JPS6040423B2 - Euphenyl-2,3,4,5-tetrahydro-1H-3-benzazepines - Google Patents

Description

[Detailed description of the invention]

The present invention relates to 1-phenyl-2,3,4,5-tetrahydro IH-3-penzazepines, and more particularly to 1-phenyl-2,3,4,5-tetrahydro IH-3-penzazepines, which have at least three substituents (one of which is preferably 6- The present invention relates to a group of novel 1-phenyl-2,3,4,5-tetrahydro IH-3-penzazepines having a lower alkylthio group. The compounds are useful as dopaminergic agents that exert significant effects at central nervous system receptors, and the invention also includes pharmaceutical compositions containing the compounds and methods of producing dopaminergic activity using the compounds. The compound of the present invention has the formula: [wherein R and R3 are each hydrogen or a carbon number of 1 to 5]
lower alkylthio, where one is alkithio; R,
and R2 each represent hydrogen, or a pharmaceutically acceptable non-maltiferous salt thereof. Compounds of formula [1) in which R is methylthio are preferred, and
Compounds containing 9-methylthio are slightly less effective than 6-methylthio compounds, but have fewer side effects. Pharmaceutically acceptable acid addition salts having similar efficacy to the free base of formula [1] can be prepared by adding inorganic or organic acids,
For example, maleic acid, fumaric acid, benzoic acid, ascorbic acid, vermic acid, succinic acid, bismethylene salicylic acid,
Methanesulfonic acid, ethanedisulfonic acid, acetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid,
It can be formed with glutamic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, cyclohexylsulfamic acid, phosphoric acid, nitric acid, etc. Certain 1-phenyl-2,3,4,5-tetrahydro-IH-3-penzazepines can be manufactured using conventional methods, such as
It is described in US Pat. However, these documents do not disclose anything about penzotri-substituted compounds, 6-methylthio-substituted compounds, and the advantages of such 6-methylthio-substituted compounds, such as the compounds of the present invention. These documents disclose 7,8-dihydroxy-substituted-1-phenyl-3-benzazepines and various intermediates thereof, some of which can be used as starting materials for the preparation of the compounds of the invention. Compounds of formula [1] can exist as diastereomers and can be resolved into d or 1 optical isomers. Resolution of optical isomers can be conveniently carried out by fractional crystallization of the salt with an optically active acid from a suitable solvent. In this specification, unless otherwise specified, all isomers are included, regardless of whether they are separated or a mixture thereof. When the isomers are separated, the desired medicinal effect is often achieved by one isomer, usually
Predominantly in the d-isomer. As is clear, the formula [
The compound of [1] has two functional hydroxy groups at the 7 and 8 positions, which may optionally be lower alkoxy derivatives having 1 to 5 carbon atoms such as methoxy, ethoxy, butoxy or isoamyloxy, or 0-acetyl, 0-propionyl or It can be changed to a lower alkanoyloxy derivative having 2 to 5 carbon atoms such as 0-valeryl. Dimethoxy or diacetoxy derivatives are the most useful, but the overall biological effects are somewhat lower. Diacyloxy derivatives generally have substantial oral activity. Formula [1
] The lower alkyl or lower alkanoyl derivative of the compound is produced by a known alkylation-acylation method. However, if, for example, in addition to O-alkylation, a lower alkyl halide is used as the alkylating agent, a lower alkylsulfonium halide is also formed at the sulfur atom during the alkylation process. For example, in reaction with methyl bromide, dimethylsulfurium bromide is formed. These sulfonium salts are optionally converted to the parent thio compound without affecting the 0-alkyl group by conventional methods such as heating in IN hydrobromic acid, saline, or other sources of bromine or chloride ions. It can be changed. Compounds of formula [1] are prepared by the cyclization reaction described in U.S. Pat. No. 3,393,192 using the appropriate 2-lower alkylthio-3,4-dimethoxyphenethylamine or the corresponding phenethyl aminomethylbenzyl alcohol as a starting material. be able to. N in formula [1]
-Substituted derivatives can also be prepared using a suitable tertiary amino alcohol in the cyclization reaction. However, a preferred method is to prepare the desired mercabutane (RSH, where RS is the same as R above) at about room temperature in a suitable inert organic solvent such as an alcoholic solvent such as methanol or ethanol. ) to obtain a compound represented by the formula: In this addition reaction, the 9-isomer is also obtained, but these mixtures can be easily separated into the 6- and 9-isomers by the method described below. In addition, a mixture of monosubstituted isomers can be prepared by 6.
It can also be used to prepare 9-disubstituted homologs. formula〔
m] with 2,3-dichloro-5,6-dicyano-1,4-penzoquinone and then reacted once again with the desired mercaptan to convert the second lower alkylthio substituent to the 9-position (or the 9-monoisomer). 6th place) can be introduced. formula

In the intermediates of [0] and [m], R, R, and R2 are the same as in the above formula [1]. In addition, this important 7,8-dialkoxy derivative is the 6-dialkoxy derivative of the compound of formula [1].
A lithium derivative (R=Li) is reacted with a suitable lower alkyl or trifluoromethyl disulfide under anhydrous conditions at room temperature or elevated temperature in an inert organic solvent in which the reactants are soluble, such as ether or tetrahydrofuran. can also be manufactured conveniently. 7,8-dimethoxy derivatives can also be produced by reacting 7,8-dihydroxy analogs with diazomethane. Of course, the dialkoxy derivatives can also be conveniently prepared by the conventional cyclization reactions described above. A compound of formula [1],
The lower alkyl ethers or esters and their non-toxic pharmaceutically acceptable addition salts have novel dopaminergic effects. It is well known that dopaminergic compounds have a dual effect on dopamine receptors in the central nervous system, particularly the brain, as well as on peripheral dopamine receptors, such as affecting the peripheral cardiovascular system. This latter effect increases pancreatic flow and produces a hypotensive effect. This can now be determined by intravenously injecting increasing doses of the compound at 5 minute intervals into anesthetized, positive pressure dogs and measuring various cardiovascular parameters. The effect on renal vascular resistance can be calculated from changes in blood flow and arterial blood pressure. The effect is the cumulative dose that produces a 15% reduction in renal vascular resistance, ED,5 value [R=B. P. (costal Hg)
/B. F. (on desk/minute)]. The penzazepine compound of formula [1] having a 6-lower alkylthio group is in particular described by Ungerstedt et al.
etal. , Brain Research 24, 485
-493 (1970)] has anti-Parkinsonian effects due to its central dopaminergic activity as demonstrated using a modification of the standard animal pharmacology test described by J.D.-493 (1970). This method was successful in drug-induced rotation in rats with extensive unilateral lesions of the substantia nigra. In summary, this test consists of quantitatively recording rotational movements in rats previously subjected to a 6-hydroxydopamine lesion of the substantia nigra dopamine system. Unilateral brain lesions in the left substantia nigra sensitize dopamine receptors in the left caudal region, causing cell degeneration in the substantia nigra. These lesions destroy the caudal neurotransmitter dopamine source, but leave the caudal cells and their dopamine receptors intact. Activation of these receptors by a drug causes a rotation in the opposite direction with respect to the lesioned side of the brain and is used as a measure of the central dopaminergic activity of the drug. Compounds known to be clinically effective in suppressing parkinsonian lachrymal complexes, such as L-dopa and apomorphine, are also active in this rat rotation test. These compounds activate direct dopamine receptors, causing the affected rats to make opposite rotational movements. Rolling activity is defined as the ability of a compound to cause 500 opposite rolls 2 hours after administration (usually intraperitoneally). The dose that causes 500 counter-rotations per 2 hours is expressed as the RD5oo value. A surprising property of the biological spectrum of the dopaminergic compound of formula [1] is that it has more central activity than activity at peripheral receptors. For example, 7,8-dihydroxy-6-methylthio 1-
Phenyl-2,3,4,5-tetrahydro-3-IH-
Penzazepine hydrobromide is RD5. oo. 18(0
．． It has a 9/k9 base of 0.06 to 0.29 (9/k9 base of 0.14), has eight times the activity of the 6-hydrogen analog, has a faster onset, and has a longer lasting activity. ED of this compound, 5
is 372 and has less IM sound than the 6-hydrogen homolog. 7.8
-dihydroxy-9-methylthio 1-phenyl 2.
3,4,5-Tetrahydro-3-IH-benzazepine hydrobromide is 9/k9 of RD5oo4.8 (9/k9 base of 3.8) and is three times more active than the 6-hydrogen congener. Higher alkylthio, i.e. other than methylthio,
as well as the 6,9-disubstituted congeners showed weaker activity in this rotational test than the preferred compound with a methylthio group. The pharmaceutical composition having dopaminergic activity of the present invention is a compound of formula [1], an isomer thereof, or a pharmaceutically acceptable acid addition salt thereof, which is sufficient to produce a desired medicinal effect in animals or humans, and The non-sedible amounts are prepared in conventional dosage unit form by combining with a non-toxic pharmaceutical carrier according to an acceptable method. Preferably, the compositions contain a non-toxically effective amount of the active ingredient selected from the range of about 2.5 9 to about 1000 9 per dosage unit, which amount is sufficient to achieve the desired biological activity and Depends on the patient's condition. The most desirable purpose of the pharmaceutical compositions and methods of the present invention is to treat Parkinson's disease and reduce or prevent seizures common in patients suffering from this central nervous system disorder. The pharmaceutical carrier used may be, for example, solid or liquid. Examples of solid carriers include lactose, white china, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Examples of liquid carriers include syrup, peanut oil, au jube oil,
Examples include water. Similarly, carriers or diluents include any known delay materials such as glyceryl mono-stearate or glyceryl distearate alone or in combination with waxes. Various dosage forms can be employed. That is, when a solid carrier is used, it can be in the form of tablets, powders or tablets in hard gelatin capsules, or troches or lozenges. The amount of solid carrier can vary widely, but preferably from about 2 hours to about 1 hour.
If liquid carriers are used, they can be sterile injectable solutions such as syrups, emulsions, soft gelatin capsules, ampoules, or aqueous or non-aqueous liquid suspensions. The pharmaceutical compositions are manufactured according to known methods, including mixing, granulating, optionally tabletting or various mixing and dissolving the ingredients appropriate to the desired end product. The above-mentioned method for producing dopaminergic activity of the present invention involves administering a non-toxic and effective amount of the compound of formula [1] or a pharmaceutically acceptable acid addition salt thereof to a patient in need of said action, usually by administering a pharmaceutically acceptable amount. It consists of administering as a carrier. The route of administration may be any route capable of effectively transporting the active compound to the dohamine receptor to be stimulated, such as oral or parenteral, with the oral route being preferred. Advantageously, the daily dose of about 1
Equal doses are administered several times a day (eg, 2-3 times) over a range of 50 females to about 1.5 days. Using this method, antiparkinsonian effects can be produced with minimal side effects. Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto. Example 17.8-dihydroxy-1-phenyl-2.
3,4,5-tetrahydro-IH-3-penzazepine hydrobromide (0.101 mol, U.S. Pat. No. 33
93192) to a suspension in methanol 275.
A solution of 25.2 mmol (0.111 mol) of 5,6-dicyano-1,4-penzoquinone in 125M methanol is added. This addition is carried out quickly under an argon atmosphere at 0° C. while observing the mixture. After heating at 0°C for 1 hour, the reaction mixture was filtered,
The orange precipitate was washed with 75 parts of cold methanol, 100 parts of ethyl acetate, then 100 parts of diethyl ether. After drying under vacuum at room temperature, 1-phenyl-2, 3, 4, 5
-Tetrahydro IH-3-Benzazepine-7・8-
Diisohydrobromide 32.8 mol (0.98 mol, 97%
). Melting point 164-16500 (decomposition) elemental analysis,
Calculated value (%) as C, 6th, 5N02・HBr・1/4LO: C, 56.34:day, 4.84:N, 4.11
Actual value (%): C, 56.02; day, 4.76; N, 4
．． 011-Phenyl-2,3,4,5-tetrahydro IH-3-penzazepine-708-dione 5 (0.
Excess methyl mercaptaso is rapidly bubbled through a suspension of 150 ml of methanol (formed from the above salt) in 150 mol of methanol. The brown quinone dissolves quickly and a pale yellow solution is obtained. This is evaporated and Zanwan (7,8-dihydroxy-6
-methylthio and 9-methylthio-1-phenyl-2
- A mixture of 3,4,5-tetrahydro-IH-3-penzazepine hydrobromide) is obtained. The 9-isomer can be crystallized directly by dissolving the residue in methanol and adding ethyl acetate up to the cloud point, but this material (2.2 night) contains a small amount of the 6-isomer. A more effective separation can be achieved by chromatography on silica gel. 3.3 ml of the isomeric compound was dissolved in 3.3 ml of methanol.
Dissolve in 2 and dilute to 80% with chloroform. Apply this solution to a silica gel column (100 layers, 4.5 x 15 skins)
Gradient elution was performed with chloroform-methanol 1000 methanol (5% to 20% methanol) with increasing methanol concentrations. The 6-monoisomer elutes first, followed by a mixture of 6- and 9-monoisomers, then the 9-monoisomer. Fractions containing the pure 6 monoisomer were combined, evaporated to give 1.4 mol, and crystallized from ethanol-ethyl acetate to give 0.64 mol of the 6 monoisomer (0.0017 mol,
11%). Melting point 258℃ (decomposition) elemental analysis, C,
7th, 9N02S・HBr, calculated value (%): C,
53.41: Sun, 5.27; N, 3.66; S, 8.3
9 Actual value (%): C, 53.41: day, 5.10: N,
3.55; S, 8.64 The fraction containing the pure 9-isomer was evaporated to a residue and directly crystallized2.
Matches 29. Recrystallization from methanol-ethyl acetate yields 1.25 mol (0.0034 mol, 22%) of the pure 9-isomer.
Melting point 270q0 (decomposition) elemental analysis, C. 7th, 9N02
As S HBr, calculated value (%): C, 53.41: day, 5.27; N, 3.66; S, 8.39 actual value (%)
:C, 53.15:Sun, 5.33:N, 3.58:S,
8.24 Example 2 6- and 9-lower alkylthio-7,8-dihydroxy-2,3,4,5-tetrahydro-1-phenyl-3
-Production of IH-benzazepine 1 The three-necked round-bottomed flask is equipped with a magnetic stirrer, argon gas introduction and discharge pipes, and a powder addition furnace. The exhaust tube passes the exhaust gas into a sodium hypochlorite solution (trademark CLOROX) to allow entrained mercaptans to be removed. Appropriate alkyl mercaptan 3~
3.7 (0.041 to 0.07 mol) of 1-phenylene-7,8-dione-2,3,4,5-tetrahydro 3 from a powder addition furnace to the methanol 300 solution.
- IH-benzazepine hydrobromide 10 days (0.03
mol). Additions are made in small portions at a rate such that the initial dark brick color of the solution changes to a pale clear color before the next portion is added. This process typically takes about 10
It takes minutes. The resulting yellow solution was simmered for an additional 15-3 minutes and then evaporated under reduced pressure. The oily residue is chromatographed on silica gel and the product is gradient eluted with 5-15% methanol in chloroform. The ratio of the 6- and 9-isomers is approximately 1:2 with the 6-isomer eluting first. However, complete separation usually requires repeated chromatography. That is, the yield of crude product is relatively high, but the isolated yield of pure isomer is relatively low. The following Table 1 shows the melting points, elemental analysis values, and isolated yields of the isomers separated as hydrobromide salts. Table 1 Example 3 Ingredients Double 9/Capsule 6-methylthio 7,8-dihydroxy-1-phenyl-2,314,5-tetrahydro-IH-3-penzazepine (as acid addition salt) 125 (as free base) Magnesium stearate 2 lactose
200 Mix these ingredients well and place in a hard gelatin capsule. The capsules are orally administered 1 to 5 times a day to patients in need of treatment to exert dopaminergic or antiparkinsonian effects. Example 4 ingredients
Female/Tablet 9-Methylthio 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro IH-3-benzazepine (as acid addition salt) 200 (as free base) Cornstarch 30
Polyvinylpyrrolidone 12 Corn starch 16 Magnesium stearate 3 Mix the first two ingredients well and form into buccal granules. The resulting tablets are dried, mixed with the remaining ingredients and compressed into tablets. The capsules or tablets thus obtained are administered orally in the dosage ranges mentioned above to animals or humans in need of central dopamine receptor stimulation, such as in the treatment of Parkinson's disease symptoms.

Claims (1)

[Claims] 1 Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R and R_3 are each hydrogen or lower alkithio, provided that one is alkithio; R_1 and R_
2 each represents hydrogen or a pharmaceutically acceptable non-toxic salt thereof. 2. The compound of item 1 above, wherein R is methylthio. 3. The compound of item 1 above, wherein R_3 is methylthio. 4. A compound of paragraph 2 or paragraph 3 above in a non-toxic, pharmaceutically acceptable acid addition form. 5. The compound of item 4 above which is a hydrobromide salt. 6. The compound of item 2 or item 3 above, which is in the form of a base. 7 Non-toxic and effective amount formula: ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R and R_3 are each hydrogen or lower alkithio, provided that one is alkithio; R_1 and R_
2 each represents hydrogen] or a pharmaceutically acceptable non-toxic salt thereof; and a pharmaceutical carrier. 8. The pharmaceutical composition of item 7 above, wherein the compound is 6-methylthio-7,8-dihydroxy-1-phenyl-1H-3-benzazepine or a non-toxic pharmaceutically acceptable acid addition salt thereof. 9 Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R_1 and R_2 are the same as below] A compound represented by the formula: R'SH [In the formula, R' means alkyl] A formula characterized in that it is reacted with the indicated mercaptan and optionally with an acid to form an acid addition salt:
▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R and R
_3 each represents hydrogen or alkylthio, provided that one of them is alkylthio; R_1 and R_2 each represent hydrogen] or an acid addition salt thereof. 10 The method of item 9 above, wherein R or R_3 is methylthio.