PT84860B - METHOD FOR PREPARING NEW TETRAHYDROFOLANTALEN DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents
METHOD FOR PREPARING NEW TETRAHYDROFOLANTALEN DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM Download PDFInfo
- Publication number
- PT84860B PT84860B PT84860A PT8486087A PT84860B PT 84860 B PT84860 B PT 84860B PT 84860 A PT84860 A PT 84860A PT 8486087 A PT8486087 A PT 8486087A PT 84860 B PT84860 B PT 84860B
- Authority
- PT
- Portugal
- Prior art keywords
- general formula
- compounds
- compound
- preparation
- tetrahydro
- Prior art date
Links
Classifications
-
- 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
Landscapes
- 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
A presente invenção diz respeito a novos derivados do tetrahidronaftaleno de fórmula geralThe present invention relates to new tetrahydronaphthalene derivatives of the general formula
na qual, o símbolo R^ representa um grupo o-, m- ou ja-hidro xifenilo; 2,3-, 2,4-, 2,5-, 2,6-, 3,4- ou 3,5-dihi droxifenilo; ou 2,3,4-, 2,3,5-, 2,4,5-, 2,4,6-,in which, R4 represents an o-, m- or ja-hydroxyphenyl group; 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl; or 2,3,4-, 2,3,5-, 2,4,5-, 2,4,6-,
3,4,5- ou 2,3,6-trihidroxifenilo.3,4,5- or 2,3,6-trihydroxyphenyl.
Os compostos de fórmula geral (l) podem existir sob a forma de isómeros trans ou cis ou sob a forma de misturas de isómeros trans/cis. Em geral, preferem-se os compostos trans de fórmula geral (i), além daqueles nos quais o símbolo R^ representa um grupo _o-, m- ou p-hidroxifenilo, especialmente p-hidroxifeniloThe compounds of the general formula (1) can exist in the form of trans or cis isomers or in the form of mixtures of trans / cis isomers. In general, trans compounds of the general formula (i) are preferred, in addition to those in which R4 represents a _o-, m- or p-hydroxyphenyl group, especially p-hydroxyphenyl
A presente invenção diz respeito, também, a um processo de preparação dos compostos de fórmula geral (i), composições farmacêuticas que contêm os compostos de fórmula geral (i), a compostos de fórmula geral (i) utilizados no tratamento e profilaxia de neoplasmas e dermatoses, assim como à utilização de compostos de fórmula geral (i) para a preparação de composições farmacêuticas para o tratamento e profilaxia de aquelas situações.The present invention also relates to a process for preparing compounds of general formula (i), pharmaceutical compositions containing compounds of general formula (i), compounds of general formula (i) used in the treatment and prophylaxis of neoplasms and dermatoses, as well as the use of compounds of general formula (i) for the preparation of pharmaceutical compositions for the treatment and prophylaxis of those situations.
Os compostos de fórmula geral (i) podem preparar-se, de acordo com a presente invenção, mediante a eli minação do(s) grupo(s) protector(es), a partir de um composto de fórmula geraisThe compounds of general formula (i) can be prepared, according to the present invention, by eliminating the protecting group (s), from a compound of general formula
II na qual, o símbolo R^^ representa um grupo R^, definidoII in which, the symbol R ^^ represents a group R ^, defined
xi. São exemplos de tais grupos protectores: éteres, especialmente o éter 2-tetra-hidropiranílico e éteres silílicos, tais como, o éter trimetilsilílico; além disso, éteres alquílicos,xi. Examples of such protecting groups are: ethers, especially 2-tetrahydropyranyl ether and silyl ethers, such as trimethylsilyl ether; in addition, alkyl ethers,
tais como, o éter metílico; e ésteres, por exemplo, ésteres de ácidos alcanocarboxilicos inferiores, tais como, acetatos e carbonatos. A eliminação dos grupos protectores pode efectuar-se de modo conhecido per se, por meio de reacção com ácidos, bases ou agentes redutores. Os grupos protectores et£ ricos, tais como, tetrahidropiranilo e trimetilsililo, podem ser eliminados por meio de reacção com ácidos, tais como, áci do £-tolueno-sulfónico ou ácidos de Lewis, tais como, BF^ BBr^. Os grupos protectores de éster, tais como, acetatos > carbonatos, eliminam-se por meio de reacção com bases, por ou ou exemplo, solução alcoólica ou aquosa de uma solução alcoólica de hidróxido de um metal alcalinosuch as, methyl ether; and esters, for example, esters of lower alkanecarboxylic acids, such as acetates and carbonates. The elimination of protecting groups can be carried out in a manner known per se, by reaction with acids, bases or reducing agents. Ethyl protecting groups, such as tetrahydropyranyl and trimethylsilyl, can be eliminated by reacting with acids, such as t-toluenesulfonic acid or Lewis acids, such as BF-BBr. Ester protecting groups, such as acetates> carbonates, are removed by reaction with bases, by or for example, alcoholic or aqueous solution of an alcoholic solution of an alkali metal hydroxide
Os compostos de fórmula geral (ll) podem obter-se por meio da reacção de um composto de fórmula geral:The compounds of general formula (ll) can be obtained by reacting a compound of general formula:
com um compostowith a compound
IIIIII
B-R (IV) nas quais, ou o símbolo A representa um resíduo -CH(CH^)p+(q)^Y“ ou -CH(CH^)p(o)(0Alk)2 e o símbolo B representa um grupo formilo, ou o símbolo A representa um grupo acetilo e o símbolo B reBR (IV) in which either the symbol A represents a residue -CH (CH ^) p + (q) ^ Y “or -CH (CH ^) p (o) (0Alk) 2 and the symbol B represents a group formyl, or the symbol A represents an acetyl group and the symbol B re
presentapresent
-CH2P(0)(0Alk)2; e o símbolo Q representa um grupo arilo, especialmente nilo, o símbolo Y representa o anião de um ácido orgânico ou inorgânico, por exemplo, Br” e o símbolo Alk re presenta um grupo alquilo inferior, por exemplo, metilo, e o símbolo R^^ tem o significado definido antes.-CH 2 P (0) (0Alk) 2 ; and the symbol Q represents an aryl group, especially nile, the symbol Y represents the anion of an organic or inorganic acid, for example, Br ”and the symbol Alk represents a lower alkyl group, for example, methyl, and the symbol R ^^ has the meaning defined before.
A reacção dos compostos de fórmula geral (ill) e de fórmula geral (IV) pode efectuar-se de acordo com os métodos conhecidos da reacção de Wittig ou da reacção de Horner. No caso da reacção de Wittig, isto é, com a utilização de um composto de fórmula geral (ill) na qual o símbolo A representa um resíduo» de fórmula geral -CH(CH^)p+(q)^Y” ou de um composto de fórmula geral (iv) em que o símbolo B represenra um resíduo de fórmula geral -CH2P+(q)^Y”, os componentes reagem um com o outro, na presença de um agente de fixação áci do, por exemplo, na presença de uma base forte, tal como, por exemplo, butil-lítio, hidreto de sódio ou o sal de sódio de di. metilsulfóxido, mas especialmente na presença de um óxido de etileno eventualmente substituído por um grupo alquilo inferior, tal como, óxido de 1,2-butileno, eventualmente no seio de um dissolvente, por exemplo, um éter tal como éter dietxlico ou tetrahidrofurano ou um hidrocarboneto aromático, tal como, benzeno, a uma temperatura compreendida entre a temperatura ambiente e o ponto de ebulição da mistura reaccional.The reaction of the compounds of general formula (ill) and of general formula (IV) can be carried out according to the known methods of the Wittig reaction or the Horner reaction. In the case of the Wittig reaction, that is, with the use of a compound of the general formula (ill) in which the symbol A represents a residue »of the general formula -CH (CH ^) p + (q) ^ Y” or a compound of general formula (iv) in which the symbol B represents a residue of general formula -CH 2 P + (q) ^ Y ”, the components react with each other in the presence of an acidic fixing agent, for example example, in the presence of a strong base, such as, for example, butyl lithium, sodium hydride or the sodium salt of di. methyl sulfoxide, but especially in the presence of an ethylene oxide optionally substituted by a lower alkyl group, such as 1,2-butylene oxide, possibly in a solvent, for example, an ether such as diethyl ether or tetrahydrofuran or a aromatic hydrocarbon, such as benzene, at a temperature between room temperature and the boiling point of the reaction mixture.
Dos iães ácidos inorgânicos Y“, são pref£ ridos; o ião cloreto, o ião bromo ou o ião hidrogenossulfato e dos -ides ácidos orgânicos, prefere-se o ião tosiloxi. 0 gru-Of the inorganic acid ions Y “, are preferred; the chloride ion, the bromine ion or the hydrogen sulphate ion and the organic acid acids, the tosyloxy ion is preferred. 0 group
po arilo Q ó, de preferência, um grupo fenilo ou um grupo fenilo substituído, tal como, £-tolilo.po aryl Q is preferably a phenyl group or a substituted phenyl group, such as, t-tolyl.
No caso da reacção de Horner, isto é, com a utilização de um composto de fórmula geral (ill) na qual o símbolo A representa um resíduo de fórmula geral -CH(CH3)-P(o) (OAlk)^ ou de um composto de fórmula geral (iv) em que o símbolo B representa um resíduo de fórmula geral -CH^PÍO)(OAlk), condensam-se os componentes com a ajuda de uma base e, de preferência, na presença de um dissolvente orgânico inerte, por exemplo, com o auxílio de hidreto de sódio em benzeno, tolueno, dimetilformamida, tetrahidrofurano, dioxano ou 1,2-dimetoxietano, ou também com o auxílio de um alcoolato de sódio no seio de um alcanol, por exemplo, metilato de sódio em metanol, a uma temperatura compreendida entre 0° e o ponto de ebulição da mistura reaccional.In the case of the Horner reaction, that is, with the use of a compound of the general formula (ill) in which the symbol A represents a residue of the general formula -CH (CH 3 ) -P (o) (OAlk) ^ or a compound of the general formula (iv) in which the symbol B represents a residue of the general formula -CH ^ PÍO) (OAlk), the components are condensed with the help of a base and, preferably, in the presence of an organic solvent inert, for example, with the aid of sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane or 1,2-dimethoxyethane, or also with the aid of sodium alcoholate in an alkanol, for example, methylate sodium in methanol, at a temperature between 0 ° and the boiling point of the reaction mixture.
Os grupos alcóxi OAlk são, especialmente, os grupos alcóxi inferiores com 1 a 6 átomos de carbono, tal como, o grupo metoxi ou etoxi.The alkoxy groups OAlk are, in particular, the lower alkoxy groups having 1 to 6 carbon atoms, such as the methoxy or ethoxy group.
Os compostos de fórmula geral (i) podem exisI tir sob as formas trans ou cis. Na presente invenção, obtem-se principalmente, sob a forma trans. Os componentes cis que se pc> dem obter, podem eventualmente separar-se, por um processo conhecido per se.The compounds of general formula (i) can exist in trans or cis forms. In the present invention, they are obtained mainly in trans form. The cis components that can be obtained may eventually separate, by a process known per se.
Os compostos iniciais de fórmulas gerais (ill) e (iv), cuja preparação não seja conhecida ou não se descreva a seguir, podem ser preparados por analogia, mediante processos conhecidos ou processos descritos a seguir.The initial compounds of general formulas (ill) and (iv), the preparation of which is not known or is not described below, can be prepared by analogy, by means of known processes or processes described below.
Os compostos de fórmula geral (i) possuem actividade terapêutica. Em particular, possuem actividade anti-seborreica, antiqueratinizante, antineoplásicaThe compounds of general formula (i) have therapeutic activity. In particular, they have anti-seborrheic, anti-keratinizing, antineoplastic activity
- 6 e antialérgica/anti-inflamatória, o que se pode demonstrar utjL lizando processos experimentais, descritos a seguir:- 6 and anti-allergic / anti-inflammatory, which can be demonstrated using experimental processes, described below:
A) a actividade na prevenção de tumores da mama, induzidos qui micamente, pode determinar-se de acordo com o processo seguinte: conservam-se ratos fêmea, Sprague-Dawley, sob condições de temperatura e luz controladas, com acesso livre a água e alimentos. Com a idade de 50 dias, administra-se 15 mg de dimetij. benz(a)antraceno, dissolvidos em óleo de amendoim, a cada rato por intermédio de uma sonda. 0 tratamento com os compostos do ensaio começa 1 dia após a administração do carcinogéneo. Regista-se os pesos corporais dos animais do ensaio e apalpam-se os tumores, semanalmente, e mede-se com uma craveira. Calcula-se os volumes de acordo com a fórmula: D.d , na qual, o sim bolo D representa o maior diâmetro do elipsóide tumoral e o símbolo d representa o menor diâmetro do elipsóide tumoral. Após 11 semanas, termina o ensaio e avalia-se. Neste ensaio utiliza-se, além de 30 animais de controlo, que recebem exclusivamente alimentação normal, os dois grupos seguintes de animais de ensaio:A) the activity in the prevention of chemically induced breast tumors can be determined according to the following procedure: female rats, Sprague-Dawley, are kept under controlled temperature and light conditions, with free access to water and foods. At the age of 50 days, 15 mg of dimetij is administered. benz (a) anthracene, dissolved in peanut oil, to each rat by means of a probe. Treatment with test compounds begins 1 day after administration of the carcinogen. The body weights of the animals in the trial are recorded and the tumors are palpated weekly and measured with a caliper. The volumes are calculated according to the formula: D.d, in which, the simile D represents the largest diameter of the tumor ellipsoid and the symbol d represents the smallest diameter of the tumor ellipsoid. After 11 weeks, the trial ends and is evaluated. In this test, in addition to 30 control animals, which receive exclusively normal food, the following two groups of test animals are used:
1. 33 ratos, aos quais se administra diariamente 30 mg/kg do composto a ensaiar, misturados com os alimentos.1. 33 rats, which are administered 30 mg / kg of the compound to be tested daily, mixed with food.
2. 36 ratos, aos quais se administra diariamente 90 mg/kg do composto a ensaiar, misturados com os alimentos.2. 36 rats, which are administered 90 mg / kg of the compound to be tested daily, mixed with food.
B) além do exposto antes, pode determinar-se a actividade anti-tumoral no condrosarcoma transplantavel do rato, de acordo com o método seguinte. Corta-se finamente o tumor sólido de um animal dador e suspende-se em um tampão de fosfato/solução f w de cloreto de sódio. Implanta-se 0,5 ml da suspensão tumoral a 30%, por via subcutânea, em ratos albinos. Reparte-se os ra tos transplantados por grupos de ensaio, de 8 animais cada um. Suspende-se os compostos do ensaio em óleo de amendoim e administra-se, por via oral, cinco vezes por semana, durante 24 dias. Faz-se a excisão dos tumores e pesa-se no 24? dia. Os re sultados expressam-se no quociente C/T que se calcula do seguin te modo:B) in addition to the above, anti-tumor activity in the rat's transplantable chondrosarcoma can be determined according to the following method. The solid tumor of a donor animal is finely cut and suspended in a phosphate buffer / sodium chloride solution (w). 0.5 ml of the 30% tumor suspension is implanted subcutaneously in albino rats. The transplanted mice are divided into test groups of 8 animals each. Test compounds are suspended in peanut oil and administered orally five times a week for 24 days. Are tumors excised and weighed at 24? day. The results are expressed in the C / T quotient that is calculated as follows:
C/T = Peso médio do tumor de controlo .C / T = Average weight of the control tumor.
Peso médio do tumor tratadoAverage weight of the treated tumor
C) Também se pode determinar a actividade anti-metaplásica em ratos, de acordo com o método seguinte. Ratos fêmea Holtzmann pesando aproximadamente, 100 g cada um, são, ovariectomizados, sob narcose de Thiogenal, após um período de adaptação de 8 dias e são utilizados no ensaio, após 14 dias adicionais. Em cada caso, coloca-se dois animais em uma jaula com acesso livre a alimentos que contêm aproximadamente, 2000 UJ. de vitami na A, determinadas analiticamente. Antes da administração oral do composto do ensaio, trata-se os animais, por via subcutânea, cada dia, durante 6 dias sucessivos com 1 /ig de benzoato de estradiol e 250 jpg de propionato de testosterona, dissolvidos em 0,1 ml de óleo de sésamo. A administração parentérica da hormona conduz à formação de uma nítida fase granular da secreção vaginal, isto é, uma metaplasia escamosa. Dois (2) dias após a administração oral do composto do ensaio, verifica-se novamente o resultado da reacção no epitélio vaginal. Utiliza-se o método da área, de acordo com Behrens e Karber, para calcular a média das doses eficazes.C) The anti-metaplastic activity in rats can also be determined according to the following method. Female Holtzmann rats weighing approximately 100 g each are ovariectomized, under Thiogenal narcosis, after an adaptation period of 8 days and are used in the trial after an additional 14 days. In each case, two animals are placed in a cage with free access to food containing approximately 2000 UJ. of vitami in A, determined analytically. Before oral administration of the test compound, the animals are treated subcutaneously each day for 6 successive days with 1 µg of estradiol benzoate and 250 jpg of testosterone propionate, dissolved in 0.1 ml of oil of sesame. Parenteral administration of the hormone leads to the formation of a clear granular phase of vaginal secretion, that is, a scaly metaplasia. Two (2) days after the oral administration of the test compound, the result of the reaction in the vaginal epithelium is checked again. The area method, according to Behrens and Karber, is used to average the effective doses.
- 8 7- 8 7
Os resultados do ensaio A-C com um composto de fórmula geral I, £-/”(E)-2-(5,6,7,8-tetrahidro-5,5,8,8-tetrametil-2-naftil)propenil7fenol, estão apresentados nos QuadrosThe results of the AC test with a compound of the general formula I, £ - / ”(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl7phenol, are presented in the Tables
I-III seguintes.Following I-III.
Quadro ITable I
A)THE)
Profilaxia dos tumores da mama induzidos quimicamente.Prophylaxis of chemically induced breast tumors.
Quadro IITable II
B)B)
Actividade do condrosarcoma transplantável do rato.Transplantable chondrosarcoma activity of the rat.
- 9 Quadro III- 9 Table III
C) Actividade anti-metaplásica no ratoC) Anti-metaplastic activity in the rat
Os compostos de fórmula geral (i) podem utilizar-se na terapia sistémica e tópica dos tumores benignos e malignos, das lesões pré-malignas e também, na profilaxia sistémica e tópica das citadas situações.The compounds of general formula (i) can be used in the systemic and topical therapy of benign and malignant tumors, pre-malignant lesions and also, in the systemic and topical prophylaxis of the aforementioned situations.
Além disso, são eficazes na terapia sistémica e tópica do acne, psoríase e outras dermatoses que são acompanhadas de uma cornificação aumentada ou alterada patologi camente, assim como, de estados dermatológicos alérgicos e inflamatórios, Também os compostos de fórmula geral (i) podem uti_ lizar-se no controlo das perturbações da membrana mucosa com al^ terações metaplásicas, degenerativas ou inflamatórias. Os compostos de fórmula geral (i) caracterizam-se, em particular, por uma baixa toxicidade ou uma tolerância aumentada em comparação com os retinóides conhecidos.In addition, they are effective in the systemic and topical therapy of acne, psoriasis and other dermatoses that are accompanied by an increased or pathologically altered cornification, as well as allergic and inflammatory dermatological conditions. Also the compounds of general formula (i) can be used to control mucosal membrane disorders with metaplastic, degenerative or inflammatory changes. The compounds of general formula (i) are characterized, in particular, by a low toxicity or an increased tolerance in comparison with the known retinoids.
As composições farmacêuticas podem admini£ trar-se por via entérica, parentérica ou tópica. Para a administração entérica são apropriadas, por exemplo, composições sob a forma de comprimidos, cápsulas, drageias, xaropes, suspensões,S£ luções e supositórios. As composições sob a forma de infusão ou soluções injectáveis são apropriadas para a administração parentericaThe pharmaceutical compositions can be administered enterally, parenterally or topically. For enteral administration, compositions in the form of tablets, capsules, dragees, syrups, suspensions, solutions and suppositories are suitable, for example. Compositions in the form of infusion or solutions for injection are suitable for parenteral administration
As doses a administrar podem variar de acordo com o modo de utilização e via de utilização, assim como de acordo com as necessidades dos doentes. Em geral, considera-se para os adultos, doses diárias de cerca de 0,1-5θ mg/ /kg, de preferência, 1-15 mg/kg.The doses to be administered may vary according to the method of use and route of use, as well as according to the needs of patients. In general, daily doses of about 0.1-5θ mg / kg are preferred for adults, preferably 1-15 mg / kg.
As composições podem administrar-se em uma dose única ou em várias doses. Cápsulas contendo cerca deThe compositions can be administered in a single dose or in several doses. Capsules containing about
5-200 mg de ingrediente activo constituem uma forma preferida de administração.5-200 mg of active ingredient is a preferred form of administration.
As composições podem conter aditivos iner tes ou activos, sob o ponto de vista farmacodinâmico. Os comprimidos ou os granulados, por exemplo, podem conter uma série de agentes de ligação, materiais de enchimento, substâncias veiculares ou dissolventes. As composições líquidas podem apre sentar-se, por exemplo, sob a forma de uma solução esterilizada que seja misoível com a água. As cápsulas podem conter um produto de enchimento ou um agente espessador, adicionados ao ingrediente activo. Além disso, também podem estar presentes aditivos bem como substâncias normalmente utilizadas como cor rectivos do sabor, agentes conservantes, estabilizantes, fixa dores da humidade, emulsionantes, conservantes, sais para variar a pressão osmótica, tampões e outros aditivos.The compositions can contain inert or active additives, from a pharmacodynamic point of view. Tablets or granules, for example, can contain a number of binding agents, fillers, carrier substances or solvents. Liquid compositions can be presented, for example, in the form of a sterile solution that is miscible with water. The capsules can contain a filler or a thickening agent, added to the active ingredient. In addition, additives may also be present, as well as substances commonly used as flavor corrective agents, preservatives, stabilizers, moisture fixers, emulsifiers, preservatives, salts for varying osmotic pressure, buffers and other additives.
As substâncias veiculares e os dissolven tes, mencionados antes, podem ser substâncias orgânicas ou inorgânicas, por exemplo, água, gelatina, lactose, amido, estearato de magnésio, talco, goma arábica, polialquilenoglicóis e similares. E um pré-requisito que todos os adjuvantes utilizados na preparação das composições não sejam tóxicos.The carrier substances and solvents mentioned above may be organic or inorganic substances, for example, water, gelatin, lactose, starch, magnesium stearate, talc, arabic gum, polyalkylene glycols and the like. It is a prerequisite that all adjuvants used in the preparation of the compositions are non-toxic.
Para utilização tópica, as substancias a_cFor topical use, substances a_c
( .* tivas utilizam-se convenientemente, sob a forma de pomadas, tinturas, cremes, soluções, loções, sprays, suspensões e si milares. Prefere-se as pomadas <e os cremes, assim como as soluções. Estas composições com finalidade para uso tópico podem preparar-se mediante a mistura de compostos de fórmula geral (i), como ingredientes activos, com substâncias veiculares só lidas ou líquidas, inertes e não tóxicos, que são habituais em tais preparações e que são apropriados para tratamento tópico. Para utilização tópica, existem soluções convenientemente apro priadas, de cerca de 0,1-5/, de preferência de 0,3-2/, assim como pomadas ou cremes a cerca de 0,1-5/, de preferência a cer ca de 0,3-2/.(. * tivas are conveniently used in the form of ointments, tinctures, creams, solutions, lotions, sprays, suspensions and similars. Ointments <and creams are preferred, as well as solutions. These compositions are intended for topical use can be prepared by mixing compounds of the general formula (i), as active ingredients, with solid or liquid, inert and non-toxic carrier substances, which are common in such preparations and which are suitable for topical treatment. topical use, there are conveniently suitable solutions, from about 0.1-5 /, preferably from 0.3-2 /, as well as ointments or creams at about 0.1-5 /, preferably around 0.3-2 /.
Eventualmente, as composições farmacêuticas podem conter um agente anti-oxidante, por exemplo, tocoferol, N-metil-r-tocoferamina, hidroxianisol butilado ou hidroxi tolueno butilado.Optionally, the pharmaceutical compositions may contain an anti-oxidant agent, for example, tocopherol, N-methyl-r-tocopheramine, butylated hydroxyanisole or butylated hydroxy toluene.
Os exemplos seguintes ilustram a presente invenção. As temperaturas são expressas em graus Celsius,The following examples illustrate the present invention. Temperatures are expressed in degrees Celsius,
Exemplo 1Example 1
Faz-se uma suspensão de 82,3 g de acetato de £-/ 2-(5,6,7,8-tetrahidro-5,5,8,8-tetrametil-2-naftil)propenil/fenilo em 2 litros de etanol e adiciona-se uma solução de 130 g de hidróxido de potássio em 600 ml de água. Após agitação à temperatura ambiente, durante 1 hora, acidifica-se a mistura com ácido clorídrico diluído, enquanto se arrefece com gelo e extrai-se, repetidamente, com acetato de etilo. Lava-se a fase orgânica, quatro vezes, com água, seca-se sobre sulfato de sódio e evapora-se. 0 resíduo cristalino obtido po12 de recristalizar-se com hexano/acetato de etilo e origina 66 g de (e)-2-(5,6,7,8-tetrahidro-5,5,8,8-tetrametil-2-naftil)-propenil7-fenol; ponto de fusão: 14O°-142°C.82.3 g of £ - / 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl / phenyl are suspended in 2 liters of ethanol and a solution of 130 g of potassium hydroxide in 600 ml of water is added. 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. Wash the organic phase four times with water, dry over sodium sulphate and evaporate. The crystalline residue obtained by recrystallizing from hexane / ethyl acetate gives 66 g of (e) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ) -propenyl7-phenol; melting point: 140 ° -142 ° C.
composto inicial pode preparar-se do seguinte modo:starting compound can be prepared as follows:
Faz-se uma suspensão de 360 g de brometo de / 1-(5,6,7j 8-tetrahidro-5,5,8,8-tetrametil-2-naftil)-etil^-tri. fenilfosfónio em 5θ0 ml de tetrahidrofurano e faz-se reagir, à temperatura de 0°C., com 410 ml de n-butil-lítio (1,6 molar em hexano). Após agitação à temperatura de 0°C,, durante 1 ho ra, adiciona-se uma solução de 94,5 S de 4-acetoxi-benzaldeído em 300 ml de tetrahidrofurano, e agita-se a mistura à temp_e ratura ambiente, durante mais 2 horas. Em seguida, verte-se a mistura reaccional em 2 litros de uma mistura de metanol/água (6:4) e extrai-se, repetidamente, com hexano. Lava-se a fase orgânica, três vezes, com água e, depois de se secar sobre sul fato de sódio, evapora-se. Após filtração do resíduo sobre gel de sílica (agente de eluição:hexano/acetato de etilo=9sl) e cristalização em hexano, obtém-se 83 g de acetato de £-/ 2-(5,6,7,8-tetrahidro-5,5,8,8-tetrametil-2-naftil)-propenií/-fenilo, sob a forma de cristais incolores; ponto de fusão: 114O-116°C.A 360 g suspension of / 1- (5,6,7j 8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -ethyl ^ -tri bromide is made. phenylphosphonium in 5θ0 ml of tetrahydrofuran and reacted at 0 ° C with 410 ml of n-butyl lithium (1.6 molar in hexane). After stirring at 0 ° C for 1 hour, a solution of 94.5 S of 4-acetoxy-benzaldehyde in 300 ml of tetrahydrofuran is added, and the mixture is stirred at room temperature for a further 2 hours. Then, the reaction mixture is poured into 2 liters of a methanol / water mixture (6: 4) and extracted, repeatedly, with hexane. Wash the organic phase three times with water and, after drying over sodium sulphate, evaporate. After filtering the residue over silica gel (eluting agent: hexane / ethyl acetate = 9sl) and crystallization from hexane, 83 g of £ - / 2- acetate (5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-naphthyl) -propenyl / -phenyl, in the form of colorless crystals; melting point: 114 O -116 ° C.
Exemplo 2Example 2
Por analogia com o Exemplo 1, mediante hidróli se do acetato de m-/~2-(5,6,7,8-tetrahidro-5,5,8,8-tetrametil-2-naftil)-propenil7-fenilo, prepara-se o m-/ (e)-2-(5,6,7,8-tetrahidro-5,5,8,8-tetrametil-2-naftil)-propenil7-fenol; pon to de fusão: 91°-93°C.By analogy with Example 1, using hydrolyzate of m- / ~ 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl7-phenyl, prepares m- / (e) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl7-phenol; melting point: 91 ° -93 ° C.
- 13 Exemplo 3- 13 Example 3
Por analogia com o Exemplo 1, mediante hidróli se do acetato de £-Z~2-(5,6,7,8-tetrahidro-5,5,8,8-tetrametil-2-naftil)-propenil7~fenilo, prepara-se o 2-Z (e)-2-(5,6,7,8-tetrahidro-5,5,θ,8-tetrametil-2-naftil)-propenil7-fenol; ponto de fusãoí 97°-99°C.By analogy with Example 1, using hydrolysate of £ -Z ~ 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl7-phenyl acetate, prepares 2-Z (e) -2- (5,6,7,8-tetrahydro-5,5, θ, 8-tetramethyl-2-naphthyl) -propenyl7-phenol; melting point 97 ° -99 ° C.
A preparação das formas de dosagem, que contem os compostos de fórmula geral (l), pode efectuar-se do modo ha bitual, por exemplo, na base dos exemplos seguintes.The preparation of the dosage forms, which contain the compounds of the general formula (1), can be carried out in the usual way, for example, on the basis of the following examples.
Exemplo AExample A
As cápsulas de gelatina endurecida podem prepa rar-se do modo seguinte:The hardened gelatin capsules can be prepared as follows:
Ingredientes mg/cápsulaIngredients mg / capsule
1. Pó seco mediante pulverização contendo 75$ do composto de fórmula geral (i)2001. Spray dried powder containing 75% of the compound of general formula (i) 200
2. Dioctilsulfossuccinato de sódio0,22. Sodium dioctylsulfosuccinate0,2
3. Carboximetilcelulose de sódio4,83. Sodium carboxymethyl cellulose4,8
4. Celulose microcristalina86,04. Microcrystalline cellulose86.0
5. Talco8,05. Talc8.0
6. Estearato de magnésio1,06. Magnesium stearate 1.0
Total:300 pó seco por pulverização, que é constituído pelo ingrediente activo, gelatina e celulose microcristalina e que possui partículas de ingrediente activo de tamanho médio < 1 μ (medidas por meio de espectroscopia de autocorrelação), é humedecido com uma solução aquosa de carboximetilcelulose deTotal: 300 spray-dried powder, which consists of the active ingredient, gelatin and microcrystalline cellulose and which has particles of active ingredient of average size <1 μ (measured by autocorrelation spectroscopy), is moistened with an aqueous solution of carboxymethylcellulose in
- 14/sódio e dioctilsulfossuccinato de sódio e, depois, é amassado.- 14 / sodium and sodium dioctylsulfosuccinate and then kneaded.
Granula-se a massa resultante, seca-se, peneira-se e mistura-se o granulado obtido com celulose microcristalina, talco e estearato de magnésio. Introduz-se o pó dentro de cápsulas de dimensão 0.The resulting mass is granulated, dried, sieved and mixed with the microcrystalline cellulose, talc and magnesium stearate. The powder is inserted into capsules of dimension 0.
Exemplo BExample B
Os comprimidos podem preparar-se do seguinte modo:The tablets can be prepared as follows:
Ingredientes mg/comprimidoIngredients mg / tablet
1. Composto de fórmula geral (i) sob a forma de um pó finamen- te moído5001. Compound of general formula (i) in the form of a finely ground powder500
2. Lactose em pó1002. Lactose powder100
3. Amido de milho branco603. White corn starch60
4. Povidone K3084. Povidone K308
5. Amido de milho branco1125. White corn starch112
6. Talco6. Talc
7. Estearato de magnésio7. Magnesium stearate
Total: 800Total: 800
Mistura-se o ingrediente activo, finamente moído, com a lactose e uma porção de amido de milho. Humedece-se a mistura com uma solução aquosa de Povidone K30 e amassa-se e, depois, granula-se a massa resultante, seca-se e peneira-se. Mistura-se o granulado com o restante amido de milho, talco e estearato de magnésio e comprime-se em comprimidos de dimensão apropriada.The finely ground active ingredient is mixed with the lactose and a portion of corn starch. The mixture is moistened with an aqueous solution of Povidone K30 and kneaded, and then the resulting mass is granulated, dried and sieved. The granulate is mixed with the remaining corn starch, talc and magnesium stearate and compressed into tablets of the appropriate size.
Exemplo CExample C
As cápsulas de gelatina mole podem preparar-se do modo seguinte:Soft gelatin capsules can be prepared as follows:
Ingredientes mg/cápsulaIngredients mg / capsule
1. Composto de fórmula geral (i) 501. Compound of general formula (i) 50
2. Triglicérido 4502. Triglyceride 450
Total: 500Total: 500
Dissolve-se 10 g do composto de fórmula geral (I) em 90 g de triglicérido de cadeia média, com agitação, gaseificação inerte e protecção contra a luz. Prepara-se esta solução, assim como a massa de enchimento das cápsulas, para introduzir em cápsulas de gelatina mole, contendo, cada uma, 50 mg de ingrediente activo.10 g of the compound of general formula (I) is dissolved in 90 g of medium chain triglyceride, with stirring, inert gasification and protection against light. This solution, as well as the filling mass of the capsules, is prepared for introduction into soft gelatin capsules, each containing 50 mg of active ingredient.
Exemplo DExample D
Pode preparar-se uma loção do seguinte modo:A lotion can be prepared as follows:
Ingrediente sIngredients
Incorpora-se o ingrediente activo no seio de uma mistura de etanol a 94$ e água, sob protecção contra a luz. Agita-se o Carbopol 934 até se completar a gelificação e ajusta-se o valor do pH com o hidróxido de sódio.The active ingredient is incorporated into a mixture of 94% ethanol and water, protected against light. The Carbopol 934 is stirred until the gelation is complete and the pH value is adjusted with sodium hydroxide.
Claims (6)
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 (2)
| Publication Number | Publication Date |
|---|---|
| PT84860A PT84860A (en) | 1987-06-01 |
| PT84860B true PT84860B (en) | 1990-02-08 |
Family
ID=25685550
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PT84860A PT84860B (en) | 1986-05-13 | 1987-05-12 | METHOD FOR PREPARING NEW TETRAHYDROFOLANTALEN DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
Country Status (20)
| Country | Link |
|---|---|
| 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) |
Families Citing this family (50)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5264578A (en) | 1987-03-20 | 1993-11-23 | Allergan, Inc. | Disubstituted acetylenes bearing heterobicyclic groups and heteroaromatic or phenyl groups having retinoid like activity |
| US5602130A (en) * | 1987-03-20 | 1997-02-11 | Allergan | Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity |
| CA2017956A1 (en) * | 1989-07-06 | 1991-01-06 | Werner Bollag | Use of retinoids |
| US5272156A (en) * | 1989-09-19 | 1993-12-21 | Allergan, Inc. | Acetylenes disubstituted with a heteroaromatic group and a 2-substituted 1,2,3,4-tetrahydroquinolinyl group having retinoid-like activity |
| US5183827A (en) * | 1989-09-19 | 1993-02-02 | Allergan, Inc. | Acetylenes disubstituted with a heteroaromatic group and a 2-substituted chromanyl, thiochromanyl or 1,2,3,4-tetrahydroquinolinyl group having retinoid-like activity |
| US5264456A (en) * | 1989-12-29 | 1993-11-23 | Allergan, Inc. | Acetylenes disubstituted with a furyl group and a substituted phenyl group having retinoid like activity |
| 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 |
| US6172115B1 (en) | 1993-02-11 | 2001-01-09 | Allergan Sales, Inc. | Method for preventing onset of restenosis after angioplasty employing an RXR-specific retinoid |
| US5475022A (en) | 1993-10-18 | 1995-12-12 | Allergan, Inc. | Phenyl or heteroaryl and tetrahydronaphthyl substituted diene compounds having retinoid like biological activity |
| US5426118A (en) * | 1993-12-30 | 1995-06-20 | Allergan, Inc. | [4-(1,2-epoxycyclohexanyl)but-3-en-1-ynyl]aromatic and heteroaromatic acids and derivatives 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 |
| US5534641A (en) | 1994-12-29 | 1996-07-09 | Allergan | Acetylenes disubstituted with 2-tetrahydropyranoxyaryl and aryl or heteroaryl groups 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 |
| 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 |
| 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 |
| 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 |
| US5648514A (en) | 1994-12-29 | 1997-07-15 | Allergan | Substituted acetylenes 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| US5917082A (en) | 1995-06-06 | 1999-06-29 | Allergan Sales, Inc. | 2,4-pentadienoic acid derivatives having retinoid-like biological activity |
| US5675033A (en) * | 1995-06-06 | 1997-10-07 | Allergan | 2,4-pentadienoic acid derivatives having retinoid-like biological activity |
| US5952345A (en) | 1995-09-01 | 1999-09-14 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
| US6218128B1 (en) | 1997-09-12 | 2001-04-17 | Allergan Sales, Inc. | Methods of identifying compounds having nuclear receptor negative hormone and/or antagonist activities |
| US6008204A (en) | 1995-09-01 | 1999-12-28 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
| US5958954A (en) | 1995-09-01 | 1999-09-28 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
| AU7598596A (en) * | 1995-11-01 | 1997-05-22 | Allergan, Inc. | 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 |
| 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 |
| US5965606A (en) | 1995-12-29 | 1999-10-12 | Allergan Sales, Inc. | Methods of treatment with compounds having RAR.sub.α receptor specific or selective activity |
| US5773594A (en) | 1996-06-21 | 1998-06-30 | Allergan | Alkyl or aryl substituted dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
| US6555690B2 (en) | 1996-06-21 | 2003-04-29 | Allergan, Inc. | Alkyl or aryl substituted dihydronaphthalene derivatives 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 |
| US5723666A (en) * | 1996-06-21 | 1998-03-03 | Allergan | Oxime substituted tetrahydronaphthalene derivatives having retinoid and/or retinoid antagonist-like 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 |
| 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 |
| US5747542A (en) * | 1996-06-21 | 1998-05-05 | Allergan | Oxo-substituted tetrahydronaphthalene derivatives having retinold 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 |
| US5728846A (en) | 1996-12-12 | 1998-03-17 | Allergan | Benzo 1,2-g!-chrom-3-ene and benzo 1,2-g!-thiochrom-3-ene derivatives |
| US5760276A (en) | 1997-03-06 | 1998-06-02 | Allergan | Aryl-and heteroarylcyclohexenyl substituted alkenes having retinoid agonist, antagonist or inverse agonist type biological activity |
| US6037488A (en) | 1997-04-19 | 2000-03-14 | Allergan Sales, Inc. | Trisubstituted phenyl derivatives having retinoid agonist, antagonist or inverse agonist type biological activity |
| US5919970A (en) | 1997-04-24 | 1999-07-06 | Allergan Sales, Inc. | Substituted diaryl or diheteroaryl methanes, ethers and amines having retinoid agonist, antagonist or inverse agonist type biological activity |
| US6313107B1 (en) | 2000-08-29 | 2001-11-06 | Allergan Sales, Inc. | Methods of providing and using compounds having activity as inhibitors of cytochrome P450RAI |
| US6380256B1 (en) | 2000-08-29 | 2002-04-30 | Allergan Sales, Inc. | Compounds having activity as inhibitors of cytochrome P450RAI |
| US6369225B1 (en) | 2000-08-29 | 2002-04-09 | Allergan Sales, Inc. | Compounds having activity as inhibitors of cytochrome P450RAI |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4326055A (en) * | 1977-12-22 | 1982-04-20 | Hoffmann-La Roche Inc. | Stilbene derivatives |
| CA1162200A (en) * | 1981-02-13 | 1984-02-14 | Michael Klaus | Process for the manufacture of indanyl (or tetrahydronaphthyl)propenyl phenyl derivatives |
| EP0084667B1 (en) * | 1982-01-23 | 1985-09-18 | BASF Aktiengesellschaft | Phenylethylene derivatives, their preparation and use as medicines |
| DE3202100A1 (en) * | 1982-01-23 | 1983-08-04 | Basf Ag, 6700 Ludwigshafen | SUBSTITUTED 4-HYDROXYANILIDES, ITS PRODUCTION AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM |
| DE3602473A1 (en) * | 1986-01-28 | 1987-07-30 | Basf Ag | VINYLPHENOL DERIVATIVES, THEIR PRODUCTION AND USE |
-
1987
- 1987-04-10 ZW ZW65/87A patent/ZW6587A1/en unknown
- 1987-04-23 IT IT20232/87A patent/IT1203954B/en active
- 1987-05-06 DK DK232087A patent/DK232087A/en not_active Application Discontinuation
- 1987-05-06 NZ NZ220215A patent/NZ220215A/en unknown
- 1987-05-06 LU LU86866A patent/LU86866A1/en unknown
- 1987-05-07 IL IL82448A patent/IL82448A0/en unknown
- 1987-05-07 FI FI872027A patent/FI872027A/en not_active Application Discontinuation
- 1987-05-08 NL NL8701101A patent/NL8701101A/en not_active Application Discontinuation
- 1987-05-11 HU HU872103A patent/HU198002B/en not_active IP Right Cessation
- 1987-05-11 FR FR878706564A patent/FR2598706B1/en not_active Expired - Fee Related
- 1987-05-11 BE BE8700505A patent/BE1001668A5/en not_active IP Right Cessation
- 1987-05-11 SE SE8701933A patent/SE8701933L/en not_active Application Discontinuation
- 1987-05-11 MC MC871883A patent/MC1817A1/en unknown
- 1987-05-12 PT PT84860A patent/PT84860B/en not_active IP Right Cessation
- 1987-05-12 GB GB8711205A patent/GB2190378B/en not_active Expired - Fee Related
- 1987-05-12 NO NO871961A patent/NO871961L/en unknown
- 1987-05-12 CN CN198787103524A patent/CN87103524A/en active Pending
- 1987-05-12 ES ES8701419A patent/ES2005572A6/en not_active Expired
- 1987-05-12 DE DE19873715809 patent/DE3715809A1/en not_active Withdrawn
- 1987-05-12 AU AU72779/87A patent/AU7277987A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| GB8711205D0 (en) | 1987-06-17 |
| IT1203954B (en) | 1989-02-23 |
| SE8701933D0 (en) | 1987-05-11 |
| NL8701101A (en) | 1987-12-01 |
| HUT43806A (en) | 1987-12-28 |
| IL82448A0 (en) | 1987-11-30 |
| DE3715809A1 (en) | 1987-11-19 |
| GB2190378A (en) | 1987-11-18 |
| NO871961L (en) | 1987-11-16 |
| SE8701933L (en) | 1987-11-14 |
| BE1001668A5 (en) | 1990-02-06 |
| NZ220215A (en) | 1990-06-26 |
| CN87103524A (en) | 1987-12-02 |
| MC1817A1 (en) | 1988-03-18 |
| PT84860A (en) | 1987-06-01 |
| HU198002B (en) | 1989-07-28 |
| LU86866A1 (en) | 1988-06-13 |
| FI872027A0 (en) | 1987-05-07 |
| GB2190378B (en) | 1990-11-14 |
| NO871961D0 (en) | 1987-05-12 |
| ZW6587A1 (en) | 1987-12-02 |
| AU7277987A (en) | 1987-11-19 |
| FI872027A (en) | 1987-11-14 |
| FR2598706B1 (en) | 1990-07-06 |
| DK232087A (en) | 1987-11-14 |
| ES2005572A6 (en) | 1989-03-16 |
| DK232087D0 (en) | 1987-05-06 |
| FR2598706A1 (en) | 1987-11-20 |
| IT8720232A0 (en) | 1987-04-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| PT84860B (en) | METHOD FOR PREPARING NEW TETRAHYDROFOLANTALEN DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM | |
| JP2516989B2 (en) | Tetrahydronaphthalene and indane derivatives | |
| EP2186792B1 (en) | 2-(a-hydroxypentyl) benzoate and its preparation and use | |
| IL30394A (en) | Phenylacetic acid derivatives | |
| US4309442A (en) | Method for controlling fertility in mammals | |
| US3934034A (en) | Hydroxy substituted diphenylalkyls for treatment of lipidemia | |
| EP0098934A1 (en) | 2-Methylseleno-benzamides | |
| CS235548B2 (en) | Method of tetrahydronaphthalene and indane new derivatives production | |
| JPS6054379A (en) | Novel 4h-1-benzopyran-4-one derivative, its preparation and its use | |
| NO174848B (en) | Analogous Process for Preparing Therapeutically Active Substitutes | |
| JP2008501670A (en) | Arylalkylsulfonamides as therapeutic agents for treating bone conditions | |
| US4855293A (en) | Anti-inflammatory compositions comprising a systemic non-steroidal anti-inflammatory drug and a cyclopentyl ether | |
| CZ283779B6 (en) | Phenylhydrazone derivative and pharmaceutical and cosmetic preparations in which it is comprised | |
| JPS638934B2 (en) | ||
| US3821401A (en) | Other publications | |
| AU1359692A (en) | N-((4,5-dihydroxy- and 4,5,8-trihydroxy-9,10-dihydro-9,10-dioxo-2-anthracene-yl) carbonyl)amino acids useful in the therapy of osteoarticular affections | |
| JPS591474A (en) | Geranylgeranylacetamide compound having piperazine ring or salt thereof | |
| CS265240B2 (en) | Process for preparing tetrahydrotetramethylnaphthylpropenylphenoles | |
| CA1056306A (en) | Pharmaceutical compositions containing 2-naphthyl-butyric acid derivatives | |
| HU216156B (en) | Process for the preparation of indolizine derivatives and the starting compound | |
| US3891699A (en) | Biphenylenealkanoic acids | |
| EP1123091A1 (en) | Combination product comprising an e-type prostaglandin ligand and a cox-2 selective inhibitor and methods of use | |
| WO1993019066A1 (en) | Imidazopyridine derivative and medicine | |
| US4103029A (en) | Amino substituted arylthio-alkanoic acids having hypolipidemic activity | |
| JPH0441134B2 (en) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM3A | Annulment or lapse |
Free format text: LAPSE DUE TO NON-PAYMENT OF FEES Effective date: 19920106 |