DE2311019A1 - IMIDAZOLIDINE DERIVATIVES - Google Patents

Description

Me invention relates to biologically active imidazolidine derivatives and especially tetra-hydro-imidazo-dibenzo-oxazepine, -thiazepines and -diazepines.

From GB-PS 1 229 252 compounds are known which differ from the compounds according to the invention in that they have a piperazine instead of an imidazolidine ring contain. These known piperazine derivatives have antihistamine and antiserotonin activity.

Surprisingly, it has now been shown that the imidazolidine derivatives the general formula:

309838/1241

CD

in which H ^ and R ₂ each have a hydrogen or halogen atom, a hydroxy, alkyl or alkoxy group with 1 to 6 carbon atoms, an acyloxy group with 1 to 8 carbon atoms or a trifluoromethyl group, E, a hydrogen atom or an alkyl group with 1 to 6 carbon atoms or an aralkyl group with 7 to 10 carbon atoms and X an oxygen or sulfur atom or the group NR ^ in which R ^ is a hydrogen atom or a lower alkyl group with 1 to 6 carbon atoms , sovae mean their pharmacologically acceptable acid addition salts and pharmacologically acceptable quaternary ammonium compounds have a completely different therapeutic effectiveness. In contrast to those described in GB-PS, the compounds according to the invention show a positive effect in the investigation of reserpine antagonism, ie they have an antidrepressive activity, while the antihistamine and antiserotonin activity of the compounds according to the invention is generally compared with the strong antihistamine and / or antiserotonin activity of the known compounds can be neglected »

The compounds of the present invention can be prepared by any known method for such compounds. However, they are best made starting from a substance with the general formula:

309838/124?

(H)

in the X, IL, I ^ and R, the meaning given above or an acid addition salt of this compound.

The starting substance II is cyclized by condensation with a Beagens of the formula:

(HD

in which X is two hydrogen atoms, an oxygen or sulfur atom and Z,. and Z ~ can be the same or different and are each reactive and leaving groups or together represent a divalent reactive group which can emerge together with the hydrogen atoms of the diamine of the formula II bonded to the two nitrogen atoms, so that a compound of the formula:

in the Z, Ϊ,

and R, have the meaning given above ,

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- • 4 -

arises.

In general, the groups Z. and Zp can be a halogen atom, a substituted or unsubstituted amino group, the group OBc or SRc, where Rc is a hydrogen atom, a hydrocarbon radical which can be substituted by heteroatoms or halogen atoms, a Rg-sulfonyl group in which Rg is Is hydrocarbon radical, or Z, and Z ₂ can together represent a sulfur or oxygen atom.

When Y is hydrogen (Ho), Z and Z are preferably halogen atoms or hydroxyl groups. Reagents of the formula III belonging to such compounds are, for example, methylene chloride, methylene bromide or methylenediol (formaldehyde solution in water or a water-containing solvent).

If Ϊ is an oxygen or sulfur atom, the most favorable groups Z. and Z _{2 are} halogen atoms, substituted or unsubstituted amino groups, ORk or SR ^ groups, where Rc is a hydrocarbon radical which can be substituted by heteroatoms or halogen atoms, or Z _x . and Zp together is a sulfur atom (when Y is a sulfur atom).

Suitable reagents of the formula III for such compounds are, for example, phosgene, thiophosgene, haloformic acid esters such as ethyl chloroformate, esters of carbonic acid such as diethyl carbonate, urea and urea derivatives such as thiourea or Η, Ν'-carbonyldiimidazole and carbon disulfide.

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In the condensation reaction according to the invention, preference is given to used as reagent III methylene halide or formaldehyde (in water), as these substances lead directly to the desired end product.

When a reagent of the formula III is used, in which Y means an oxygen or sulfur atom, the resulting compound must be additionally reduced to the to obtain desired end product. Any suitable reducing agent can be used for such reduction e.g. metal hydrides such as sodium hydride, lithium aluminum hydride or diborane. The reduction can can also be carried out catalytically by hydrogenation in the presence of a metal or a metal compound.

When Z. and / or Z ~ denote halogen atoms, usually an agent that can bind the hydrogen halide released during the condensation reaction, such as pyridine, Triethylamine, etc. are added to the reaction mixture.

The condensation reaction can be carried out in any suitable solvent. When methylene halide is used as reagent III, an aprotic polar solvent such as dimethyl sulfoxide, suIfolane or acetonitrile is preferably used. However, it is also ~ possible to carry out the condensation exclusively in the reagent, for example methylene chloride, or a formaldehyde solution in the absence of a further solvent. In certain cases, for example when urea is used as reagent III, the reaction can be carried out in the melt.

The acid addition salts of the compounds according to the invention are

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the conventionally prepared by reacting the free base with a pharmaceutically suitable acid such as hydrochloric acid, hydrogen bromide or hydriodic acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid or benzoic acid.

The pharmaceutically acceptable quaternary ammonium compounds, especially the quaternary alkylammonium compounds with 1 to 4 carbon atoms of the alkyl group, are obtained by reacting the compounds of the general formula I with an alkyl halide, for example methyl iodide or methyl bromide.

It is apparent from the above general formula I before ago that compounds of the invention possess an asymmetric carbon atom. Consequently, optical antipodes are possible, which are also encompassed by the invention. These optical antipodes can be isolated from the racemic mixture in a conventional manner. It is also possible to split the racemic starting material II into the optical antipodes and then carry out the condensation reaction or split an intermediate product into the optical antipodes during the synthesis.

It is of course possible to introduce or modify substituents on one or both phenyl nuclei after the condensation. For example, a hydroxy group can be acylated or converted to an alkoxy group, an amino group to a halogen atom, a methoxy group to a hydroxy group, etc.

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The substituent R, on the N -nitrogen atom can be introduced by alkylation or aralkylation of the unsubstituted nitrogen atom (R, = H) or by Acylation of the unsubεsituierten nitrogen atom and subsequent reduction of the carbonyl group of the N-acyl compound thus obtained.

It is also evident and known that the alkyl or to convert aralkyl-substituted N-nitrogen atom (of formula I) into the unsubstituted nitrogen atom, e.g. by heating with chloroformic acid ester and subsequent hydrolysis of the compound thus obtained.

As indicated above, the compounds according to the invention have antidepressant activity. You can take it both orally as well as parenterally, preferably in a dose of 0.01 to 1 mg per kg of body weight. in the Mixing with suitable additives, the compounds can form fixed dose units, such as pills, tablets and coated tablets be pressed. If desired, they can also be filled into capsules together with excipients. With the help of appropriate Liquids can contain the compounds as injection preparations in the form of solutions, emulsions or suspensions administered.

Compounds according to the invention which are preferably used are:

2,6-dimethyl-1,2,3,13b-tetrahydro-imidazo / ~ 3 »4-d_7-dibenzo- / ~ * b, f 7- (i »4)

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2-methyl-1,2,3,13b - tetrahydro-imidazo ^ ~ 3,4-d_7-dibenzo-, f_7- (i »4) -oxazepine,

2,12 ~ dimethyl-1,2,3,13b-tetrahydro-imidazo / ~ 3 $ 4-d_7-dibenzo , f_7- (i, 4) -oxazepine.HCl,

2-methyl-12-chloro-1,2,3,13b-tetrahydro-imidazo / * "3,4-d_7-

2,9-dimethyl-2,3,9,13b-tetrahydro-9H-imidazo / ^ 3,4-d_7-

2-methyl-12-trifluoromethyl-1,2,3,13b-tetrahydro-imidazo / 7'3,4-d_7 "

(1 _f 4) -thiazepia,

The invention is illustrated in more detail by the following examples.

The following nomenclature and numbering are used.

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I,?, 3,13b-! Ifetrnhydro-imid.T / .o [3, it-dJ-dibe! IKo [b, oxazepine

1,2,3113 *> - Tetrahydro-imidazo [3, ^ - d] -dibenzo [b, f] (l, lf) -thiazepine

l ,. ' ¹ , 3,13b-Tetmhydro-9H-imidai'.o [3,4-d] -dibenzo [b, fj (l, lf) -diazepine

- 10 -

309838/1247

MM ₁

1 l-aminomethy 1 -10, 1 1 -dihydrodibenzo [b, f] (1, O-oxnx.epin

h.Y 1-10,11 -di hydroi bt> n7.o [b, Γ j (1, Ί) -ili i, -r / .op L ti ·

ll-aminomethyl-10, ll-dihydro-5H-dibenzofb.ejd ^ j-diazepine

example ±

Production of 2-methyl-i, 2,3,13 "b-tetrahydro-imidazo /""3,4-d_7 dibenz o ^" b, ij (1,4) - oxa ζ ep in

2 g of H-methylaminomethyl-IO ^ I-dihydro-dibenzo / 'b ^^ ZCij ^) - oxazepine were added to a mixture of 40 cnr ethanol and 15 CBr of a 40% solution of formaldehyde in water . The mixture was refluxed for 30 minutes, then to a volume of approximately 25 in vacuo

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- 11 -

evaporated. A further 30 cnr of water were added and the resulting precipitate was filtered off and recrystallized from ethanol. In this way, 1.6 g of the pure product, Ip. 102 to 103 ⁰ C The tartrate of this compound melted at 113 to 115

Example 2

In the manner described in Example 1, the following were prepared:

1. 2,6-Dimethyl-1,2,3,13b-1etrahydro-imidazo / "* 3,4-d_7-dibenzo- >, f_7 (i, 4) -oxazepine; M.p. 84 to 86 ° C

2. 2,10,11-trimethyl-i, 2,3,13b-tetrahydro-imidazo / ~ 3,4-d_7 dibenzo / ~ b, f_7 (i, 4) -oxazepine; Mp. 105-106 ^° C

3. 2-methyl-7-methoxy-1,2,3,13b-tetrahydro-imidazo / f 3,4- d_dibenzo ^ ~ b, f_7 (i, 4) -oxazepine; Pp. 96 to 99 ° C

4. 2-propyl-1,2,3i13b-tetrahydro-imidazo / ~ 3,4-d_7-dibenzo-

, f_7 (i, 4) oxazepine; Mp 93 to 95 ° C

5. 2,12-dimethyl-1,2,3,13b-tetrahydro-imidazo / ~ 3,4-d_7-dibenzo ^ ~ b, f_7 (1,4) -oxazepine.HCl; Mp 183-185 ° C

6. 2-Benzyl-1,2,3,13b-tetrahydro-imidazo / ~ 3,4-d 7- <übenzo ^ ~ b, f_7 (1,4) -oxazepine

Example 3

Production of methyl iodide salts (quaternary ammonium compounds

genj

A. 300 mg of the product obtained in Example 1 2-methyl

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nmr T ^ -

1,2,3 »13b-tetrahydro-imidazo / ~ 3,4-d 7-dibenzo / ~ b, f 7 (1,4) -oxazepine were heated to the boil for 5 minutes in 10 cm ether and 2 cur methyl iodide. The mixture was cooled and the precipitate obtained is filtered off and extracted from ethanol re-crystallized. Mp. Of the CH, J salt 192 to 194 ° C.

B. In the same way, the CH ₅ J salt of 2,6-dimethyl 1,2 _t 3,13b-tetrahydro-imidazo ₍ / ~ 3,4-d_7-dibenzo / ~ b, Ij- (i, 4) -oxazepine (Example 2.1) produced. Mp. Of the CH ^ J salt - 184 to 186 ⁰ C.

Example 4

Preparation of 2-methyl-6-chloro-1,2,3 _ί 13b-tetrahydroimidazo - ^ "3» 4-d _-> 7-dibenzo ^ "" b, f_7 (1,4) -thiazepine and other derivatives

a) 1.5 g of S-chloro-H-methylaminomethyl-lOjii-dihydro-dibenzo - / "b, f 7 (if4) -thiazepine were dissolved in 20 cm ^ of ethanol and then 10 cm? of a formaldehyde solution in water was added. The mixture was ^{heated to 0} ° C. for 40 minutes and then evaporated to a volume of 15 cm in vacuo. After 10 cm of water had been added, the precipitate was filtered off and recrystallized all at once from methanol, giving 1.1 g of pure product . * - pp. 145 to 147 ⁰ C

b) In the same way, the 2-methyl compound (Jp. 147 to 1VO ⁰ C), the 2-methyl-12-chlorine compound (mp. 113 to 115 ⁰ C) and the 2-methyl-6-trifluoromethyl compound ( Melting point 145 to 147 ^° C.).

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Example £

Preparation of 2,9-dimethyl-1 ^^ imidazo ^ ~ 3 »4-d_7-dibenzo ^ ~ b, f_7 (i, 4 -) - diazepine and others Derivatives

a) 8 g of f ^ methyl-ii-methylaminomethyl-lOjii-dihydro ^ H-dibenzo / ~ b, e__7 (i »^) - diazepine became a mixture of 75 cnr ethanol and 25 cnr of a 40% formaldehyde solution put in water. The mixture was left to stand for 30 minutes and then in a vacuum to a third of the

■ χ

Evaporated in volume. Finally 4-0 cnr water was added and the mixture extracted with ether. The ether extracts were washed with water, dried over anhydrous sodium sulfate and evaporated. The yellow oil that remained was chromatographed over silica gel. After evaporation, the methanol eluate gave 5 * 6 g of the crystalline substance. Mp. 100 to 102 ⁰ C after recrystallization from ethanol.

b) In the same way, the 2-ethyl-9-methyl compound (melting point 98 to 100 ° C) was ind the corresponding 12-methoxy, 12-hydroxy and 12-methyl compounds produced.

Example 6 Separation of

2-methyl-1,2,3-13b-tetrahydro-imidazo ^ "~ 3j4-d_7-dibenzof_7 (1,4) -oxazepine (Hacemat)

6 g (racemic) 2-methyl-1,2,3,13b-tetrahydro-imidazo- / ~ 3 »4 - d 7-dibenzo / ~ b, f 7 (i, 4 -) - oxazepine were in 400 cnr dissolved in absolute ethanol. Then a solution of 2.8 g of 2 (R), 3 (R) -tartaric acid (natural tartaric acid) in 100 cm ^{5 of} ethanol was added. The mixture was left to stand overnight and then the crystals were filtered off with suction. the

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Crystals were put into 1N NaOH, and then the mixture was extracted with benzene. Then the benzene layer was washed with water, dried over ite ^ SO ^ and evaporated to dryness. The backrest had a rotation f °

from Γoijf = +37

The extraction process described above was repeated three times, yielding a product with a constant

Rotation of ^ "α_7§ °» + 62 °; mp. 134 to 135 ° C.

In the same way, the levorotatory enantiomer with 2 (S), 3 (S) -tartaric acid (synthetic) was obtained from the mother liquors of the dextrorotatory enantiomer. / ~ oc_7tj = -62 °.

Example 7

Preparation of 2-methyl-1,2,3,13b-tetrahydro-imidazo / "" 3j4-d_7- dibenzo / ~ b, f 7 (i »4) -oxazepine

A. 2 g of 11-methylaminomethyl-10,11-dihydro-dibenzo / ~ "b, f 7- (i, 4) -oxazepine were dissolved in 12 cm of methylene chloride and then 12 cm of dimethyl sulfoxide and 5 cm of triethylamine was added. the mixture was 4 hours heated under reflux. the excess methylene chloride and triethylamine were evaporated in vacuo. the residual liquid was diluted with $ 0 cnr water. the mixture was allowed to stand for 1 hour and the obtained when filtering precipitate from ethanol to crystallize, mp. 100 to 102 ° 0.

B. Following the procedure described above (reagent III = methylene chloride) the following compounds were prepared:

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2-methyl ~ 12-chloro-1,2,3, 13b-tetrahydro-imidazo / ~ 3 | dibenzo- ^ fb, f_7 (i, 4) -thiazepine; Pp. 112 to 114 ° C,

2-methyl-1,2 * 3,13b-tetrahydro-imidazo ^ -3, (i, 4) -thiazepine; Mp. 147 to 149 ⁰ C,

2,9-Dimethrl-i ^^,
, 4) diazepine; M.p. 102 ^° C.

example 8th

2 ~ Hethyl-1,2,3,13b-tetrahydro-imidazo / ~ 3 , 4-d_7-dibenzof_7 (i »4) -oxazepine

2 g of diamine H-methylaminomethyl-IOjii-dihydro-dibenzo- / ~ b, f _- 7 (i « ^z '-) - oxazepine were dissolved in CSp and the solution was refluxed for 6 hours. During the refluxing a residue precipitated out and was filtered off. This residue, 2-methyl-3-thio-1,2,3,13btetrahydro-imidazo / ~ 3, ^/ i'-d_7-dibenzo / "" b, f_7 (1,4) -oxazepine was immediately dissolved in THF and then 1.5 g of MAlH _{2 were} added. The mixture was heated under refluxing under stirring for 3 hours. The mixture was then

ο ^

cooled to 0 C and added dropwise 6 cur of water, and stirred for a further hour and then filtered. The filtrate was evaporated to dryness in vacuo. After recrystallizing the residue obtained from ethanol, the pure compound was obtained. Mp. 102 to 103.5 ⁰ C.

The same product was obtained if, instead of CS ₂ *, phosgene or ethylchlorofonniate was used in a suitable solvent or urea (in the melt).

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In the manner described ia Example Λ obtained 1,2,3j13b-TetifthydroifflidäZo ^ f 3 »4-d_7-dibenzo ^""b, F_7 (i, 4) oxazepine, starting from H-Aminomethyl-IOjH-dihydro-TJF (1 _t 4) -oxazepine.

PATENT INSPECTION i

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Claims (6)

PATENT CLAIMS in the R _x . and R ^ each represent a hydrogen or halogen atom, a hydroxy, alkyl or alkoxy group with 1 to 6 carbon atoms, an acyloxy group with 1 to 8 carbon atoms or a trifluoromethyl group, R, a hydrogen atom or an alkyl group with Λ to 6 carbon atoms or an aralkyl group with 7 to 10 carbon atoms and X is an oxygen or sulfur atom or the group NR ^, in which R ^ is a hydrogen or a lower alkyl group with 1 to 6 carbon atoms, as well as their pharmacologically acceptable acid 309838/1247 - 2Γ- addition salts and pharmacologically acceptable quaternary ammonium compounds . 2) Process for the preparation of the compounds according to claim 1 , characterized in that a compound of the formula: (H) in which R,., R ₂ »R * and X have the meaning given above or an acid addition salt thereof is cyclized by processes known per se. 3) Process according to claim 2, characterized in that the cyclization is carried out with a reagent of the formula: .1
Ϊ = C ^ (III) , ^Z 2 in der.Y two hydrogen atoms, one sulfur or one oxygen atom and Z _x . and Zp are identical or different and mean leaving or reactive groups in the condensation reaction or can together be a divalent group, used and then, if Y is an oxygen or sulfur atom, the resulting compound is reduced and optionally to a quaternary one 309638/1247 " ⁵ " Ammdtiiuja compound or an acid addition salt converts. 4) Process according to claim 2 or 3, characterized in that the reagent used for the cyclization is ethylene halide or an aqueous solution of formaldehyde or phosgene, a haloformic acid ester or OS ₂ . 5) Method according to claim 2 to 4, characterized that the starting substance, the end product or an intermediate product of the synthesis in splits the optical isomers 6) Use of the compounds according to claim 1 for the preparation of antidepressant agents. 62XtIf 309838/1247