GB2190378A - Pharmaceutically active tetrahydronaphthalene derivatives - Google Patents

Pharmaceutically active tetrahydronaphthalene derivatives Download PDF

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GB2190378A
GB2190378A GB08711205A GB8711205A GB2190378A GB 2190378 A GB2190378 A GB 2190378A GB 08711205 A GB08711205 A GB 08711205A GB 8711205 A GB8711205 A GB 8711205A GB 2190378 A GB2190378 A GB 2190378A
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compounds
compound
general formula
formula
tetrahydro
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GB8711205D0 (en
GB2190378B (en
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Michael Klaus
Peter Loeliger
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Priority claimed from CH1938/86A external-priority patent/CH668962A5/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)

Description

1 GB2190378A 1
SPECIFICATION
Tetrahydro naphthaline derivatives The present invention is concerned with novel tetrahydronaphthalene derivatives of the general 5 formula E 3c CH3 CH 3 1 1 C CH - R 10 R3C CH 3 15 wherein R' represents o-, m- or p-hyroxyphenyl; 2,21-, 2,4-, 2,5-, 2,6, 3,4- or 3,5-dihydroxyphenyi; or 2,3,4-, 2,3,5- 2, 4,5-, 2,4,6-, 3,4,5- or 2,3,6-trihydroxyphenyi.
The compounds of formula 1 can exist as trans or cis isomers or as cis/trans isomer mixtures.
In general, there are preferred the trans compounds of formula 1, furthermore those in which R' 20 is o-, m- or p-hydroxyphenyl, especially p-hydroxypheny].
The invention is also concerned with a process for the manufacture of the compounds of formula 1, pharmaceutical preparations based on the compounds of formula 1, the compounds of formula 1 in the treatment and prophyl-axis of neoplasms and dermatoses as well as the use of the compounds of formula 1 in the manufacture of pharmaceutical preparations for the treatment 25 and prophylaxis of such conditions.
The compounds of formula 1 can be manufactured in accordance with the invention by cleaving off the protecting group(s) from a compound of the general formula H 3 C CH 3 CH 3 30 CH - R11 35 H3C ca3 wherein R' I signifies a residue R' in which the hydroxy group(s) is/are protected.
As protecting groups there come into consideration all conventional hydroxy protecting groups. 40 Examples of such protecting groups are ethers, especially the 2- tetrahydropyranyl ether and silyl ethers such as the trimethylsily ether; further, alkyl ethers such as the methyl ethers; and esters, e.g. lower-alkanecarboxylic acid esters such as acetates and carbonates. The cleavage of the protecting groups can be carried out in a manner known per se by treatment with acids, bases or reduction agents. Ether protecting groups such as tetrahydropyranyl and trimethylsilyl can be 45 cleaved off by treatment with acids such as p-toluenesulphonic acid or Lewis acids such as 13F3 or BBr3. Ester protecting groups such as acetates or carbonates are removed by treatment with bases, e.g. alcoholic or aqueous-alcoholic alkali hydroxide solution.
The compounds of general formula 11 can be obtained by reacting a compound of the general formula 50 1SC CH 3 A 55 H 3 C CH 3 60 with a compound of the general formula 2 GB2190378A 2 B-R" IV in which either A represents a residue -CH(CHjP1-(Q),Y- or - CH(CHjP(O)(0Alk)2 and B represents formyl, or A represents acetyl and B represents a residue -CH,P+(Q6Y or CH2P(O)(OA]k)2; and Q signifies aryi, especially phenyl, 5 y- signifies the anion of an organic or inorganic acid, e.g. Br-, and Alk signifies lower-alkyl, e.g. methyl, and R" signifies the same as above.
The reaction of the compounds of formulae Ill and N can be carried out according to the known methods of the Witting or Homer reaction. 10 In the case of the Witting reaction, i.e. with the use of a compound of formula Ill with A=-CH(CH3WIQ)ly- or of formula IV with B=-CH2PIQ6y-, the components are reacted with one another in the presence of an acid-binding agent, e.g. in the presence of a strong base such as e.g. butyllithium, sodium hydride or the sodium salt of dimethyl sulphoxide, but especially in the presence of an optionally lower alkyl-substituted ethylene oxide such as 1,2-butylene oxide, 15 optionally in a solvent, e.g. in an ether such as diethyl ether or tetrahydrofuran or in an aromatic hydrocarbon such as benzene, in a temperature range lying between room temperature and the boiling point of the reaction mixture.
Of the inorganic acid ions Y- the chloride ion, the bromide ion or the hydrosulphate ion is preferred and of the organic acid ions the tosyloxy ion is preferred. The aryl residue Q is 20 preferably a phenyl residue or a substituted phenyl residue such as p- tolyl.
In the case of the Homer reaction, i.e. with the use of a compound of formula Ill with A=-CH(CH3)-P(O)(0Aik)2 or of formula IV with B=-CH,P(O)(0Alk)2, the components are con densed with the aid of a base and preferably in the presence of an inert organic solvent, e.g.
with the aid of sodium hydride in benzene, toluene, dimethylformamide, tetra hydrofura n, dioxan 25 or 1,2-dimethoxyethane, or also with the aid of a sodium alcoholate in an alkanol, e.g. sodium methylate in methanol, in a temperature range lying between 0' and the boiling point of the reaction mixture.
The alkoxy residues 0Alk are especially lower alkoxy residues with 1-6 carbon atoms such as methoxy or ethoxy. 30 The compounds of formula 1 can exist in trans or cis form. In the process they are mainly obtained in the transform. Cis components which may be obtained can be separated, if desired, in a manner known per se.
The starting materials of formulae Ill and IV, insofaras their preparation is not known or is not described hereinafter, can be prepared in analogy to known methods or to methods described 35 hereinafter.
The compounds of formula 1 have therapeutic activity. In particular, they possess antiseborrho eic, antikeratinizing, antineoplastic and anti-allergic/anti-inflammatory activity, which can be de monstrated using the test procedures described hereinafter; (A) The activity in the prevention of chemically-induced breast tumours can be determined 40 according to the following procedure. Female Sprague-Dawley rats are kept under temperature controlled and light-controlled conditions, with free access to drinking water and feed. At the age of 50 days 15 mg of dimethylbenz (a) anthracene dissolved in arachis oil are administered to each rat by means of a probang. The treatment with the test compounds begins 1 day after the administration of the carcinogen. The body weights of the test animals are recorded and the 45 tumours are palpated weekly and measured with a vernier caliper. The volumes are calculated according to the formula D - - d 2 50 2 in which D represents the larger diameter of the tumour ellipsoid and d represents the smaller diameter of the tumour ellipsoid. After 11 weeks the test is terminated and evaluated. In this test there are used in addition to 30 control animals, which receive exclusively normal feed, the 55 following two groups of test animals:
1. 33 rats to which are administered daily 30 mg/kg of test compound mixed with the feed.
2. 36 rats to which are administered daily 90 mg/l<g of test compound mixed with the feed.
(B) Furthermore, the activity on tumours can be determined on the transplantable chondrosar coma of the rat according to the following method. The solid tumour of a donor animal is finely 60 minced and suspended in phosphate buffer/sodium chloride solution. 0.5 mi of the 30% tumour suspension is implanted subcutaneously into albino rats.
The transplanted rats are divided into test groups of in each case 8 animals. The test compounds are suspended in arachis oil and administered orally five times per week for 24 days. The tumours are excised and weighed on day 24. The results are expressed in the 65 GB2190378A 3 quotient C/T which is calculated as follows:
Average tumour weight of treated.
C/T= Average tumour weight of treated. 5 (C) The antimetaplastic activity can also be determined in rats according to the following method. Female Holtzmann rats weighing approximately 100 g are ovarectomized under Thio genal narcosis after an adaptation period of 8 days and are used in the test after a further 14 days. In each case two animals are placed in a cage with free access to feed which contains 10 approximately 2000 IU of vitamin A determined analytically. Prior to the oral administration of the test compound the animals are treated subcutaneously each day on 6 successive days with 1 pg of estradiol benzoate and 250 pg of testosterone propionate dissolved in 0.1 m] of sesame oil. The parenteral hormone administration leads to the formation of a clear granular stage in the vaginal smear, i.e. a squamous metaplasia. 2 days after the oral administration of the test 15 substance the result of the reaction is again read off on the vaginal epithelium. The area method according to Behrens and Karber is employed to calculate the average effective dosages.
The results of test A-C with a compound of formula 1, P-[(E)-2-(5,6,7,8tetrahydro-5,5,8,8- tetramethyi-2-naphthyi)propenyllphenol, are presented in Tables 1-111 hereinafter.
20 Table I
A) Prophylaxis of chemically-induced breast tumours. 25 0 Table 11
B) Activity on transplantable chondrosarcoma of the rat 40 Dosage Quotient C/T of tumour weight of the [mg/kg] untreated control animals and of the 45 -D.O. treated animals 3.8 Table 111 50
C) Antimetaplastic activity in the rat.
Compound Relative activity 55 all-Trans-retinoic acid 1 Compound 1 0.91 60 Dosage Rats with Average number Average tumour [mg/kg] tumours of tumours per volume per rat P.O. rat [% of controls] in mm3 [% of 3 controls] 68 52.4 72.6 35 14.1 3.9 1 1 3 4 GB2190378A 4 The compounds of formula 1 can be used for the topical and systemic therapy of benign and malignant neoplasms, of premalignant lesions and also for the systemic and topical prohylaxis of the said conditions.
Furthermore, they are suitable for the topical and systemic therapy of acne, psoriasis and other dermatoses which are accompanied by an intensified or pathologically altered comification, 5 as well as of inflammatory and allergic dermatological conditions. Further, the compounds of formula 1 can also be used for the control of mucous membrane disorders with inflammatory or degenerative or metaplastic changes. The compounds of formula 1 are characterized, in particular, by a low toxicity or an improved tolerance in comparison to known retinoids.
The pharmaceutical preparations can be administered enterally, parenterally or topically. For 10 enteral administration there are suitable e.g. preparations in the form of tables, capsules, dragees, syrups, suspensions, solutions and suppositories. Preparations in the form of infusion or injection solutions are suitable for parenteral administration.
The dosages in which the preparations are administered can vary according to the mode of use and route of use as well as according to the requirements of the patients. In general, daily 15 doses of about 0. 1-50 mg/kg, preferably 1- 15 mg/kg, come into consideration for adults.
The prepartions can be administered in one dosage or several dosages. Capsules containing about 5-200 mg of active substance are a preferred administration form.
The preparations can contain inert or pharmacodynamically active additives. Tablets or granu lates e.g. can contain a series of binding agents, filler materials, carrier substances or diluents. 20 Liquid preparations can be present, for example, in the form of a sterile solution which is miscible with water. Capsules can contain a filler material or thicknening agent in addition to the active substance. Furthermore, flavourimproving additives as well as the substances usually used as preserving, stabilizing, moisture-retaining and emulsifying agents, salts for varying the osmotic pressure, buffers and other additives can also be present. 25 The previously mentioned carrier substances and diluents can be organic or inorganic sub stances, e.g. water, gelatine, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like. It is a prerequisite that all adjuvants used in the manufacture of the preparations are non-toxic.
For topical use the active substances are conveniently used in the form of salves, tinctures, 30 creams, solutions, lotions, sprays, suspensions and the like. Salves and creams as well as solutions are preferred. These preparations intended for topical use can be manufactured by mixing the compounds of formula 1 as active ingredients with non-toxic, inert, solid or liquid carriers which are usual in such preparations and which are suitable for topical treatment.
For topical use there are suitable conveniently about 0.1-5%, preferably 0.3-2%, solutions as 35 well as about 0.1-5%, preferably about 0.3-2%, salves or creams.
If desired, the pharmaceutical preparations can contain an antioxidant, e. g. tocopherol, N methyi-,-tocophera mine, butylated hydroxyanisole or butylated hydroxytoluene.
The following Examples illustrate the invention. The temperatures are given in degree Celsius.
40 Example 1
82.3 g of p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethy]-2naphthyi)propenyi]phenyI acetate are suspended in 2 1 of ethanol abnd a solution of 130 g of potassium hydroxide in 600 mi of water is added thereto. After stirring at room temperature for 1 hour the mixture is acidified with dilute hydrochloric acid while cooling with ice and extracted repeatedly with ethyl acetate. 45 The organic phase is washed four times with water, dried over sodium sulphate and evaporated.
The crystalline residue can be recrystallized from hexane/ethyl acetate and gives 66 g of p-[(E) 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethy]-2-napthyl)propenyllphenol, melting point 140-1420.
The starting material can be prepared as follows:
360 g of [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyi-2-naphthyi)ethylltriphenylphosph onium bro- 50 mide are suspended in 500 m[ of tetrahydrofuran and treated at 0' with 410 m[ of n-butyllithium (1.6 molar in hexane). After stirring at 0' for 1 hour a solution of 94.5 g of 4-acetoxy benzaldehyde in 300 mi of tetrahydrofuran is added thereto and the mixture is stirred at room temperature for a further 2 hours. The reaction mixture is subsequently poured into 2 1 of methanol/water (6:4) and extracted repeatedly with hexane. The organic phase is washed three 55 times with water and, after drying with sodium sulphate, evaporated. After filtration of the residue over silica gel (elution agent hexane/ethyl acetate=9:1) and crystallization from hexane there are obtained 83 9 of p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyi-2 -napthyi)propenyi]phenyl acetate in colourless crystals, melting point 114-116'.
60 Example 2
In analogy to Example 1, by the hydrolysis of m-[2-(5,6,7,8-tetrahydro-5, 5,8,8-tetramethy]-2- napthyi)propenyi]phenyl acetate there was manufactured m-[(E)-2-(5,6,7,8- tetrahydro-5,5,8,8-tetramethy]-2-naphthyi)propenyllphenol, melting point 91-930.
GB2190378A 5 Example 3
In analogy to Example 1, by the hydrolysis of o-[2-(5,6,7,8-tetrahydro-5, 5,8,8-tetramethyi-2- naphthyi)propenyllphenyl acetate there was manufactured o-[(E)-2-(5,6,7,8- tetrahydro-5,5,8,8-tet- ramethyl-2 -naphthyi)propenyi]phenol, melting point 97-990.
The manufacture of dosage forms containing the compounds of formula 1 can be effected on 5 the usual manner, e.g. on the basis of the following Examples.
Example A
Hard gelatine capsules can be manufactured as follows:
10 Ingredients mgIcapsule 1. Spray-dried powder containing 75% of compound 1 200 2. Sodium dioctyl sulphosuccinate 0.2 3. Sodium carboxymethylcellulose 4.8 4. Microcrystalline cellulose 86.0 15 5. Talc 8.0 6. Magnesium stearate 1.0 Total 300 20 The spray-dried powder, which is based on the active substance, gelatine and microcrystalline cellulose and which has an average particle size of the active substance of <111 (measured by means of autocorrelation spectroscopy), is moistened with an aqueous solution of sodium carboxymethylcellulose and sodium dioctyl sulphosuccinate and kneaded. The resulting mass is granulated, dried and sieved, and the granulate obtained is mixed with microcrystalline cellulose, 25 talc and magnesium stearate. The powder is filled into size 0 capsules.
Example B
Tablets can be manufactured as follows:
30 Ingredients: mgltablet 1. Compound 1 as a finely milled powder 500 2. Lactose powd. 100 3. Maize starch white 60 4. Povidone K30 8 35 5. Maize starch white 112 6. Talc 16 7. Magnesium stearate 4 Total 800 40 The finely milled substance is mixed with lactose and a portion of the maize starch. The mixture is moistened with an aqueous solution of Povidone K30 and kneaded, and the resulting mass is granulated, dried and sieved. The granulate is mixed with the remaining maize starch, talc and magnesium stearate and pressed to tablets of suitable size. 45 Example C
Soft gelatine capsules can be manufactured as follows:
Ingredients mglcapsule 50 1. Compound 1 50 2. Triglyceride 450 Total 500 55 g of compound 1 are dissolved in 90 g of medium-chain triglyceride with stirring, inert gasification and protection from light. This solution is processed as the capsule fill mass to soft gelatine capsules containing 50 mg of active substance.
Example D 60
A lotion can be manufactured as follows:
6 GB2190378A 6 Ingredients:
1. Compound 1, finely milled 3.0 g 2. Carbopol 934 0.6 9 3. Sodium hydroxide q.s. ad pH 6 5 4. Ethanol, 94% 50.0 g 5. Demineralized water ad 100.0 g The active substance is incorporated into the ethanol, 94%/water mixture under protection from light. Carbopol 934 is stirred in until gelling is complete and the pH valve is adjusted with 10 sodim hydroxide.

Claims (10)

  1. CLAIMS 1. Compounds of the general formula
    15 3' CH3 CH3 1 C err - R1 CX,'1 1 - 20 H3C CH 3 wherein R' represents o-, m- or p-hydroxyphenyl; 2,3, 2,4-, 2,5-, 2,6-, 3, 4- or 3,5-dihydroxy phenyl; or 2,3,4-, 2,3,5-, 2,4,5-, 2,4,6,- 3,4,5- or 2,3,6trihydroxyphenyi. 25
  2. 2. Compounds in accordance with claim 1, wherein the olefinic double bond has the trans configuration.
  3. 3. p-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyi-2naphthyi)propenyi]phenol.
  4. 4. m-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyi-2napthyl)prope'nyllphenol.
  5. 5. o-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyi-2naphthyi)propenyi]phenol. 30
  6. 6. Compounds of formula 1 for use as medicaments.
  7. 7. A process for the manufacture of compounds of general formula 1 in claim 1, which process comprises cleaving off the protecting group(s) from a compound of the general formula H3C CH3 CH 3 35 11 CH - R 40 H 3C CH3 wherein W' signifies a residue R' in which the hydroxy group(s) is/are protected.
  8. 8. Pharmaceutical preparations containing a compound of general formula i and a pharmaceu- 45 tical carrier.
  9. 9. The use of a compound of general formula 1 for the manufacture of pharmaceutical preparations for the treatment of neoplasms and dermatoses.
  10. 10. The novel compounds, preparations and process as described hereinbefore.
    Printed for Her Majesty's Stationery Office by Burgess & Son (Abingdon) Ltd, Dd 8991685. 1987.
    Published at The Patent Office, 25 Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.
GB8711205A 1986-05-13 1987-05-12 Tetrahydronophthalene derivatives and anti-cancerous compositions containing them Expired - Fee Related GB2190378B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH1938/86A CH668962A5 (en) 1986-05-13 1986-05-13 New hydroxy:phenyl:propenyl substd. naphthalene cpds.
CH74287 1987-02-26

Publications (3)

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GB8711205D0 GB8711205D0 (en) 1987-06-17
GB2190378A true GB2190378A (en) 1987-11-18
GB2190378B GB2190378B (en) 1990-11-14

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GB8711205A Expired - Fee Related GB2190378B (en) 1986-05-13 1987-05-12 Tetrahydronophthalene derivatives and anti-cancerous compositions containing them

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CN (1) CN87103524A (en)
AU (1) AU7277987A (en)
BE (1) BE1001668A5 (en)
DE (1) DE3715809A1 (en)
DK (1) DK232087A (en)
ES (1) ES2005572A6 (en)
FI (1) FI872027A (en)
FR (1) FR2598706B1 (en)
GB (1) GB2190378B (en)
HU (1) HU198002B (en)
IL (1) IL82448A0 (en)
IT (1) IT1203954B (en)
LU (1) LU86866A1 (en)
MC (1) MC1817A1 (en)
NL (1) NL8701101A (en)
NO (1) NO871961L (en)
NZ (1) NZ220215A (en)
PT (1) PT84860B (en)
SE (1) SE8701933L (en)
ZW (1) ZW6587A1 (en)

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US5324840A (en) * 1992-06-11 1994-06-28 Allergan, Inc. Method of treatment with compounds having retinoid-like activity and reduced skin toxicity and lacking teratogenic effects
US5455265A (en) * 1993-02-11 1995-10-03 Allergan, Inc. Method of treatment with compounds having selective agonist-like activity on RXR retinoid receptors
US5489584A (en) * 1994-12-29 1996-02-06 Allergan, Inc. Acetylenes disubstituted with a 5-amino or substituted 5-amino substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US5498755A (en) * 1994-08-23 1996-03-12 Chandraratna; Roshantha A. Disubstituted aryl and heteroaryl imines having retinoid-like biological activity
US5514825A (en) * 1994-12-29 1996-05-07 Allergan, Inc. Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US5516904A (en) * 1989-12-29 1996-05-14 Allergan, Inc. Acetylenes disubstituted with a heteroaromatic group and a substituted phenyl group having retinoid like activity
US5534516A (en) * 1989-09-19 1996-07-09 Allergan Acetylenes disubstituted with a heteroaromatic group and a 2-substituted chromanyl, thiochromanyl or 1, 2, 3, 4-tetrahydroquinolinyl group having retinoid-like activity
US5534261A (en) * 1995-01-17 1996-07-09 University Of Southern California Retinoid-based compositions and method for preventing adhesion formation using the same
US5543534A (en) * 1994-12-29 1996-08-06 Allergan Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity
US5556996A (en) * 1994-12-29 1996-09-17 Allergan Oxiranyls disubstituted with a phenyl group and a substituted chromanyl or tetrahydroquinolinyl group having retinoid like activity
US5599967A (en) * 1994-12-29 1997-02-04 Allergan Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl of heteroaryl group having retinoid-like biological activity
US5602135A (en) * 1993-10-18 1997-02-11 Allergan Phenyl or heteroaryl and tetrahydronaphthyl substituted diene compounds having retinoid like biological activity
US5602130A (en) * 1987-03-20 1997-02-11 Allergan Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity
US5616712A (en) * 1995-05-16 1997-04-01 Allergan Acetylenes disubstituted with a phenyl or heteroaryl group and a 2-thio-1,2,3,4-tetrahdroquinolinyl, 2-alkylthio-3,4-dihydroquinolinyl or 2-alkoxy-3,4-dihydroquinolinyl group having retinoid-like biological activity
US5618943A (en) * 1994-12-29 1997-04-08 Allergan Acetylenes disubstituted with a 5 OXO substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US5618836A (en) * 1993-12-30 1997-04-08 Allergan [4-(1,2-epoxycyclohexanyl)but-3-en-1-ynyl]aromatic and heteroaromatic acids and derivatives having retinoid-like biological activity
US5618931A (en) * 1994-12-29 1997-04-08 Allergan Acetylenes disubstituted with a 5 substituted dihydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US5663367A (en) * 1995-06-06 1997-09-02 Allergan 2,4-pentadienoic acid derivatives having retinoid-like biological activity
US5663357A (en) * 1995-11-22 1997-09-02 Allergan Substituted heteroarylamides having retinoid-like biological activity
US5663347A (en) * 1987-03-20 1997-09-02 Allergan Disubstituted acetylenes bearing heterobicyclic groups and heteroaromatic or phenyl groups having retinoid like activity
US5672710A (en) * 1995-11-03 1997-09-30 Allergan Sulfides, sulfoxides and sulfones disubstituted with a tetrahydronaphthalenyl, chromanyl, thiochromanyl or tetrahydroquinolinyl and substituted phenyl or heteroaryl group, having retinoid-like biological activity
US5675024A (en) * 1995-11-22 1997-10-07 Allergan Aryl or heteroaryl amides of tetrahydronaphthalene, chroman, thiochroman and 1,2,3,4,-tetrahydroquinoline carboxylic acids, having an electron withdrawing substituent in the aromatic or heteroaromatic moiety, having retinoid-like biological activity
US5677323A (en) * 1989-09-19 1997-10-14 Allergan Acetylenes disubstituted with a heteroaromatic group and a 2-substituted chromanyl, thiochromanyl or 1, 2, 3, 4, -tetrahydroquinolinyl group having retinoid-like activity
US5688957A (en) * 1995-12-29 1997-11-18 Allergan (3"-thioxacyclohex-1"-enyl)!-but-3'-ene-1'-ynyl!aryl and (3"-thioxacyclohex-1"-enyl)!-but-3'-ene-1'-ynyl!heteroaryl carboxylic acids and esters having retinoid-like biological activity
US5698700A (en) * 1994-12-29 1997-12-16 Allergan Acetylenes disubstituted with 2-tetrahydropyranoxyaryl and aryl or heteroaryl groups having retinoid-like biological activity
US5723666A (en) * 1996-06-21 1998-03-03 Allergan Oxime substituted tetrahydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity
US5739338A (en) * 1996-11-05 1998-04-14 Allergan N-aryl substituted tetrahydroquinolines having retinoid agonist, retinoid antagonist or retinoid inverse agonist type biological activity
US5741896A (en) * 1996-06-21 1998-04-21 Allergan O- or S- substituted tetrahydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity
US5747542A (en) * 1996-06-21 1998-05-05 Allergan Oxo-substituted tetrahydronaphthalene derivatives having retinold and/or retinoid antagonist-like biological activity
US5763635A (en) * 1996-06-21 1998-06-09 Allergan Tetrahydronaphthalene derivatives substituted in the 8 position with alkyhidene groups having retinoid and/or retinoid antagonist-like biological activity
US5808124A (en) * 1996-06-21 1998-09-15 Allergan O- or S-substituted dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity
US6025388A (en) * 1995-04-26 2000-02-15 Allergan Sales, Inc. Method for inhibiting gene expression promoted by AP1 protein with RARβ selective retinoids and method for treatment of diseases and conditions with such retinoids
US6172115B1 (en) 1993-02-11 2001-01-09 Allergan Sales, Inc. Method for preventing onset of restenosis after angioplasty employing an RXR-specific retinoid
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US5591858A (en) * 1994-12-29 1997-01-07 Allergan Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US5618943A (en) * 1994-12-29 1997-04-08 Allergan Acetylenes disubstituted with a 5 OXO substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US5543534A (en) * 1994-12-29 1996-08-06 Allergan Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity
US5489584A (en) * 1994-12-29 1996-02-06 Allergan, Inc. Acetylenes disubstituted with a 5-amino or substituted 5-amino substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US5723620A (en) * 1994-12-29 1998-03-03 Allergan Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity
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US5514825A (en) * 1994-12-29 1996-05-07 Allergan, Inc. Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US5534261A (en) * 1995-01-17 1996-07-09 University Of Southern California Retinoid-based compositions and method for preventing adhesion formation using the same
US6025388A (en) * 1995-04-26 2000-02-15 Allergan Sales, Inc. Method for inhibiting gene expression promoted by AP1 protein with RARβ selective retinoids and method for treatment of diseases and conditions with such retinoids
US6369100B1 (en) 1995-04-26 2002-04-09 Allergan Sales, Inc. Method for inhibiting gene expression promoted by AP1 protein with RARβ selective retinoids and method for treatment of diseases and conditions with such retinoids
US5616712A (en) * 1995-05-16 1997-04-01 Allergan Acetylenes disubstituted with a phenyl or heteroaryl group and a 2-thio-1,2,3,4-tetrahdroquinolinyl, 2-alkylthio-3,4-dihydroquinolinyl or 2-alkoxy-3,4-dihydroquinolinyl group having retinoid-like biological activity
US5675033A (en) * 1995-06-06 1997-10-07 Allergan 2,4-pentadienoic acid derivatives having retinoid-like biological activity
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US5672710A (en) * 1995-11-03 1997-09-30 Allergan Sulfides, sulfoxides and sulfones disubstituted with a tetrahydronaphthalenyl, chromanyl, thiochromanyl or tetrahydroquinolinyl and substituted phenyl or heteroaryl group, having retinoid-like biological activity
US5663357A (en) * 1995-11-22 1997-09-02 Allergan Substituted heteroarylamides having retinoid-like biological activity
US5675024A (en) * 1995-11-22 1997-10-07 Allergan Aryl or heteroaryl amides of tetrahydronaphthalene, chroman, thiochroman and 1,2,3,4,-tetrahydroquinoline carboxylic acids, having an electron withdrawing substituent in the aromatic or heteroaromatic moiety, having retinoid-like biological activity
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US5747542A (en) * 1996-06-21 1998-05-05 Allergan Oxo-substituted tetrahydronaphthalene derivatives having retinold and/or retinoid antagonist-like biological activity
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GB8711205D0 (en) 1987-06-17
IT1203954B (en) 1989-02-23
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FI872027A (en) 1987-11-14
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IL82448A0 (en) 1987-11-30
ZW6587A1 (en) 1987-12-02
FR2598706A1 (en) 1987-11-20
IT8720232A0 (en) 1987-04-23
NZ220215A (en) 1990-06-26
HUT43806A (en) 1987-12-28
GB2190378B (en) 1990-11-14
HU198002B (en) 1989-07-28
SE8701933L (en) 1987-11-14
PT84860B (en) 1990-02-08
LU86866A1 (en) 1988-06-13
MC1817A1 (en) 1988-03-18
AU7277987A (en) 1987-11-19
FR2598706B1 (en) 1990-07-06
NO871961D0 (en) 1987-05-12
NO871961L (en) 1987-11-16
DK232087D0 (en) 1987-05-06
DK232087A (en) 1987-11-14
CN87103524A (en) 1987-12-02
BE1001668A5 (en) 1990-02-06
NL8701101A (en) 1987-12-01
ES2005572A6 (en) 1989-03-16
PT84860A (en) 1987-06-01
DE3715809A1 (en) 1987-11-19

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