GB2091255A - 1,4-Disubstituted piperazine derivatives and process for the preparation thereof - Google Patents

1,4-Disubstituted piperazine derivatives and process for the preparation thereof Download PDF

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Publication number
GB2091255A
GB2091255A GB8138720A GB8138720A GB2091255A GB 2091255 A GB2091255 A GB 2091255A GB 8138720 A GB8138720 A GB 8138720A GB 8138720 A GB8138720 A GB 8138720A GB 2091255 A GB2091255 A GB 2091255A
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piperazine
butyl
methyl
benzimidazolyl
substituted
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Kyorin Pharmaceutical Co Ltd
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Kyorin Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pyridine Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

This invention relates to 1,4- disubstituted piperazine derivatives represented by the general formula, <IMAGE> wherein R1 represents a 1-methyl benzimidazole, 1-benzyl benzimidazole or benzoxazole group; R2 represents a methyl group; and pharmaceutically acceptable acid addition salts thereof.

Description

SPECIFICATION 1,4-Disubstituted piperazine derivatives and process for the preparation thereof This invention relates to 1,4-disubstituted piperazine derivatives and to processes for their preparation. In particular, it concerns 1,4-disubstituted piperazine derivatives which may be useful in human medicine having excellent analgesic activity.
This invention provides 1,4-disubstituted piperazine derivatives of the general formula:
wherein R, represents a 1-methyl benzimidazole, 1-benzyl benzimidazole or benzoxazole group; R2 represents a methyl group; and pharmaceutically acceptable acid addition salts thereof.
The compounds according to this invention may be prepared in various ways.
1) First, piperazines of the general formula [IV] are prepared by reacting piperazines of the general formula [Il] with o-phenylenediamine (Ill]. Then the resulting piperazines of the general formula [IV] are reacted with alkylating agents of the general formula [V].
wherein R2 is as defined hereinbefore; R3 is a methyl or benzyl group; X is a halogen group.
2) Piperazines of the general formula [IV] are reacted with phosphorous pentoxide:
wherein R2 is as defined herein before.
3) Piperazines of the general formula [Vll] are reacted with acid halides of the general formula [Vll]:
wherein R, and R2 are as defined hereinbefore; X is a halogen atom.
1,4-Disubstituted piperazine derivatives of this invention may be used in free bases or in pharmaceutically acceptable acid addition salts thereof, such as hydrochloride, maleate, fumarate and tartrate, as medicines.
The analgesic effect and acute toxicity of the compounds of this invention are given in the following Table: Writhing testy, Bradykinin tests Tonicity3 Test EDs0(mg/kg) rabbit LD50(mg/kg) Compound mice iv inhibit. mice sc po (mg/kg) ratio(%) po Example 2 7.7 63.6 10 100 1039 Example 4 6.4 42.0 10 100 404 Example 8 2.7 17.3 20 100 270 Aminopyrine 21.2 68.0 60 50 920 1) Writhing test according to R. Koster et al., Fed. Proc., 18, 412 (1959).
2) Bradykinin test according to H. Takagi et al., Japan J. Pharmacol., 26, 634 (1976).
3) Calculations according to the Up and Down method.
Thus, the compounds of this invention are considered to be useful in human medicine, having excellent analgesic activity.
The following examples are illustrature of the processes and products of this invention, but are not to be construed as limiting.
Example 1 1 (4-(2-Benzimidazolyl)buWI]-4-p-toluyl piperazine 2 maleate o-Phenylenediamine (9.7g) and 1-(4-carbethoxy butyl)-4-p-toluyl piperazine (HCI salt: mp, 181 C) (33g) were added to a mixture of sodium (2.3g) and ethanol (150ml). The solvent was removed in vacuo. The residual mixture was heated at 140-160"C for 4 hours, after cooling poured into water and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo. The residue was dissolved in ethyl acetate and added to a solution of maleic acid (20g) and ethyl acetate (200ml). The precipitate formed was filtered, dried and recrystallized from isopropanol to yield 20.8g of colorless crystals, melting point 144-145"C.
C H N Anal. Calcd. for C3,H36N409: : 61.17 5.96 9.21 Found : 61.17 6.01 9.28 Example 2 1 [4-(-Benzyl-2-benzimidazolyl)butyl]-4-p4oluyl piperazine 2 maleate 1 [4-(2-Benzimidazolyl)butyl]-4-p-toluyl piperazine 2 maleate (Example 1, 1 7g) was dissolved in water (150ml), neutralized with sodium carbonate and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and evaporated in vacuo. To a mixture of the residue and acetone (100ml) was added powdered potassium hydroxide (5g) and dropwise benzyl bromide (5.3g) with stirring. The reaction mixture was stirred at room temperature for 1 hour, poured into water and extracted with chloroform.The chloroform layer was washed well with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was dissolved in ethyl acetate and added to a solution of maleic acid (6.5g) and ethyl acetate (100ml). The precipitate formed was filtered, dried and recrystallized from isopropanol to yield 1 5g of colorless crystals, melting point 145-146"C.
C H N Anal. Calcd. for C38H32N4Og: 65.32 6.06 8.02 Found 65.30 6.09 7.97 Example 3 1-[4-(1 Benzyl-2-benzimidazolyl)butyl]-4-p-toluyl piperazine 1 -[4-(1 Benzyl-2-benzimidazolyl) butyl]-4-p-toluyl piperazine 2 maleate (Example 2,7g) was suspended in water (50ml), neutralized with sodium carbonate and extracted with chloroform.
The chloroform layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residual solid was recrystallized from ethyl acetate to yield 4g of colorless crystals, melting point 94-95"C.
C H N Anal.Calcd. for C30H34N40 : 77.22 7.35 12.01 Found : 77.01 7.46 11.88 Example 4 1 -[4-( 1 -Methyl-2-benzi midazolyl) butyl]-4-p-toluyl piperazine 2 maleate The compound was obtained by the same procedure as in Example 2 from a mixture of 1-[4 (2-benzimidazolyl) butyl]-4-p-toluyl piperazine, methyl iodide and powder potassium hydroxide in acetone. Melting point was 140-141 'C.
C H N Anal. Calcd. forC32H38N409: 61.73 6.15 9.00 Found 61.62 6.23 8.99 Example 5 1-[4-(1 -Methyl-2-benzimidazolyl) butyl]-4-p-toluyl piperazine 1-[4-(1-Methyl-2-benzimidazolyl) butyl]-4-p-toluyl piperazine 2 maleate (prepared according to the procedure of Example 4) (6.2g) was dissolved in water (100ml), neutralized with sodium carbonate and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residual solid was recrystallized from ethyl acetate to yield 3.3g of colorless crystals, melting point 84-85"C.
C H N Anal. Calcd. for C24H30N40 : 73.81 7.74 7.73 Found 73.65 7.82 7.51 Example 6 1 -[4-( 1 -Methyl-2-benzimidazolyl) butyl]-4-p-tolyulpiperazine 3/2 fumarate A solution of 1-[4-(1-Methyl-2-benzimidazolyl) butyl]-4-p-toluyl piperazine (prepared according to the procedure of Example 5) (3.9g) and ethyl acetate (50ml) was added to a solution of fumaric acid (2.5g) and acetone (50ml). The precipitate formed was filtered, dried and recrystallized from isopropanol to yield 5g of colorless crystals, melting point 191.5-192.5"C.
C H N Anal.Calcd. for C30H36N407 : 63.81 6.43 9.92 Found 63.64 6.66 9.68 Example 7 1 -[4-(1 -Methyl-2-benzimidazolyl) butyl]-4-p-toluyl piperazine 3/2 succinate The compound was obtained by the same procedure as in Example 6 from a mixture of 1-[4 (1-methyl-2-benzimidazolyl) butyl]-4-p-toluyl piperazine and succinic acid. Melting point was 130-131"C.
C H N Anal.Calcd. for C30H39N407 : 63.38 6.92 9.87 Found 63.51 6.71 9.58 Example 8 1-[4-(2-Benzoxazolyl) butyl]-4-p-toluyl piperazine maleate A mixture of 1-[4-o-hydroxyphenyl carbamoyl) butyl]-4-p-toluyl piperazine (HCI salt: mp.
250"C) (409) and phosphorus pentoxide (6g) was heated at 150-170 C for 4 hours. After cooling, the residue was poured into an aqueous sodium carbonate solution and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was dissolved in ethyl acetate and added to a solution of maleic acid (717g) and ethyl acetate (150my). The precipitate formed was filtered, dried and recrystallized from methanol-isopropanol to yield 359 of colorless crystals, melting point 150-151'C.
C H N Anal.Calcd. for C27H3,N306 : 65.70 6.33 8.51 Found : 65.52 6.36 8.49

Claims (10)

1. 1,4-Disubstituted piperazines corresponding to the general formula:
wherein R, represents a 1-methyl benzimidazole, 1-benzyl benzimidazole or benzoxazole group; R2 represents a methyl group, and pharmaceutically acceptable acid addition salts thereof.
2. 1-[4-(1-Benzyl-2-benzimidazolyl) butyl]-4-p-toluyl Piperazine described in claim 1, which is represented by the formula:
and 2 maleate thereof.
3. 1-[4-(1-Methyl-2-benzimidazolyl) butyq-4-p-toluyl piperazine described in claim 1, which is represented by the formula:
and 2 maleate, 3/2 fumarate and 3/2 succinate thereof.
4. 1-[4-(1-Methyl-2-benzimidazolyl) butyll-4-p-toluyl piperazine maleate described in claim 1, which is represented by the formula:
5. A process for the preparation of compounds represented by the following formula [lalt which consists in first preparing 1-[4-(2-benzimidazolyl) butyl]-4substituted piperazine (t by reacting the appropriately 1-(4-carbethoxy butyl)-4substituted piperazine [Il] with o-phenylenediamine [III], then reacting the resulting 1-[4-(2-benzimidazolyl) butyl]-4-substituted piperazine [lVj with an alkylating agent [V] in the presence of potassium hydroxide.
wherein R2 represents a methyl group; R3 is a methyl ar benzyl group.
6. A process for the preparation of compounds represented by the following formula [Ibl which consists in preparing 1-[4-(2-benzoxazolyl) butyl]-4-substituted piperazine [lbj by reacting the appropriately 1 -[4-0-hydroxy phenylcarbamoyl) butyl-4-substituted piperazine [Vl] with phosphorus pentoxide.
wherein R2 represents a methyl group.
7. A process for the preparation of compounds represented by the formula [I] which consists in preparing 1-(4-substituted) butyl-4-substituted piperazine [I] by reacting the appropriately 1 (4-substituted) butyl piperazine [VII] with substituted benzoyl halide [VIII].
wherein R, represents a 1-methyl benzimidazole, 1-benzyl benzimidazole or benzoxazole group; R2 represents a methyl group; X represents a halogen atom; and pharmaceutically acceptable acid addition salts thereof.
8. A compound (I) as claimed in Claim 1 substantially as herein described with reference to any of the specific examples.
9. A pharmaceutical composition comprising a compound (I) as defined in any of claims 1 to 4 and 8, or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier or diluent therefor.
10. A compound (I) as defined in any of claims 1 to 4 and 8, or a pharmaceutical composition as claimed in Claim 9, for use as an analgesic,
GB8138720A 1980-12-23 1981-12-23 1,4-Disubstituted piperazine derivatives and process for the preparation thereof Withdrawn GB2091255A (en)

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JP55182632A JPS57106663A (en) 1980-12-23 1980-12-23 1,4-disubstituted piperazine derivative and its preparation

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KR (1) KR830007608A (en)
AU (1) AU7877481A (en)
BE (1) BE891580A (en)
DE (1) DE3151123A1 (en)
FR (1) FR2496661A1 (en)
GB (1) GB2091255A (en)
IT (1) IT1142620B (en)
SE (1) SE8107680L (en)
ZA (1) ZA818900B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4835154A (en) * 1987-06-01 1989-05-30 Smithkline Beckman Corporation 1-aralykyl-5-piperazinylmethyl-2-mercaptoimidazoles and 2-alkylthioimidazoles and their use as dopamine-βhydroxylase inhibitors
US5149700A (en) * 1990-05-30 1992-09-22 American Home Products Corporation Substituted arylsulfonamides and benzamides

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU3248600A (en) * 1999-03-03 2000-09-21 Merck & Co., Inc. Inhibitors of prenyl-protein transferases

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2297045A1 (en) * 1975-01-10 1976-08-06 Delalande Sa NEW (AROYL-2 'ETH-1' YL) -1 (ACETAMIDO-4 '' PIPERAZIN-1 '' YL METHYL) -2 BENZIMIDAZOLES WITH GASTRIC AND ANTIULCEROUS ANTI-SECRETORY PROPERTIES
YU39992B (en) * 1976-04-02 1985-06-30 Janssen Pharmaceutica Nv Process for obtaining new piperazine and piperidine derivatives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4835154A (en) * 1987-06-01 1989-05-30 Smithkline Beckman Corporation 1-aralykyl-5-piperazinylmethyl-2-mercaptoimidazoles and 2-alkylthioimidazoles and their use as dopamine-βhydroxylase inhibitors
US5149700A (en) * 1990-05-30 1992-09-22 American Home Products Corporation Substituted arylsulfonamides and benzamides

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BE891580A (en) 1982-04-16
ZA818900B (en) 1982-12-29
DE3151123A1 (en) 1982-08-12
FR2496661A1 (en) 1982-06-25
SE8107680L (en) 1982-06-24
AU7877481A (en) 1982-07-01
IT1142620B (en) 1986-10-08
IT8125742A0 (en) 1981-12-21
JPS57106663A (en) 1982-07-02
KR830007608A (en) 1983-11-04

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