JPS5915911B2 - Method for producing indoline compounds - Google Patents

Description

[Detailed description of the invention] The present invention relates to a method for producing an indoline compound.

Following the introduction of reserpine and chlorpromacine in early psychotherapeutic medicine in the 1950's, significant efforts have been made in the search for other tranquilizers with improved biological profiles.

Now, certain indoles, more specifically 2-monosubstituted-5-aryl-1,2,3,4-tetrahydro-γ-carporin and 2-monosubstituted-4-aryl-1,2,3
- The 4-tetrahydropyrrolo[3.4-b]indole series was found to be extremely effective as a tranquilizer.

r-Carbolines are not new in the chemical and patent literature, with antihistamine activity being claimed in UK Patent No. 721171 and anti-inhibitory activity being claimed in US Patent No. 34
19568, 3687960, 3705902 and 3
718657, antitrypanosomal activity is claimed in German patents 2117286 and 2115738, sedative and anesthetic activity in US patent 3466293 and tranquilizing activity in US patent 3687961 and 3755584.

Fused pyrrolo[3,4-b]indole ring systems are relatively new in the chemical literature, and the first successful preparation was for SOu
thwich,. etal. , J. Org. Chem.
, Z5, 1133 (1960).

These simple 2-monosubstituted-1,2,3,4-tetrahydropyrrolo[3,4-b]indoles were prepared and tested for anticancer activity, but did not exhibit this activity. The tranquilizers of the present invention are alkylene of the formula: A has 1 or more carbon atoms.

] and its pharmaceutically acceptable acid addition salts.

formula [In the formula, X. Z and n are as defined above.

The compound according to the present invention is a useful intermediate in producing the tranquilizer according to the present invention.

The compounds according to the invention are the most similar to this! Known compound, 5-phenyl-2-methyl-1,2,3,4-
Tetrahydro-gamma-calporin (British patent! 72117
1) and 5-phenyl-2-benzyl-1.2.3.
4-tetrahydro-γ-calporin (Spickett
．． J. Med. Chem. , Dan, 436 (1966))
It showed a more significant and unexpected excellent mental stabilizing effect.
The method for synthesizing the starting compound of the present invention is schematically represented as follows.

In the formula, X. Z and n are as defined above.

In practice, a compound of the formula can be synthesized from commercially available 1-carpoethoxy-4-piperidone or 1-carboethoxy-3-pyrrolidinone and the requisite phenylhydrazine using the classic fissure indole synthesis method, i.e. approximately equivalent It is conveniently prepared by a synthetic method consisting of heating molar amounts of the appropriate phenylhydrazine hydrochloride and piperidone in a reaction-inert solvent, such as absolute ethanol.

The arylation of is carried out by reacting with an appropriately substituted p-bromobenzene derivative, and a 2-3 times molar excess of the bromobenzene derivative gives the product in optimum yield. It will be done.

Equimolar amounts plus as much as 100% excess of cuprous bromide and sodium carbonate are used in this reaction, and the reaction is carried out using a solvent that is inert to the reaction, nitrobenzene, hexamethylphosphoramide or N- 125-225°C, preferably 175-200°C in methyl-2-pyrrolidione
Conducted at a temperature of Hydrolysis of the compound related to the appropriate 2-carboethoxy-5-aryl-1.2.
This is done by heating a solution of 3,4-tetrahydrocarboline in ethanol with at least 2 molar equivalents of potassium hydroxide.

This series of reactions is preferred for the preparation of starting compounds of formula 1a.

The synthesis method of the present invention can be represented diagrammatically as follows.

The ω-haloalkylnitrile of the compound of formula 1a is carried out under the same alkylation conditions as described above.

Further reaction of the nitrile with the required Grignard reagent provides the desired ketone.

Although it is preferred to use 4 moles of Grignard per mole of nitrile, a small excess of this can also be used to obtain the desired product. As in Grignard Reaction 5, this reaction is preferably carried out in a solvent inert to the reaction, such as diethyl ether. Regarding the starting materials necessary in the synthesis of the compounds of the invention, these compounds are either commercially available, their preparation methods are described in the chemical literature, or they can be prepared by methods known to those skilled in the art. can.

For example, phenylhydrazine is commercially available or Wa
gner and ZOOlc, ``TSyntheticO
rganicChemistry”.JOhnWile
y&SOns. NewYOrk,. N. Y. , 1956
, synthesized by reduction of phenylhydrazinium salt as described in Chapter 26, and 1-substituted-4
- Piperidone is a commercially available reagent or available from McElvain and ROrig,. J. Am. Chem. SOc. , L
', 1826 (1948), and ω
-Haloalkylarylketone is U.S. Patent No. 299747
2 (C.A.L. 11603 [1962]) and 1-alkyl-3
-Pyrrolidinone is produced by Casy,. etal. , J. Ph
arm. PharmaOl. ll(3), 157(1
965).

As mentioned above, the compounds in this invention can be acid addition salts.

This salt compound can be converted to its acid addition salt by reacting with an acid in an aqueous or non-aqueous medium. Similarly, the acid addition salt is regenerated in the free base form upon treatment with an equivalent amount of a base, such as an aqueous solution of an alkali hydroxide, or an equivalent amount of a metal cation that forms an insoluble precipitate with the acid anion. The base thus regenerated can be reconverted into the same or a different acid addition salt. In utilizing the chemotherapeutic activity of these compounds according to the invention, it is of course preferred to use pharmaceutically acceptable salts.

Water-insoluble or toxic salts may be unsuitable or insufficient for certain pharmaceutical uses due to water insolubility, high toxicity, or lack of crystallinity; It can be converted to the corresponding pharmaceutically acceptable base by decomposition as described above, or it can be converted to the desired pharmaceutically acceptable acid addition salt. Examples of acids that provide pharmaceutically acceptable anions are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, sulfite, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid and It is gluconic acid.

As mentioned above, the compounds of formula 1 according to the invention, with the exception of those in which R is hydrogen, which are useful as intermediates, are useful as tranquilizers in mammals. The tranquilizers of the invention are characterized by reducing psychotic manifestations in humans, such as hallucinations, defiance, suspicion, emotional or social autism, anxiety, agitation and tension. A method for detecting and comparing the tranquilizing activity of this class of compounds, which is highly correlated with human effects, was developed by A. Weissman,. et
al. , J. PharmaOl. Exp. Ther.
, Lke Jl 339 (1966) and QuintOn.
etal. , Nature, l? Hiki, 178 (1963
) antagonism of amphetamine-induced symptoms in rat studies. Gamma-carporin and pyrrolo[3,4-b]indole and their pharmaceutically acceptable salts, which are useful as tranquilizers, can be administered neat or in admixture with other therapeutic agents.

They can be administered alone or with pharmaceutical carriers selected on the basis of the route of administration and standard pharmaceutical practice. For example, they can be administered orally in the form of tablets or capsules containing excipients such as starch, lactose, or certain clays. These can be administered in the form of elixirs or oral suspensions containing the active ingredient and emulsifying and/or suspending agents. They can be injected subcutaneously, and for this purpose these compounds or suitable derivatives can be prepared in the form of sterile aqueous solutions.
Such aqueous solutions should, if necessary, be suitably buffered and should contain other solutes, such as saline or glucose, to make them isotonic. Although the use of the invention generally relates to the treatment of mammals, the preferred subject is humans.

In determining effective doses for human treatment, extrapolation of the results of animal studies is often employed to estimate a correlation between the efficacy of the animal studies and the proposed human dose. When commercially used standards are available, dosage levels for clinical candidates in humans are often determined by comparing the efficacy of compounds according to the invention with the standards in animal studies. be. For example, if a standard tranquilizer is effective in humans when administered at a rate of 100 to 400 η/day, if a compound of the invention has comparable activity to this standard in a test, it will be effective in humans at a similar dose. It is assumed that a comparable response would be obtained. Obviously, the physician must ultimately determine the most appropriate dosage for a particular individual, and this will depend on the particular patient's age, weight and response, as well as the type and severity of symptoms and the dosage. This will vary depending on the pharmacological properties of the particular drug being administered.

Generally, a small amount is administered initially and the dosage is gradually increased until the optimal level is determined. When a composition is administered orally, greater amounts of active ingredient are often required to achieve the same degree of effectiveness than when administered subcutaneously. Taking into account the aforementioned factors, the compounds according to the invention will produce a tranquilizing effect when administered to humans at a rate of approximately 1-10 ψ/day, preferably 1-50 η/day. .

In individuals to whom the compounds according to the invention exert a conjunctive effect, the dosage may be 5 to 1, administered in one or two divided doses.
50 immediately/week. It goes without saying that these values are exemplary and may be higher or lower in individual cases. The invention is further illustrated by the following examples. Example 18-Fluoro-5-(p-fluorophenyl)-2-(3-benzoylpropyl)-1,2,3,4-tetrahydro-γ-carporin (1:X and Z=F:n=2; A=1(AI2)3-;M-1C-;Y-H)A. 25.0 t ( 0.088 mol) of 8-fluoro-5-(
p-fluorophenyl)-1.2●3.4-tetrahydro-γ-carpoline, 18.3t (0.1232 mol) of promoptylonitrile, 27.7y (0.264 mol) of sodium carbonate and A mixture of 100 η of potassium iodide is heated to reflux temperature for 2 hours.

The mixture is subsequently cooled and poured into an equal volume of water. The organic solvent layer is separated and concentrated in vacuo, and the residual oil is taken up in methylene chloride and washed with water and then with concentrated salt solution. The methylene chloride layer was dried over magnesium sulfate and concentrated under reduced pressure to give 30
y red oil is obtained. Treatment of a small amount of the product with hydrogen chloride gas in diethyl ether gives the hydrochloride salt,
Melting point: 234-236°C. B. 8-Fluoro-5-(p-
fluorophenyl)-2-(3-benzoylpropyl)
8077!711 of phenylmagnesium iodide prepared under standard Grignard reaction conditions from 4,8TfL1 of bromobenzene and 1.1t of magnesium powder.
A solution of 4.07 (0.114
mole) of 8-fluoro-5-(p-fluorophenyl)
-2-(3-cyanopropyl)-1,2,3,4-tetrahydro-γ-calporin is added dropwise over 30 minutes.

The reaction mixture is heated to reflux for 1 hour, then cooled and the ether is decanted from the precipitate that forms. The residue is washed several times with ether and then added to 80 ml of 12N hydrochloric acid in ice. The acid mixture is then heated under reflux for 1.5 hours, cooled to room temperature and treated with sufficient 1,0N sodium hydroxide solution to make the solution basic. The product, separated as an oil, is extracted in ether. Removal of the solvent gives the product as the free base, 3.87. Converting a small sample to the hydrochloride salt, melting point 208-211°C. Test procedure and results The effect of the compounds according to the invention on the pronounced symptoms induced by amphetamine was investigated by QuintO
It was tested in rats with a rating scale modeled after that reported by Halliwell, Halliwell, and WeissrrBn.

Groups of 5 rats were approximately 26cfn x 42cm in size.
In x 16 crn and placed in a covered plastic cage. After a short period of acclimation in the cage, each group of rats is treated intraperitoneally (1.p.) with the test compound. These rats were then treated with d-amphetamine, 5η/1<g, I.
p. Treat with. One hour after amphetamine administration, each rat was observed for characteristic amphetamine behavior as it moved through the cage. Based on the amphetamine dose and response, it was possible to determine the effective dose of compound (ED5O) required to antagonize or block the characteristic amphetamine behavior of cage movements for 50% of the rats tested. . The chosen evaluation time is 60-80 hours after treatment with this drug.
This corresponds to the time when the effect of amphetamine is maximal, which is minutes. Using the procedure described above, the following compounds were tested for their ability to block the effects of amphetamine on behavior.

Claims (1)

[Claims] 1 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, X is fluoro, Z is fluoro, n is 2, and R is a formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ is a substituted alkylene, A is an alkylene having 1 to 5 carbon atoms, and M is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼. ] In producing the indoline compound and its pharmaceutically acceptable acid addition salt, a compound of the formula ▲ where there is a mathematical formula, chemical formula, table, etc. ▼ (where X and Z are as defined above),
It is reacted with a compound of the formula Cl-A-CN [wherein A is as defined above], and then a compound of the formula ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ [in the formula, Hal is a halogen. A method characterized by reacting with a compound of ] and, if necessary, reacting the generated base with an acid to generate an acid addition salt.