JPS62252783A - Benz-heterocyclic compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel heterocyclic and heterocyclic-tetrahydrobyridyl and piperazinyl-alkoxybenz heterocyclic compounds that have useful neuroleptic properties due to their dopamine autoreceptor heptagonist activity.

The invention therefore has as its object the use of these new compounds as antipsychotic agents for the treatment and management of psychoses, such as schizophrenia.

Accordingly, the present invention provides the following formula: (where Het is selected from the following groups, n is an integer from 2 to 5, = represents a single bond or a double bond, 1 and X is C or N) and A phenyl which is xyl or substituted with lower alkyl, lower alkoxy, lower thioalkoxy, halogen or trifluorotetramedel; is 2-13- or 4-pyridinyl or is lower alkyl, lower alkoxy or halogen 2-15- substituted with
t or 4-pyridinyl; 2-14- or 5-pyrimidinyl; or 2-14- or 5-pyrimidinyl substituted with lower alkyl, lower alkoxy or halogen; -2-pyrazinyl; or lower 2 substituted with alkyl, lower alkoxy or halogen
-pyrazinyl; 2- or 3-chenyl which is 2- or 5-y-enyl or substituted with lower alkyl or halogen; 2-'' or 3-furanyl or which is substituted with lower alkyl or halogen; Ta2
- or 3-7-ranyl; 2- or 5-thiazolyl or 2- or 5-thiazolyl substituted with lower alkyl or halogen) or a pharmaceutically acceptable acid addition salt thereof ( However, in the formula, X is excluded by N).

The present invention also relates to pharmaceutical compositions containing an antipsychotically effective amount of a compound of formula (1), or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier.

The present invention further provides an effective amount of the formula for patients with psychosis, such as schizophrenia! or a pharmaceutically acceptable acid addition salt thereof, in unit dosage form.

In compounds of formula 1, the term "lower alkyl" refers to 1-
Straight-chain or branched alkyl groups having 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl,
Butyl, 5ec-butyl, isobutyl, tert-butyl, amyl, isoamyl, neo are meant to include methyl, hexyl, and the like.

Examples of halogens include fluorine, chlorine or bromine.

Lower alkoxy and thioalkoxy are O-alkyl or S-alkyl having 1 to 6 carbon atoms as defined above for "lower alkyl".

Preferred embodiments 111 of the invention are compounds of formula I, where n is 3 or 4.

Another preferred embodiment is n is 3 or 4, A is phenyl or phenyl substituted with methyl, methoxy, thiomethoxy or chloro: 2-13- or 4-pyridinylte, or methyl, chloro or 2-13- or 4-pyridinyl substituted with bromo; 2-. 4-j or 5-pyrimidinyl; 2-pyrazinyl or 2-j azolyl, with the proviso that it is not muenyl or substituted phenyl as mentioned above.

Yet another preferred embodiment is that n is 3 or 4 and A is phenyl, 2-. 3- or 4-viridyl, 2-
14- or 5-pyrimidyl, 2-pyrazinyl or 2
-thiazolyl, a compound of formula (1) as defined above.

Particularly preferred embodiments are as follows.

1-[3-C6-benzofuranyloxy]p4-
4-phenylpiperazine, 1-(3-((3,4-dihydroμm2H-1-benzopyran-7-yl)oxy]propyl)-4-phenylpiperazine, 4-(5-(3,6-dihydro-4 -7 enil 1 (
2H)-pyridinyl)propoxy)-1EI-indole, 4-(4-(3,6-dihydro-4-phenyl-1(
2H)-pyridinyl)butoxy]-indole, 5-C4-[3,6-dihydoμm4-phenyl-1(2
H)-pyridinyl)butoxy]-indole, 6-C3
-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)propoxy)-11-indole, 6-C3-(4-phenyl-1-piradinyl)propoxy) -5-(2H)- Benzofuranone, 6-(3-
(4-(2-pyrimidinyl)-1-pimeirazinyl]propoxy]-2H-1,4-pensochitidine-3(4H
)-one, 6-[3-C4-<2-pyrimidinyl)-1-piperazinyl]propoxy]-1H-indole, 6-[3-
<4-phenyl-1-piperazinyl)propoxy]quinoline, 6-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butoxy]quinoline, 6-C4-(3,6-dihydro-4-phenyl- 1(2
H)-pyridinyl)butoxy]quinoline, 5-(4-[
4-(2-pyrimidinyl)-1-piperazinyl]butoxy]quinoline, 5-[3-(3,6-dihydro-4-phenyl-1(
2H)-pyridinyl)propoxy]isoquino7line, 5
-(3-(4-phenylhyhalazinyl)futepoxy]-
1H-benzimidazole, 1,3-dihydro-5-(3-(4-phenyl-1-piperazinyl)p4poxy]-2H-indol-2-one, 5-[3-(4-(2-pyridinyl) )-1-Biyazinyl]propoxy]isoquinoline, ・5-C3-C4
-phenyl-1-piradinyl)propoxy]isoquinoline, 5-[3-[4-(2-pyrimidinyl)-1-piperazinyl]flopoxy]isoquinoline, 5-(4-[4-(
2-pyrimidinyl)-1-piperazinyl]butoxy]quinoline, 7-(3-(4-(2-pyridinyl)-1-piperazinyl)propoxy]quinoline, 7-[3-<4-phenyl-1-piperazinyl)propoxy [Quinoline, 7-[3-[4-(2-pyrimidinyl)-1-piperazinyl]propoxy]quinoline, 5-(3-(4-(2-pyridinyl)-1-piradinyl]propoxy]-1- Isoquinolitool, 3.4-dihydro-5-(3-[4-(2-pyridinyl)-1-piperazinyl]propoxy-1(2H)-isoquinoline, 7-(3-(4-(2-pyridinyl)-1) -piperazinyl]propoxy]isoquinoline, 7-(3-(4-(2
-pyrimidinyl]-1-piradinyl]propoxy]isoquinoline, or a pharmaceutically acceptable acid addition salt thereof.

The compounds of this invention form pharmaceutically acceptable acid addition salts with organic and inorganic acids. Examples of acids suitable for salt formation are hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid,
Examples include ascorbic acid, maleic acid, and methanesulfonic acid. These salts are prepared by contacting the compound in its free base form with a sufficient amount of the desired acid in the conventional manner.

For compounds in free base form, the salt can be treated with a base.
You can regenerate it and make it. For example, a dilute aqueous base solution can be used.

For this purpose K is sodium hydroxide, potassium carbonate,
Dilute solutions of each of ammonia and sodium bicarbonate are suitable. Although the free base forms of the compounds differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents,
However, the salts are otherwise equivalent for the purposes of this invention to their respective free base forms.

The compounds of the invention can exist in unsolvated as well as solvated forms, such as hydrated forms. Generally, the solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, etc., are the same as the unsolvated forms for purposes of this invention.

The compound of the present invention having formula I is prepared by first converting a hydroxybenz heterocyclic compound of the formula (wherein Bet has the above definition) into a compound of the formula z -(OH2)n-Y m [wherein n is 2 to 5]. is an integer, 2 and Y are the same or different and are a leaving group such as a halogen or a sulfonyloxy group (for example a methanesulfonyloxy or p-)luenesulfonyloxy group). and then reacting the product of formula (1) with an amine of formula (wherein X and A have the above definitions) and optionally converting the resulting free base to a pharmaceutically acceptable acid by known methods. It can be produced by converting it into an addition salt.

The reaction of a compound of formula (1) with a compound of formula (2) is carried out in an inert solvent, preferably a polar solvent such as a ketone (such as acetone or medelisobu f/I/ketone) and an acid scavenger such as sodium carbonate or preferably potassium carbonate in anhydrous form. in the presence of *at the reflux temperature of the above solvent.

The intermediate product of formula (1) is then reacted with a suitable amine' in a polar aprotic solvent such as dimethylformamide in the presence of a neutralizing agent such as sodium bicarbonate. This reaction is carried out at elevated temperatures e.g.
Performed at °C.

An alternative method for preparing compounds of formula ■ is to first prepare compounds of formula
l (2%X in the formula,
A and n have the above definitions).
d, J, Chem, J 435 (1982) K and the compound of formula
and a benzoheterocyclic compound having the following. This reaction can also be carried out in a solvent such as dimethylformamide in the presence of an acid neutralizing agent such as sodium bicarbonate at an elevated temperature e.g.
It is well implemented.

Suitable benz heterocyclic derivatives, which are compounds of formula (1), and amine conductors, which are compounds of formula V, are either commercially available or can be prepared by well-known methods.

The compounds of this invention are novel chemical entities that are useful as formulations for the treatment of psychoses such as schizophrenia.

The antipsychotic activity of representative compounds of the present invention was confirmed by the motor activity inhibition-screen drop test described below.

Animal weight 20-30t non-fasted 5w1ss-Webs+te
Nine r-strain male mice (obtained from Buakberg TJabe) are divided equally into three groups to test each drug dose.

Thus, data for each dose level was generated in three separate groups of three mice each.

Drugs A minimum of three dose levels (10, 30 and 100 ysg/kg) are tested for each drug. Treatments are administered by intraperitoneal administration 1 hour before testing. All doses are calculated as layer compounds. The compound is dissolved or suspended in % methocel. Control animals are injected with methocel.

test The two-part test procedure begins 1 hour after injection.

First, perform a screen test (“Pharmc-Bi
ochsm, Behav, J 6.551-355.
(see 1977).

Simply put, this test involves placing a mouse on an individual wire screen, then using it as a mouse. , I/C rotates 180 degrees at the start of the 60 second observation period.

Record the number of mice that fall from the inverted screen.

Immediately after the screen test, the final stage of testing was performed by placing each group of three mice in one actop 7 otometer.
photometer) ([Life 5scienceJ
22°1067-1076, (1978)). This actophotometer consists of a cylindrical chamber, the center of which is occupied by another cylindrical body containing six 7-cell illuminators located at the periphery of the chamber.

Six interruptions in the beam count as one count. Locomotor activity is recorded by computer at 10 minute intervals for 600 minutes.

Data Data obtained from the screen test is expressed as the percentage of mice falling off the screen. Data derived from the locomotor activity of drug-treated mice are compared to the activity of vehicle-treated animals and are expressed as percent inhibition of locomotor activity. All measurements listed for locomotor inhibition are based on data accumulated over 1 hour. The test stage evaluation for both is A = 60-100! %, C! =31~5
9%, and l=+Q~30%. The overall dosage rating is obtained according to the following criteria:

Screen test A-N or C = A A -,, A = O C-11 or 0 Teng 0 All other combinations 1,000 N 10019/'# Overall dose rating is A for doses below The compound is considered active. Using this procedure, the indicated doses, ie, the overall dose ratings for the compound listed under 1D5Q reported in Table 1 below, were obtained in humans.

The antipsychotic activity of representative compounds of the present invention is also shown in “Mo1.
Pharmacol J 12.800 (1976)] and was also confirmed by the [5H]haloperidyl binding assay, which indicates an excellent correlation between binding amount and clinical efficacy.

[3H]-Halo is the relative affinity of the lidol-binding compound for the donosignature receptor.
□ng-kana type with hood-shaped crown hair (ho masu)
[5H]-halo was evaluated based on its ability to displace ridol from striatal membranes prepared from rats.

(Ra) K was decapitated, the brain removed, and the striatum dissected. The filaments were homogenized in 40 volumes of 50 nM Tris buffer (pi 47.6) and centrifuged.

re-homogenize the let in 50 volumes of the same buffer;
Used for binding assay. Urine temperature tissue weight of homogenate 2Q/
yd, 100 μt of test agent or solvent and 0.6
1011I containing nM [3H]-haloRridol
50 nM of t) Lys-Het buffer (pi(7,6
). Non-specific binding was determined in the presence of α1 μM (tri)-butaclamol. Samples were incubated for 40 minutes at 25°C in a shaking water bath. Incubation was carried out under reduced pressure through a glass fiber filter (Whatman GF'/B) at high speed.
When I met him, K ended it. Those filters are 10-
of Tris-Het buffer three times. The filter was subjected to a 101Rt syntellation cocktail (Beckman Reader-8o1v).
HP) and shaken for 1 hour. Radioactivity retained on the filter was measured by liquid scintillation spectrophotometry. The measured CSO was calculated from a non-wireless computer curve fitted to the data obtained from four tests, each performed in triplicate.

The properties of representative compounds of the invention are also reported in Table 1.

Table 1 1 5.9 300 2A 4.8 <100
2B 3.7 100 2C! 3.5 <1002
D 2.7 70 2Hto00 2F2.5 402G
t4 502
Hα5 10 2nd 2.8
1002J 3.2
20021 0
．． 5 902L
D, 9 502M
11
172 N 7.7
18020 α18
362P
3 [6452Q α29
2062 R19,5947 2s 7.7
1842T Q, 17
2302U
O, 105027 to 9002
W 6.1
6512X 4.4
4315 4.
9 1204
Q, 4 1605
8.8 5
The compounds of this invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. As will be apparent to those skilled in the art, the following dosage forms contain as active ingredient either a compound of formula I, a corresponding pharmaceutically acceptable salt thereof, or a mixture of said compound and/''! or a salt thereof. can contain.

For preparing pharmaceutical compositions from the described compounds according to this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Examples of solid form preparations include powders, tablets, dispersible granules, capsules, cachets and herbal medicines.

Examples of liquid form formulations include solutions, suspensions and emulsions. For example, an aqueous solution or an aqueous propylene glycol solution may be used for parenteral injection.

Preferably, the formulation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as tablets, capsules, and powders packaged in vials or ampoules. Also, the unit dosage form can be a capsule, cachet, or tablet itself, or it can be the quantity of any of these in packaged form.

The amount of active compound in a unit dose formulation varies from 1 mg to 100 Mf depending on the individual application and the potency of the active ingredient.
l can be varied or adjusted.

When used therapeutically as an antipsychotic, the compound used in the pharmaceutical method of the present invention has a dosage of approximately α1 per kg of body weight per day.
It is administered at an initial dosage of 9 to about 10,119 cm. The daily dose is approximately 1.089 to approximately 10 per kPK body weight.
M9 is preferred.

The method for producing the compound of the present invention will be explained below with reference to Examples, but the present invention is not limited thereto.

Example 1 2.3-dihydro-2,2-dimethyl-7-(3-(4
-phenyl)-1-bilysinyl)-fluoroxy4H
-Benzopyran-4-one Method A 100-mg DMF containing 5t sodium bicarbonate
7r (0,026 mol) in 7-(3-chlorobutanoxy)-2,5-';hydro2,2-dime? Lou 4. T1-benzobilan-4-one and 4.5f (
A mixture of 0.019 mol) of N-phenylpiperazine was stirred at 80-90°C for 18 hours.

The mixture was filtered and the liquid was evaporated in vacuo. The residue was dissolved in CH2Cl2, washed with water, dried over MgSO4 and the solvent was evaporated in vacuo.

The obtained oil was dissolved in 40-2-propanol,
7 by treatment with an excess of 20% isopropanolic hydrogen chloride.
．． 3f (64%) of the product was obtained as the dihydrochloride salt.

Melting point 220-222°.

5,8F (103 mol) of 2,3-dihydro-2,2-dimedel-7-hydroxy-4H-benzobilan-4-one, 51 of anhydrous potassium carbonate and 7f<0.05 mol) in DMF of Method B 100d. of N/-(3-chloropropoxy)-N-phenylpiperazine at 80%
Stirred at ~90°C for 20 hours. This mixture was filtered and P
feL was evaporated in vacuo. CB20t21 residue
Dissolve 1N NaOH.

Washing with water, drying (Mg5o4) and evaporation of the solvent in vacuo afforded the crude product 11F.

This material was dissolved in 40-2-propanol and
Treatment with hydrogen chloride as in the method gave the same dihydrochloride salt. Melting point: 220-222°C. Yield 60%.

Example 2 The following compounds were produced using Method A of Example 1.

1 (2H)-pyridinyl)propoxy) -2,3-
Dihydro-2,2-dime? Ru 4H-benzobilan-4
B, 6-(3-(4-7enyl-1-piperazinyl)propoxy)-3-(2H)-benzofuranone, mp 12
9-131°C (from ethyl acetate): c, 6-[3-(3
,6-dihydro-4-phenyl-1(2H)-pyridinyl)propoxy-3(2H)-benzofuranone, melting point 112-114°C (from diethyl ether); D, 1-[3-((3,4- Dihydro!: l-2B-1-
Benzopyran-7-yl]oxy]propyl]-4-phenylpiperazine, mp 84-86°C (from ethyl acetate); 1,4-Benzoxazin-5C4H)-one, melting point 143-145°C; F,
4-[3-(3,6-dihydro-4-phenyl-1(2
H)-pyridinyl)propoxy]-indole, melting point 1
47-150°C; a, 4-(4-(3,6-dihydro-4-7enyl-1(21
)-pyridinyl]butoxy]-1H-indole, melting point 130-132°C; H,5-C4-(3,6-dihydro-4-phenyl-1
(2H)-pyridinyl)butoxy]-1H-indole, melting point 117-119°C;
(2) I)-pyridinyl)propoxy]-1H-indole hydrate; melting point 198-202°C; :r, 6-[3
-[4-(2-pyrimidinyl)-1-pyracinyl]propoxy)-18-indole, melting point 150-151°C
; 6-(3-(4-phenyl-1-piradinyl)propoxy)-quinoline-hydrate, melting point 114-11
6°C: I, 6-(4-(4-(2-pyrimidinyl)-1-piradinyl]butoxy]-quinoline trihydrochloride hand hydrate, melting point 240-246°C; M, 6-(4- (3,6-dihydro-4-7enyl-1
(2H)-pyridinyl)butoxy]quinoline t8 hydrochloride, -hydrate, melting point 180-192°C; L 5-(4-
(4-(2-pyrimidinyl)-1-piveracinyl]butoxy]-quinoline t9hydrate, melting point 107-110°C; 0.5-(3-(3,6-dihydro-4-phenyl-1
(2H)-Pyridinyl]propoxy]isoquinoline dihydrochloride, melting point 230-232°C; P, 5-(3-(4-(2-pyridinyl)-1-pyridinyl)propoxy]-isoquinoline□, trihydrochloric acid Salt, melting point 260-263°C (decomposition); Q,, 5-(
3-(4-phenylni-1-piradinyl)propoxy]
Isoquinoline, hydrochloride, melting point 125°C (decomposition); ; E+, 5-(4-(4-(2-pyrimidinyl)-1-piradinyl]butoxy]quinoline, dihydrate, melting point 10
7-110°C; T, 7-(3-[4-(2-pyridinyl)-1-py/%
? , Fdinyl]pnboxy]quinoline trihydrochloride, -hydrate, melting point 257-259°C (decomposed); 0.7-[3-
<4-phenyl-1-piperazinyl]propoxy]quinoline, melting point 100-102°C; V, 7-(3-(4-(
2-pyrimidinyl)-1-piperazinyl]propoxy]
Quinoline, -hydrate, melting point 223-225°C; W, 5-[3-C4-<2-pyridinyl)-1-piperazinyl]propoxy]-1-isoquinolitool, melting point 153-155°C; ! , 3.4-dihydro-5-C3-C4-<2-pyridinyl)-1-piperazinyl]propoxy-1(2E
Ri-isoquinoline, dihydrochloride, melting point 235-240°C;
Y, 7-(3-(4-(2-pyridinyl)-1-piperazinyl)propoxy]isoquinoline, dihydrate, melting point 212-216°C and z, 7-(5-(4-(2-pyrimidinyl) -1-Pradinyl]propoxy]isoquinoline, trihydrate, melting point 228-231°C.

Example 3 5-(3-(4-Phenylhydrinyl]propyloxy)-1H-benzimidazole trihydrochloride, sodium metal trihydrate (0,37F, 16 mmol) 110-
was dissolved in absolute ethanol. To this solution was added 2.01 F (15 mmol) of 5-hydroxy-1H-benzimidazole while cooling in an ice bath. The resulting solution was stirred at 0°C for 30 minutes.

Then, 3,57f (15
mmol) of 1-(3-chloropropoxy)-4-phenylbi was added with a solution of radin, and stirring was continued for 16 hours at room temperature. The solvent was evaporated in vacuo and the residue was purified by medium pressure liquid chromatography (M)K on silica gel using ethyl acetate as eluent. t5 of the obtained material
f (30%) was dissolved in 10-isopropanol and a saturated solution of hydrogen chloride in isopropanol was generated, which was filtered, washed with ether and air-dried. A sticky white solid was obtained, exhibiting properties as 5-(3-(4-phenylpyrazinyl)propyloxif-1H-benzimidazole trihydrochloride, trihydrate).

Example 4 Using the procedure of Example 3 to prepare 1.3-)hydro-5-[3
-<4-phenyl-1-piperazinyl)propoxy]-
2H-indol-2-one was prepared. Melting point 166~
178C.

Example 5 1-[3-[6-penzo7ranyloxy]propyl]-
6-[3-(4-
phenyl-1-piperazinyl)propoxy]-3(2H
)-benzofuran (91.0.25 mol) was reduced.

The mixture was evaporated and partitioned between water and ethyl acetate. Evaporate the ethyl acetate layer and add alcohol (7,5
f) was obtained. Melting point 80-85°C.

The above intermediate (4f) was stirred in 10% hydrochloric acid (3otwt) and 10m trifluoroacetic acid at room temperature for 2 hours and then made basic. The reaction mixture was extracted with methylene chloride and evaporated to give 4f as an oil.

This crude product was treated with isopropanol Hot 3. tl(
85%) was converted to the dihydrochloride salt. Melting point 187-189
℃.

Example of the production process for the starting material award A: 2,3-dihydro-2,2-dimedel-7-hydroxybenzobilan-4-one "Chem, Pharm, Bull, J 25.27
88 (1977).
Dihydro''-2s2-dimethyl-7-medoxybenzobilan-4-one 2C1 (0.1 mol) was refluxed in 15 Of pyridine hydrochloride for 1 hour and then poured into 1 t of water.

The solid was collected on a filter and recrystallized from isopropanol to give the product 11f (60%).

Melting point 164-167°C.

2,3-dihydro-2,2-dimethyl-7-(3-
chloropropoxy) -4H-1-benzobilane-4-
The product obtained above was refluxed for 16 hours with 11t of 3-bromo-1-propropane and 10t of anhydrous potassium carbonate in acetone. The mixture was filtered and concentrated. The residue was filtered over silica gel in ethyl acetate to give 142 (70%) of the product, isolated as an oil.

Example B 6-(3-chloropropoxy)-3-(22)-benzofuranone", 7.0ham, Soc, J 1950, 3211
6-hydroxy-5-(2H
)-benzofuranone was FC refluxed with 3-bromo-1-chloropropane and anhydrous potassium carbonate in acetone as described in Example A to give the desired product.

Melting point 78-81°C (from diethyl ether/petroleum ether).

Example a 7-(3-chloropropoxy)benzopyran "J, oh
Em, 8oc, J 1958, 1191 7-hydroxybenzobilan-4-one obtained by K as described in P
Hydrogenation over ct/charcoal catalyst gave the corresponding 7-hydroxybenzobilane.

The above benzopyran was dissolved in acetone as described above.
Treatment with -bromo-1-chloropropane and potassium carbonate gave 7-(3-chloropropoxy)benzopyran as an oil.

Example D 7-(3-chloropropoxy)-2H-1,4-benzoxazin-3(4H)-one 7-hydroxy-2H-1,4-benzoxazin-5(
4H)-one in ethylene glycol 7-ethyl ether was treated with 3-7'romo-1-chloropropane and sodium metal to give the desired product in 65% yield. Melting point: 95°C.

Example 1 6-hydroxyindole 75-5,0fC20,6 mmol) of 4-benzyloxy-2-nitrotoluene and 5. A solution of OtC41.9 mmol) in N,N-dimethylformamide dimethyl acetal was diluted under argon with
It was refluxed for 2 hours. Cool the mixture and add 1.91
2,4 dissolved in water containing 1tt concentrated HCt
A solution of 1F semicarbazide hydrochloride was added. A precipitate formed immediately. After further cooling, the precipitate was filtered and washed with cold water and ether.

The solid was then dried under vacuum. Yield 5. Of<7
4.6%).

The semicarbazone obtained above was mixed with 10% P in ethanol.
Catalytic reduction using C1/carbon produced 6-hydroxyindole (38% yield, mp 124-126 °C) and 3
A mixture of -amino-4-methylphenols was obtained, which was separated by column chromatography.

Example F 5-hydroxy-1U-(zuimidazole 2C1(0
, 114 mol) of 4-methoxy-1,2-phenylenediamine hydrochloride m't - 30t of 88% formic acid, 15- of concentrated H
Refluxed for 8 hours with et and 90-m water. The solvent was then removed in vacuo and the residue was dissolved in 100-conc. NH40.
treated with H, extracted twice with 200-dichloromethane,
Drying with Mg5OA and condensation gave a thick oil,
This was converted to HCl salt. Melting point 212-215℃ (1
2.8f.

60%). This compound (12,Of, 65 mmol) was refluxed with 125 g of concentrated HBr for 3 hours under argon. After evaporation in vacuo, the residue was dissolved in water and neutralized with solid NILHOO5. The product was recrystallized from water to give 7.79 (88%) 5-hydroxy-
1H-benzimidazole was obtained.

Melting point 216-218°C.

Patent applicant: Warner-Lambert Kompany et al.
given name

Claims (1)

[Claims] 1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ I (In the formula, Het is the following groups ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Numerical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ , ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, n is an integer from 2 to 5, ■ represents a single bond or double bond, and X is C or N and A is phenyl or phenyl substituted with lower alkyl, lower alkoxy, lower thioalkoxy, halogen or trifluoromethyl; 2-
, 3- or 4-pyridinyl, or substituted with lower alkyl, lower alkoxy or halogen
-, 3- or 4-pyridinyl; 2-, 4- or 5-
2-, 4- or 5-pyrimidinyl which is pyrimidinyl or substituted by lower alkyl, lower alkoxy or halogen; 2-pyrazinyl which is 2-pyrazinyl or substituted by lower alkyl, lower alkoxy or halogen; 2- or 3-thienyl or substituted with lower alkyl or halogen
- or 3-thienyl; 2- or 3-furanyl or substituted with lower alkyl or halogen; 2- or 3-furanyl; 2- or 5-thiazolyl or substituted with lower alkyl or halogen; 2- or 5-thiazolyl) or a pharmaceutically acceptable acid addition salt thereof (provided that X
is N, Het is ▲ has a mathematical formula, chemical formula, table, etc. ▼ or ▲ has a mathematical formula, chemical formula, table, etc. ▼ and A is phenyl or substituted phenyl). 2) The compound according to claim 1, wherein n is 3 or 4. 3) A is phenyl, or methyl, methoxy,
phenyl substituted with thiomethoxy or chloro; 2
-, 3- or 4-pyridinyl or substituted with methyl, chloro or bromo; 2-, 4- or 5-pyrimidinyl;
3. A compound according to claim 2 which is 2-pyrazinyl or 2- or 5-thiazolyl. 4) A is phenyl, 2-, 3- or 4-pyridinyl,
4. A compound according to claim 3 which is 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl or 2- or 5-thiazolyl. 5) 7-[3-(3,6-dihydro-4-phenyl-1
The compound according to claim 4, which is (2H)-pyridinyl)propoxy]-2,3-dihydro-2,2-dimethyl-4H-benzopyran-4-one. 6) The compound according to claim 4, which is 6-[3-(4-phenyl-1-piperazinyl)propoxy]-3-(2H)-benzofuranone. 7) Claim 4 which is 1-[3-[6-benzofuranyloxy]propyl]-4-phenylpiperazine
Compounds described in Section. 8) The compound according to claim 4, which is 1-[3-[(3,4-dihydro-2H-1-benzopyran-7-yl)oxy]propyl]-4-phenylpiperazine. 9) The compound according to claim 4, which is 6-[3-[4-(2-pyrimidinyl)-1-piperazinyl]propoxy]-2H-1,4-benzoxazin-3(4H)-one. 10) 4-[3-(3,6-dihydro-4-phenyl-
The compound according to claim 4, which is 1(2B)-pyridinyl)propoxy]-1H-indole. 11) 4-[4-(3,6-dihydro-4-phenyl-
The compound according to claim 4, which is 1(2H)-pyridinyl)butoxy]-1H-indole. 12) 5-[4-(3,6-dihydro-4-phenyl-
The compound according to claim 4, which is 1(2H)-pyridinyl)butoxy]-1H-indole. 13) 6-[3-(3,6-dihydro-4-phenyl-
The compound according to claim 4, which is 1(2H)-pyridinyl)propoxy]-1H-indole. 14) The compound according to claim 4, which is 6-[3-[4-(2-pyrimidinyl)-1-piperazinyl]propoxy]-1H-indole. 15) 6-[3-(4-phenyl-1-piperazinyl)
5. The compound according to claim 4, which is [propoxy]quinoline. 16) The compound according to claim 4, which is 6-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butoxy]quinoline. 17) 6-[4-(3,6-dihydro-4-phenyl-
5. The compound according to claim 4, which is 1(2H)-pyridinyl)butoxy]quinoline. 18) 5-[3-(3,6-dihydro-4-phenyl-
The compound according to claim 4, which is 1(2H)-pyridinyl)propoxy]isoquinoline. 19) The compound according to claim 4, which is 5-[3-(4-phenylpiperazinyl)propoxy]-1H-benzimidazole. 20) 1,3-dihydro-5-[3-(4-phenyl-
1-piperazinyl)propoxy]-2H-indole-
5. The compound according to claim 4, which is a 2-one. 21] The compound according to claim 4, which is 5-[3-[4-(2-pyridinyl)-1-piperazinyl]propoxy]isoquinoline. 22) 5-[3-(4-phenyl-1-piperazinyl)
5. The compound according to claim 4, which is [propoxy]isoquinoline. 23) The compound according to claim 4, which is 7-[3-[4-(2-pyridinyl)-1-piperazinyl]propoxy]quinoline. 24) 7-[3-(4-phenyl-1-piperazinyl)
5. The compound according to claim 4, which is [propoxy]quinoline. 25) The compound according to claim 4, which is 5-[3-[4-(2-pyridinyl)-1-piperazinyl]propoxy]-1-isoquinolinol. 26) 3,4-dihydro-5-[3-[4-(2-pyridinyl)-1-piperazinyl]propoxy-1(2H)
- The compound according to claim 4, which is isoquinoline. 27) The compound according to claim 4, which is 7-[3-[4-(2-pyridinyl)-1-piperazinyl]propoxy]isoquinoline. 28) There are formulas, ▲mathematical formulas, chemical formulas, tables, etc. for antipsychotic effective doses.
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ , ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ - n is an integer from 2 to 5, ■ represents a single bond or double bond, and X is C or N and A is phenyl or phenyl substituted with lower alkyl, lower alkoxy, lower thioalkoxy, halogen or trifluoromethyl; 2-
, 3- or 4-pyridinyl, or substituted with lower alkyl, lower alkoxy or halogen
-, 3- or 4-pyridinyl; 2-, 4- or 5-
2-, 4- or 5-pyrimidinyl which is pyrimidinyl or substituted by lower alkyl, lower alkoxy or halogen; 2-pyrazinyl which is 2-pyrazinyl or substituted by lower alkyl, lower alkoxy or halogen; 2- or 3-thienyl or substituted with lower alkyl or halogen
- or 3-thienyl; 2- or 3-furanyl or substituted with lower alkyl or halogen; 2- or 3-furanyl; 2- or 5-thiazolyl or substituted with lower alkyl or halogen; 2- or 5-thiazolyl) or a pharmaceutically acceptable acid addition salt thereof (provided that X
is N, Het is ▲ or ▲ is a formula, chemical formula, table, etc. ▼ and A is phenyl or substituted phenyl) is pharmaceutically acceptable A pharmaceutical composition for the treatment of mental illness, which the composition contains together with a carrier. 29) A method for treating psychosis, which comprises administering the pharmaceutical composition according to claim 28 in unit dosage form to a patient suffering from psychosis.