GB2122200A - Polyene compounds - Google Patents

Polyene compounds Download PDF

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Publication number
GB2122200A
GB2122200A GB08317129A GB8317129A GB2122200A GB 2122200 A GB2122200 A GB 2122200A GB 08317129 A GB08317129 A GB 08317129A GB 8317129 A GB8317129 A GB 8317129A GB 2122200 A GB2122200 A GB 2122200A
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formula
alkyl
ethyl
pharmaceutically acceptable
methyl
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GB2122200B (en
GB8317129D0 (en
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Ernst Peter Krebs
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/74—Unsaturated compounds containing —CHO groups
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/46—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid
    • C07C57/50—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid containing condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Compounds of the formula <IMAGE> wherein R<1> is a group of the formula <IMAGE> R<2> is hydroxy, lower-alkoxy, amino, mono-(lower-alkyl)amino or di-(lower-alkyl)- amino, R<3> is lower-alkyl or halogen, R<4> is lower-alkyl, R<5> is lower-alkoxy, R<6> is hydrogen or lower-alkyl and R<7> is lower-alkyl or halogen, and pharmaceutically acceptable salts of the carboxylic acids of formula I can be used for the treatment of neo-plasms and dermatoses. The compounds of formula I can be obtained by forming the side-chain from corresponding cyclic and aliphatic for components by means of a Wittig or Horner reaction.

Description

SPECIFICATION Polyene compounds The present invention is concerned with novel polyene compounds, a process for their manufacture and pharmaceutical preparations which contain these polyene compounds.
The polyene compounds provided by the present invention are compounds of the general formula
wherein R1 is a group of the formula
or
R2 is hydroxy, lower-alkoxy, amino, mono-(lower-alkyl)amino or di-(lower-alkyl)amino, R3 is lower-alkyl or halogen, R4 is lower-alkyl, R5 is lower-alkoxy, R6 is hydrogen or lower-alkyl and R7 is lower-alkyl or halogen, and pharmaceutically acceptable salts of the carboxylic acids of Formula I.
Preferred groups of formula (c) are those in which R3, R4 and R7 are lower-alkyl, R5 is lower-alkoxy and R6 is hydrogen.
Alkyl groups and the alkyl moieties present in alkoxy and alkylamino groups preferably contain up to 6 carbon atoms. They can be straight-chain or branched-chain such as, for example, the methyl, ethyl, isopropyl or 2-methylpropyl group, with methyl being especially preferred.
Methylamino and ethylamino are examples of alkylamino groups and diethylamino is an example of a dialkylamino group.
The compounds of formula I and the pharmaceutically acceptable salts of the carboxylic acids of formula I can be manufactured in accordance with the invention by reacting a compound of the general formula R'A with a compound of the general formula
wherein R1 and R2 have the significance given above and either A represents a l-(triphenyl- phosphonium)-ethyl group of the formula
in which X represents phenyl and Y represents the anion or an organic or inorganic acid, and B represents formyl; or A represents acetyl and B represents a dialkoxyphosphinylmethyl group of the formula
in which Z represents a loweralkoxy group; and, if desired, converting a carboxylic acid ester obtained into a carboxylic acid or a carboxylic acid amide and, also if desired, converting a carboxylic acid obtained into a pharmaceutically acceptable salt.
The chloride, bromide or hydrosulphate ion is the preferred inorganic acid anion denoted by Y and the tosyloxy ion is the preferred organic acid anion denoted by Y.
The reaction of a formyl compound of formula 11 with a phosphorane is carried out in a manner known per se in the presence of an acid-binding agent, for example in the presence of a strong base such as, for example, butyl lithium, sodium hydride or the sodium salt of dimethyl sulphoxide, if desired in a solvent, for example in an ether such as diethyl ether or tetrahydrofuran or in an aromatic hydrocarbon such as benzene, at a temperature between room temperature and the boiling point of the reaction mixture.
The reaction of a phosphonate of formula II with a compound of the formula R'COCH3 is also carried out in a manner known per se in the presence of a base and, preferably, in the presence of an inert organic solvent, for example in the presence of sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxan or 1 ,2-dimethoxyethane or in the presence of a sodium alcoholate in an alkanol (e.g. sodium methylate in methanol), at a temperature between OOC and the boiling point of the reaction mixture.
The reactions described earlier can also be carried out in situ, i.e. without isolating the phosphonium salt or phosphonate in question.
A carboxylic acid ester of formula I can be hydrolyzed in a manner known per se, for example by treatment with alkalis, especially by treatment with aqueous-alcoholic sodium or potassium hydroxide solution at a temperature between room temperature and the boiling point of the reaction mixture, and the resulting carboxylic acid can be amidated either via an acid halide or, as described hereinafter, directly.
A carboxylic acid of formula I can be converted in a manner known per se, for example by treatment with thionile chloride, preferably in pyridine, or with phosphorus trichloride in toluene, into the acid chloride which can be converted into an ester by reaction with an alcohol or into a corresponding amide by reaction with an amine.
A carboxylic acid ester can be converted directly into the corresponding amide, for example by treatment with lithium amide. The lithium amide is advantageously reacted at room temperature with the ester in question.
A carboxylic acid of formula I forms pharmaceutically acceptable salts with bases, especially with alkali metal hydroxides and preferably with sodium hydroxide or potassium hydroxide.
Formula I hereinbefore is intended to embrace cis and trans forms.
The compounds of formula I can occur as cis/trans mixtures which, if desired and in a manner known per se, can be separated into the cis and trans components or isomerized to the all-trans compounds. The all-trans (all-E) compounds are preferred.
The compounds of formula I and pharmaceutically acceptable salts of the carboxylic acids of formula I are useful as medicaments. They can be used for the topical and systemic therapy of benign and malignant neoplasms and of premalignant lesions as well as for the systemic and topical prophylaxis of these conditions.
They are also suitable for the topical and systemic therapy of acne, psoriasis and other dermatoses accompanied with an intensified or pathologically altered cornification as well as of inflammatory and allergic dermatological conditions. Further, the compounds of formula I and physiologically acceptable salts of the carboxylic acids of formula I can also be used for the control of disorders of the mucous membranes associated with inflammatory or degenerative or metaplastic changes and for the oral treament of rheumatic diseases, especially those of an inflammatory and degenerative kind which affect the joints, muscles, tendons and other parts of the locomotor system.
Examples of such diseases are primary cronic polyarthritis, spondylarthritis ankylopoetica Bechterew and psoriatic arthritis.
The tumour-inhibiting activity of the compounds of formula I and pharmaceutically acceptable salts of the carboxylic acids of formula I is significant. In the papilloma test [Europ. J. Cancer 10, 731 - 737 [1974J] a regression of tumours induced with dimethylbenzanthracene and croton oil has been Observed. The diameters of the papillomae decrease in the course of 2 weeks by about 49% following the intraperitoneal administration of 50 mg of ethyl (ail-E)-4-methyl-7-(5,6,7,8-tetrahydro-5-5,8,8- tetramethyl-2-naphthyl)-2 ,4,6-octatrienoate.
The compounds of formula I and pharmaceutically acceptable salts of the carboxylic acid of formula I can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations for systemic administration can be manufactured, for example, by adding a compound of formula I or a pharmaceutically acceptable salt of a carboxylic acid of formula I as the active ingredient to non-toxic, inert, solid or liquid carriers which are customary per se in such preparations. The pharmaceutical preparations can be administered enterally or parenterally. For enteral administration there are suitable, for example, pharmaceutical preparations in the form of tablets, capsules, dragées, syrups, suspensions, solutions and suppositories.For parenteral administration there are suitable pharmaceutical preparations in the form of infusion or injection solutions.
The dosages in which the compounds of formula I and the pharmaceutically acceptable salts of the carboxylic acids of formula I are administered can vary according to the type of use, the mode of use and the requirements of the patients.
The compounds of formula I and the pharmaceutically acceptable salts of the carboxylic acids of formula I can be administered in amounts of about 0.01 to about 5 mg daily in one or more dosages. A preferred administration form comprises capsules containing about 0.1 mg to about 1.0 mg of active substance.
The pharmaceutical preparations can contain inert as well as pharmacodynamically active additives. Tablets or granulates, for example, can contain a series of binding agents, filling materials, carrier substances or diluents. Liquid preparations can take the form, for example, of a sterile solution which is miscible with water. Capsules can contain, in addition to the active substance, a filling material or thickening agent. Furthermore, flavour-improving additives, substances usually used as preserving, stabilizing, moisture-retaining and emulsifying agents as well as salts for varying the osmotic pressure, buffers and other additives can also be present.
The previously mentioned carrier substances and diluents can be organic or inorganic substances; for example, water, gelatine, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like. A prerequisite is that all adjuvants used in the manufacture of the pharmaceutical preparations are non-toxic.
For topical administration the compounds of formula I and pharmaceutically acceptable salts of the carboxylic acids of formula I are conveniently used in the form of salves, tinctures, creams, solutions, lotions, sprays, suspension and the like. Salves, creams and solutions are preferred. These pharmaceutical preparations for topical administration can be manufactured by mixing a compound of formula i or a pharmaceutically acceptable salt of a carboxylic acid of formula I as the active ingredient with non-toxic, inert, solid or liquid carriers which are customary per se in such preparations and which are suitable for topical treatment.
For topical administration there are conveniently used about 0.01 % to about 0.3%, preferably 0.2% to 0.1%, solutions and about 0.05% to about 5%, preferably about 0.05% to about 1%, salves or creams.
If desired, an antioxidant (e.g. tocopherol, N-methyl-y-tocopheramine, butylated hydroxyanisole or butylated hydroxytoluene) can be incorporated in the pharmaceutical preparations.
The following Examples illustrate the present invention: Example 1 23.4 g of [1 -(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]-triphenylphosphonium bromide in 1 50 ml of dry tetrahydrofuran were treated slowly at --150C while stirring with 26.25 ml of 1.6 molar butyl lithium (in hexane). After 30 minutes, there were added dropwise at the same temperature 6.72 g (40 mmol) of ethyl (all-E)-5-formyl-4-methyl-2,4-pentadienoate in 30 ml of tetrahydrofuran and the mixture was subsequently stirred at room temperature for a further 2 hours.
After the addition of ethyl acetate, the organic phase was shaken with 0.1 N hydrochloric acid, washed neutral with water, dried over magnesium sulphate and concentrated on a rotary evaporator. Two-fold crystallization of the residue from about 100 ml of ethanol gave 3.47 g (24%) of ethyl (all-E)-4-methyl 7-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2,4,6-octatrienoate of melting point 87.5- 890C. A further 1.6 g of pure product could be obtained from the mother liquors by chromatography.
The ethyl (all-E)-5-formyl-4-methyl-2,4-pentadienoate can be prepared as follows: (a) 43.23 g of triethyl phosphonoacetate are added to 4.63 g of sodium hydride in 100 ml of dry tetrahydrofuran. 25.0 g (0.18 mol) of y-acetoxy-tiglic aldehyde in 50 ml of tetrahydrofuran are subsequently added dropwise at 0--5 0 C. The mixture is stirred at room temperature for 20 hours, diluted with 200 ml of ethyl acetate, washed with saturated sodium chloride solution and dried over magnesium sulphate. Concentration and distillation at 1 030C/0.35 mmHg give 28.6 g (76%) of ethyl 6-acetoxy-4-methyl-2,4-hexadienoate.
(b) 27.5 g of ethyl 6-acetoxy-4-methyl-2,4-hexadienoate, 20 g of sodium carbonate and 2 ml of triethanolamine are heated to reflux for 3 hours in 250 ml of ethanol. After the addition of ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Distillation at 11 00C/0.4 mmHg give 1 5.7 g (71%) of ethyl 6-hydroxy-4methyl-2,4-hexadienoate.
(c) 11.7 g of ethyl 6-hydroxy-4-methyl-2,4-hexadienoate in 200 ml of dichioromethane are stirred at room temperature for 4 hours with 30 g of manganese (lV) oxide. The solution is filtered and concentrated and the residue is then recrystallized from hexane/cyclohexane. There are obtained 9.1 g (78%) of ethyl 5-formyl-4-methyl-2 ,4-pentadienoate of melting point 48--49 OC.
Example 2 In a manner analogous to that described in Example 1 , from 1 -methyl-3-(2,6,6-trimethyl-1 -cyclo hexen-1-yl)allyltriphenylphosphonium chloride and ethyl 5-formyl-4-methyl-2,4-pentadienoate there is obtained ethyl 4;7-dimethyl-9-(2,6,6-trimethyl- 1 -cyclohexen- 1 -yl )-2,4,6,8-nonatetraenoate of melting point 65-660C (from methanol).
Example 3 In a manner analogous that described in Example 1 , from 1 -methyl-3-(2,3,6-trimethyl-4 methoxyphenyl)allyltriphenylphosphoniu m chloride and ethyl 5-formyl-4-methyl-2,4-pentadienoate there is obtained ethyl (all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-4,7-dimethyl-2,4,6,8- nonatetraenoate.
Example 4 9 g of ethyl (all-E)-4-methyl-7-(5,6,7,8-tetrahydrn-5,5,8,8-tetramethyl-2-naphthyl)2,4,6-octa trienoate are dissolved in 200 ml of ethanol and the solution is treated with a solution of 8.2 g of potassium hydroxide in 20 ml of water. After stirring at room temperature for 1 8 hours, the mixture is poured into ice-water, acidified with 2N sulphuric acid and the precipitated acid is filtered off. After recrystallization from methanol, there are obtained 7.8 g of (ail-E)-4-methyl-7-(5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-naphthyl)-2,4,6-octatrienoic acid in the form of yellow crystals of melting point 232 --2340C.
Example 5 4.5 g of (all-E)-4-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2,4,6- octatrienoic acid are dissolved in 200 ml of tetrahydrofuran and the solution is treated with 2.6 g of 1,1 '-carbonyldiimidazole. After stirring at room temperature for 3 hours, the mixture is cooled to 5 1 OOC and a stream of ethylamine is introduced during 1 hour. After removing the cooling bath, the mixture is stirred at room temperature overnight. The mixture is subsequently poured into ice-water, acidified with 6N sulphuric acid and extracted with ethyl acetate. The organic phase is washed with 2N sodium carbonate solution and with saturated sodium chloride solution, dried over sodium sulphate and evaporated. After a further purification of the crude product by chromatography on silica gel using methylene chloride/acetone (95:5) for the elution and recrystallization from toluene, there are obtained 1.6 g of N-ethyl 4-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2,4,6-octa- trienamide in the form of yellow crystals of melting point 1 50-1 590C.
Example A Capsules can contain the following ingredients: Ethyl (all-E)-4-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8-tetra methyl-2- naphthyl)-2,4,6-octatrienoate 0.1 mg Wax mixture 50.5 mg Vegetable oil 98.9 mg Ethylenediaminetetraacetic acid trisodium salt 0.5 mg

Claims (8)

Claims
1. Compounds of the general formula
wherein R1 is a group of the formula
R2 is hydroxy, lower-alkoxy, amino, mono-(lower-alkyl)amino or di-(lower-alkyl)-amino, R3 is lower-alkyl or halogen, R4 is lower-alkyl, R5 is lower-alkoxy, R6 is hydrogen or lower-alkyl and R7 is lower-alkyl or halogen and pharmaceutically acceptable salts of the carboxylic acids of formula I.
2. Compounds according to claim 1, wherein R' is a group of formula (c) and R3, R4 and R7 are lower-alkyl, R5 is lower-alkoxy and R6 is hydrogen.
3. Ethyl (all-E)-4-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2,4,6- octatrienoate.
4. Ethyl 4,7-dimethyl-9-(2,6,6-trimethyl- 1 -cyclohexen- 1 -yl)-2,4,6,8-nonatetraenoate, ethyl (all E)-9-(4-methoxy-2,3,6-trimethylphenyl)-4,7-dimethyl-2,4,6,8-nonatetraenoate, (all-E)-4-methyl-7 (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2,4,6-octatrienoic acid or N-ethyl 4-methyl-7 (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2,4,6-octatriena mide.
5. Ethyl (all-E)-5-formyl-4-methyl-2,4-pentadienoate.
6. Compounds of formula I given in claim 1 and pharmaceutically acceptable salts of the carboxylic acids of formula I for the treatment of neoplasms, premalignant lesions, acne, psoriasis or rheumatic diseases of an inflammatory or degenerative kind.
7. A pharmaceutical preparation based on a compound of formula I given in claim 1 or a pharmaceutically acceptable salt of a carboxylic acid of formula I.
8. A process for the manufacture of compounds of formula I given in claim 1 and pharmaceutically acceptable salts of the carboxylic acids of formula I, which process comprises reacting a compound of the general formula R1Awlth a compound of the general formula
wherein R1 and R2 have the significance given in claim 1 and either A represents a 1 (triphenylphosphonium)-ethyl group of the formula
in which X represents phenyl and Y- represents the anion of an organic or inorganic acid, and B represents formyl; or A represents acetyl and B represents dialkoxyphosphinylmethyl group of the formula
in which Z represents a lower-alkoxy group; and, if desired, converting a carboxylic acid ester obtained into a carboxylic acid or a carboxylic acid amide and, also if desired, converting a carboxylic acid obtained into a pharmaceutically acceptable salt.
GB08317129A 1982-06-24 1983-06-23 Polyene compounds Expired GB2122200B (en)

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CH3889/82A CH651007A5 (en) 1982-06-24 1982-06-24 POLYEN CONNECTIONS.

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GB8317129D0 GB8317129D0 (en) 1983-07-27
GB2122200A true GB2122200A (en) 1984-01-11
GB2122200B GB2122200B (en) 1986-05-08

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GB08510717A Expired GB2156351B (en) 1982-06-24 1985-04-26 An ester

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AU (1) AU560027B2 (en)
BE (1) BE897118A (en)
CA (1) CA1276032C (en)
CH (1) CH651007A5 (en)
DE (1) DE3321662A1 (en)
DK (1) DK159392C (en)
FR (1) FR2529201B1 (en)
GB (2) GB2122200B (en)
IE (1) IE55285B1 (en)
IL (1) IL69028A0 (en)
IT (1) IT1212753B (en)
LU (1) LU84870A1 (en)
NL (1) NL8302136A (en)
NZ (1) NZ204628A (en)
PH (1) PH20070A (en)
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EP0312412A1 (en) * 1987-10-16 1989-04-19 L'oreal Norbornane derivatives, method for their preparation and cosmetic and medicinal compositions containing them
WO1996005165A1 (en) * 1994-08-10 1996-02-22 F. Hoffmann-La Roche Ag Retinoic acid x-receptor ligands

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GB2163159B (en) * 1984-08-13 1987-10-14 Oreal 1-substituted derivatives of 4-methoxy-2, 3, 6-trimethylbenzene, process for their preparation and medicinal and cosmetic compositions containing them
DE4033568A1 (en) * 1990-10-22 1992-04-23 Henkel Kgaa BICYCLIC COMPOUNDS WITH ANTISEBORRHOIC EFFECT

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AT207831B (en) * 1957-11-27 1960-02-25 Hoffmann La Roche Process for the preparation of polyenecarboxylic acid esters and their saponification products
AT222103B (en) * 1958-08-07 1962-07-10 Bayer Ag Process for the preparation of 2-trans-β-ionylideneacetic acid
CH529742A (en) * 1970-02-02 1972-10-31 Hoffmann La Roche Process for the production of vitamin A acid amides
AT340902B (en) * 1974-03-29 1978-01-10 Hoffmann La Roche PROCESS FOR PRODUCING NEW POLYENE COMPOUNDS
DE2456959A1 (en) * 1974-12-03 1976-06-16 Basf Ag 4- (E) - AND 4- (Z) -7-METHYL-9- (2,6,6TRIMETHYL-1-CYCLOHEXEN-1-YL) -NONA-2,4,6,8TETRAEN CARBONIC ACID, ITS DERIVATIVES AND CONTAINING THEM PREPARATIONS
CH624373A5 (en) * 1975-11-14 1981-07-31 Hoffmann La Roche Process for the preparation of polyene compounds
CA1111441A (en) * 1976-12-20 1981-10-27 Werner Bollag Polyene compounds
LU77254A1 (en) * 1977-05-04 1979-01-18
US4169103A (en) * 1978-04-12 1979-09-25 Hoffmann-La Roche Inc. Nonatetraenoic acid derivatives
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0312412A1 (en) * 1987-10-16 1989-04-19 L'oreal Norbornane derivatives, method for their preparation and cosmetic and medicinal compositions containing them
FR2621912A1 (en) * 1987-10-16 1989-04-21 Oreal NOVEL NORBORNANE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND COSMETIC AND MEDICAMENT COMPOSITIONS CONTAINING SAME
US5047575A (en) * 1987-10-16 1991-09-10 L'oreal Norbornene carboxylic acids and esters
WO1996005165A1 (en) * 1994-08-10 1996-02-22 F. Hoffmann-La Roche Ag Retinoic acid x-receptor ligands
CN1091092C (en) * 1994-08-10 2002-09-18 霍夫曼-拉罗奇有限公司 Retinoic acid X-receptor ligands

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IT1212753B (en) 1989-11-30
DK159392B (en) 1990-10-08
CA1276032C (en) 1990-11-06
ZA834473B (en) 1984-03-28
AT392780B (en) 1991-06-10
AU560027B2 (en) 1987-03-26
LU84870A1 (en) 1985-03-29
JPS5910547A (en) 1984-01-20
DK287083A (en) 1983-12-25
BE897118A (en) 1983-12-23
NL8302136A (en) 1984-01-16
GB2156351A (en) 1985-10-09
FR2529201B1 (en) 1988-08-19
AU1620183A (en) 1984-01-05
IT8321721A0 (en) 1983-06-21
CH651007A5 (en) 1985-08-30
JPH0441134B2 (en) 1992-07-07
SE8303539D0 (en) 1983-06-20
PH20070A (en) 1986-09-18
IE831471L (en) 1983-12-24
NZ204628A (en) 1985-07-31
ATA230583A (en) 1990-11-15
DK287083D0 (en) 1983-06-21
FR2529201A1 (en) 1983-12-30
IE55285B1 (en) 1990-08-01
GB2156351B (en) 1986-05-14
DK159392C (en) 1991-03-04
IL69028A0 (en) 1983-10-31
GB2122200B (en) 1986-05-08
SE454984B (en) 1988-06-13
DE3321662C2 (en) 1992-11-26
DE3321662A1 (en) 1983-12-29
GB8317129D0 (en) 1983-07-27
GB8510717D0 (en) 1985-06-05
SE8303539L (en) 1983-12-25

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