DE1470415A1 - Process for the preparation of 1,4-benzodiazepine-2-mercapto compounds - Google Patents

Description

WABNT5B-LAMB1BT PHiBMACEUTICAL COMI *.
Delaware / USA

U70A1S

Process for the preparation of 1,4-bengodiazepine-2-meroapto- Links.

The present invention deals with new ones 1,4 ~ B6nzodiasepin ~ 2HBUH> eapto ~ Yer bonds and a novel Process for the preparation of these compounds

The compounds of the present invention have the following Structural formula

In the structural formula above, B ^ denotes hydrogen and a lower alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, laobutyl or amyl and cyoloparaffin such as cyclopropyl, cyclopropylmethyl, cyolobutyl, cyelobutylmethyl, cyclepentyl or cyolopentylmethyl and B ₂ denotes hydrogen, fluorine , Bromine and iodine, alkox, and alkyl. The present invention also relates to compounds of the following formula

909815/1 1 36

OR (GlNAU

where B ₁ and E _{2 have} ^the above meaning «

The object of the present invention is to create a method of introducing a sulfur atom into the 2-position of a 1,4-benzodiaepine.

Another object of the present invention is to provide a process for the alkylation of 1 _t 4-benzodiazepine-2-thiones to give 2-alkylmercapto-1 _f 4-benzodiazepines.

Other objects of the present invention will emerge from the following, in-depth description

1 _v 4- ~ Benzodiazepine and its derivatives have a strong effect on the central nervous system in that they show sedative, antispasmodic and anti-anxiety effects * therefore represents a significant advance in technology.

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BATH ORIGINAL

Bs has already been used in many therapeutic agents Sulfur atom introduced instead of oxygen. This change creates compounds with different and by no means foreseeable pharmacological effects · E.g. one can recommend barbituric acid by substituting a Oxygen atoms are stronger due to sulfur in the 2-position give sleep-inducing effect · Furthermore, for example by SrsatB of the oxygen atom of the hydroxyl group in hypozanthine j obtained the anti-metabolite 6-mercaptopurine from sulfur. Eia Another example of such a structural change is x.B · the BrsatB of oxygen through sulfur in urea and Urea derivatives.

These sulfur compounds can be compared to their corresponding Oxygen analogs are the same or different Pharmacological effects «inherent, but almost always have increased toxicity. For example, 6-thioguanine is fifty times more toxic than guanine.

Xs now showed that when sulfur was introduced into the 2-position of certain 1 »4-bensodiazepine compounds not only The mentioned pharmacological effect is retained, but also surprisingly the toxicity of the resulting Sulfur analogs are markedly reduced.

^{90981 5/1136} BAD ORlGWAL

A new compound according to the invention can e.B. by 3-hour refluxing of 7 ~ chloro-5-phenyl ~ 1H ~ 1 »4-benso- · diaBepin-2- (3H) -one with phosphorus pentasulfide in the presence of τοη Pyridln made willows. The sulfur occurs easily in dl 2-position, with 7-chloro-5-phenyl-1H-1,4-benzoil.iasepia ~ 2- (3H) -thione forms · Furthermore, this compound can sweck · Preparation of a 7-chloro-2 (»ethylthio) -5-phenyl-3H-1,4-bensodlasepins be methylated. This last connection is a more effective ataraxic agent than the starting material,

-IH-i »4 ~ bensodiaiepin-2- (3H)« - oa ·

The following examples serve to illustrate the invention without limit them su.

example 1

Trade trip phosphorus pentasulfide is obtained by extraction using Purified pyridine using a Sajhlet extractor. The phosphorus pentasulfide crystallizes from the pyridine extract from »is filtered off» washed with pyridine and dried.

3 »68 g of the purified phosphorus pentasulphide are put into a SoxhlethUlse given »4.05 g of 7-chloro-5-phenyl-1H-1» 4-bensodiaBeplIfc ^ -2- (3H) -one are dissolved in pyridine and the solution is boiled for three hours under flow conditions. Thereafter the pyridine is evaporated and the reaction process

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BATH ORIGINAL

obtained T-chloro-S-phenyl-IH-i, 4-bensBodiazepin-2- (3H) -thione. This residue is triturated with hot methanol, the alcoholic solution is filtered off and the washed residue is further washed with dilute sodium hydroxide and dried.The dried thione compound can be recrystallized from ethanol and has a melting point of ⁰

Example 2
4.5 g of a phosphorus pentasulfide purified according to Example 1 are mixed with 4.5 g of 7-chloro-5-phenyl-1-methyl-1 _f 4- (3H) - overnight

conditions benzodiazepin-2-one in fyridine under reflux / boiled · The reaction mixture is cooled, the pyridine evaporated, the residue extracted with chloroform and finally the extract chromatographed on acidic, washed aluminum oxide. After discarding the first portion, the compound i-methyl-5-phenyl-7-chloro-1H-1 _f 4-benBodiazepine-2- (3H) -thione is eluted from the aluminum oxide, the chloroform is evaporated and the residue is dissolved in acetonitrile dissolved. The compound mentioned begins to crystallize out of the acetonitrile. The crystalline product is separated by filtration and, according to the Irooknen a melting point of 159-160 ⁰ C. The compound can be recrystallized from ethanol and then has the same melting point of 159-160 ⁰ G.

BAD ORlGJNAU

909815/1136

Example 3

To a solution of 4.29 g of 7-chloro-5-phenyl-1H-1,4-benzodiazepine-2- (3H) -thione in a mixture of 60 ml of toluene and 60 ml of dimethylformamide in a bis-bath, 864 mg of sodium hydride are obtained and after the evolution of hydrogen has ceased, 2.57 g of methyl iodide admitted. The mixture is stirred for one hour and then filtered. The residue contains the reaction product 7-chloro-5-phenyl-2-mathylthio-3H-1,4-benzodiazepine. It is dissolved in ether, filtered again and the ether evaporates. The residue, which has been recrystallized twice from ethanol, melts at 133-1 / 55 ° C

For the person skilled in the art, of course, modifications of the method described in the above examples are within the scope of the present invention Invention possible.

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ORIGINAL IWSPECTED

Claims (1)

Claim [1. [Process for the preparation of a 1,4-benzodiazepine-2-mer "apt6" Compound of the formula in which B ₁ denotes hydrogen »lower alkyl or cyoloparaffin and B ₂ denotes hydrogen, halogen, alkoxy or alkyl, characterized in that a compound of the formula CH 909815/1136 BATH ORIGINAL f HI U 4 la der B ₁ and I ₂ dl «obijt Btdtutuag besl« B «ii _f alt tinem \ la tlata in «rt« a organic «Itt ·! «Mf * 9« ts% will · 2 · Terfahrtn aae «Anepruch 1 ₉ by e« kennieleha «t» that al · thioai «raaf« altt «l Äoephorpaataeulfid r« rw «adet» ■ 1 9 · Twrfahren aiih d «n AnaprtUihan 1 or 2, thereby marked« a * t _# dal al «iatrt ·· orga & leoJtee Leeungeelttel lyridlm, SlthlaAillm« TetrallA or Ooiaolla Terwendet · 4 · Terfaltt ^ n nor Heretellum * a Ter ^ induaf of the Tormel im der I ₁ W * »ftwr * to £ f ₉ Iie * ifalkyl or Gyoloparaffin and I ₂ fMfttretoff _t Halo * ea, Aiko *? »Dar Alky * eedeutea, 90 9815/1136 BATH ORIGINAL / WP 15 by using a Yerbindunf tar formula in the B ₁ the above meaning fceaitst »with an allylizing agent in the presence of an inert organic amigam1tt # lumeeetat · 5. Terfahren naoh Anspruoh 4 ", because Auroh is labeled" 4ass al " AlkylationMeans methyl iodide and sodium hydride Ter "end" t will, 6 · Method according to claims 4 or 5, Aaduroh identified, that an Oemieof ▼ of toluene and dimethylformamide is used as inert organic solvent. 909815/1 136 BATH ORIGINAL