.2) for 18 hours. The precipitate was collected, washed with water and recrystallized from methanol to give the final product as an orange solid. The melting point of the product thus obtained ranged from 235 to 237 ° C (with decomposition).

Example 32

Preparation of 6-chloro-10- (methylthio) -4H-thieno [3,4-b] [1,5] benzodiazepine.

To this stirred suspension of 0.7 g of 6-chloro-4,9-dihydro-10H-thieno [3,4-phi] [1,7] benzodiazepine-10-thione in 10 ml of dioxane was added dropwise to a stirred suspension at the same time at a temperature ranging from 30 to 40 ° C a solution of 0.95 g of potassium hydroxide in 10 ml of methanol and 0.8 g of methyl sulfate. After the addition was complete, the mixture was stirred for 3 hours, then diluted with methanol and finally filtered. The filtrate was concentrated to a volume of 20 ml and then diluted with water. This gave a precipitate which was collected, washed with water and then recrystallized from a mixture of methanol and water to give the final product as yellow crystals. The melting point of the product thus obtained was in the range of 152 to 154 ° C.

Example 33

Preparation of 6-chloro-10- (methyl-1-piperazinyl) -4H-thieno4^WITHЗ_t4-α7β-enzodiazepine.

A solution of 0.7 g of 6-chloro-10- (methylthio) -4H-thieno [3,4-b] [1,5] benzodiazepine in 3.5 aB of N-methylpiperazine was treated with 1-2 drops of ice acetic acid, and then the solution was heated at reflux for 4 days. The resulting solution was concentrated to dryness and the residue was heated with dilute acetic acid. The resulting acidic solution was filtered, cooled and finally basified with concentrated ammonium hydroxide solution. This produced a precipitate which was collected, washed with water and finally recrystallized from a mixture of acetone and petroleum^plot^y in range^and from 3 ° to 6 ° C ^{), or}m^{That was} obtained finite ^pgenus^kt in ^podo^bfive yellow crystals. The melting point of the product thus obtained ranged from 14⁸ ° C to 149 ° C ⁽ for decomposition ⁾ .

Example 34

Preparation of a mixture of 7-chloro-1,3,4,9-tetrahydro-4-methyl-10-yeno-4-b⁷ OF"^l,OF⁷be ^ zod^andazep^andnl^O-on a ⁶-chloro-1,3,3,9,6-trahydro-9-ihlyl-1H-Uenoeno 3^,4-b^/E/1,27^benzodiazepin-10-one.

In this example, the solution was 2.8 g of mathyl-tetrah^yDru-4-oxo-3-thiophenecarboxi^láhere and 4^{, 0g} 5-chloro-2^-me^th^ylaminoan^ilinu ve ²⁰⁰ m^£ The solution was cooled and the resulting solid was collected and recrystallized from ethyl acetate to give the final product as a yellow solid. The melting point thus follows^andwith^toan^éhO ^pgenus^ktu moved in the range^and from ²³³ Deň: 32 ° C ^d235 ° C ⁽ for decay ⁾ .

Example 35

Preparation of 7-chloro-4-methyl-4,9-dihydro-10H^thienoZ ”^3,4-) j7 / *^1,5⁷benzod^andand that^pin-10-one ·

0.53 g of 7-chloro-14-ethyl-ethyl-3, 4, 9 was added to the suspension^1tttrahydr^O110H1thi^tnoZ^_3,4-^b7 OF^_l^,and⁷Ьtnzodiaze^pin1l01onu ⁽ which^and tyta ^connravena ро ^ ирод podta example^at 34) at 5 m^£ such^Eit was added after cities^{| k}ov^Eamount of 0.27 g of N-chlorosuccinirnide. The resulting solution was heated on a steam bath for 15 to 20 minutes, then cooled, diluted with water and finally filtered. This procedure was created. The precipitate was recrystallized from methanol to give the final product as a yellow solid. The melting point of the product thus obtained is^movein the range^and od 244 ^d246 ° C ⁽ za roz^kland^dat ⁾ .

Example 36

Preparation of 7-chloro141-mttyl-4,91-ditydro-10Hthieno / 3,4-b⁷ OF^_l,and^7bt ^ nzo^diazt^Frin1l⁰1thionu ·

In this example, a mixture of 0.5 g of 7-chloro-4-methyl-14,9-ditydro-10Hthie (3,4-)⁰, gT ^ nztest ^ nW-on a ^0,5 ^G sulphide foafore ^ ho in 5 rn. of dry pyridine stirred and heated at reflux for 4 hours. The resulting mixture was concentrated to dryness and^potom d^andand stirred with 10 aC ^N sodium carbonate solution for 18 hours. The precipitate was collected, washed with water and finally crystallized from methanol to give the final product as a yellow solid. The melting point of the product thus obtained was in the range of 238 to 240 ° C.

Example 37

Preparation of 7-Chloro-4-methyl-110- (methylthio) 14Hth^andtno / “3,4-Ь⁷ tenzodiazephsine.

Following the procedure in this example, 1.1 g of 7-chloro-4-methyl-14,91-dihydrO110H1-thitnoZ23.41Ь was added to the stirred suspension.⁷ Z ~ 1.5⁷bβnzodiaztpin-10-thione in 15 aC dioxane ^pdriver^andin^andn po ka^pkách at the same time ^při ta^plotác^h in the range of 30 to 40 ° C^,3 ^G tydr^OPotassium xide ¹5 m⁰ mettanota a ^1,1 ^G Methyl sulfate. After tulle^přda^veto ^actC^En the resulting mixture was stirred for 3 hours, then diluted with methanol and finally filtered. The filtrate was concentrated to a volume of 20, diluted with water, and the resulting precipitate was collected. Further, recrystallization from methanol / water gave the final product as dark yellow crystals. The melting point of the product thus obtained was in rosmes^and from 1% to ¹5⁸ Noc: 2 ° C.

Example 38

Preparation of α-Chloro-4-methyl-1- (4-methyl-1-piporasinyl) 4H-thione / 3^,4^-b7 / “l_t£ 7bonzodiazop^andnudiohloгiзtenu ·

In this example, the rostok was 0.7. 7-Chloro-4-methyl-10- (mothylthio) 4H-thione [3,4-b] Z] -benzodiazepine in 3_t5 N- · o^thylpiperazine s^pracujte^andn ¹ to glacial acetic acid droplets and then the resulting residue was heated and refluxed for 4 days. The resulting solution was then concentrated to dryness and the residue was heated with dilute acetic acid solution. The resulting acidic rostok was filtered, cooled and salified using concentrated ammonium hydroxide rostoku '. The sticky precipitate was collected and separated and then dissolved in chloroform. After drying, the chloroform solution was concentrated under reduced pressure to give an oily matter. The ethanolic solution of this oily matter was treated with 70% perchloric acid solution and then diluted with water. This precipitated a precipitate which was collected and then recrystallized from ethanol to give the final product as a white solid.^E mass. ^Teplota tán^{í t}and^kto sískané^ho the product ranged in rosmes o^d 2¹² ° C to ²¹5 Deň: 32 ° C ⁽ sa rosklad ⁾ ·

Example 39

Preparation of 7-methyl-10-10-4- (2-hydroxyethyl) -1β-piperazinyl-4H-thieno-3,4-b7 / 1, 7⁷enzodiasop^andnu ♦

According to this procedure ^byl rosto^to and,¹0-bi8 (· othy^lth^ando) -4H-thieno / 3,4-77Zl^,$⁷bonsodiasopine in excess of N^-(2-hydroxyo^thy^l-pipoogazine and ^lThe acid was heated to pH te^plO^tIn Rosmes o^{d 1}4⁰ Deň: 32 ° C ^dO ¹⁶⁰ ° C Mon ^dboth days. Crafted rosto^{k by}I did not pour into water and the product was separated.

Example 40

Preparation 6en^andtгoe10e⁽iebenzy^l-^l-^pand^pβrazif, t^l )-4^Ηthiene (3,4-7,7) -S-enzo azepine.

According to the procedure of this example, the solution of 6-nimro-10- (oemhyimeio) -4Hthiwio [1,4-c]⁷ Z ^ 1 | 5⁷benzodiaze^pifu v ^přeb^yN, N, N, N, a ^lmiddle acids ^vinegaré, heatⁱⁿandⁿ at te t te in rlzoez^and from '140 ° C to 16⁰ Deň: 32 ° C ^po do^bat ² The resulting solution was poured into water and the resulting product was collected.

Example 41

Preparation 7- ^ ΊΜχγ-10- ⁽iefeft¹-¹-^pand^peгaziny¹ b-4^Hthi.anog '3 »4-b⁷ / “1» -7Ььп2 odi ааерхт.

^ stu ^ m ^pO^dle totato ^exík^ladu b^yl solution 7ee^ydrox^tE¹0e⁽meme^ththil⁾-4^Hor 3,4,4-b7,11,7befzodiaze^Frinu v ^exE^byt^tou N-^Fef^ylE^pand^peraz^andand acetic acid, heated ^při te^plotě lying^and in range^and od 14⁰ to 160 ° C ^pfor 2 days.

The resulting solution was poured into water and the resulting product was collected.

Example 42 ^Příprava 7-^tr^ifluormete^yi.-^iOE/^{^} and-⁽²-dioath^ylaminoθtl^etl⁾.beta.-diphenyl / [eta] &amp; lt; 4 &amp; gt;

According to this example, b^yl solution 7-mrifluorometetle10e (oemeylteil) e4H-thieno /^3, 4^-b⁷ /”^l,of^7benzod^andazepine v ^exE^by2-d^andmeme^ylamiflete^tlaoinu al^EThe acetic acid was added ^pThrow in the range^and from 140 to 160 ° C ^pfor 2 days. The clarified solution was poured into water and the product was separated.

Example 43

Preparation of 6-methylaulfonyl-10-β-piperazinyl) -4Hthieno [3,4-b] -4,7,7benz odiazepine The solution of 6-methylaulfonyl-10- (methylthio) 4H-thieno [3,4] - $&gt; 7 ^ * I_tJ / benzodiazepine in excess piperazine and glacial acetic acid, heated in a pressure vessel at 150 οθ for dpbú 2 days · The obtained solution was poured into water and the resulting product was separated ·

Example 44

Preparation of 6-methoxy-10- (4-methyl-1-piperazinyl) 4H-thieno [3,4-b7] 1,57-benzodieepine

A solution of 6-methoxy-10- (methylthio) -4Hthieno [3,4-b] [1,4] benzodiazepine in an excess of N-methylpiperazine and glacial acetic acid was heated at reflux for 2 days. into water and the resulting product was separated ·

Example 45

Preparation of 7-methyl-10- (4-methyl-1-piperazinyl) -4H-thieno [3,4-b] -1,1-benzodiazepine.

A solution of 7-methyl-10- (4-methylthio) -4H-thieno [3,4-b7 / 1,2,7] bentodiazepine in an excess of N-methylpiperazine and glacial acetic acid was heated at reflux for 2 days. was poured into water and the product formed was separated ·

Example 46

Preparation of 10- (4-methyl-1-piperazinyl) -4H-thieno [3,4-b] 1,57-benzodiazepine.

The mixture was 2.32 ^G (Q-dihydro-10H-thieno)³,⁴-^⁷ /’1»5⁷benzodiazepine-10-thione, 23 αS of N-methylpiperazine and 3 drops of glacial acetic acid refluxed with stirring for 18 hours. The resulting reaction mixture was poured hot into a 400 cc stirred water / ice mixture. The resulting product was extracted with methylene chloride, dried over potassium carbonate and passed over magnesium silicate. Finally, recrystallization from hot ethanol was carried out to give the final product in the form of yellow talc. The melting fence thus obtained^Ehim ^pgenus^tomove here^bova^land within range^and from ¹⁹² ° C to 194 ° C.

Example 47

PMpravenie 1⁰- / 4-met^h1 ', 3'-J, 3'-di-1H-totono-3,4-b⁷ / “1, 57bsnzodiazs^pinu^h^pfrom this ^pŘ^íklThe series was ridiculous^and 2,16 ^G 4,9-dihydro-1^0H-th^andsno / ”3,4-p⁷/ “I, 5⁷Nszziaziazin-10-one and 1.06 ^G sodium carbonate^Ehim at 25⁰ n-toluene ^noseyes in small portions with stirring 1.90 g of p-toluenesulfonyl chloride. The reaction mixture was heated^pŘ^and temperature 60 ° C ^pabout the time ¹ hours and ^pabout ^byto this mixture ^atgiven ⁶ grams of N-methylpiperazine. The reaction mixture was heated at reflux for 8 hours, cooled and treated with aqueous sodium carbonate solution and then several times with 1 N hydrochloric acid. The resulting acidic mixture was basified with 1 N sodium hydroxide solution. This gave a solid which was filtered, chromatographed and finally recrystallized from hot ethanol to give the final product as yellow crystals. The melting point of the product thus obtained was in the range from 192 to 194 ° C.

Example 48

Preparation 10- (4-msthy1-1-)^pand^perazinyl) -4H-thieno [3,4-b] benzothiazide].

2.16 grams of 4,9-dihydro-10H-thieno [1,4] S7 / 1,57benzodiazide was added to the mixture.^pof in-10-one and 2.02 g of triethylamine in 250 cc of benzene was added dropwise with stirring 1.08 g of a solution of trimethylchlorosilane in 50 m ”of benzene. After the addition was complete, the mixture was refluxed for 9 hours and then 6 grams of N-methyl-piperazine was added to the reaction mixture. The reaction mixture was then refluxed for an additional 8 hours, cooled and extracted several times with 1 N hydrochloric acid solution. The combined acid extracts were basified with 1 N sodium hydroxide solution. By this procedure a solid was collected, which was collected by filtration, further purified by chromatography and finally recrystallized from hot ethanol to give the final product as yellow crystals. The melting point of the product thus obtained was in the range of approx^mefrom 192 to 194 ° C.

Example 49 ^přprava 10-⁽4-methyl-1p^ipnraz^andn^yl)-4^H-th^andnnc^/3,4-b7 / ”1, ^j77enzodiaze^pi.nu.

A mixture of 2.16 grams of 4,9-dihydro-10H-thieno [eta] &amp; lt; 4 &amp; gt;^b7 ^ i, 5^7benzediaze^pin-1⁰-en and 3.3⁸ grams ^Fnn^yi,^bis 4-mnt^{hy |}-l-^pand^pnraziny^|)of phosphinate at 250 m^£ diphenylamine, for^hřv^andon ^pat 235 °^{C p}for 1 hour. ^PThe reaction mixture was cooled and finally extracted several times with 1 N hydrochloric acid solution. The aqueous layer was separated and basified. That procedure precluded it^pevn^and hmeta^, which b^yland about the people, ^pO^tom ^wasand ei^{ft ě}na chromato^Graf^andck^y and finally crystallized from hot ethanol to give the final product as yellow crystals. Temperature^andthus obtained for^duktu ranged from about^d 19^{2 d}194 ° C.

Example 50

Preparation of 10- (4-methyl-1-piperazinyl) -6- (trifluoromethyl-4-thieno) -3^,4-b⁷ / '^ F ^ enzodiaze ^ nu.

^PO^dle of this example^kland^dat ^wasand mechanically mixing the mixture ²2 mC of melt and ^2,3 m^£ ami^dat, ^toteré ^wasand reoccupied in a nitrogen atmosphere, ^atwhich ^{to this}about mixtures ^waso not sprayed ^1,2 m ^-t rach rach rach rach.. The reddish solution obtained^was The reaction mixture was treated with 4.75 N-methylpiperazine and then 2.6 ml of toluene, which were not sprayed into the reaction mixture. The resulting yellow-brown slurry was treated with a solution^was pHjusted by heating 3,⁰ gramme^at 4,⁹-d^andh ^ dro-⁶-^(i.e.r^andF^luormn^thy^and)-10^H-thinne / ~ 3,4-e⁷/ 1,5/^benzediazepin-10-one, 2.4 ml of N-methylpipnrazine and 5-toluene on a hot plate. After two hours of refluxing reaction, the hot mixture was treated with 2 g diatomaceous earth and then^waso added 3.3 m^ifthat^prep^yiand^lkehe^lua ^2,9 m^£ The filtrate was washed thoroughly with toluene and the layers of the filtrate were separated. with a concentrated ammonium hydroxide solution, the melting point of the product thus obtained was in the range from 198 to 199 ° C.

Example 51

Preparation of 10- (1-piperazinyl) -1-trifluoromethyl) 4H-thieno [3,4-b] [1,3] benzodiazepine.

The same procedure as described in Example 50 was followed except that an equivalent molar amount of piperazine was used instead of N-methylpiperazine. Next, a hot solution containing 35 toluene, 3.7 ml of anisole and 1.9 ml of titanium tetrachloride was treated with 5.9 g of anhydrous piperazine and 5 ml of toluene, after which a hot mixture containing 2.9 g of piperazine was added, 4-9 g of 4,9-dihydro-6- (trifluoromethyl) -10H-thieno [3,4-b] 3,4-benzodiazepin-10-one and 7 uf of toluene. and the reaction mixture was treated with 4 grams diatomaceous earth, 6.5 mL of isopropyl alcohol and

The mixture was filtered and extracted with toluene. The toluene layer was separated and extracted with a 10% hydrochloric acid solution, and the aqueous layer was basified with ammonium hydroxide to give a precipitate. The product has a yellow color and crystallized from an ether / hexane mixture to give the final product. · Melting point: 164-165 ° C.

Example 52

Preparation of 10- (4-methyl-1-piperazinyl) -7- (trifluoromethyl) -4H-thieno-3,4-benzodiazepine

The procedure was similar to that described in Example 50 except that 4,9-dihydro-7- (trifluoromethyl) -10H-thieno [3,4-b] [1,5] benzodiazepine- 10-on 6- (trifluoromethyl) isomer · The resulting hot mixture containing 49 l and 32 m of toluene, 3.3 αβ anisole and 1.7 mc of tetrachloride was prepared.

7.0 g of N-methylperoperazone and 3.8 and 8 of toluene, and then a hot mixture containing 4.3 grams of 4,9-dihydro-7- (trifluoromethyl) -10H-thieno [theta] was added to the reaction mixture.³^^-b^{7 OF}l^,2^7fenzodiazep^On-^I0-onu^, 3^,5 m. N-Methyl-erazoline and 7^,2 m? toluene. The reaction mixture was allowed to react for 2 hours at reflux, after which 2.7 grams were formed^andn^Fuzr^andov^E hl^and4^,7 The reaction mixture was filtered and extracted with toluene. The toluene layer was removed and extracted with a 10% hydrochloric acid solution. The aqueous layer was basified with ammonium hydroxide solution to form^žlTue^{á p}obviously^íž bo^dtand out^and se ^pbent in the range from ^AND33 up to °5 ° C, ^přičemž ^pfor recruiting and smas^and eteru a ^hexanu b^yland ^tE^plrotation in the range of I75 to ^AND76 Deň: 32 ° C.

Example 53

Preparation of 4-methyl-10- (n-methyl-1-piperazinyl) -4Hthieno [f] - b⁷ Benzodiazepine.

A solution consisting of 42 m. Dry toluene, 4.5 mf anisole and 2.3 m. Titanium tetrachloride was stirred mechanically, to which 9.3. 5N-toluene and reaction ^wasand keep^andto within o^{d 30 d}by 55 ° C. ^TO the^toit due to smas^O bylo d^álE

4.5 grams 1,3_ϊ4,9-tetrahydro-1OH-thenoeno-3,4,4,7-benzodiazepin-10-one and 4.7 ml of N-meth^yleOe^θгazine, and the resulting solution was refluxed for 3 hours.

The reaction mixture was then cooled and treated with 6.5 m. Ozopropyl alcohol, 4 grams of filter aid and 5.8 grams of concentrated ammonium hydroxide. This gave a solid which was filtered and washed well with toluene. The organic layer was extracted with a solution of 3 N hydrochloric acid, whereupon the product precipitated under the effect of concentrated ammonium hydroxide solution with constant cooling. The product obtained was stripped, washed, dissolved in methylene chloride and passed through magnesium silicate. Finally, recrystallization from hot ethanol was performed to give the final product as yellow crystals. The melting point of the product thus obtained was in the range of^d 64 ^d67 ° C «

Example 54

At^right 10- (4-Methyl-X-)^piperaz^andny^(l)-^4H-th^andeno (3,4-b7) ”, 57eenzodiazepine ·

A mixture of 148 to dry toluene, 15.9 to anisole and 8.13 to titanium tetrachloride was added by mechanical mixing, to which 32.9 to N-methylpiperazine and 17.7 to dry toluene were added. and ^reakční t^epl^Ot^and was maintained in the range of ³⁰ to ⁵⁵ Deň: 32 ° C. ^{To that}to re^akčn^{í smě}si. ^by^l° ^jkeep going^epdriven 15^,9 ^Gframes 1 ^^^ - tetrahydro-WH-thieno / '³,⁴^⁷ /η.^/^ηζοάίβζιβpin-10-one and 16.6 ml N-methylpiperazine and the resulting solution was refluxed for 6.5 hours ·

Then b^yl^and The reaction mixture was cooled and added ²³ ač izo^pro^pollenand^lkO^h14 grams of filtering agent and 21% concentrated ammonium hydroxide solution. Tímt^O of^půaobe^m b^yla obtained ^pevn^and mass^, which b^yland separated ^filtrací a ^promyta řádn^Etoluene. The organic layer was extracted with 3 N hydrochloric acid and the extract was treated with concentrated ammonium hydroxide solution with cooling to precipitate the product. The product thus obtained was separated, dried, dissolved in methylene chloride and passed through magnesium silicate. Finally, recrystallization from hot ethanol was performed to give the final product as yellow crystals. T^epthe melting point of the thus obtained crystals^at se ^poh ^ bova^land in the range of 197 to 100 ° C.

Example 55

Preparation of 4-methyl-10- (⁴-mettwl-l-^pand^peraziin (1H) -M-eno (R) -beta⁷ /~^l,£7^benzodiaze^Frinu ·

By the procedure of this example, a solution of 1.5 g of 10-ethoxy-4-methyl-4H-thieno [3,4-67]^l,of^/E®nzo^diazep^andn^fluoro^bsteed^átu ve ²⁰⁰ to methylene chloride^andWash with two 50 parts aliquots of XN sodium carbonate solution. After drying the mixture and evaporating the methylene chloride^ikland ^žlTue^and O^lejov^certain wt^, . ktar^and b^ylaz^pgulls^andto 4 to N-methylpi^pera^ofand^nu and 0.225 grams of ammonium chloride, the mixture was heated and stirred at reflux for 24 hours. The mixture was concentrated on a steam bath under an air stream. The residue was dissolved in 2 N acetic acid solution and filtered. The resulting filtrate was cooled and basified with concentrated ammonium hydroxide solution. The product was a precipitate which was filtered off, dissolved in chloroform, dried over magnesium sulfate and filtered again, and the solution was evaporated to dryness. The product was recrystallized from ethanol to give pale yellow crystals. The melting point of the product thus obtained was between 83 and 85 ° C.

Example 16

Preparation of 10-Ethyl-4-methyl-4H-heen (3,4-b) (1)_l5 / benzldiazepinflulгobllh.

According to ^toho^to pří^kladu ^by “nz^tok ^{4.6 g} 4,⁹-d^andhy^drl-⁴-mn^thy¹-l^OH-^th^Enno / 3,4-^b7/ “^^ benzodiazep ^ - ^ - onu v Ю⁰ m^- mn^thy^lenc^hlsteed^edThe mixture was cooled to about 0 ° C and then 8 grams of hrenhiyllxoniualuoroborah was added over 0.1 hour and dissolved in 100 m^C meh^hylnnchlor^anddu. ^INsolution ^{m was p}onec^háAfter stirring at 21 DEG C. for 17 hours, the reaction mixture was brought to a temperature of 100 DEG C. After addition of the ether, the product was obtained as a crystalline salt, after crystallization from a mixture of methylene chloride and ether. pale yellow crystals of the title compound formed. The melting point of the product thus obtained was in the range of Ηδ to¹77 Deň: 32 ° C ⁽ za rozktadu ⁾ .

Example 17

Preparation 10- (⁴(methyl-1-piperazeoyl) -4H7^ll_&gt;5^nnθOdOdiazo^atinu.

The mixture consisted of 2.2 grams of 4,9-dii^ydrl-1^OH-h^iesnl7^3,4-1n⁷ 7 “l^,of⁷bnnzl^deazn^pen-¹⁰-onu_&gt; WITH.¹ grams ae ^ yl)^pand^pby erosion and 0.1 grams of p-holosulfonic acid, placed in a pressure vessel and heated ^at te^plO^{te 1}9° °^C after ^dO^bat ^{24 h}from^andn · Ta ^ o vzn^ikl^and the reaction mixture was dissolved in chloroform and washed with water. The chloroform solution was dried over magnesium sulfate and then concentrated under reduced pressure. yielding 2.0 grams of brown glass. Purification of this material gave the final product as yellow crystals. The melting point of the product thus obtained was in the range from 192 to 194 ° C.

Example 18

Preparation 10- (⁴(methyl-1-piperazoyl) -4H^tiieno / * 3^l 4-S^{/ 2}~^l,_&lt;1⁷beozo^deazn^penu ·

In this example, the mixture was 2.16 grams - 4,9-diyl-10H-thieoo7,4,4-b⁷and 2.2⁸ grams of corundum. ^ s ^ redn ^ o in 2⁰ m^- toluene • refluxed with stirring for 4 hours. The solvent was removed under reduced pressure and the residue was decomposed^pu3těn ve ²⁰ O^E dimethylaminamide; and 3 ^Gframework^h N-methyl^piperazi.nu. Reeks mixture b^yla zahHvéína po ^dobu ¹8 hotHn ^{at t}E^ploté ¹⁰⁰ ° C, ^pthen cooled and poured into water. This gave a solid which was collected and recrystallized from hot ethanol to give the final product as yellow crystals. Temperature t^andn^and thus obtained^h of crystals ^poh^yin the range^and from 192 to 194 ° C.