WO1993012070A1 - New tetrahydronaphthalene derivatives - Google Patents

New tetrahydronaphthalene derivatives Download PDF

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Publication number
WO1993012070A1
WO1993012070A1 PCT/HU1992/000058 HU9200058W WO9312070A1 WO 1993012070 A1 WO1993012070 A1 WO 1993012070A1 HU 9200058 W HU9200058 W HU 9200058W WO 9312070 A1 WO9312070 A1 WO 9312070A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
general formula
tetrahydro
naphthyl
benzyl
Prior art date
Application number
PCT/HU1992/000058
Other languages
English (en)
French (fr)
Inventor
Ildikó BALLÓ
László Dobay
Elemér Ezer
János Fischer
György Hajós
Judit MATÚZ
Ede MÁRVÁNYOS
Katalin Sághy
László Szporny
Original Assignee
Richter Gedeon Vegyszeti Gyár Rt.
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 Richter Gedeon Vegyszeti Gyár Rt. filed Critical Richter Gedeon Vegyszeti Gyár Rt.
Priority to EP93901878A priority Critical patent/EP0618894A1/en
Priority to JP5510766A priority patent/JPH07502039A/ja
Publication of WO1993012070A1 publication Critical patent/WO1993012070A1/en
Priority to NO942306A priority patent/NO942306L/no
Priority to FI942927A priority patent/FI942927A7/fi

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the invention relates to new tetrahydro- naphthalene derivatives of general formula ( I)
  • R 1 represents a hydrogen atom
  • R 2 represents a hydrogen atom, a C ⁇ _ 4 alkoxycarbonylalkyl or benzyl group, or R 1 and R 2 together represent a group of formula - (CH 2 ) 3 -,
  • R 3 represents a hydroxy, C ⁇ _ alkoxy or benzyl- oxy group or a group of general formula (A) ,
  • R 5 represents a C1- 4 alkyl group, and n represents 0, 1, 2, 3 or 4, and their pharmaceutically acceptable salts, further ⁇ more to a process for preparing the same.
  • Compounds of general formula (I) may be in
  • the alkyl groups can be linear or branched saturated hydrocarbon groups, i.e. methyl, ethyl, n- or isopro- p ⁇ l, furthermore n-, sec- or t-b tyl groups.
  • the new compounds of general formula (I) proved to be biologically active, they exerted significant antiulcer, i.e. cytoprotective effect.
  • the invention relates furthermore to pharma- ceutical compositions containing new tetrahydro- naphthalene derivatives of general formula (I) - wherein R 1 , R 2 , R 3 and n have the same meaning as above - and their pharmaceutically acceptable salts, furthermore to a process for preparing the same.
  • the therapeutic effect of the compounds of general formula (I) was studied in the following tests.
  • the invention also relates to a process for preparing new tetrahydronaphthalene derivatives of general formula (I) - wherein R 1 , R 2 , R 3 and n have the same meaning as above - w h i c h c o m p r i s e s - reacting an activated derivative of 4- ⁇ xo-4-
  • R 1 and R 2 have the same meaning as above, and R 4 represents a ⁇ - 4 alkoxy or benzyloxy group or a group of formula A - wherein R 5 represents a C _4 alkyl group - , and if desired, submitting to acidolysis the compounds of general formula (I) - wherein R 1 and R 2 have the same meaning as above and R 3 stands for a t- butyloxy group - and/or if desired, reacting an activated derivative of a compound of general formula (I) - wherein R 1 and
  • R 2 have the same meaning as above and R 3 stands for a hydroxy group - with a piperazine derivative contain-
  • SUBST ⁇ UTE SHEET ing a group of formula A - wherein R 5 has the same meaning as above - or are converted with an inorganic or organic base to a salt.
  • the 4-OXO-4-(5,6,7,8-tetrahydro-2-naphthyl- 2(E)-butenoic acid of general formula (II) can be prepared from 1,2,3,4-tetrahydronaphthalene and maleic anhydride in a Friedel-Krafts reaction according to D. Papa et al: J. Am. Che . Soc. : 10_, 3356, 1948.
  • the amide formation between the compounds of general formulas (II) and (III) is performed by activating in situ first 4-oxo-4-
  • the carboxy group of the compound of formula (II) can be activated by not less than stoichiometric amounts of a carbodiimide type reagent, i. e. dicyclohexyl- carbodiimide, in an inert organic solvent, preferably in a halogenated aliphatic hydrocarbon, advantageously in dichloromethane, at a preferred temperature range of 0°C to 20°C.
  • a carbodiimide type reagent i. e. dicyclohexyl- carbodiimide
  • an inert organic solvent preferably in a halogenated aliphatic hydrocarbon, advantageously in dichloromethane, at a preferred temperature range of 0°C to 20°C.
  • An other preferred type of activation is the mixed anhydride method, wherein a chloroformic acid ester, preferably ethyl chloroformate is applied.
  • the reaction is performed in an inert organic solvent, i. e. in a cyclic ether, preferably in tetrahydrofu- ran, in the presence of stoichiometric amounts of a t- amine base, preferably in triethylamine, at a preferred temperature range of -20°C to 0°C.
  • a compound of general formula (I)- wherein R 1 and R 2 have the same meaning as above and R 3 is a hydroxy group - is reacted with a piperazine
  • SUBSTITUTESHEET derivative the acid is activated by either of the above methods, i. e. either by the mixed anhydride or the carbodiimide method.
  • the compounds of general formula (I) - wherein R 1 and R 2 have the same meaning as above and R 3 stands for a hydroxy group - can be converted by known methods with an organic or inorganic base into an alkali metal, alkali earth metal or zinc salt.
  • the compounds of general formula (I) - wherein R 1 , R 2 and R 3 have the same meaning as above - prepar ⁇ ed by the process of the invention, can be isolated by known methods, i. e. filtration, and purified by re- crystallization.
  • the compounds of the invention can be converted into pharmaceutical formulations suitable for parenteral or enteral administration by mixing them with non-toxic, inert solid or liquid carriers and/or additives.
  • Water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc, and plant oils, such as peanut oil, olive oil, etc., can be used as carriers.
  • the active ingredient can be formulated as is usual in pharmaceutical compositions, in solid forms, i.e. round or rectangular tablets, coated tablets, capsules, i. e. gelatine capsules, pills, or suppositories.
  • compositions can contain, if required, the usual auxiliary materials, such as preservatives, stabilizers, wetting agents, emulsifying agents, etc. They can be prepared by usual methods, so in the case of solid formulations, by sieving, mixing, granulating and pressing.
  • auxiliary materials such as preservatives, stabilizers, wetting agents, emulsifying agents, etc.
  • the formulations can.be submitted to the usual pharmaceutical technological procedures, .i. e. sterilization.
  • the solution is cooled to -15°C, thereafter 2.01 ml (0.022 mole) of ethyl chloroformate, dissolved in 10 ml of anhydrous dichloromethane, then at -15°C 4.0 g (0.022 mole) of L-proline ethyl ester hydrochloride, dissolved in 10 ml of anhydrous dichloromethane are added.
  • the reaction mixture is stirred first at -15°C for 30 minutes, then at room temperature for 2 hours, and the mixture is extracted with the following solutions in the order listed: 1 N hydrochloric acid, water-, 5 % sodium carbonate and saturated sodium chloride solu ⁇ tion.
  • the organic layer is dried over sodium sulfate and evaporated.
  • the evaporation residue is crystallized from a mixture of cyclohexane-petroleum ether (1:1) .
  • SUBSTITUTE SHEET solution is extracted with water and saturated sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evapo ⁇ rated, to give an oil. Yield: 6.50 g (99 %) .
  • the precipitated dicyclohexylurea is filtered, and the filtrate is extracted with the following solvents in the order listed: 1 N hydrochloric acid, water, saturated sodium carbonate solution and finally sodium chloride solution.
  • the organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue crystallizes upon the addition of diethyl ether. Yield: 1.3 g (41 %) . M.p.: 112-114°C.
  • the organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated.
  • the reaction mixture is cooled to -15°C, then a solution of 2.01 ml (22 mmole) ethyl chloroformate in 20 ml of anhydrous tetrahydrofuran are added, and thereafter the above prepared solution of 3.7 g (22 mmole) of L-proline t- butyl ester in 20 ml of anhydrous tetrahydrofuran.
  • the reaction mixture is stirred for 30 minutes at -15°C, for 30 minutes at room temperature, then it is poured on 200 ml of water and extracted with dichloromethane.
  • the organic layer is extracted with the following solutions in the order listed: 5 % sodium carbonate solution, saturated sodium chloride solution and finally water.
  • the organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue crystallizes upon the addition of petroleum ether.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/HU1992/000058 1991-12-19 1992-12-18 New tetrahydronaphthalene derivatives WO1993012070A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP93901878A EP0618894A1 (en) 1991-12-19 1992-12-18 New tetrahydronaphthalene derivatives
JP5510766A JPH07502039A (ja) 1991-12-19 1992-12-18 新規テトラヒドロナフタレン誘導体
NO942306A NO942306L (no) 1991-12-19 1994-06-17 Nye tetrahydronaftalenderivater
FI942927A FI942927A7 (fi) 1991-12-19 1994-06-17 Menetelmä terapeuttisesti käyttökelpoisten tetrahydronaftaleenijohdannaisten valmistamiseksi

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU914021A HU209487B (en) 1991-12-19 1991-12-19 Process for producing tetrahydro-naphtaline derivatives and pharmaceutical compositions containing them as active agents
HU4021/91 1991-12-19

Publications (1)

Publication Number Publication Date
WO1993012070A1 true WO1993012070A1 (en) 1993-06-24

Family

ID=10966554

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU1992/000058 WO1993012070A1 (en) 1991-12-19 1992-12-18 New tetrahydronaphthalene derivatives

Country Status (12)

Country Link
EP (1) EP0618894A1 (enrdf_load_stackoverflow)
JP (1) JPH07502039A (enrdf_load_stackoverflow)
CN (1) CN1074213A (enrdf_load_stackoverflow)
CA (1) CA2126198A1 (enrdf_load_stackoverflow)
FI (1) FI942927A7 (enrdf_load_stackoverflow)
HU (1) HU209487B (enrdf_load_stackoverflow)
IL (1) IL104196A0 (enrdf_load_stackoverflow)
NO (1) NO942306L (enrdf_load_stackoverflow)
NZ (1) NZ245534A (enrdf_load_stackoverflow)
TW (1) TW223623B (enrdf_load_stackoverflow)
WO (1) WO1993012070A1 (enrdf_load_stackoverflow)
ZA (1) ZA929913B (enrdf_load_stackoverflow)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1566212A (enrdf_load_stackoverflow) * 1966-12-30 1969-05-09
WO1988009785A1 (en) * 1987-06-10 1988-12-15 Richter Gedeon Vegyészeti Gyár RT Butenoic acid amides, their salts, pharmaceutical compositions containing them and process for preparing same
US4923888A (en) * 1987-09-25 1990-05-08 Richter Gedeon Vegyeszeti Gyar Rt Butenoic acid amides, their salts, and pharmaceutical compositions containing them

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1566212A (enrdf_load_stackoverflow) * 1966-12-30 1969-05-09
WO1988009785A1 (en) * 1987-06-10 1988-12-15 Richter Gedeon Vegyészeti Gyár RT Butenoic acid amides, their salts, pharmaceutical compositions containing them and process for preparing same
US4923888A (en) * 1987-09-25 1990-05-08 Richter Gedeon Vegyeszeti Gyar Rt Butenoic acid amides, their salts, and pharmaceutical compositions containing them

Also Published As

Publication number Publication date
HU209487B (en) 1994-06-28
NO942306D0 (no) 1994-06-17
EP0618894A1 (en) 1994-10-12
FI942927A0 (fi) 1994-06-17
JPH07502039A (ja) 1995-03-02
HU914021D0 (en) 1992-03-30
NO942306L (no) 1994-06-17
CA2126198A1 (en) 1993-06-24
TW223623B (enrdf_load_stackoverflow) 1994-05-11
FI942927A7 (fi) 1994-06-17
CN1074213A (zh) 1993-07-14
IL104196A0 (en) 1993-05-13
ZA929913B (en) 1993-06-24
NZ245534A (en) 1995-07-26
HUT63147A (en) 1993-07-28

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