CA2010059A1 - Benzazepines - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Novel 2,3,4,5-tetrahydro-1H-3-benzazepines, which in the 7-position have a methoxymethyloxy group, in the 8-position hydrogen, halogen or a nitro group and in the 5-position have an optionally substituted phenyl ortho-fused ring-system, with interesting effects on the central nervous system.

Description

5~

New Benzazepines This invention relates to novel methoxymethyl ethers of

2,3,4,5-tetrahydro-lH-3-benzazepines and pharmaceutically acceptable acid addition salts thereof, to methods for their preparation, to pharmaceutlcal compositions ontain-ing them, and to their use in the treatment of certain disorders in the central nèrvous system.

In the last decade intensive pharmacological research con-cerning benzazepines has taken place. The pharmacological properties of benzazepines depend to a large extent on the substituents. Various substituted benzazepines exhibiting neuroleptic, anti-aggressive, anti-Parkinson and vascular effects are known.
In US patent specification No. 3,393,192 (Schering Corp.) derivatives of 5-phenyl-2,3,4,5-tetrahydro-1~ 3-benzazepine having, inter alia, hydroxy, lower alko~y or halogen in the 7- and/or 8-position are describedr These compounds are claimed to be useful as an~ibacterials, antidepressants, antihypertensives and analgetics.

In US Patent No. 4,751,222 (NOVO Industri A/S) 2,3,4,5-tetrahydro-lH-3-benzazepines having a heterocyclic or an ortho-fused heterocycllc ringsystem in the 5-positlon are described. These compounds are claimed to have antipsycho-tic and antidepre~ive effects.

In GB patent specification 1,268,243 (Wallace & Tiernan Inc.) various 1,2,4-5-~etrahydro-3H,3-benzazepines ara described as useful analgetics.

2 2~ j9 The present invention describes methoxymethyl ethers of 2,3,4,5-tetrahydro-lH-3-benzazepin-7-ols with various substituents in the 5-position having interesting effects on the dopaminergic central nervous system.

The 7-methoxymethyloxy-2,3,4,5-te-trahydro-lH-3-benzaze-pines of the invention has the general formula I

o o~t--R2 1 ~
~.

wherein R1 is hydrogen, halogen or nitro0 R2 is hydrogen or C1 6-alkyl R3 is hydrogen or Cl 6-alkyl R4 is furyl, thienyl, pyridyl or ringsystems consi-sting of phenyl ortho condensed with a benzen, cyclohexan, cyclohexen, cyclopentan or cyclopenten ring in which rings one of the carbon atoms may be exchanged with oxygen, sulphur or nitrog~n and pharmaceutically acceptable acid addition salts thereof, exhibits useful pharmacological proper-ties by action on the central dopaminergic system.

Compounds of the general ~ormula I exhibit strong antidopa-minergic effect. Thus, they potently inhibit stereotyped gnawing behaviour in mice induced by methylphenidate (i.e Acta Pharmacol. Toxicol. 31, 1972, 488), and they also

3 ~ s~

inhibit conditioned avoidance response and amphetamine cue in rats.

The compounds of formula I may be presented as a mixture of optical isomers which may be resolved into the indivi-dual pure isomers, This resolution may conveniently be per-formed by fractional crystallization, from various solvents of the salts of compounds of the formula I with optical active acids or by other methods known from the literature, e.g. chiral column chromatography. Therefore, this inven-tion includes all isomers, whether resolved or mixtures thereof.

Particularly valuable embodiments of this invention are non-toxic, pharmaceutically acceptable acid addition salts of benzezepines of formula I. Such salts include those derived from inorganic and organic acids such as hydro-chloric, hydrobromic, sulphuric, phosphoric, methanesul-fonic, acetic, lactic, maleic, phthalic and tartaric acids.
These salts may be prepared by methods known to professio-nals skilled in the art.

The compounds of this invention are formulated in~o conven-tional pharmaceutical composi~ions according to known tech-niques. The dosage formulation will preferably contain the active compounds in the range of 0.5 mg to about 1000 mg for oral dosing. Typical dosage for antipsychotic effect would vary between about 0.5 to 10 mgJkg per day divided in 2 or 3 doses, administered orally.

The pharmaceutical carriers employed can be conven~lonal solid or liquid carriers. Example~ of solid carriers are lactose, terra alba, sucrose, talcum, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid.
Examples of liquid carriers are syrup, peanut oil, olive oil and water.

2~ 5g If a solid carrier for oral administration is used, the preparation can be tableted, placed in hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. If a liquid carrier is used, the preparation may, for example, be in the form of syrup, an emulsion, a soft gelatin capsule, a sterile in~ectable solution or a~
aqueous or non-aqueous liquid suspension.

The compounds of this invention are active in a number of assays predictive for antipsychotlc effect. In all models they show a strong anti-dopaminergic effect, both after intravenous and oral administration.

Table 1 shows the ED50 values for selected compounds in the methylphenidate induced gnawing test in mice.

TABLE 1.

COMPOUND ED50 ~mg/kg) (+)-8-chloro-7-methoxymethyloxy-3-methyl-5-(benzofuran-7-yl)-2,3,4,5-tetrahydro-lH- 2.0 3-benzazepine (~)-8-chloro-7-methoxymethyloxy-3-methyl-5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5- 5.4 tetrahydro-lH-3-benzazepine - _ _ The 2,3,4,5-tetrahydro-lH-3-benzazepin~s of the general formula I can be prepared by the following method using starting materials prepared as described in US Patent

4,751,222:

)05g HO ~ N-R2 ClCH20C
R~R 3 ~ R4R3 The compound of the invention, together with a conventional ad~uvant, carrier, or diluent, and if desired in the form of a pharmaceutically-acceptable acid addition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or cap-sules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile iniectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingre-dients in conventional proportions, ~ith or without additio-nal active compounds or principles, and such unit dosage forms may contain any suitable effective central nervous ~0 system ailment alleviating amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing one ~1) milligram of active ingredient or, more broadly, one (1) to thirty (30) milli-grams, per tablet, are accordingly suitable representative unit dssage forms.

The compounds of this invention can thus be used for the formulation of pharmaceutical preparations, e.g., for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.

Conventional excipients are such pharmaceutically accepta~le organic or inorganic carrier substances suitable for paren-teral or oral application which do not deleteriously react with the active compound.

Examples of such carriers are water, salt solutions, alco-hols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxilliary agents, such as lubricants, pre-servatives, stabilizers, wetting agents, emulsifiers, saltfor influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compound.

For parenteral application, particularly suitable are injec-table solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated cas-tor oil.

Ampoules are convenient unit dosage forms.

For oral application, particularly suitable are tablets, dragees, or capsules having talc and/or a carbohydrate car-rier or binder or the like, the carrier pre~erably being lactose and/or corn starc~ and/or potato starch. A syrup, elixir or like can be used when a sweetened vehicle can be employed. Generally, as to broader ran~es, the ¢ompounds of the invention are dispensed in unit dosage ~orm compris~ng 0.05-100 mg in a pharmaceutically-acceptable c~rrier per unit dosage.

A typical tablet, which may be prepared by conven~ional tab-letting techniques, contains:

7 2~1~o~

Active compound 1.0 my Lactosum 67.8 mg Ph.Eur.
Avicel 31.4 mg Amberlite IRP 88 1.0 mg Magnesii stearas 0.25 mg Ph.Eur.

The following examples illustrate the preparation of the novel compounds of this inventlon:

8 ~ i9 Example 1.

(+)-5-(7-benzofuranyl)-8-chloro-7-methoxymethyloxy-3-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine.

(+)-5-(7-benzofuranyl)-8-chloro-3-methyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-ol (1.64 g, 0.005 mol) i5 suspended in dry ethanol (50 ml). Potassium-tert.-butylate (1.12 g, 0.010 mol) and potassiumiodide (0.10 g) are added. To the resulting solution chloromethyl methyl ether (0.84 g, 0.010 mol) is added. The reaction mixture is stirred for 3 hours. The resulting suspension is filtered and the fil-trate evaporat~d to dryness under reduced pressure. The residue is chromatographed on a silicia-gel column, using dichloromethane/methanol (25:1) as the eluent. The frac-tions containing the product are collected and evaporated to dryness under reduced pressure.

Yield: 1.17 g (63~) light yellow oil.

Microanalysis: Calc. for C21H22ClN03: C 67.8%, H 6.0~, N 3.8%.

Found: C 67.5%, H 6.0%, N 3.6%.

Identity: NMR 400 mHz 'H-chemical shifts in ppm.
CDC13 as solvent, TMS as internal standard.

(~r, ppm): 2.39(S,3H); 2.43 (d,lH) 2.88 (M,2H~; 3.16 (M,3H); 3.30 (S,3H); 4.76 (d,lH); 4.90 (Q,2H); 6.46 (S,lH); 6.82 (d,lH); 7.06 (d,lH~; 7.20 (S,lH); 7.25 (t,lH), 7.57 (d,lH) and 7.62 (d,lH) 2~0~

Example Z.

(+)-8-chloro-5-(2,3-dihydro-benzofuran-7-yl)-7-methoxy-methyloxy-3-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine.

(+)-8-chloro-5-(2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-lH-3-ben azepin-7-ol`(4.95 g, 0.015 mol) and potassium-tert butylate (1.85 g, 0.016 mol) are dissolved in dry tetrahydrofuran (40 ml) at 5C.
Chloromethyl methyl ether (1.51 g, 0.019 mol) is added, -the temperature raising to 35C. The reaction mixture is stirred for three hours, then evaporated to dryness under reduced pressure. The residue is partitioned between water and toluene after adjusting the pH to 8.0 by addi-tion of 1 N sodiumhydroxide. The toluene phase is dried over magnesium sulphate, and evaporated to dryness under reduced pressure. The residue is crystallized from ethyl-acetate (11 ml).
Yield: 3.1 ~ (55%) white crystals.
Mp: 111 - 113C.

Microanalysis: Calc. for C21H24ClN03: C 67.5%, H 6.5%, N 3.8%.

Found: C 67.5%, H 6.6%, N 3.7%.

Identity: NMR 400 mHz 'H-chemical shifts in ppm.
CDCl3 as solvent, TMS as internal standard.

(dr, ppm): 2.37 (broad S,4H); 2.8-3.1 (M,5H); 3.23 (t,2H); 3.40 (S,3H~ 4.40 (t,lH); 4.52 (t,2H); 5.00 (S,2H); 6.57 (S,lH), 6.83 (M,2H) and 7.14 (M,2H) ~ S~

Example 3 ~ 5-(2,3-dihydrobenzofuran-7-yl)-7-methoxymethyloxy-3-methyl-8-nitro-2,3,4,5-tetrahydro-lH-3-benzazepine.

( -t ) -5-(2,3-dihydrobenzofuran-7-yl)-3-methyl-8-nitro-2,3,4,5-tetrahydro-lH-3-benzazepin-7-ol (68.0 mg, 2.0 mmol) and potassium-tert-butylate (24.0 mg, 2.2 mmol) are dissolved in dry tetrahydrofuran (10 ml) at 23C. Chloro-methyl methyl ether (20.0 mg, 2.5 mmol) is added. The reaction mixture is stirred for 22 hours, filtered and the filtrate evaporated to dryness under reduced pressure.
The resulting light yellow oil is purified using reverse phase HPLC (column 16 mm x 250 mm, Cl~ 7~; eluent ace-tonitril/O.lM ammoniumsulphate pH 3.3 (30:70), isocratic).
The fractions containing the product are pooled. The pH
is adjusted to 9.0, and the product extracted into dichlo-romethane. The organic phase is evaporated to dryness under reduced pressure.

Yield: 30 mg (3g%), light yellow oil.

Example 4 (+)-5-(2,3-dihydrobenzofuran-7-yl)-8-iodo-7-methoxy-methyloxy-3-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine.

~ 5-(2,3-dihydrobenzofuran-7-yl)-8-iodo-3-methyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-ol (126.0 mg, 3.0 mmol) and potassiumm-tert-butylate 37.0 mg, 3.3 mmol) are dissolved in dry tetrahydrofuran (10 ml) at 20C. Chloro-methyl methyl ether (30.0 mg, 3.8 mmol) is added. The reaction mixture is stirred for 3.5 hours then poured into 5% sodiumhydrogencarbonate (20 ml~. The product is extracted into dichloromethane (2 x 15 ml). The organic phase is evaporated to dryness under reduced pressure.

Yield: 100 mg (71%), yellow oil.

The product is purified by reverse fase HPLC as discribed in example 3.

Example 5 8-chloro-7-methoxymethyloxy-3 methyl-5-(1,2,3,4-tetrahydronapth-6-yl)-2,3,4,5-tetrahydro-1-H-3-benzazepine.

8-chloro-3-methyl-5-(1,2,3,4-tetrahydronapth-6-yl)-2,3,4,5-tetrahydro-lH-3-benzazepin-7-ol (103.0 mg, 3.0 mmol) and potassium-tert-butylate (37.0 mg, 3.3 mmol3 are dissolved in dry tetrahydrofuran (10 ml) at 20C.
Chloromethyl methyl ether (30.0 mg, 3.8 mmol) is added.
The reaction mixture is stirred for two days, then poured into 5% sodiumhydrogencarbonate (20 ml). The product is extracted into dicloromethane (2 x 15 ml~, and the organic phase is evaporated to dryness under reduced pressure.

Yield: 95 mg (82~) light yellow oil.

The product is purified by reverse phase HPLC as discribed in example 3.

Claims (8)

12

1.
7-methoxymethyloxy-2,3,4,5-tetrahydro-1H-3-benzaze-pines having the general formula I
I
wherein R1 is hydrogen, halogen or nitro R2 and R3 is hydrogen or C1-6-alkyl R4 is furyl, thienyl, pyridyl or ringsystems consi-sting of phenyl ortho condensed with a benzen, cyclohexan, cyclohexen, cyclopentan or cyclopenten ring in which rings one of the carbon atoms may be exchanged with oxygen, sulphur or nitrogen and pharmaceutically acceptable acid addition salts thereof.

2. Compounds according to claim 1 wherein R3 is hydrogen.

3. Compounds according to claim 1 wherein R1 is halogen or nitro.

4. A compound of claim 1 which is:

(+)-8-chloro-7-methoxymethyloxy-3-methyl-5-(benzofuran-7-yl)-2,3,4,5-tetrahydro-1H- 3-benzazepine or (+)-8-chloro-7-methoxymethyloxy-3-methyl-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5- tetrahydro-1H-3-benzazepine.

5. A method for the preparation of a compound of formula I characterized in reacting a compound of formula II

(II) with a compound of the formula III

C1CH2OCH3 (III) to form a compound of the invention.

6. A pharmaceutical composition containing a com-pound of claim 1 or a pharmaceutically acceptable acid addition salt thereof.

7. A method of treating a central nervous system ailment in a person in need of such treatment characterized in administering to said person an amount of a compound of claim 1 effective in alleviation of such an ailment.

8. A method of treating a central nervous system ailment in a subject in need of such treatment comprising the step of administering to said subject an amount of a compound of Claim 1 which is effective for the alleviation of such ailment in the form of a pharmaceutical composition thereof, in which it is present together with a pharmaceutic-ally acceptable carrier or diluent.