EP0000758A1 - Dihydronaphthalene derivatives, their preparation and pharmaceutical compositions - Google Patents

Dihydronaphthalene derivatives, their preparation and pharmaceutical compositions Download PDF

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Publication number
EP0000758A1
EP0000758A1 EP78100551A EP78100551A EP0000758A1 EP 0000758 A1 EP0000758 A1 EP 0000758A1 EP 78100551 A EP78100551 A EP 78100551A EP 78100551 A EP78100551 A EP 78100551A EP 0000758 A1 EP0000758 A1 EP 0000758A1
Authority
EP
European Patent Office
Prior art keywords
compound
compound according
amino group
dihydronaphthalene
membered cyclic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP78100551A
Other languages
German (de)
English (en)
French (fr)
Inventor
Oka Yoshikazu
Itoh Katsumi
Hirata Minoru
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
Original Assignee
Takeda Chemical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries Ltd filed Critical Takeda Chemical Industries Ltd
Publication of EP0000758A1 publication Critical patent/EP0000758A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C07D295/116—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings with the doubly bound oxygen or sulfur atoms directly attached to a carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

  • the present invention relates to novel and useful 1,2-dihydronaphthalene derivatives.
  • the principal object of the present invention is to provide the novel 1,2-dihydronaphthalene derivatives (I) and their acid addition salts which have the excellent pharmacological activities, and another object is to provide a pharmaceutical composition comprising one or more of these compounds.
  • a further object is to provide an industrially feasible method for producing these compounds.
  • the 1,2-dihydronaphthalene derivatives of the formula (I) and salts thereof may be produced in good yield, for example, by subjecting a compound of the formula wherein A and n have the same meanings as defined above to dehydration reation.
  • This dehydration reaction is generally accomplished by placing a compound (II) under conditions of dehydration in an appropriate solvent. While the conditions of dehydration may be established by any technique per se known to one skilled in organic chemistry, preferred techniques include the following. Thus, by way of example, one may conduct the reaction by the presence of a mineral acid, e.g. hydrochloric acid, sulfuric acid or nitric acid; a Lewis acid, e.g.
  • An alternative procedure comprises reacting the starting compound with a dehydrating agent such as an acid anhydride, e.g. acetic anhydride, propionic anhydride, phthalic anhydride or phosphoric anhydride, or an acid halide, e.g.
  • a dehydrating agent such as an acid anhydride, e.g. acetic anhydride, propionic anhydride, phthalic anhydride or phosphoric anhydride, or an acid halide, e.g.
  • the 1,2-dihydronaphthalene derivatives (I) thus produced may be isolated in the form of free base or as an acid addition salt, by conventional separation and purification procedures such as extraction, concentration, neutralization, filtration, recrystallization, distillation and column chromatography.
  • the free base may be converted to physiologically acceptable acid addition salts such as inorganic acid salts (e.g. hydrochloride, hydrobromide, sulfate, nitrate) or organic acid salts (e.g. maleate, fumarate, malate, tartrate, toluenesulfonate, naphthalenesulfonate, methanesulfonate).
  • novel 1,2-dihydronaphthalene derivatives of the formula (I) and salts thereof according to this invention have an excellent vasodilator action and are characterized by having excellent hypotensive as well as cerebral blood flow increasing actions based upon the said vasodilator action and also by their low toxicity,
  • these compounds are of value as drugs, for example, for the treatment of circulatory failure such as hypertension and impaired cerebral circulation, and as peripheral vasodilators in mammalian animals (human beings; domesticated animals such as dogs and cats; laboratory animals such as rats and mice).
  • the compound of this invention may be administered orally or parenterally either as it is or as formulated with suitable pharmaceutically acceptable carriers, excipients or diluents in such varied dosage forms as powders, granules,- tablets, capsules and injections.
  • suitable pharmaceutically acceptable carriers, excipients or diluents in such varied dosage forms as powders, granules,- tablets, capsules and injections.
  • the dosage may be chosen depending on the disease to be managed and the route of administration. For instance, when the present compounds are administered to adult humans as a drug for the treatment of the disturbance of cerebral circulation, e.g.
  • advantageous dose levels are of about 10 to 500 mg., especially about 20 to 200 mg. daily by the oral route, or about 1 to 50 mg., especially about 2 to 20 mg. daily by the intravenous route,
  • the preferred dosage is about 20 to 200 mg. daily by the oral route.
  • the starting compound (II) employed in this invention may be easily produced, for example by the method described in "Archiv der Pharmazie” 275, 54 et seq. (1937) by a method similar thereto, by the following route of synthesis:
  • the starting compound (II) has several isomers with respect to the asymmetric carbon atom and, normally, are obtained as a mixture of such isomers, although the compound (II) may be obtained stereospecifically in certain instances.
  • the racemic mixture may be resolved, if desired, by the conventional method, e.g. by salt formation with an optically active acid or base. In this invention, both such an isomer of compound (II) and a racemic mixture of such isomers may be employed.
  • the starting compound (III) in the above reaction scheme may be easily produced, for example by the method described in United States Patent No. 3,322,760 (1967) or a method similar thereto.
  • naphthalenone was obtained as an oil.
  • This oily product was dissolved in 50 ml. of methanol and stirred with 2.5 g. of sodium borohydride at room temperature for 30 minutes.
  • the reaction mixture was diluted with 500 mf. of water and extracted with chloroform.
  • the extract was dried and the solvent was distilled off under reduced pressure.
  • 2-((4-benzhydryl-l-piperazinyl)methyl]-6-dimethylamino-1,2,3,4-tetrahydro-1-naphthalenol as an oil.
  • This oil was dissolved in 50 ml. of ethanolic HCl and the solution was heated under reflux for 2 hours. Upon cooling there was obtained 1.5 g. of 3- .
  • [(4-benzhydryl-1-piperazinyl)methyl)-7-dimethylamino-1,2-dihydronaphthalene hydrochloride as colorless needles melting at 190-195°C(decomposition).
  • Example 1 The reaction and treatment of Example 1 was repeated except that 1-benzhydrylhomopiperazine hydrochloride was used as the starting compound and that the reaction mixture, resulting from the refluxing with ethanolic hydrochloric acid in the last step, was dilufed with ethyl acetate to obtain crystals.
  • 1-benzhydrylhomopiperazine hydrochloride was used as the starting compound and that the reaction mixture, resulting from the refluxing with ethanolic hydrochloric acid in the last step, was dilufed with ethyl acetate to obtain crystals.
  • the present compound (1) may be administered, for example in the following dosage forms.
  • the ingredients (1) and (2) are"mixed with 17 mg. of corn starch and the mixture is granulated with a paste prepared from 7 mg. of corn starch. To the granules are added the ingredient (4) and 5 mg. of starch and the entire mixture is compression-molded into a tablet 7 mm, in diameter.
  • Dogs weighing 5.5 to 12 kg. were anaesthetized with sodium pentobarbital (30 mg./kg., intravenous injection), and the increase in vertebral blood flow following the administration of the test compounds (intravenous injection) was determined with an electromagnetic flowmeter set around the right vertebral artery.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (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)
EP78100551A 1977-08-02 1978-07-31 Dihydronaphthalene derivatives, their preparation and pharmaceutical compositions Withdrawn EP0000758A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP93089/77 1977-08-02
JP9308977A JPS5427587A (en) 1977-08-02 1977-08-02 1,2-dihydronaphthalene compound and its preparation

Publications (1)

Publication Number Publication Date
EP0000758A1 true EP0000758A1 (en) 1979-02-21

Family

ID=14072788

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100551A Withdrawn EP0000758A1 (en) 1977-08-02 1978-07-31 Dihydronaphthalene derivatives, their preparation and pharmaceutical compositions

Country Status (4)

Country Link
US (1) US4199582A (enrdf_load_stackoverflow)
EP (1) EP0000758A1 (enrdf_load_stackoverflow)
JP (1) JPS5427587A (enrdf_load_stackoverflow)
IT (1) IT7868827A0 (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0113226A1 (en) * 1982-12-24 1984-07-11 Fujisawa Pharmaceutical Co., Ltd. Benzhydrylpiperazine derivatives, processes for the preparation thereof and pharmaceutical compositions comprising the same

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS608274A (ja) * 1983-06-27 1985-01-17 Fujisawa Pharmaceut Co Ltd 新規キナゾリノン誘導体およびその製造法・並びに抗アレルギ−剤
US4590274A (en) * 1985-01-03 1986-05-20 E. I. Du Pont De Nemours And Company Antihypertensive 1-[bis-(substituted phenyl)methyl]-4[2-(1,2,3,4-tetrahydro-substituted naphthalen-1-ylidene)ethyl]piperazines

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2220242A1 (de) * 1971-05-12 1972-11-16 Hokuriku Seiyaku Co. Ltd., Katsuyama, Fukui (Japan) Verfahren zur Herstellung von Piperazinderivaten
GB1342753A (en) * 1970-07-20 1974-01-03 Richardson Merrell Spa Dihydronaphthalene derivatives and higher or lower bicyclo homologues thereof and the preparation thereof
DE2718669A1 (de) * 1976-04-29 1977-11-10 Takeda Chemical Industries Ltd 1,2-dihydronaphthalinderivate, verfahren zu ihrer herstellung und sie enthaltende arzneimittel

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2220188B2 (de) * 1972-04-25 1976-07-08 Demag Ag, 4100 Duisburg Universal-rechenkuehlbett mit wendeeinrichtung

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1342753A (en) * 1970-07-20 1974-01-03 Richardson Merrell Spa Dihydronaphthalene derivatives and higher or lower bicyclo homologues thereof and the preparation thereof
DE2220242A1 (de) * 1971-05-12 1972-11-16 Hokuriku Seiyaku Co. Ltd., Katsuyama, Fukui (Japan) Verfahren zur Herstellung von Piperazinderivaten
DE2718669A1 (de) * 1976-04-29 1977-11-10 Takeda Chemical Industries Ltd 1,2-dihydronaphthalinderivate, verfahren zu ihrer herstellung und sie enthaltende arzneimittel

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 31, nr. 9, 10 May 1937, C. MANNICH, F. BORKOWSKY & WAN-HOLIN: "Tetralin derivatives with basic side chains", Arch. Pharm. 275, 54-62 (1937) *
CHEMICAL ABSTRACTS, vol. 74, nr. 21, 24 May 1971, Columbus, Ohio (USA) VIOLLAND, ROBERT et al: "Potential psychotropes. IX Synthesis and structure of compounds derived from 3-amino -1 - tetralol and related to various psychotomimetics", page 383, column 1, abstract nr. 111791f; & Bull. Soc. Chim.Fr. 1971, (1), pages 307 to 311 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0113226A1 (en) * 1982-12-24 1984-07-11 Fujisawa Pharmaceutical Co., Ltd. Benzhydrylpiperazine derivatives, processes for the preparation thereof and pharmaceutical compositions comprising the same
US4591590A (en) * 1982-12-24 1986-05-27 Fujisawa Pharmaceutical Co., Ltd. Benzhydrylpiperazine derivatives, processes for the preparation thereof and pharmaceutical composition comprising the same

Also Published As

Publication number Publication date
JPS5427587A (en) 1979-03-01
US4199582A (en) 1980-04-22
IT7868827A0 (it) 1978-07-31
JPS6131105B2 (enrdf_load_stackoverflow) 1986-07-17

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PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

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Withdrawal date: 19810326

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Inventor name: MINORU, HIRATA

Inventor name: YOSHIKAZU, OKA

Inventor name: KATSUMI ITOH