WO1993012070A1 - New tetrahydronaphthalene derivatives - Google Patents
New tetrahydronaphthalene derivatives Download PDFInfo
- 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
Links
- 0 *C(*C(*)=O)N(*)C(C=CC(c1cc(CCCC2)c2cc1)=O)=O Chemical compound *C(*C(*)=O)N(*)C(C=CC(c1cc(CCCC2)c2cc1)=O)=O 0.000 description 1
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.
Landscapes
- 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)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP93901878A EP0618894A1 (en) | 1991-12-19 | 1992-12-18 | New tetrahydronaphthalene derivatives |
JP5510766A JPH07502039A (en) | 1991-12-19 | 1992-12-18 | New tetrahydronaphthalene derivatives |
NO942306A NO942306L (en) | 1991-12-19 | 1994-06-17 | New tetrahydronaphthalene derivatives |
FI942927A FI942927A (en) | 1991-12-19 | 1994-06-17 | Process for the preparation of therapeutically useful tetrahydronaphthalene derivatives |
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 (en) |
JP (1) | JPH07502039A (en) |
CN (1) | CN1074213A (en) |
CA (1) | CA2126198A1 (en) |
FI (1) | FI942927A (en) |
HU (1) | HU209487B (en) |
IL (1) | IL104196A0 (en) |
NO (1) | NO942306L (en) |
NZ (1) | NZ245534A (en) |
TW (1) | TW223623B (en) |
WO (1) | WO1993012070A1 (en) |
ZA (1) | ZA929913B (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR1566212A (en) * | 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 |
-
1991
- 1991-12-19 HU HU914021A patent/HU209487B/en unknown
-
1992
- 1992-12-18 JP JP5510766A patent/JPH07502039A/en active Pending
- 1992-12-18 WO PCT/HU1992/000058 patent/WO1993012070A1/en not_active Application Discontinuation
- 1992-12-18 NZ NZ245534A patent/NZ245534A/en unknown
- 1992-12-18 EP EP93901878A patent/EP0618894A1/en not_active Withdrawn
- 1992-12-18 CA CA002126198A patent/CA2126198A1/en not_active Abandoned
- 1992-12-19 CN CN92113838A patent/CN1074213A/en active Pending
- 1992-12-20 IL IL104196A patent/IL104196A0/en unknown
- 1992-12-21 TW TW081110291A patent/TW223623B/zh active
- 1992-12-21 ZA ZA929913A patent/ZA929913B/en unknown
-
1994
- 1994-06-17 FI FI942927A patent/FI942927A/en not_active Application Discontinuation
- 1994-06-17 NO NO942306A patent/NO942306L/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR1566212A (en) * | 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 |
---|---|
NO942306D0 (en) | 1994-06-17 |
JPH07502039A (en) | 1995-03-02 |
IL104196A0 (en) | 1993-05-13 |
CA2126198A1 (en) | 1993-06-24 |
TW223623B (en) | 1994-05-11 |
FI942927A0 (en) | 1994-06-17 |
EP0618894A1 (en) | 1994-10-12 |
FI942927A (en) | 1994-06-17 |
NZ245534A (en) | 1995-07-26 |
HUT63147A (en) | 1993-07-28 |
HU914021D0 (en) | 1992-03-30 |
ZA929913B (en) | 1993-06-24 |
CN1074213A (en) | 1993-07-14 |
NO942306L (en) | 1994-06-17 |
HU209487B (en) | 1994-06-28 |
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