DE2051012A1 - 1,6-methano-(10)-annulenes - with anti-inflammatory analgesic antipyr hypocholesterolaemic and fibrinolytic activity - Google Patents

Abstract

Title cpds. have formula (I): (where R is H, 1-6C alkyl, 3-6C monocycloalkyl, 1-6C alkoxy or is not >12C carboxylic acyloxy; R1 is H or 1-6C alkyl; R2 is H or 1-6 C alkyl, or together with R1 is methylene or together with R1 and the attached C-atom is 3-6C monocycloalkyl; R3 is -CHO, -CH2R4, -COOR5, -CON(R6)2 or -CONHOH in which R4 is OH or a hydrolysable ether or ester; R5 is H, 1-6C alkyl or an alkali metal, and each R6 is H or 1-6C alkyl; and X is CH2, CCl2 or CF2). (I) in which R1 is H and R2 is 1-3 C alkyl or R1+R2 is methylene are anti-inflammatories, analgesics and antipyretics. (I) in which R1 is H and R2 4-6C alkyl or CR1R2 is a monocycloalkyl gp. are hypocholesterolaemics and fibrinolytic agents.

Description

Novel Cyclodecane Pentaene Compounds The present invention relates to novel cyclodecane pentaene compounds of the following formulas A and B; in which R represents hydrogen, lower alkyl, a lower monocyclic alkyl group, lower alkoxy or a lower carboxylic acyloxy group; R is hydrogen or lower alkyl; R² is hydrogen, lower alkyl, together with R¹ is methylene or together with H¹ and the carbon atom to which R¹ and R² are bonded a lower monocyclic alkyl group; R³ is -CHO, -CH2R4, -COOR5, -CON (R6) n or -CONHOH, where R4 is hydroxy or the hydrolyzable esters or ethers thereof, R5 is hydrogen, lower alkyl or an alkylimetal and R is each hydrogen or lower Denotes alkyl; and X is methylene, dichloromethylene or difluoromethylene.

The benzo drawing "low alkyl" as used herein refers to a straight or branched chain saturated acyclic aliphatic hydrocarbon group with 1-6 carbon atoms; for example his hests listed for it, such as methyl, Ethyl; Propyl, butyl, pentyl and hexyl and the various isomers thereof. "Monocyclic lower alkyl groups" contain 3-6 carbon atoms, such as cyclopropyl1 Cyclobutyl, cyclopentyl and cyclohexyl. The term "lower alkoxy" refers to refers to the group "lower alkyl 0", where "lower alkyl" of the above definition corresponds to. The term "lower carbopxylic acyloxy group" refers to or 12 refers to a carboxylic acyloxy group of up to 8 / carbon atoms of straight, branched or cyclic chain structure derived from carboxylic anhydrides, such as acetic anhydride, trifluoroacetic anhydride, propionic anhydride, n-caproic anhydride, Benzoic anhydride, heptanoic anhydride, acetic propionic anhydride, maleic anhydride, Phenylacetic anhydride, p-methoxybenzoic anhydride, trimethyl acetic anhydride, Butyric anhydride, etc., preferably of lower alkanoic anhydrides with up to to 12 carbon atoms. The one used here description "Hydrolyzable esters and ethers" refers to those physiologically acceptable hydrolyzable ester groups and labile ether groups used in pharmaceutical Technique commonly used, such as acetate, propionate, butyrate, trimethylacetate, Valerate, methyl ethyl acetate, caproate, tert-butyl acetate, 3-methyl pentanesate, enanthate, Caprylate, triethyl acetate, pearl gonate, docanoate, undecanoate, benzoate, phenyl acetate, Diphenyl acetate, cyclopentyl propionate, methoxyacetate, aminoacetate, diethylaminoacetate, Trichloroacetate, B-chloropropisnate, bicyclo- [2.2.2] -octane-1'-carboxylate, adamantoate, Dyhydrogen phosphate, dibenzyl phosphate, sodium ethyl phosphate, sodium sulfate, sulfate, Tetrahydropyran-2'-yl ether, tetrahydrofuran-2'-yl ether, 4'-methoxytetrahydrofuran-4'yl ether etc.

The compounds according to the invention can be prepared by the method shown below: In the above formulas: R1 represents hydrogen, lower alkyl, a lower monocyclic alkyl group or lower alkoxy; R¹ 'represents hydrogen or lower alkyl; represents hydrogen, lower alkyl or, together with R¹ 'and the carbon atom to which R and R are bonded, represents a lower monocyclic alkyl group; denotes -CH2R4 'or -COOR5', where R4 'denotes hydroxy or a customary hydrolyzable ether thereof and R denotes hydrogen; R "represents lower alkoxy or a lower carboxylic acyloxy group; R't 'means hydrogen, lower alkyl or a lower monocyclic alkyl group; and R, R1, R2, R3 and X have the meanings already given.

In one embodiment of the method presented above, a 6-lower alkoxynaphthalene compound (1; R '= lower alkoxy) with an alkali metal and an alcohol in a lower alkyl amine or diamine or in liquid ammonia to form the corresponding 6-lower alkoxy-1,4,5,8-tetrahydro-naphthalene (2; R '= lower alkoxy) implemented.

The alkali metals suitable and preferred in this reaction are Sodium, potassium and lithium. This reaction usually occurs in the presence of one monohydric lower alkanols with 1-6 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-nutanol, isobutanol, sec-butanol, tert-butanol, n-amyl alcohol etc., alone or in a mixture with other organic liquid reaction media, such as dioxane, tetrahydrifuran, diethyl ether, glyme, dimethyl sulfoxide, hexane, etc. The reaction also takes place at temperatures between about -8D0C. up to 100 ° C. for the time sufficient to form the product, which is usually is between about 5 minutes to about 2 weeks.

Then the compound (2) for the formation of the corresponding 6-oxo-1,4,5,6,7, 8-hexahydronaphthalene (3) is treated with an acid such as oxalic acid, acetic acid, etc. The compound (3) is then, for example, sodium borohydride to form the corresponding 6-hydroxy compound (4) reduced. To the 6-hydroxy-1y4,5, G, 7,8-hexahydronaphthalene (3) the group # CX2 is added, in which X stands for hydrogen, chlorine or fluorine through the C-9,10 double bond, whereby the corresponding 6-hydroxy-9,10-bridged-1,4,5,6,7,8,9,10-octanhydronaphthalene is obtained (5) receives. The compound (5) obtained is treated with, for example, chromic acid in pyridine 6-oxo compound (6) is oxidized. The 9,10 bridged 6-oxo-1,4,5,7,8,9,10-heptahydronaphthalene (6) is converted into the corresponding enol ethers and enol acetates by customary known processes (7) converted. In this process, either or both of the 9,10-bridged-1,4,5,8,9,10-hexahydro-6-enol- and 9,10-bridged-1,4,7,8,9-hecahydro-6 enol products are formed, resulting from depends on the conditions used. They can be separated according to the usual procedures, and any material or a mixture thereof is used to produce the compound (8) suitable. Then the compounds (7) obtained with'einem benzoquinone for Formation of the corresponding 6-lower-alkoxy- and -low-carboxylic-acyloxy-1,6-bridged- [10] -annulenes (8; R = lower alkoxy or lower carboxylic acyloxy) at the additin of the sCX2 group will usually do so in situ and in the presence of a inert, liquid organic reaction medium formed.

Suitable media include those below for the benzoquinone reagent mentioned as well as the chlorinated hydrocarbon solvents, such as methylene chloride, Chloroform and carbon tetrachloride.

The halocarbene reagent is made from a halogenoform and Alkali.metalltert.-alkoxide or from an alkali or alkaline earth metal salt of a trihaloacetic acid, such as Sodium trichloroacetate, or from a phenyl trihalomethyl mercury such as phenyl trifluoromethyl mercury and phenyltrichloromethylmercury.

The halocarbene reagent is made by adding a halo form, wherein the halogen I is as defined above with an alkali alkoxide, preferably one Alkali metal tert-alkoxide, converts. In one process, this becomes the halogenoform and the reaction mixture containing the alkali metal tertiary alkoxide at the boiling point heated and for a period sufficient for the formation of the halocarbene reagent, the is between about 30 minutes to about 5 hours, refluxed. Suitable. Halogen terms useful in the above process include chlorine form, bromodichloromethane and chlorodifluomethane. The alkali metal tertiary alkoxides which can be used in the above process include potassium tertiary butoxy and sodium tertiary amylate.

The reaction can also be carried out by changing the starting compound and a phenyl trihalomethyl mercury such as phenyl trifluoromethyl mercury and Phenyltrichloromethylquecxksilber, reacted together. This reaction is expedient in a liquid organic reaction medium as mentioned above.

and at temperatures of about 250C. up to the boiling point of the reaction mixture.

In another process, the starting compound is treated with an alkali or alkaline earth metal salt of a trihaloacetic acid in an organic solvent, preferably diglyme or triglyme, at a temperature above the decomposition temperature of the salt implemented. (for details see U.S. Patent 3,338,928, which is hereby included in the present application.) In those cases where X stands for hydrogen, the methylene group is derived from the zinc / copper pair and methylene iodide reagent educated. The reagent of the zinc / copper pair and methylene iodide is made from zinc dust, a copper salt such as cuprous chloride and methylene iodide. Usually The reagent is made by adding a mixture of the copper salt and zinc dust and an organic solvent such as diethyl ether with methylene iodide usually at the reflux temperature of the mixture. (See U.S. Patent 3 408 372, which is hereby incorporated into the present application.) The last Step (7 # 8) takes place under reaction with a benzoquinone. This reaction takes place expediently in the presence of an inert, liquid organic Realetionsmed ums. Suitable media include the normally used organic solvents, such as tetahydrofuran, dioxane, dimethylformamide, n-hexane, toluene, benzene, mesitylene, Diethyl ether, the muno or di-lower alkyl ethers of diethylene glycol or triethyle.nglycol, such as diglyme and triglyme, etc. In addition, reaction occurs at temperatures between approximately 0 ° C. to the boiling point of the reaction mixture and reflux for the termination the reaction is of sufficient duration, ranging from a few minutes to about 48 hours amounts to.

The reaction can be carried out in the presence of an anhydrous acid, such as p-toluenesulfonic acid, Hydrochloric acid, perchloric acid and sulfuric acid can be carried out; the use of this However, acid is not necessary in the preferred embodiments according to the invention.

Suitable benzoquinones for this reaction include the o- and p-benzoquinones, those unsubstituted or with one or more groups such as acyl, cyano and halogen groups (the latter including bromine, chlorine and fluorine) may be substituted, Typical Benzoquinones include 1,2-benzoquinone, 1,4-benzoquinone, 2,3-dichloro-5,6-dicyano-1 14-benzoquinone, tetrachloro-1,2-benzoquinone, 2,3-difluoro-1,4-benzoquinone, 2,3-dibenzoyl-1,4-benzoquinone, 2,3-dicyano-1,4-benzoquinone, tetrachloro-1,4-benzoquinone, 2,3-difluoro-1,2-benzoquinone, 2,3-dicyano-1,2-benzoquinone, etc. Preferred is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

In carrying out this reaction, the starting compound will be (7) and the benzoquinone mixed and in any order or manner kept in touch. Then the reaction mixture is used for the completion of the Reaction kept for sufficient time in the specified temperature range. After finished Reaction, the reaction mixture is used in the usual manner for recovery and isolation of the desired product, e.g.

by dilution, chromatography, decanting, filtering, distilling, Evaporation, etc.

The indicated reaction consumes the reaction participants in one Ratio of 1 mole of starting compound (7) per 2 moles of benzoquinone reagent. Although therefore the use of chemically equivalent amounts of the reactants is preferred this is not a necessity; a certain amount of the desired product will be made using any proportions In practice Amounts of benzoquinone of about 2-50 moles, preferably about 2-5 moles, per mole of starting compound used.

every where / X in the starting material stands for chlorine is used as an intermediate 1,8-dichloromethano-2,5-dihydrop-10 / -annulene was formed. This is easily done in the 1,6-dichloromethane [10] annulene product is converted by first converting it to the Reacts corresponding 3,4-dibromo compound and then dehydrobrominated.

Where each X in starting material (7) is fluorine, use results of about 1 mole of benzoquinone, 1,6-difluoromethano-2,5-dihydro-ÄlD7-annulene is predominant. If amounts of benzoquinone above about 2 moles per mole of Ausganys material (7) are used, this gives 1,6-difluoromethano- [10] -annulene.

In the above reaction sequence (1 to 10), the 6-unsubstituted (R = hydrogen) or 6-substituted (R = lower alkyl or lower monocyclic Alkyl) naphthalene (1) as indicated above into the corresponding 1,4,5,8-tetrahydronaphthylene compounds (2) converted. The group is then connected to this connection; CX2 in the above Wise added, whereby the 6-unsubstituted, 6-lower-alkyl- or 6-lower-monocyclic-alkyl-9,10-bridged-1,4,5,8,9,10-hexahydronaphthalene (9) obtained, which with benzoquinone in the manner described to the corresponding 6Lunsubstituted, 6-lower-alkyl- or 6-lower-monocyclic-alkyl-1,6-bridged-10j-annulenes (8) is wrapped around.

Dorn are the compounds (s) according to procedures that are in any Sequence and to be carried out to the necessary or desired extent1 in converted into the compounds of formula (1U) in the manner described below. The formula (10) stands for the 2- and 3-substituted compounds according to the invention of the above formulas (A) and (B). The substituent R in formulas (8) and (10) varies corresponding to the production process from the compounds of the formulas (7) and (9). The α-carbon atom alkyl groups (R1, R2 = alkyl) and the # carbon atom spiro groups (R1 and R2 with the bonded carbon atom = monocyclic alkyl) can be used in of the starting compound (1) (R¹ 'and R²' definitions) be present or in the Connections (8) are introduced. In any case, the alkyl groups can through Alkylation of a lower alkyl ester of an acid of the formulas (1) or (8) and subsequent hydrolysis of the ester to the free acid are introduced. In education of the monoalkyl compounds, i.e. one of the substituents R¹ '(R¹) and R²' (R²) Hydrogen, an equivalent amount of an alkylating agent is used. Dialkyl compounds are made with at least 2 equivalents of alkylating agent where the alkyl groups are the same, or in succession with one equivalent each where the alkyl groups are different. The alkylation can be carried out by treating an alkyl ester of the acid with an alkali metal hydride alkylating agent such as sodium hydride and a lower alkyl iodide in an organic solvent, the ethers, e.g. 1,2-dimethoxyethane, and subsequent removal of the ester group by treatment with a base, e.g. an alkali metal hydroxide or carbonate, in a lower alcohol such as methanol to form the corresponding free acid.

The compounds of the invention having a low monocyclic Bpiroalkyl group in combination with the α -carbon atom are produced, by adding a lower alkyl ester of an acid of formula (8) or (1) (R¹ '= R² '= hydrogen) with an α, # - dibromoalkane, such as 1,3-dibromopropane, 1,4-dibromobutane or 1,5-uribromopentane, and sodium hydride in an organic solvent such as Glym, implements. The α-spirocyclopropyl group is introduced by treatment of α-exomethylene with methylene iodide and a zinc / copper pair accordingly the well-known Simmons-Smith conditions.

The processes of the invention having a carbon exomethylene group (R¹ and R² together denominated methylene) are made by hanging one lower alkyl ester of an acid of formula (8) with formaldehyde or paraformaldehyde and an alkali metal alkoxide in dimethyl sulfoxide. Then the i -ethylene ester can are hydrolyzed to the corresponding acid.

The groups to be worked out represented by R3 in formula (10) are introduced using the compounds (8). Alkali metal salts of acids (8) can be prepared by treatment with a molar equivalent of one Alkali metal bicarbonates, such as sodium or potassium bicarbonate, or by titration a solution of the acid (8) with an alcohol solution of the corresponding alkali metal alkoxide, such as sodium methoxide, potassium methoxide, etc.

The lower alkyl esters of the acids (8) can be obtained directly by treatment the acid with essential diazoulcan, such as diazomethane or diazoethane, or by Treatment of the alkali metal salts of the acids (8) with a low alkyl iodide or bromide, such as methyl iodide, ethyl iodide, etc., in one organic Solvents such as dimethylacetamide or dimethylformamide can be obtained.

For example, the acids or esters can be mixed with lithium aluminum hydride in tetrahydrofuran are reduced to form the corresponding alcohol (10; R³ = CH2DH); the latter can then e.g. with chromic acid in pyridine, by Moffatt conditions or with silver oxide oxidized to the aldehyde (10; R3 = CHU).

The compounds of the formula (10) according to the invention in which R3 is -CH2-R4 (where R4 is hydroxy) can be used to achieve the corresponding hydrolyzable esters and ethers are esterified and etherified. The esterification takes place, for example, by treating the free hydroxy compound with a carboxylic acid anhydride or carboxylic acid halide in pyridine, etc. to obtain the esters of organic acids. Inorganic acid esters1 e.g. the sulfates, are produced by treatment the free hydroxy compound with a sulfur trioxide / trimethylamine complex in Pyridine or by methods such as those described by Kornel et al in Steroids 4, (1964) Kirdani, Steroids 6 (1965) and Bernstein, Steroids 7, 577 (1966). Phosphate esters can be obtained from the free hydroxy compounds e.g. by treatment with B-cyanoethyl phosphate in the presence of N, N'-dicyclohexylcarbodiimide in pyridine or according to the method of Wendler, Chem.SInd. 1174 (1987) or U.S. Patents 2 936 313, 3 248 408 or 3 254 100. The alkali metal salts of Esters can be made by treatment with a base1 such as sodium ethyl instead of sodium or potassium bicarbonate etc., can be obtained. By regulating the base size, the mono- and disalts getting produced.

By treating a free alcohol of formula (10) with dihydropyran or dihydrofuran in the presence of an acid catalyst, the tetrahydropyranyl and tetrahydrofuranyl ethers. Tetrahydropyranyl and tetrahydrofuranyl ethers is also obtained by reacting the free alcohol with about one molar equivalent 2-benzoyloxytetrahydropyran or

2-Benzoyloxytetrahydrofuran in an inert organic solvent under practically neutral conditions. The 4-methoxytetrahydropyran-4'-yl ethers are produced by reacting the free alcohol with an excess of 4-methoxy-5,6-dihydro-u1-pyran in the presence of a small amount of an acidic catalyst such as p-toluenesulfonic acid, around room temperature.

3 6 n n Treatment of an acid of the formulas (A) and (B) with thionyl chloride and subsequent treatment with anhydrous ammonia or lower alkyl or lower dialkylamine. By treating an acid of formulas (A) and (B) with Hydroxyamine hydrochloride in the presence of sodium methoxide gives the new ones Hydroxamic acids of formula (10) (R³ = -CONHOH).

The novel compounds of the above formula (A) according to the invention (in which R = R "') can also be prepared by the process shown below, in which Ac stands for an acyl group, for example a lower carboxylic acyl group such as acetyl, R7 an acid-labile protective group such as tetrahydropyran-2-yloxy, tetrahydrofuran-2-yloxy, tert-butyloxy, etc., X 'denotes dichloromethylene or difluoromethylene and X has the meaning given above.

In performing the above procedures, 2-naphthylacetic acid becomes (I) by treatment with an alkali metal, such as sodium, KaliUm or lithium, in liquid ammonia in the presence of a lower alcohol such as ethanol to 1,4,5,8-tetrahydro-2-naphthalacetic acid (II) tert-Uutanol etc., / Reduced. The acid (II) is treated with a reducing agent, such as lithium aluminum hydride, for the formation of 2- (1 ', 4', 5 ', 8'-tetrahydro-2'-naphthyl) ethanol (III) treated. The conversion of (II) to (III) can also be done by first the corresponding alkyl ester of (II), e.g. by treating (II) with Diazomethane in ether to form the methyl ester of (II), and the alkyl ester of (II) then reacts with lithium aluminum hydride to form the alcohol (III) the alcohol (III) is used in the usual way, e.g. by treatment with a carboxylic acid anhydride, such as acetic anhydride, esterified in pyridine; the carboxylic ester obtained (IV) is formed with one of sodium trichloroacetate or sodium chlorodifluoroacetate Dichlorocarbene or difluorocarbene reacted, whereby the acetate of 2- (9 ', 10'-dichloromethylene-1', 4 ', 5', 8 ', 9', 10'-hexahydro-2'-naphthyl) ethanol (V; X '- CC12; Ac = acetyl) and the acetate of 2- (9 ', 10'-difluoromethylene-1', 4 ', 5', 8 ', 9', 10'-hexahydro-2'-naphthyl) ethanol (V; X '= CF2; Ac "acetyl). This reaction takes place in an organic Solvents such as diglyme or monoglyme at elevated temperature, e.g. at return flow.

A compound of the formula (V) in which X 'stands for dichloromethylene, is with an alkali metal in liquid ammonia to form 2- (9 ', 1D'-methylene-1', 4 ', 5', 8 ', 9', 10'-hexahydro-2'-naphthyl) -ethanol (VI) treated, for example, with dihydropyran or dihydrofuran in a hydrocarbon solvent in the presence of an acid catalyst such as p-toluenesulfonic acid, and then etherified with bromine in an inert organic solvent, like chloroform, Carbon tetrachloride, etc., to form the tetrahydropyrar 2-yl ether or tetrahydrofuran-2-yl ether of 2- (2 ', 3', 6 ', 7'-tetrabromo-9', 10'-methylenedecahydro-2'-naphthyl) ethanol (VII) is brominated. The tetrabromo compound (VII) is after treatment with a base, such as an alkali metal hydroxide or alkoxide, e.g. sodium hydroxide, sodium methoxide, Potassium tert-butoxide or sodium tert-butoxide, in an organic solvent, such as ether, ethanol, diglyme, dioxane, hexamethylphosphoramide, dimethyl sulfoxide, tetrahydrofuran etc., into the corresponding tetrahydropyran-2-yl ether or tetrahydrofuran-2-yl ether of 2 '- (1', 6'-methanocyclodecapentaen-3'yl) ethanol (VIII) converted by Treatment with acid hydrolyzes into the corresponding free alcohol (IX; X; CH2) will. The alcohol (IX) is mixed with chromium trioxide in pyridine, Jones' reagent or after oxidized to the corresponding aldehyde (X) by the process of US Pat. No. 3,248,380, which after further oxidation is converted into the acid (XI).

A tetrabromo compound of the formula (V ') is obtained by treatment of a compound of formula (V) with bromine in one of the inert ones described above organic solvents. The 9 ', 10'-dichloromethylene-2', 3 ', 6', 7'-tetrabromo-or 9'10'-difluromethylene-2 ', 3', 6 ', 7'-terfabromo compound (V') is then described as above reacted with a base to form alcohol (XI), in which X is dichloromethane or difluoromethane stands. The corresponding aldehydes and acids of the formulas (X) and (XI) are obtained by oxidation of the alcohol (IX) in the manner described above.

The alkali metal salts and lower alkyl esters of the acids (XI) are prepared in the above manner. In the manner described, the α-carbon alkyl, spiral alkyl and exomethylene groups are also introduced into the acids (xi) R for low alkoxy or a lower carboxylic acyloxy group can also be prepared by the following process: In the above formulas, Ac, R7, X 'and X have the meanings already given. In carrying out the above process, 2- (6'-methoxy-1 ', 4', 5 ', 83'-tetrahydro-2'-naphthyl) ethanol (XII) (prepared by the above-described reduction of 6 -Methoxy-2-naphthyl acetic acid or 2- (6'-meth oxy-2'-naphthyl) -ethanol) with an acid such as oxalic acid ,,, acetic acid, etc., to form 2- (6'-oxo-1 ' , 4 ', 5', 7 ', 8'-hexahydro-2'-naphthyl) -ethanol (XIII) treated, which, after the above-described reduction of the 6-Dxo to the 6-Hydroxy compound, treated with sodium trichloroacetate or sodium chloride fluoroacetate and then oxidized will; 2- (6'-oxo-9 ', 10'-dichloromethylene-1', 4 ', 5', 6 ', 7', 8 ', 10'-octahydro-2'-naphthyl) ethanol and 2- (6'-oxo-9 ', 10'-difluoromethylene-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'-octahydro-2'-naphthyl) -.

ethanol. Then, with dihydropyran or dihydrofuran, the corresponding Tetrahydropyran-2 "-yl ether or tetrahydropyran-2" -yl ether of the formula (XIV) etherified. A 9 ', 10'-dichloromethylene of formula (XIV) is then made using an alkali metal converted into the 6'-hydroxy-9 ', 19'-methylene derivative (XV) in liquid ammonia, that after oxidation, e.g. with chromium trioxide in pyridine, the ether of 2 '- (6'-Oxo-9', 10'-methylene-1 ', 4', 5 ', 6', 7 ', 8', 9 ', 10 '-octahydro-2'-naphthyl) ethanol (XVI) provides; The compounds of the formulas (XVI) or (XIV) can be converted into the corresponding 7,8-dehydro compounds (XVIII). This transformation can directly with 2,3-dichloro-5,6-dicyan-1,4-benzoquinene in dioxane under reflux, Selenium dioxide, etc., or you can first use the 7'-bromine intermediate (XVII) by treatment with cupribromide in a lower alcohol1 such as methanol and then by treatment with an alkali halide and an alkali metal carbonate or bicarbate or frda'lkali metal salt, such as lithium bromide and sodium bicarbinate, Dehydrobrominate lithium chloride and sodium carbonate, lithium bromide and calcium carbonate, etc. The tetrahydropyran-2 "-yl ether or tetrahydrofuran-2" -yl or -tert-butyl ether a 2- (6'-oxo-9 ', 10'-methylene, -dichloromethylene or -difluromethylene-1 ', 4', 5 ', 6', 9 ', 10'-hexahydro-2'-naphthyl) -athncls (XVIII) is with a carboxylic acid anhydride, such as acetic anhydride, propionic anhydride, Butyric anhydride, etc., and an alkali metal acetate such as sodium acetate to obtain of the ether of acyloxy-1 ', 6'-methano-, -dichloromethano- or -difluoromethanocyclodecateraen-3'-yl) ethanol (XIX), e.g. the tetrahydropyran-2 "-yl or tert-butyl ether of 2- (8'-acetoxy-1'6'-methanocyclodecatetraen-3'-yl) ethanol (XIX; Ac is acetyl, X stands for CH2, R stands for tetrahydropyran-2 "-yloxy or tert-butoxy) treated. Compound (XVIII) is prepared from the tetrahydropyran-2 "-yl- or tert-butyl ether of 2- (6'-oxo-9 ', 10'-m, ethylene-1', 4 ', 5', 6 ', 9', 10'-hexahydro-2'-naphthyl) ethanol (XVII; X stands for CH2, R7 stands for tetrahydropyran-2 "-yloxy or tert-butyloxy). A cyclodecatetraene of formula (XIX) was prepared using N-bromosuccinimide in carbon tetrachloride, a palladium catalyst, 2,3-dichloro-5,6-dicyano-1-4, -benzoquinone etc., converted to the corresponding cyclodecapentaene (XX). An ether of the formula (XX), e.g. the tetrahydropyran-2 "-yl or tert-butyl ether of 2- (8'-acetoxy-1 ', 6'-methanocyclopentaen-3'-yl) ethanol (XX; Ac stands for acetyl, X stands for CH2, H is tetrahydropyran-2 "-yloxy or tert-butyloxy) is then hydrolyzed by treatment with an acid to provide the corresponding free alcohol, which oxidizes to the aldehyde and the acid by one of the above processes can be.

The compounds of the formula (A) in which H is lower alkoxy are prepared from the compounds of the formula (XX) by treatment with a base, for example an alkali metal bicarbonate such as potassium bicarbonate, in aqueous methanol and subsequent treatment with a lower alkyl ortho ester such as for example njEdrig alkyl orthoformate, for example methyl orthoformate, ethyl orthoformate, n-propyl orthoformate, etc., in the presence of an acid catalyst such as p-toluenesulfonic acid. By this process, the compounds of the formula (XX) can be converted into the compounds of the formula (XXI), and the latter can be oxidized to the corresponding aldehydes and acids by the above processes. In the following formula, X has the meaning given and alkyl is lower alkyl.

The above compounds (XXI) can also be according to those described above Alkylation processes into the corresponding mono- or dialkyl-substituted derivatives being transformed.

The alternative treatment methods described immediately above for the preparation of the compounds of the formula (A) also apply to the preparation of the compounds of the formula (B), where the starting materials (I) and (XII) are the corresponding C-1 substituted naphthalene compounds, e.g.

1 # naphthylacetic acid and 6-methoxy-1-naphthylacetic acid instead der 2-Naphthyl.essigsaure or 6-methoxy-2-naphthylessigsäure can be used.

The starting compounds of the formulas (1) and (I) can be selected from 2-TEtralon by treating it with one equivalent of an alkyl or cycloalkyl magnesium bromide in an ether to form the corresponding 2-alkyl- and 2-cycloalkyl-3,4-dihydronaphthalene the latter by heating with palladium-on-animal charcoal as Catalyst with formation of the corresponding 2-alkyl- or 2-cycloalkylnaphthalene becoming dehydrated.

The 2-substituted naphthalenes obtained (including the 2-lower alkoxynaphthalenes) are then with acetyl chloride in nitrobenzene in the presence of at least 3 molar Equivalents of aluminum chloride to the corresponding 6-substituted 2-acetylnaphthalene implemented. The compound obtained is treated with morpholine in the presence of sulfur to about 150 ° C. heated and the compound obtained with conc. Hydrochloric acid to reflux heated; the corresponding 2- (6'-substituted-2'-naphthyl) acetic acid compound is obtained in this way.

The addition of an alkyl substituent in the C-.:9 position takes place by esterification of the 2- (6'-substituted-2'-naphthyl) acetic acid derivative in the usual way Way, e.g. by treatment with a diazolene, such as diazomethane, in ether formation of the corresponding alkyl ester. Then the ester product is made with sodium hydride in an ether solvent such as 1,2-dimethoxyethane, and then with an alkyl halide, such as methyl iodide, to the corresponding alkyl 2- (G'-substituted-2'-naphthyl) propionate treated.

Similarly, the compounds with an i: carbon exomethylene group or a lower monocyclic alkyl group in combination with the α-carbon atom (R = lower alkoxy o (he is a lower carboxylic acyloxy group) by procedure produced above for compounds in which R = hydrogen the Starting compounds of formulas (1) and (I) in the C-1 series are formed by the 2-substituted naphthalenes are first prepared in the manner described above. The latter are mixed with 2 molar equivalents of hydrogen in the presence of a platinum, Palladium or nickel catalyst, etc. to the correspondingly substituted tetralin reduced (hydrogenation of the unsubstituted ring is preferred; if both rings are substituted, you get two products with different ring saturation). Then the substituted tetralin is e.g. with chromium trioxide in glacial acetic acid or BN sulfuric acid oxidized to the 6 "substituted 1-tetralone.

The implementation of the 1-tetralone with one or more equivalents a 1-Carboalkoxyalkylidentriphenylphosphorans, such as 1-Carbomethoxyäthylidentriphenylphosphoran, provides the corresponding 1-carboalkoxyalkylidene tetralins. These result after heating with palladium-on-animal charcoal as a catalyst, the corresponding 1-naphthyl acetic acid ester derivatives.

The 1-carboalkoxyalkylidene triphenylphosphorane reagent is expediently formed for this purpose by reacting triphenylphosphine with a 2-halocarboxylic acid ester in one organic reaction medium, which is then reacted with a base.

For example, by reacting 6-methoxy-1-tetralone with a triphenylphosphorane derived from ethyl 2-halopropionate, 1,1- (1 - (,. rboethoxyeth-1 ', 1'-ylidene) -6-methoxytetralin. The dehydration dessedlben gives ethyl-6-methoxy-1-naphthyl - # - methylacetate, which after hydrolysis gives 6-methoxy-1-naphthyl - # - methyl acetic acid.

The compounds according to the invention exhibit due to a chirality of the bridge head in the annulene ring system has a geometric isomerism. Farther are the compounds having an asymmetric carbon atom, i.

1 and 2 are those in which R and R are different / and not both stand for water, optically active. From the present invention any of those obtained from asymmetric carbon atoms and / or a chirality Isomers and mixtures thereof. These isomers can in the usual way, e.g. by forming salts of acids with active amines such as brucine, cinchinone, Methylamine, morphine, quinidine, quinine, strychnine, etc., - and subsequent separation of the diastereoisomeric salts by fractional crystallization and regeneration separated from the free acid.

The compounds of the formulas (A) and (B) according to the invention, in which one R for hydrogen and the other for an alkyl group with 1-3 carbon atoms and those in which R and R together represent methylene are therapeutic effective anti-inflammatory, analgesic and antipyretic agents They are used to treat and cause inflammation of the skin, bones and muscles related pain, such as contact dermatitis, bursitis, arthritis, pruritis, etc. They can be administered and used in the same way as phenylbutazone. For example, they can be used to treat painful arthritis and disorders of the skeletal. Humans and muscle sysLemsi animals such as cats, dogs, horses, etc., administered orally.

The compounds of formulas (A) and (B) in which one of the substituents R¹ and R² for hydrogen and the other for an alkyl group of 4-6 carbon atoms stands, and those in which R¹ and R² are each alkyl as well as those in which R1 and R2 and the carbon atom to which R and R are bonded for a lower monocyclic alkyl group are 1) hypocholestoreome agents and 2) fibrinolytic agents. They are therefore suitable 1) for reducing serum cholesterol levels and 2) for the treatment (resolution) of thromboembolic symptoms by lysis / of preformed fibrin They can be used in the same way as agents with similar effectiveness used and administered such as 1) various sterols and 2) actase or thrombolysin.

The following examples illustrate the present invention for alleviating acne. In the present application, the term "bridged" refers to a methano or dihalomethano group of the formula # CX2 in which each X has the meaning given. In the present arm message, the root names "[10] -Annulen" and "Cyclodecapentaen" can be used interchangeably and refer to the following core: EXAMPLE 1 4.0 g of aluminum chloride were slowly added to a mixture of 1.6 g of β-methoxynaphthalene, 1.1 g of acetyl chloride and 20 cc of nitrobenzene. The mixture obtained was stirred for 48 hours at 25 ° C., then washed free of chloride with water, dried over sodium sulfate and evaporated under reduced pressure. The remaining 2-acetyl-6-methoxynaphthalene was refluxed for 2 hours in 2 cc of morpholine containing 0.5 g of sulfur, then filtered and evaporated. The thioamide derivative obtained was extracted with diethyl ether, the extracts combined and evaporated.

The residue was concentrated in 10 cc. Hydrochloric acid reflux for 2 hours heated to 250C. cooled and made alkaline with aqueous sodium hydroxide.

The mixture was then extracted with ether and the extracts discarded.

The aqueous layer was acidified and the precipitated 6-methoxy-2-naphthylacetic acid filtered off in a similar manner from the corresponding naphthalene starting materials 6-methyl-2-naphthylacetic acid, 6-ethyl-2-naphthylacetic acid, 6-ethoxy-2-naphthylacetic acid, 6-cyclopropyl-2-naphthylacetic acid, 6-propyl-2-naphthylacetic acid, 6-n-butyl-2-naphthylacetic acid, 6-cyclopentyl-2-naphthylacetic acid, 6-isopropyl-2-naphthylacetic acid, 6-cyclobutyl-2-naphthylacetic acid, 6-hexyl-2-naphthylacetic acid, 6-pentyl-2-naphthylacetic acid, acetic acid, 6-hexyl-2-naphthylacetic acid, 6-pentyl-2-naphthylacetic acid, 6-isopropyloxy-2-naphthylacetic acid and 2-naphthylacetic acid manufactured.

e e i s p i e 1 2 To a mixture of 22 g of methyl 2- (6-methoxy-2'-naphthyl) acetate (prepared by treating 20.5 g of 2- (6'-methoxy-2'-naphthyl) acetic acid with 4.5 g of diazomethane in ether) and 2.5 g of sodium hydride in 150 cc of 1,2-dimethoxyethane 25 g of methyl iodide were added. The reaction mixture was allowed to stand for a few hours left, then diluted with ethanol and with water and extracted with methylene chloride. The extracts were combined, washed neutral with water, over sodium sulfate dried and filtered and evaporated; methyl 2- (6'-methoxy-2'-naphthyl) propionate was obtained in this way.

This compound was hydrolyzed to the corresponding acid with a base.

Similarly, the other 6-substituted products of Example 1 converted to the corresponding propionic acid and ester.

Example 3 To a solution of 1 chemical equivalent of triphenylphosphine 1 chemical equivalent of ethyl 2-bromo-n-propionate was added in 30 cc of benzene and the mixture is refluxed for 1 hour. Then it was filtered and that insoluble material recovered and added to 50 cc of tetrahydrofuran. It was 1 Equivalent of sodium methoxide was added and the mixture until a solution was formed touched.

The Wittig reagent thus prepared became 1 chemical equivalent 6-Methoxy-1-tetralone added and the mixture obtained at temperatures between 150-200 ° C. heated until the reaction was complete, which was done using a chromatographic plate was displayed. The cool reaction mixture was triturated with hexane and the crystalline Triphenylphosphine oxide filtered off. The filtrate; 6-methoxy-1,1- (1'-carbethoxyethy-1 ', 1'-ylidene) tetralone contained was concentrated under vacuum and the residue with 5% palladium-on-animal charcoal as a catalyst (100 mg per g ester) at 180 ° C. 5 hours heated; in this way, ethyl 6-methoxy-1-naphthyl-α-methyl acetate was obtained.

A suspension of 1 g of ethyl 6-methoxy-1-naphthyl-α-methyl acetate in 60 cc of methanol was mixed with a solution of 1 g of potassium carbonate in 6 cc of water treated. The mixture was refluxed for 1 hour, cooled in ice, and diluted with water. The solid formed was filtered off, washed with water and dried; the 6-methoxy-, 1-naphthylmethyl acetic acid obtained from Acetone / hexane was recrystallized.

Similarly, Example 1 was correspondingly 6-substituted 1-naphthyl-α-methyl acetic acid compounds.

Example 4 Liquid ammonia to which dried over stable sodium and had been distilled (600 cc), 300 cc of dry tetrahydrofuran and 150 cc of dry methanol were mixed with stirring. After mixing were under 10 g of 2-naphthylacetic acid were added with constant stirring. The mixture obtained was 5 g of lithium wire in 0.5 g portions are added over the course of 2 hours, with the reaction mixture was kept at reflux temperature. After the reaction time the ammonia became Allowed to evaporate, and there were 100 cc of water and then 200 cc of 10% hydrochloric acid added, the reaction mixture was extracted with ethyl acetate and the extracts dried over sodium sulfate and evaporated. The residue after evaporation was recrystallized from methanol to give (1 ', 4', 5 ', 8'-tetrahydronaphth-2'-yl) acetic acid.

According to the above procedure, the starting compounds of Example 1, 2 and 3 the corresponding (1 ', 4', 5 ', 8'-tetrahydronaphth-1'-yl) acetic acids and the corresponding 6-substituted derivatives thereof.

B e i p i 1 e 1 5 A solution of 10 g of 6-methoxynaphth-2-ylacetic acid in 500 cc of methanol was saturated with 10 cc of methanol with gaseous hydrochloric acid was treated. After maintaining this treatment for 6 hours at 20 ° C.

the solution was evaporated to give methyl 6-methoxynaphth-2-ylacetate.

A solution of 1 g of methyl 6-methoxynaphth-2-ylacetate in 50 cc of tetrahydro Furan was stirred into a suspension of 1 g of lithium aluminum hydride within 30 minutes added in 50 com anhydrous tetrahydrofuran.

The mixture was refluxed for 2 hours then caution 5 cc of ethyl acetate and 2 cc of water were added. Sodium sulfate was then added, the mixture was filtered and the solid thus obtained with hot ethyl acetate washed. The combined organic solutions were evaporated to give 2- (6'-methoxynaphth-2'-yl) -ethonol, which can be further purified by recrystallization from acetone / hexane.

The compound thus produced was treated according to Example 4 and gave 2- (6'-methoxy-1 ', 4', 5 ', 6'-tetrahydro-2' -) ethanol.

Example 6 To a mixture of 2 g of 2- (6'-methoxy-1 ', 4', 5 ', 8'-tetrahydronaphth-2'-yl) Ethanol and 35 cc of methanol became a solution of 0.1 g of oxalic acid in 5 cc of water added. The mixture was left to stand for about 2 hours at room temperature, then diluted with water and extracted with methylene chloride. The methylene chloride extracts were combined, washed, dried and evaporated and yielded 2- (6'-Oxo-1 ', 4', 5 ', 6', 7 ', 8'-hexahydronaphth-2'-yl) ethanol.

Example 7 A solution of 1 g of 2- (6'-Oxo-1 ', 4', 5 ', 6', 7 ', 8'-hexahyronaphth-2'-yl) ethanol in 50 cc of tetrahydrofuran became a suspension with stirring within 30 minutes from 1 g of lithium aluminum hydride in 50 cc of anhydrous tetrahydrofuran added and this mixture was refluxed for 2 hours. 5 cc were added to the mixture Ethyl acetate and 2 cc of water were added. Sodium sulfate was then added to the mixture was filtered and the solid thus obtained was washed with hot ethyl acetate. The combined organic solutions were evaporated to give Z- (6'-hydroxy-1 ', 4', 5 ', 6', 7 ', 8'-hexahydronaphth-2'-yl) ethanol, which can be further purified by recrystallization from acetone / hexane.

Example 8 2.65 g of zinc dust and 0.75 g of cuprous chloride were used in 12.5 ccm of diethyl ether and the resulting solution heated to boiling and 30 Refluxed for minutes under a nitrogen atmosphere. Thereafter the mixture was brought to 0 ° C. cooled and there was 1.5 cc (5 g) of methylene iodide admitted. After the addition, the mixture was carefully heated to the boiling point and refluxed for 30 minutes. Then 1 g of hydroxy-1 ', 4', 5 ', 6', 7 ', 8'-hexahydronaphth-2'-yl) -äzthanol, dispersed in 2 cc of diethyl ether, added to the mixture, which was cooled in ice water became.

The resulting mixture was at 00C for 135 minutes. held, then on Room temperature warmed up, kept at this temperature for 1 hour and then to the Heated to reflux. After 90 minutes under reflux, the reaction mixture was cooled, and 5 cc of a saturated aqueous ammonium chloride solution were added. The ether solution was made with saturated aqueous sodium sulfite and then washed with water. The ether solution was dried and evaporated and the crude product is chromatographed on 10 g of silica gel, using a 1: 1 mixture eluted from ether and hexane; thus obtained 2- (6'-hydroxy-9 ', 10'-methano-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'-octahydronaphth-2'-yl) -ethanol as a product.

For example 9 part A 40 g of methyl 2- (6'-hydroxy-1 ', 4', 5 ', 6', 7 ', 8'-hexahydrinaphth-2'-yl) propionate (prepared according to Example '- 5-7) and 42.5 g of potassium tert-butoxide were under Stir to 2 liters of ether at -550C. added. To the obtained mixture, 36 g of chloroform was added in 200 cc of ether added, the resulting reaction mixture was at room temperature let come and then filtered and evaporated; the residue was obtained from ether / hexane recrystallized to give 2- (6'-hydroxy-9 ', 10'-dichloromethano-1', 4 ', 5', 6 ', 7', 8 ', 9', 10 ' octahydronaphth-2'-yl) propionic acid methyl ester as product.

Part B To a refluxed solution of 1 g of 2- (6'-hydroxy-1 ', 4', 5 ', 6' 7 ', 8'-hexahydronaphth-2'-yl) propionic acid methyl ester in 10 cc of dimethyltribthylene glycol ether was added 10 cc of a 50% w / v solution with stirring and under a nitrogen blanket added from sodium trichloroacetate. The solution was cooled and filtered and the filtrate was evaporated to dryness under reduced pressure. The residue thus obtained was chromatographed on alumina, eluting with hexane / methylene chloride; thus obtained 2- (6'-hydroxy-9 ', 10'-dichloromethano-1', 4 ', 5', 6 ', 7', 6 ', 9', 10'-octahydronaphth-2'-yl ) -propionic acid methyl ester as a product.

Part C 1 g of 2- (6'-hydroxy-1 ', 4', 5 ', 6', 7 ', 8'-hexahydronaphth-2'-yl) propionic acid methyl ester and 2.7 g of phenyltrichloromethylmercury were in 50 cc dry Dissolved benzene and the resulting mixture for 3 hours under a nitrogen atmosphere heated to reflux. Then became; another g of the mercury reagent added, and it was refluxed for a further 5 hours. After the reflux period of 5 hours a further 1.7 g of mercury reagent were added and the resulting mixture was filtered and the filtrate evaporated to dryness; - So you got an oil on silica gel was chromatographed. The fractions were eluted with hexane / ethyl acetate and gave the 2- (6'-hydroxy-9 ', 10'-dichloromethano-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'-octahydronaphth-2 ' yl) propionic acid methyl ester as the product.

For example 1 10 4 g (6'-hydroxy-1 ', 4', 5 ', 6', 7 ', 8'-hexahydronaphth-2'-yl) -acetic acid and 2.5 g of potassium tert-butoxide were dissolved in 200 cc of diethyl ester at -550C. dispersed. Then 5 g of chlorodifluoromethane in 50 cc of ether were added and the mixture up Let come room temperature. The solution was filtered and evaporated and the residue at -20 ° C. recrystallized from ethyl acetate; this gave the (6'-Hydrocy-9 ', 10'-difluarrslethano-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'-octahydronaphth-2'-yl) - acetic acid as a product.

The procedures of Parts B and C of Example 9 were repeated, wherein the starting material of the first paragraph of Example 10 and sodium chlorodifluoroacetate btw. Phenyltrifluoromethylmercury was used; the (6'-hydroxy-9 ', 10'-difluoromethanmo-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'-octahydronaphth-2'-yl) - acetic acid as a product.

Example 1 11 A solution of 6 g of 2- (6'-hydroxy-9 ', 10'-methane-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'-octahydronaphth -2'-yl) acetic acid in 120 cc of pyridine became a mixture of 6 g of chromium trioxide in 20 cc of pyridine added. DiC reaction mixture was left to stand at room temperature for 15 hours diluted with ethyl acetate and filtered through Celite diatomaceous earth. The filtrate was washed well with water, dried and evaporated to dryness giving 2- (6'-oxo-9 ', 10'-methano-1', 4 ', 5', 6 ', 7', 8 ', 9', 10 '-octahydronaphth-2'-yl) acetic acid, which can be further purified by recrystallization from acetone / hexane.

Similarly, the above procedure was used to prepare the 6'-oxo compounds corresponding to the products of Example 9 and the reduced ethanols / derivatives thereof applied via the selectively protected ethanol hydroxyl group.

Example 12 A mixture of 1 g (6'-Oxo-9 ', 10'-methano-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'-octahydronaphth-2 ' -yl) acetic acid, 15 cc of acetic anhydride and 0.2 g of sodium acetate were refluxed for 1 hour, then into a dilute one for hydrolysis of any excess anhydride Poured sodium bicarbonate solution and this mixture extracted with methylene chloride. The methylene chloride extracts were combined, washed, dried, evaporated and chromatographed and gave the (6'-acetoxy-9 ', 10'-methano-1', 4 ', 5', 8 ', 9', 10'-hexahydronaphth-2'-yl) -acetic acid.

Similarly, by using the appropriate carboxylic anhydride, such as Propionate, butyrate, valerate, etc., the other enol esters according to the invention will.

Example 1 13 A mixture of 3 g (6'-Oxo-9 ', 10'-methano-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'-octahydronaphth-2 '-yl) acetic acid, about 2 equivalents of zinc powder and 200 occm dry tetrahydrofuran was about 2 hours at 50-600C. touched. Stirring was continued until formation was complete of the zinc enolate, which was followed by thin-layer chromatography. The mixture was allowed to stand and cool and then decanted under anhydrous conditions. About 50 cc of dimethyl sulfate and the mixture were added to the solution thus obtained stirred, then at room temperature until the enol ether is completely formed left standing, followed by thin layer chromatography, and finally poured in water. This mixture was extracted with methylene chloride, the extracts were washed, dried, evaporated and chromatographed to give the (6'-methoxy-9 ', 10' methano-1 ', 4', 5 ', 8', 9 ', 10'-hexahydronaphth-2'-yl) -acetic acid.

The other enol esters according to the invention such as the ethoxy, propyloxy, butyloxy compounds, etc.

For example 14,200 mg (6'-acetoxy-9 ', 10'-methano-1', 4 ', 5', 8 ', 9', 10'-hexahydronaphth-2'-yl) -acetic acid methyl ester were dispersed in 6 cc of dioxane at room temperature with stirring. To the received Mixing was added while stirring and cooling the reaction mixture to 250C. 1 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone admitted. The resulting mixture was heated to boiling point and under for 4 hours Reflux, then the solution was cooled and dissolved in ethyl acetate poured. The resulting mixture was filtered and the filtrate was washed twice with water, dried over magnesium sulfate, filtered through 10 g of neutral clay and evaporated; so the 8-acetoxy-1,6-methano- [10] -annulene-3-acetic acid methyl ester was obtained as Product. This product can also be called (1 ', 6'-Methano-8'-acetoxycyclohexapentaen-3'-yl) -acetic acid are designated.

Similarly, the other enol esters and ethers were the present Invention (see Examples 12 and 13) converted into the corresponding Ännulenprodukte, e.g. the methyl esters of: 8-methoxy-1,6-methano- [10] -annulene-3-acetic acid, 8-butyloxy-1,6-difluoromethano- [10] -annulene-3-acetic acid, 2- (8-methoxy-1,6-dichloromethano- [10] -annulen-3-yl) -ethanol, 8-propionyloxy-1,6-dichloromethano- [10] -annulene-3-acetic acid, 8-propionyloxy-1,6-methano- [10] -annulene-3-acetic acid, 8-ethoxy-1,6-methano-ffi102-annulene-3-acetic acid, 2- (8-propyloxy-1,6-methano- [10] -annulen-3-yl) -ethanol, 2- (8'-ethoxy-1 ', 6'-methano- [10] -annulen-3-yl ) propionic acid, 2- (8'-methoxy-1 ', 6'-methano- [10] -annulen-3-yl) -propinoic acid and 2- (8'-acetoixy-1', 6'-difluoromethano- [10] -annulene -3-yl) propionic acid.

Example 15 The procedures of Examples 6, 9 and 10 were followed using the G-substituted, -low-alkyl- and -monocyclic lower-alkyl compounds of Example 1 ,. 2 and 3 repeated, creating the corresponding 9g, 10'-bridged-1 ', 4 -', 5 ' 18 ', 9', 10'-hexahydronaphthalene methyl ester was obtained. These connections were made with Benzoquinone treated according to Example 14 and gave e.g.

the methyl esters of (1 ', 5'-methano- [10] -annulen-3-yl) -acetic acid, thano (1,6-dichloromethano- [10] -3-yl) -acetic acid, (1,6-difluoro- [10] -annulen-3-yl) -acetic acid and the various 8-substituted compounds, such as (8-methyl-1,6-methano- [10] -annulen-3-yl) -acetic acid, (8-ethyl-1,6-difluoromethano- [10] -annulen-3-yl) -acetic acid, 8-propyloxy-1,6-difluoromethano- [10] -annulen-3-yl) -acetic acid, (8-Cyclopropyl-1,6-methano- [10] -annulen-3-yl) -acetic acid etc.

For example 1 16 1 g of methyl 2- (9 ', 10'-dichloromethano-1', 4 ', 5', 8 ', 9', 10-hexahydronaphth-2'-yl) propionate was dispersed in 50 cc of dioxane at room temperature. To the mixture obtained 5 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone were added at room temperature with stirring admitted. Then the reaction mixture was heated to boiling point and 6 hours held under reflux.

It was then chromatographed on 25 g of silica gel, with Ether / hexane was eluted; the 2- (1 ', 6'-dichloromethano-2', 5'-dihydro- [10] -annulen-3'-yl) propionic acid was obtained in this way.

67 mg of 2- (1 ', 6'-dichloromethano-2', 5'-dihydro-ffi102-annulan-3 yl) propionic acid were dispersed in 15 cc of methylene chloride at room temperature. The received Solution was at -80 ° C. cooled, and at this temperature slowly became 1 molar Equivalent of bromine, dispersed in 1.8 cc of methylene chloride, was added. After 10 minutes the solution was evaporated and the residue was recrystallized from 1: 1 ether / methanol; thus obtained 2- (1 ', 6'-dichloromethano-3', 4 '-. dibromo [10] -annulen-3'-yl) propionic acid, which was dispersed in 6 cc of dimethylformamide at room temperature with stirring.

0.2 cc of diazabicyclonones was added to the solution obtained. To 3 day Standing the reaction mixture at room temperature was made the solution poured into water, acidified with dilute HCl and extracted with ether. The ether extracts were isolated and washed 3 times with water. The washed Material was dried over magnesium sulfate and evaporated to give the 2- (1 ', 6'-dichloromethano-; 10l-annuien-3-yl} propionic acid as a product.

B e i s p i e 1 17 1 g 2- (6'-methyl-9 ', 10'-difluoromethano-1', 4 ', 5', 8'-tetrahydronaphth-2'-yl) Methyl propionate was added to 10 cc of dioxane at room temperature with stirring added. The resulting mixture was heated to 25 ° C. held, and was stirred with stirring 1 chemical equivalent of tetrachloro-1,4-benzoquinone added.

The temperature of the reaction mixture was then raised to the boiling point.

After refluxing for 6 hours, the obtained was poured into ethyl acetate Mixture washed with water and filtered through neutral clay. The filtrate was washed with water, dried and evaporated to give the methyl ester 2- (8'-methyl-1 ', 6'-difluoromethyl-2', 5'-dihydro- [10] -annulen-3'-yl) propionic acid.

EXAMPLE 18 The product described in Example 17 was used with Treated bromine, and the resulting dehydrobrominate was used as in Example 16 for preparation of 2- (8'-methyl-1 ', 6'-difluoromethano- [10] -annulen-3'yl) propionic acid as the product implemented.

Example 19 Example 17 was made with about 2 chemical equivalents Tetrachlor-1, 4-benz, oquinone repeated. Hydrolysis was preferably obtained in this way from the methyl ester, 2- (8'-methyl-1 ', 6'-dichloromethano- [10] -annulen-3'-yl) propionic acid as a product.

Ex. 1.20 According to the above procedures, those in the following Column A mentioned starting compounds with the corresponding ones mentioned in column B. Reactants implemented, giving the corresponding, listed in column C. Products received.

A 2- (1 ', 1'-dimethyl-2'-hydroxyethyl) -9,10-methano-1,4,5,8,9,10-hexahydronaphthalene, 2- (1'-ethyl-1'-methyl-2'-acetoxyethyl) -9,10-dichloromethano-1,4,5,8,9,10-hexahydronaphthalene, 2- (1'-ethyl-1'-methyl-2'-carbamoylethyl) -9,10-methano-1,4,5,8,9,10-hexa-hydronaphthalene, 1-carbopropoxymethyl-9,10-difluoromethano-1,4,5,8,9,10-hexahydronaphthalene, 1- (2'-hydroxyethyl) -9,10-methano-1,4,5,8,9,10 -hexahydronaphthalene, 2- (2'-n-butoxyethyl) -9,10-dichloromethano-1,4,5,8,9,10-hexahydronaphthalene, 2-carboxymethyl-9, 10-methano-1,4,5,8,9, 10-hexahydronaphthalene B 1,2-benzoquinone, tetrachloro-1,2-benzuchinone, Tetrachloro-1,4-benzoquinone, 2,3-difluoro-1,2-benzoquinone, 2,3-difluoro-1,4-benzoquinone, 2,3-Dicyan-1,2-benzoquinone, 2,3-dicyan-1,4-benzoquinone, 2,3-dichloro-5,6-dicyan-1,4-benzoquinone C. 3- (4 ', 1'-dimethyl-2'-hydroxyethyl) -1,6-methano- [10] -annulene, 3- (1'-ethyl-1'-methyl-2'-acetoxyethyl) -1, 6-dichloromethano- [10] -annulene, 3- (1'-Ethyl-1'-methyl-2'-carbamoylethyl) -1,6-methano- [10] -annulene, 3-carbopropoxymethyl-1,6-difluoromethano- [10] -annulene, 2-formyl-1,6-methano- [10] -annulene, 3- (2'-n-butoxyethyl) -1,6-dichloromethano- [10] -annulene and 3-carboxyethyl-1,6-methano- [10] -annulene.

The following examples show the products according to the invention compounds obtained can be worked out further.

Example 1 21 A solution of 1 g of 3-carbomethoxymethyl-1,6-methano- [10] -annulene in 50 cc of tetrahydrofuran became a suspension with stirring within 30 minutes from 1 g of lithium aluminum hydride in 50 cc of anhydrous tetrahydrofuran was added and this mixture is refluxed for 2 hours. Then carefully 5 cc Ethyl acetate and 2 cc of water were added. Sodium sulfate was then added, the mixture was filtered and the solid thus obtained with hot ethyl acetate washed. The combined organic solutions were evaporated to give 1,6-methano-3- (2'-hydroxy ethyl) - [10] -annulene, which is further purified by recrystallization from acetone / hexane can be.

EXAMPLE 1 22 A mixture of 1 g of 1,6-methano-3- (2'-hydroxyethyl) - [10] -annulene, 1 g of p-toluenesulfonic acid monohydrate, 50 cc of acetic acid and 25 cc of acetic anhydride were allowed to stand at room temperature for 24 hours, then eaten in water and stirred. This mixture was then washed with methylene chloride extracted and these extracts dried and evaporated; in this way, 1,6-methano-3- (2'-acetoxyethyl) - [10] -annulene was obtained, the acetone / ether was recrystallized.

Similarly, those were made by the above procedures hydroxyl-containing annulene products converted into the corresponding acetate esters. That The above process can also be used with other carboxylic acid anhydrides to produce the corresponding carboxylate esters of the hydroxy-containing annulene products applied such as propionate, butyrate, valerate, caproate, enanthate and caprylate.

B e i 5 p i e 1 23 2 cc dihydropyran were added to a solution of 1 g 1,6-methano-3- (2'-hydroxyethyl) - () J-annulene in 15 cc benzene was added. About 1 cc was distilled off to remove moisture, and to the cooled solution 20 mg of p-toluenesulfonyl chloride were added. This mixture was for 4 days Left to stand at room temperature, then and aqueous sodium carbonate solution and with Washed water, dried and evaporated. The residue became more neutral Chromatographed clay, eluting with Xther / hexane; 1,6-methano-3- (2'-tetrahydropyran-2'-yloxyethyl) - [10] -annulene was obtained, the earth recrystallized from Sither / Hexane.

If the dihydropyran is replaced by dihydrofuran in the above process, the corresponding tetrahydrofuran-2'-yloxy compound is obtained in this way.

Furthermore, the above process can be used with other hydroxyannulene products can be used to produce the appropriate ethers.

Example 24 A solution of 1 chemical equivalent of 1,6-methano-3- (2'-hydroxyethyl) - [10] -annulene in 30 cc of benzene was heated to reflux; to eliminate moisture about 2 cc distilled off. The mixture was cooled to room temperature; it 1 chemical equivalent of sodium hydride was added then 2 chemical equivalents were added Cyclopentyl bromide in 10 ccm of enzene was added dropwise within 20 minutes. The mixture was refluxed for 20 hours, then the sodium bromide precipitate became filtered off and the organic phase dried and evaporated; so you got 1,6-Methano-3- (2'-cyclopentyloxyethyl) - [10] -annulene, which is obtained by recrystallization was further purified from pentane.

The above procedure made the corresponding other annulene products the corresponding cyclopentyloxy compounds prepared.

Example 25 A solution of 1 g of 1,6-difluoromethano-3-carboethoxymethyl- [10] -annulene in 50 ccm of ethylene glycol was mixed with a liner solution of potassium hydroxide in 1 for 3 hours cc of water heated to reflux, then the reaction mixture was poured into ice water and the solid formed is filtered off, washed neutral with water and dried. This gave 1,6-difluoromethanocarboxymethyl- [10] -annulene, which was obtained from methylene chloride / ether was recrystallized.

According to the above process, other annulene ester products according to the invention can be obtained the corresponding carbic acid compounds are produced, B. e i s p i e l 26 To a solution of 10 g of 1,6-difluoromethano-3-carboxymethyl- [10] -annulene in 200 cc of ethanol the theoretical amount of potassium hydroxide, in 200 cc of 90% Dissolved methanol, added. The reaction mixture was concentrated under vacuum and gave the potassium salt of 1,6-difluoromethano-3-carboxymethyl- [10] -annulene.

According to the above process, other annulene products according to the invention the corresponding metal salts are produced.

In addition, other metal salts according to the invention can be prepared by analogous processes getting produced.

B e i 5 p i e l 27 A solution of 10 g of 3-carbsXymethyl-8-methyl-1,6-dichiromethano-g10g-annulene in 50 cc of thionyl chloride was heated to reflux for 1 hour. Then the solution evaporated to dryness and gave the corresponding acid chloride, which resulted in a conc. essential ammonia solution was added. The resulting solution was evaporated and gave the amides of 1,6-dichloromethano-3-carboxymethyl-8-methoxy- [10] -annulene.

According to the above process, other annulene products according to the invention the corresponding carboxamide compound can be prepared.

For example 28 2 g (1,6-methano-8-acetoxy- [10] -annulen-3-yl) -acetic acid in 20 cc of diethyl ether became an ethereal solution of 1.2 molar equivalents Diazomethane added. The mixture obtained was at OOC. stand for about 1 hour left and then evaporated under reduced pressure; this gave the methyl ester of 1,6-methano-3-carbomethoxymethyl-8-actoxy- [10] annulene.

Example 1 29 A solution of 6 g of 1,6-difluoromethano-3- (2'-hydroxyethyl) - [10] -annulene in 120 cc of pyridine became a mixture of 6 g of chromium trioxide in 20 cc of pyridine added, the reaction mixture was left to stand for 15 hours at room temperature, diluted with ethyl acetate and filtered through Celite diatomaceous earth. The filtrate was washed well with water, dried luld evaporated to dryness and gave 1,6-difluoromethano-3-formylmethyl- [10] annul.

Example 30 A mixture of 3 g of methyl 2- (8'-methoxy-1 ', 6'-difluoromethano- [10] -annulene 3'-yl) propionic acid, 1 molar equivalent of sodium methoxide, 1 molar equivalent Hydroxylamine hydrochloride and 5D ccm methanol were left to stand for about 16 hours, then the mixture was filtered and the filtrate evaporated.

The residue was neutralized by adding aqueous 1N hydrochloric acid and extracted with ether. The iitherextralcte were combined, washed with water, dried and evaporated; thus obtained 2- (8'-methoxy-1 ', 6' difluoromethano- [10] -annulen-3'-yl) propionylhydroxamic acid.

The following examples illustrate the elaboration of the α W carbon atom.

Example 31 0.05 mol of (1,6-methano- [10] -annulen-3-yl) -acetic acid methyl ester was dissolved in 25 com of dimethyl sulfoxide containing 0.05 mol of sodium ethoxide; then gaseous formaldehyde was introduced up to a weight increase of 3 g. The mixture was stirred for 6 hours at room temperature, then was diluted 50 cc HCl added. The solution was extracted with ether and the extracts washed, dried and steamed; the 2- (1 ', 6'-methano- [10] -annulen-3-yl) -acrylic acid methyl ester was obtained in this way.

The above methyl ester can be prepared by methods known per se, e.g. hydrolyzed with aqueous sodium hydroxide to the corresponding acrylic acid compound will.

B e i S p i. C, 1 32 A mixture of 7 g methylene iodide and 3 g zinc-copper pair in 15 cc of anhydrous ether, the mixture was refluxed for 3 hours under nitrogen.

Then the mixture was cooled and there was 2 g of 2- (1 ', 6'-methano-D107-annulen-3'-yl) -acrylic acid methyl ester added. This mixture was refluxed for 2 hours, then in 200 cc of 2% strength Poured aqueous sodium carbonate and extracted twice with 100 ccm of ether each time. These Extracts were dried over sodium sulfate and evaporated under reduced pressure. The residue was used to remove unreacted methylene chloride at 0.01 Maintained mm and then recrystallized from hexane; this gave 1,6-methano-3- (1 ', 1'-ethylenecarbomethoxymethyl) - [10] -annulene.

If 1 33 0.1 mol (1, H.lethano-L102-annulen-3-yl) -acetic acid methyl ester was dissolved in 100 cc of glyme; then there were 0.1 moles of sodium hydride and 0.1 moles of 1,4-dibromobutane added. The mixture was at 90 ° C for 4 hours. heated, then another 0.1 Moles of sodium hydride added. The mixture was kept at 90 ° C. for a further 3 hours. heated and cooled down. To the mixture obtained, 1 l of water was added and the solution with Ether extracted. The extracts were washed, dried and evaporated and gave 1,6-methano-3- (1 ', 1'-butylenecarbomethoxymethyl) - [10] -annulene.

The corresponding acid was produced by basic hydrolysis. In the above procedure, instead of 1,4-dibromobutane, 1,3-dibromopropane and 1,5-dibromopentane were used used, the corresponding '1', 1'-propylene and 1 ', 1'-pentylene products were obtained.

Example 34 To a mixture of 22 g of the methyl ester of 1,6-methano-8- (1'-carbomethoxymethyl) - [10] -annulene, 1 equivalent of sodium hydride and 150 cc of 1,2-dimethoxyethane became 1 equivalent of methyl iodide added. The reaction mixture was left to stand for a few hours and then with Diluted ethanol and water. The mixture was extracted with methylene chloride and the extracts combined, washed, dried and evaporated; this gave 1,6-methano-3 (1'-carbomethoxyeth-1'-yl) - [10] -annulene.

By repeating the above procedure with 2 equivalents each time Sodium hydride and methyl iodide gave the corresponding 1,6-methano-3- (2'-carbomethoxypro-2'-yl) - [10] -annulene or 2- (1 ', 6'-methano- [10] -annulene-3'-y1) -isobutyric acid.

In the above procedure, when the methyl iodide was used, other lower alkyl iodides became replaced; the corresponding alkylated products were obtained, e.g.

2- (1 ', 6'-methano- [10] -annulen-3'-yl) -butanoic acid, 2-ethyl-2- (1', 6'-methano- [10] 'annulen-3'-yl ) -butanoic acid, 2- (1 ', 6'-methano- [10] -annulen-3'-yl) -pentanoic acid, etc.

Example 35 A solution of 10 g of 2-naphthylacetic acid in 100 cc of a 1: 1 mixture of ethanol and ether turned into 15 g of sodium in 500 cc of liquid ammonia at -78 ° C. after about 1 hour the excess sodium was added by addition destroyed by ammonium chloride, and about 50 cc of water were added. then the reaction mixture was allowed to come to room temperature, whereupon about 2n0 cc of water and then about 400 cc of ether were added. The ether layer was separated, washed, dried over magnesium sulfate and evaporated; 1,4,5,8-tetrahydro-2-naphthyl was obtained in this way acetic acid, which is further purified by recrystallization from aqueous methanol can be.

By repeating the above procedure with 2- (6l4slethuxy-2'-naphthyl) ethanol 2- (6'-methoxy-1 ', 4', 5 ', 8'-tetrahydro-2' naphthyl) -dthanol was obtained as starting material.

Example 1 36 (A) A solution of 1 g of 1,4,5,8-tetrahydro-2-naphthylacetic acid in dry tetrahydrofuran was about .48 hours with a molar excess heated to reflux on lithium aluminum hydride and then with water and ethyl acetate diluted. The ethyl acetate layer was separated, washed, dried and evaporated and gave 2- (1 ', 4', 5 ', 8'-tetrahydro-2'-naphthyl) ethanol.

(B) A mixture of 1 g of the above compound and 4 cc of pyridine 4 cc of acetic anhydride was left to stand at room temperature for 15 hours, then poured into water and extracted a few times with ethyl acetate. These extracts were combined, washed with dilute I1C1 and water, dried and evaporated; the acetate of 2- (1 ', 4', 5 ', 8'-tetrahydro -2'-naphthyl) ethanol.

Was identified in the procedure of Part A 64Methoxy-2-naphthylacetic acid as Used starting material, 2- (6'-methoxy-2'-naphthyl) ethanol was obtained.

As an alternative to the procedure of Part A of this example, the Acid into the methyl ester before the reaction, e.g. by treatment with diazomethane, etc. which is then converted by treatment with lithium aluminum hydride at about Room temperature can be converted into alcohol for about 2 hours.

Example 1 37 (A) A solution of 5 g of the acetate of 2- (1 ', 4', 5 ', 8'-tetrahydro-2'-naphthyl) ethanol in 100 cc diglyme was at about 1350C. heated. Then it slowly became a solution from 1.5 equivalents of sodium trichloroacetate in 100 cc diglyme within about 1 hour added. The reaction mixture was allowed to cool to about room temperature left and then diluted with water and ethyl acetate. The ethyl acetate layer was separated, washed, dried over magnesium sulfate and evaporated to give a mixture containing the acetate of 2- (9 ', 19'-dichloromethylene-1', 4 ', 5', 8 ', 9', 10'-hexahydro-2'-naphthyl) ethanol which was separated by chromatography.

In the above procedure, sodium chlorodifluoroacetate was used instead of sodium trichloroacetate used, the acetate of 2- (9 ', 10'Oifluoro'-methylene-1', 4 ', 5', 8 ', 9', 10'-hexahydro-2'naphthyl) ethanol was obtained.

(B) A solution of 0.75 g of the acetate of 2- (D '? 1Q'-dichloromethylene-1', 4 ', 5', 8 ', 9', 10'-hexahydro-2'-naphthyl) - ethanol in 50 cc of ether became a solution of 500 mg of sodium in 150 cc of liquid ammonia added with stirring. After 2 hours, ammonium chloride turned to disappear of the blue color was added and the ammonia was allowed to evaporate. After extraction with ether one obtained 2- (9 ', 10'-methylene-1', 4 ', 5', 8 ', 9', 10'-hexahydro-2'-naphthyl) -ethanol, which can be further purified by chromatography.

B e i 5 p i e 1 38 (A) 2 cc dihydropyran were made into a solution 1 g of 2- (9 ', 10'-methylene-1', 4 ', 5', 8 ', 9', 10'-hexahydro-2'-naphthyl) ethanol in 15 cc Benzene added. To remove moisture, about 1 ccm was distilled off, and 10 mg of p-toluenesulfonic acid were added to the cooled solution. This mixture was left to stand at room temperature for 4 days, then with aqueous sodium carbonate solution and water, dried and evaporated.

The residue was chromatographed on neutral clay, whereby eluted with hexane; the tetrahydropyran-2 "-yl ether of 2- (9 ', 10'-methylene-1', 4 ', 5', 8 ', 9', 10'-hexahydro-2'-naphthyl) ethanol was obtained in this way.

(a) To a solution of 1 g of the above tetrahydropyran-2'1-yl ether in 100 cc of carbon tetrachloride containing a trace of pyridine became 2 molar Equivalents of bromine in 50 cc of carbon tetrachloride were added. The reaction mixture was left to stand at room temperature for about 20 hours, washed, dried and evaporated; in this way the tetrahydropyran-2 "-yl ether of 2- (2 ', 3', 6 ', 7'-tetrabromo-9', 10'-methylenedecahydro-2'-naphthyl) -flthapol was obtained.

1 g of the above 2,3,6,7-tetrabromo compound was dissolved in 15 cc of tetrahydrofuran dissolved, then about A g of potassium tert-butoxide were added. The reaction mixture was stirred for about 3 hours and then diluted with water and ether. The ether layer was separated, washed, dried and evaporated to give the tetrahydropyran-2 "-yl ether of 2- (1 ', 6'-methanocyclodecapentaen-3'-yl) ethanol.

Example 39 (A) To a solution of 1 g of tetrahydropyran-2 "-yl ether of 8- (1 ', 6'-Methanocyclodesagentaen-3'-yl) -ethanol in 30 cc of acetic acid 0.5 cc of 2N hydrochloric acid was added. The mixture was left for about 5 hours at room temperature left to stand, then diluted with water and extracted with methylene chloride. These Extracts were washed neutral with water, dried and evaporated to give 2- (1 ', 6'-methanocyclodecapentaen-3'-yl) ethanol (B) A mixture of 1 g of 2- (1', 6'-methanecyclodecapentaen-3'-yl) ethanol and 55 cc of pyridine became a mixture of 1 molar equivalent of chlorine trioxide in 20 cc pyridine added. The reaction mixture was left at room temperature for 15 hours stand elase, dilute with ethyl acetate and filter. The filtrate turned out fine with Washed dilute hydrochloric acid and water, dried and evaporated to give 2- (1 ', 6'-methano-cyclodecapentaen-3'-yl) -ethanol or 1,6-methano-cyclodecapentaen-3-ylacetaldehyde).

(C) The procedure of Part 8 was performed using the one prepared above Aldehyde repeated from starting material; this gave 1,6-methanocyclo decapentaen-3-ylacetic acid.

8 0 i 5 p i e 1 40 The procedure of Example 38 (Part B) was repeated, where the starting material is the acetate of 2- (9 ', 10'-dichloromethylene-1', 4 ', 5', 8 ', 9', 10'-hexahydro-2'-naphthyl) ethanol and the acetate of 2- (9 ', 10'-difluoromethylene-1', 4 ', 5', 8 ', 9', 10-hexahydro-2'-naphthyl) ethanol instead of the tetrahydropyran-2 "-yl ether of 2- (9 ', 10'-methylene-1', 4 ', 5', 8 ', 9', 10'-hexahydro-2'-naphthyl) ethanol was used; 2- (1 ', 6'-dichloromethanocyclodecapentaen-3'-yl) ethanol was obtained in this way or 2- (1 ', 6'-difluoromethanocyclodecapentaen-3'-yl) ethanol.

By repeating Example 39 (Part B) with 2- (1 ', 6'-dichloromethanocyclodecapentaen-3'-yl) ethanol and 2- (1 ', 6'-dichloromethanocyclodecapentaen-3'-yl) ethanol as a starting material obtained 2- (11'6'-dichloromethanocyclodecapentaen-3'-yl) ethanol or 2- (1 ', 6'-dichloromethanocyclodecapentaen-3'-yl) -jthanal, after treatment according to Example 38 (Part C) the corresponding acid, i.e. 1,6-dichloromethanocyclodecapentaen-3-ylacetic acid and 1,6-dichloromethanocyclodecapentaen-3-ylacetic acid.

EXAMPLE 41 To a solution of 1 g of 1,6-methanocyclodecapentaen-3-ylacetic acid in 25 cc of ethanol an aqueous solution of 1 molar equivalent was obtained with stirring Potassium bicarbonate added. This mixture was kept until the carbon dioxide evolution ceased stirred and then evaporated; the potassium salt of 1,6-methanocyclodecapentaen-3-ylacetic acid was obtained in this way If sodium bicarbonate was used in the above procedure, the corresponding result was obtained Sodium salt.

The salts can also be prepared by making a solution of the free acid with an alcohol solution of the corresponding alkali metal alkoxide up to titrated to neutrality.

B e i 5 p i e 1 42 A mixture of 1 g of the sodium salt of 1,6-methanocyclodecapentaen-3-ylacetic acid, 3 cc of methyl iodide and 20 cc of dimethylacetamide was left in the dark for 5 hours touched. The excess methyl iodide was reduced by evaporation under reduced pressure Pressure removed. Then the mixture was poured into water and a few times with ether extracted. The combined ether extracts were washed, dried and evaporated and gave the methyl ester of 1,6-methanocyclodecapentaen-3-ylacetic acid.

In the above procedure, instead of methyl iodide, other low ones were used If alkyl iodides were used, the corresponding lower alkyl esters were obtained. several hours The free acids can also be obtained by / treatment with a lower diazoalkane, such as Diazomethane, diazoethane, etc., converted into ether in -the lower alkyl esters will.

B e i s, o i e 1 43 To a mixture of 22 g of the methyl ester of 1,6-methanocyclodecapentaen-3-ylacetic acid, 2.5 g of sodium hydride and 150 cc of 1,2-dimethoxyethane 25 g of methyl iodide were added. The reaction mixture was allowed to stand for a few hours left, then diluted with ethanol and water and extracted with methylene chloride. The combined extracts were washed, dried and evaporated to give the methyl ester of 2- (1 ', 6'-methanocyclodecapentaen-3'-yl) propionic acid.

Example 44 A mixture of 25 g of the methyl ester of 2- (1 ', 6'-methanocyclodecapentaen-3'-yl) propionic acid, 15 g of sodium carbonate, 200 cc of methanol and 25 cc of water were left to stand for 24 hours left, acidified by adding dilute HCl and extracted with methylene chloride. These extracts were combined, washed, dried and evaporated to give 2- (1 ', 6'-methanocyclodecapentaen-3'-yl) propionic acid.

B e i s p i e 1 45 A mixture of 2 g of 2- (6'-methoxy-1 ', 4', 5 ', 54-tetrahydro-2'-naphthyl) ethanol and 35 cc of methanol was heated to reflux, then 3.5 cc of acetic acid was added. This mixture was refluxed for about 15 minutes and then allowed to cool diluted with water and extracted with methylene chloride. The combined methylene chloride extracts were washed, dried and evaporated to give 2- (6'-Oxo-1 ', 4', 6 ', 7', 8'-hexahydro-2'-naphthyl) ethanol, according to the procedure of Example 37 (Part A) in 2- (6'-Oxo-9 ', 10'-dichloromethylene-1', 4 ', 5', 6 ', 7', 8 ', 9', 10 '-octahydro-2'-naphthyl) ethanol and 2- (6'oxo-9 ', 10'-difluoromethylene-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'-octahydro-2'-naphthyl) ethanol was converted.

Example 1 46 Was 2- (6'-Oxo-9 ', 10'-dichloromethylene-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'-octahydro-2'- naphthyl) ethanol Subjected to the procedure of Example 38 (Part A) there was obtained the tetrahydric pyran-2 "-yl ether of 2- (6'-oxo-9 ', 10'-dichloromethylene-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'-octahydro-2'-naphthyl) ethanol , according to Example 37 (Part B) in the tetrahydropyran-2 "-yl ether of 2- (6'-hydroxy-9 ', 10'-methylene-1', 4 ', 5', 6 ', 7', 8 ' , 9'10'-octahydro-2'-naphthyl) ethanol was converted. The 6'-hydroxy derivative obtained in this way was according to Example 39 (part B) to the te'trahydropyran-2 "-yl ether of 2- (6'-0xo-9 ', IO'-nrethyur 1 ', 4', 5 ', 6', 7 ', 8', 9 ', 10'-octahydro-2'-naphthyl) ethanol oxidized.

B e i 5 p i e l 47 A mixture of 2.0 g of tetrahydropyran-2 "-yl ether from 2- (6'-Dxo-9 ', 10'-' methylene-1 ', 4', 5 ', 6', 7 ', 8', 9 ', 10'-octahydro-2'-naphthyl) - ethanol, 2.3 g of cupribromide and 200 cc of methanol were refluxed for 24 hours, then poured into water and extracted with chloroform. The organic extracts were dried over magnesium sulfate and evaporated. The residue became on silica chromatographed and gave the tetrahydropyran-2 "-yl ether of 2- (6'-oxo-7'-bromo-9 ', 10'-methylene-1', 4 ', 5', 6 ', 7', 8 ', 9 ', 10'-octahydro-2'-naphthyl) ethanol.

A mixture of 1-g of the above 7-8romium compound 1.2 g of lithium bromide and 100 cc of dimethylformamide was 20 hours at about 900C. stirred, then in water poured and extracted with ether. The ether extracts were washed well with water, dried and evaporated. The residue was chromatographed on alumina and gave the tetrahydropyran-2 "-yl ether of oxo-9 ', 10'-methylene-1', 4 ', 5', 6 ', 9', 10'-hexahydro-2'-naphthyl) ethanol.

As an alternative to the above process, the 7,8-dehydro compound of the tetrahydropyran-2 "-yl ether of 2- (6'-0xo-9 ', 10' -methylek-1 ', 4i, 5', 8 ', 7', 8 ', 9', 10'-octahydro-2'-naphthyl) ethanol by dehydration using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone be prepared in dioxane under reflux.

8 e i s p i e 1 48 A mixture of 1 g of the tetrahydropyran-2 "-yl ether of 2- (6'-Dxo-9 ', 10'-methylene -1', 4 ', 5', 6 ', 9', 10'-hexahydro-2'-naphthyl) ethanol, 15 cc of acetic anhydride and 0.2 g of sodium acetate were refluxed for 1 hour and then in dilute sodium bicarhenate solution to hydrolyze the excess anhydride poured. This mixture was extracted with methylene chloride and the combined Washed extracts, dried and evaporated; the totrahydropyran-2 "-yl ether was obtained in this way of 2- (1 ', 6'-methano-8'-acetoxycyclodecatetraen-3'-yl) ethanol.

Example 49 A mixture of 2 g of the tetrahydropyran-2 "-yl ether of 2- (1 ', 6'-methano-8'-acetoxycyclodecatetraen-3'-yl) ethanol and 1 molar equivalent N -romosuccinimide in 100 cc carbon tetrachloride was refluxed for about 1.5 hours heated, cooled and filtered. The filtrate was concentrated and left to residue 0.5 g calcium carbonate and 25 ccm dimethylformamide were added. The reaction mixture was refluxed for about 30 minutes and cooled.

The mixture was filtered and the filtrate evaporated; so received the tetrahydropyran-2 "-yl ether of 2- (1 ', 6'-methano-8'-acetoxycyclodecapentaen-3'-yl) ethanol, - which has been purified by chromatography.

The tetrahydropyran-2 "-yl ether of 2- (1 ', 6'-methano-8'-acetoxycyclodecapentaen-3'-yl) ethanol was according to the procedure of Example 39 in 2- (1 ', 6'-methano-8'-acetoxycyclodecapentaen-3'-yl) ethanol, 2- (1 ', 6'-methano-8'-acetoxycyclodecapentaen-3'-yl) ethanol or 1,6-methano-8-acetoxycyclodecapentaen-3-ylacetic acid converted.

B e i 5 p i e 150 1 g of the tetrahydropyran-2 "-yl ether of 2- (1 ', 6'-methano-8'-acetoxycylodeca Pentaen-3i-yl) ethanol was treated with 1 g of potassium bicarbonate at room temperature for 15 hours left to stand in 10 cc of water and 90 cc of methanol, then under reduced pressure concentrated and troubled. The residue became in about 10 cc of anhydrous dioxane and added to this mixture 1 cc of methyl orthoformate and a trace of p-toluenesulfonic acid added. The mixture was left to stand * at room temperature / about 30 minutes, diluted with water, shaken and extracted with methylene chloride. The United Extracts were washed, dried and evaporated to give 2- (1 ', 6'-methano- 4 8'-methoxycyclodecapentaen-3'-yl) ethanol, which is prepared according to the method of Example 39 (Parts B and C) was converted to the corresponding aldehyde and acid.

Example 51 Were the tetrahydropyran-2't-yl ether of 2- (6'-0xo-9 ', 10'-dichloromsthyien-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'-octahydro-2'-naphthyl) ethanol and the tetrahydropyran-2 "yl ether of 2- (6'-Dxo-9 ', 10' -difluoromethylene? ', 4', 5 ' , 6 ', 3', 8 ', 9', 10'-octahydro-2'-naphthyl) ethanol treated according to Example 47 d 48, the tetrahydropyran-2 "-yl ether of 2 '- (1', 6'-dichloromethane-8'-acetoxycyclodecatetraen-3'-yl) ethanol was obtained in this way and the tetrahydropyran-2 "-yl ether of difluoromethano-8'-acetoxycyclodecatetraen-3'-yl) ethanol; after further treatment according to the procedures of Example 49, they gave the tetrahydropyran-2 "-yl ether - con 2- (1 ', 6'-dichloromethano-8'-acetoxycyclodecaperitaen-3'-yl) ethanol, 2- (1', 6'-dichloromethano-8'-acetoxycyclodecapentaen-3'-yl) ethanol, 2- (1 ', 6'-dichloromethano-8'-acetoxydecapentaen-3'-yl) ethanol and 1,6-dichloromethano-8-acetoxycyclodecapentaen-3-ylacetic acid and the tetrahydropyran-2 "-yl ether of 2- (1 ', 6'-dichloromethano-8'-acetoxycyclodecapentaene / * Stirred for about 15 minutes and then at room temperature 3'-yl) ethanol, 2- (1 ', 6'-difluoromethano-8'-acetoxycyclodecapentaen-3'-yl) ethanol, 2- (1', 6'-difluoromethano-8'-acetoxycyclodecapentaen-3'-yl) ethanol and 1,6-difluoromethano-8-acetoxycyclodecapentaen-3-ylacetic acid.

Example 5ü was made with the tetrahydropyran-2 "-yl ether of 2- (1 ', 6'-dichloromethano-8'-acetoxycyclodecapentaen-3'-yl) ethanol and the tetrahydropyran-2 "-yl ether of 2- (1 ', 6'-difluoromethano-6' -acetoxycyclodecapentaen-3 ' -yl) ethanol repeated, this gave 2- (1 ', 6'-dichloromethano-8'-methoxycyclodecapentaen-3'-yl) ethanol, 2- (1 ', 6'-dichloromethano-8'-methoxycyclodecapentaen-3'-yl) -ethenal and 1,6-difluoromethano-8'-methoxycyclodecapentaen-3-ylacetic acid and 2- (1 ', 6'-difluoromethano-8'-methoxycyclodecapentaen-3'-yl) ethanol, 2- (1', 6'-difluoromethano-8'-methoxycyclodecapentaen-3'-yl) ethanol and 1,6-difluoromethano-8-methoxycyclodecapentaen-3-ylacetic acid.

By following the procedure of Example 42, 1,6-difluoromethano-8-methoxycyclodecapentaen-3-ylacetic acid was obtained and 1,6-difluoromethano-8-methoxycyclodecapentaen 3-ylacetic acid in the corresponding Converted to methyl ester. The methyl ester obtained in this way was alkylated according to Example 43 and then hydrolyzed according to Example 44 and gave Z- (1 ', 6' »dichloromethano-8'-methuxycyclodecapentasn-3'-yl) propionic acid or 2-C1 ', 6'-difluoromethano-3'-msthoxycyclodecapentaen-3'-yl) propionic acid.

Example 52 A suspension of 1 g of 2- (8-'methoxy-1,6-methano-cyclodecapentaen-3'-yl) Propionic acid in 10 cc of 4B * aqueous hydrofluoric acid was added for about 90 minutes at 0 ° C. stirred, and then diluted with water and ethyl acetate. The ethyl acetate layer was washed, dried and evaporated to dryness under reduced pressure and the residue is chromatographed.

Thus, 2- (6'-oxo-9 ', 10'-methylene-5', 6 ', 9', 10'-tetrahydro-2'-naphthyl) propionic acid was obtained.

A mixture of 1 g of 2- (6'-Dxo-9 ', 10'-methylene-5', 6 ', 9', 10'-tetrahydro-2'-naphthyl) propinic acid, 15 cc of acetic anhydride and 0.2 g of sodium acetate were refluxed for about 1 hour heated and then poured into water for hydrolysis of excess anhydride. Then the mixture was extracted with methylene chloride and the combined extracts washed, dried and evaporated; thus obtained 2- (8'-acetoxy-1 ', 6'-methanocyclodecapentaene 3'-yl) propionic acid.

By repeating the procedure of this example with 2- (8'-methoxy-i "- '6'-difluoromethano-cyclodecapentaen-3'-yl) propionic acid and 2- (8'-methoxy-1 ', 6'-dichloromethanocyclodecapentaen-3'-yl) propionic acid as a starting material the 2- (6'-acetoxy-1 ', 6'-difluoromethanocyclodecapentaen-3'-yl) propionic acid was obtained or 2- (8'-acetoxy-1 ', 6'-dichicrmethanocyclodecapentaen-3'-yl) propionic acid.

B e i 5 p ie 1 ~ 53? 6'-methoxy-1 ', 4', 5 ', 8'-tetrahydro-1'-naphthyl) propanol, prepared from 2- (6'-methoxy-1'-naphthyl) propanol according to Example 35, was converted into 2- (6'-0xo-1 ', 4', 5 ', 6', 7 ', 8'-hexahydro -1'-naphthyl) propanol and converted this to 2- (6'-oxo-9 ', 10'-dichloromethylene-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'- octahydro-1'-naphthyl) propanol and 2- (6'-oxo-9 ', 10'-difluoromethylene-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'-octahydro-1'-naphthyl) propanol implemented.

Was 2- (6'-nxo-9 ', 10'-dichloromethylene-1', 4 ', 5', 6 ', 7', 8 ', 9''10'-octahydro-1'-, naphthyl) propanol was subjected to the procedure of Example 38 (Part A) one the corresponding tetrahydropyran-2 "-ylether, which according to the method of Example 37 (Part B) to the tetrahydropyran-2 "-yl ether of 2- (6'-hydroxy-9 ', 10'-methylene-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'-octahydro-1'-naphthyl) propanol was reduced. The latter gave by treatment according to Example 39 (Part B) the tetrahydropyran-2 "-yl ether of 2- (6'-oxo-9 ', 10'-methylene-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'-octahydro- 1'-naphthyl) propanol.

The tetrahydropyran-2 "-yl ether of 2- (6'-oxo-9 ', 10'-methylene-1', 4 ', 5', 6 ', 7', 8 ', 9 ', 10'-octahydro-l'-naphthyl) propanol was dehydrated according to Example 47 and delivered the tetrahydropyran-2 "-yl ether of 2- (6'-oxo-9 ', 10'-methylene-1', 4 ', 5', 6 ', 9', 10'-hexahydro-1'-naphthyl) - propanol, which was treated according to the procedures of Examples 48 and 49 and the tetrahydropyran-2 "-yl ether of 2- (1 ', 6'-methano-8'-acetoxycyclodeca-3', 6 ', 8', 10'-tetraen-2'-yl) propanol, the Tetrahydropyran-2 "-yl ether of 2- (1 ', 6'-methano-8'-acetoxycyclodecapentaen-2'-yl) -propanol, / 2- (1', 6'-methano-8'-acetoxycyclodecapentaen-2 ' yl) propanol and 2- (1 ', 6'-methano-8'-acetoxycyclodecapentaen-2-yl) -propanal and 2- (1', 6'-methano-8'-acetoxycyclodecapentaen-2'-yl) -propionic acid delivered.

2- (6'-Methoxy-1'-naphthyl) propanol can be obtained by alkylating 6-methoxy-1-naphthylacetic acid to form 2- (6'-methoxy-1'-naphthyl) propionic acid according to the procedures of Example 43 and subsequent reduction with lithium aluminum hydride, etc. according to the Procedure of Example 36 can be prepared.

/ * the tetrahydropyran-2 "-yl ether of Became the tetrahydropyran-2 "-yl ether of 2- (1 ', 6'-methano-8'-acetoxycyclodecapentaen-2'-yl) -' propanol according to example 50 treated, so one got methano-B'-methoxycyclodecapentaen-2'-yl) -propanol, that to the corresponding aldehyde and acid according to the procedures of Example 39 (Parts B and C) namely 2- (1 ', 6'-methano-8'-methoxycyclodecapentaen-2'-yl) -propanal and 2- (1 ', 6'-methano-8'-methoxycyclodecapentaen-2'-yl) propionic acid.

8 ei sp ie 54 (A) The tetrahydropyran-2 "-yl ether of 2- (6'-oxo-9'-10'-dichloromethylene-1 ', 4', 5 ', 6', 7 ', 8', 9 ', 10'-octahydro-1'-naphthyl) propanol was according to Example 47 to the tetrahydropyran-2 "-yl ether of 2- (6'-0xo-9 ', 10' -dichloromethylene-1 ', 4', 5 ', 6', 9 ', 10'-hexahydro-1 '-naphthyl propanol dehydrated, the tetrahydropyran-2 "- yl ether of 2- (1 ', 6'-dichloromethano-8'-acetoxycyclodeca-3', 6 ', 8', 10'-tetraen-2'-yl) propanol, the tetrahydropyran-2 "-yl ether of 2- (1 ', 6'-dichloromethano-8'-acetoxycyclodecapentaen-2'-yl) propanol, 2- (1 ', 6'-dichloromethano-8'-acetoxycyclodecapentaen-2'-yl) -propanol, 2- (1', 6'-dichloromethano-8'-acetoxycyclodecapentaen-2'-yl) -propanal and provided 2- (1 ', 6'-dichloromethano-8'-acetoxycyclo'decapentaen 2'-yl) propionic acid. According to Example 50, the 8-acetoxy compounds thus obtained can be converted into the corresponding 8'-methoxy compounds are converted.

(B) According to Example 37 (Part A), 2- (6'-Oxo-1 ', 4', 5 ', 6', 7 ', 8'-hexahydro-1'-naphthyl) propanol in 2- (6'-oxo-9 ', 10'-difluoromethylene-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'-octahydrc -naphthyl) propanol converted using dihydropyran to give the corresponding totrahydropyran-2 "-yl ether was etherified. The tetrahydropyran-2 "-yl ether of 2- (6'-oxo-9 ', 10'-difluoromethylene 1 ', 4', 5 ', 6', 7 ', 8', 9 ', 10'-octahydro-1'-naphthyl) propanol was continued according to the procedure of Part A of this example (instead of the tetrahydropyran-2 " yl ethers of 2- (6'-oxo-9 ', 10'-dichloromethylene-1', 4 ', 5', 6 ', 7', 8 ', 9', 10'-octahydro-1 '- naphthyl) -propanol) and gave the corresponding 9 ', 10'-difluoromethylene compounds and 1', 6'-difluoromethano compounds.

Example 35 was carried out using 1-naphthylacetic acid repeated as starting material; 1 ', 4', 5 ', 8'-tetrahydro-1'-naphthyl) were thus obtained according to Example 36 into the acetate of 2- (1 ', 4', 5 ', 8'-tetrahydro-1'-naphthyl) ethanol was converted. This compound was treated according to Example 37 to give the acetate of 2- (9 ', 10' - dichloromethylene-1 ', 4', 5 ', 8', 9 ', 10'-hexahydro-1-naphthyl) -ethanol, the acetate of 2- (9 ', 10'-difluoromethylene-1', 4 ', 5'-8', 9 ', 10'-hexahydro-1'-naphthyl) ethanol and 2- (9 ', 10'-methylene-1', 4 ', 5'-8', 9 ', 10'-hexahydro-1'-naphthyl) ethanol. Then became Example 38 with 2- (9 ', 10'-methylene-1', 4 ', 5', 8 ', 9', 10'-hexahydro-1'-naphthyl) ethanol repeated and the end product was the tetrahydropyrBn-2 "-yl ether of methano-cycodecapentaen-2'-yl) ethanol, which after treatment according to Example 39 the free alcohol, the aldehyde and the acid, i.e. Z- (1 ', 6'-methanocyclodecapentaen-2'-yl) -ethanol, 2- (1', 6'-methanocyclodecapentaen-2'-yl) -ethanol and 1,6-methanocyclodecapentaen-2'-ylacetic acid.

By repeating this example with 2- (1,4aphthyl) propionic acid The starting material was 2- (1 ', 6'-methano-cycodecapentaen-2'-yl) propanol as end products, 2- (1 ', 6'-methanocyclodecapentaen-2'-yl) -propanal and 2- (1', 6'-methano-cyclodecapentaen-2'-yl) -propionic acid. These propanol, propanal and propionic acid compounds can also be obtained by alkylation of the corresponding Alkyl esters of 1,6-methanocyclodecapentaen-2-ylacetic acid according to Example 43 and subsequent hydrolysis to obtain the free acid as well Reaction of the free acid or the alkyl ester (see. Example 36) to achieve of alcohol are produced; the latter can then, e.g. with chromium trioxide in pyridine, for Aldehyde are oxidized.

B e i 5 p i e 1 56 A solution of 1 g 2- (8'4-methoxy-1 ', 6'-methano-cyclodecapentaene - 3'-yl) -propionic acid, 2 cc thionyl chloride in 2D cc benzene was about 2 hours refluxed, cooled and evaporated. The residue was in anhydrous Dissolved dioxane and saturated the solution with a stream of anhydrous ammonia. Then, after about 20 hours, water was added and the mixture under reduced pressure Evaporated pressure. The residue was taken up in methylene chloride with water washed, dried and evaporated to give the 2- (8'-methoxy-1 ', 6'-methanocyclodecapentaene -3'-yl) propionic acid amide.

B e i 5 p i e 1 5? A mixture of 1 g of 2- (8'-methoxy-1 ', 6'-methanocyclodecapentaen-3'-yl) Propanol, 3 cc pyridine and 3 cc acetic anhydride were added at room temperature left to stand for about 15 hours, then poured into water and extracted with ethyl acetate. The combined extracts were washed with dilute hydrochloric acid and water, dried and evaporated; the acetate of 2- (8'-methoxy-1 ', 6'-methanocyclodecapentaen-3'-yl) propanol was obtained in this way.

Similarly, using an equivalent one obtained Amount of other lower carboxylic anhydride, such as propionic anhydride, nutric anhydride n-caproic anhydride, trimethyl acetic anhydride, trichloroacetic anhydride, etc., instead of acetic anhydride the corresponding esters.

ß e i s p i e 1 58 A mixture of 1 g of the methyl ester of 2- (8'-methoxy-1 ', 6'-methanocyclodecapentaen-3'-yl) propionic acid and 20 cc of anhydrous tetrahydrofuran was added to a dry ice / acetone bath -750C. cooled 'and with a previously cooled solution of 0.6 g of lithium aluminum hydride treated in 20 cc of anhydrous tetrahydrofuran. Then the reaction mixture allowed to come to room temperature and reflux for about 15 minutes. then the reaction mixture was cooled, poured into ice water and washed several times Ethyl acetate extracted. The combined extracts were washed neutral with water, dried and evaporated to give 2- (8'-methoxy-1 ', 6'-methanocycodecapentaen-3'-yl) propanol.

B e i 5 p i e 1 59 A mixture of 3 g of the methyl ester of 2- (8'-methoxy-1 ', 6'-methano-cyclo decapentaen-3'-yl) propionic acid, 1 g sodium methoxide, 1.5 g hydroxylamine hydrochloride and 50 cc of methanol was left to stand for about 16 hours, then filtered and the Evaporated filtrate. The residue was purified by adding 1N aqueous hydrochloric acid neutralized and extracted with ether. The combined extracts were washed with water washed, dried and evaporated to give 2- (8'-methoxy-1 ', 6'-methanocyclodecapentaen-3'-yl) propionic hydroxamic acid.

B e 1 5 p i e 1 60 A mixture of 1 g 2- (8'4dethoxy-1 ', 6'-methanocyclodecapentasn-3'-yl) propanol, 1 c sulfur trioxide / trimethylamine complex and 40 cc pyridine was at 40 C. 2 1/2 Stirred for days, then poured into about 200 com saturated sodium bicarbonate solution and extracted with ethyl acetate and with n-butanol. The combined n-butanol extracts were dried over sodium sulfate and evaporated under reduced pressure. Of the The residue was taken up in methanol and treated with a carboxylic acid ion exchange resin for about 10 minutes ("Amberlite IRC-50", acid cycle) stirred. The mixture was filtered and that filtrate evaporated under reduced pressure; the 2- (8'-methoxy-1 ', 6'-methane-clodecapentaen-3'-yl) propanol-2-sulfate monosodium salt was obtained in this way.

B e i 5 p i e 1 61 A mixture of 2 g of 2- (3'-methoxy-1 ', 6'-methanocyclodecapentrlen-3'-yl) propanol and 2 molar equivalents of ß-cyanoethyl phosphate in pyridine was with a pyridine solution from 8 molar equivalents of N, N'-dicyclohexylcarbodiimide.

combined and the reaction mixture at room temperature for 24 hours ditched. Then it was diluted with a small amount of water and at about 5 ° C. Left for 2 days. The mixture was then reduced under reduced pressure Pressure evaporated to dryness and the residue in about 35 cc aqueous methanol (1: 1) added. This mixture was mixed with about 12 cc of 5S / O aqueous sodium hydroxide solution treated and concentrated after about 1 hour at room temperature under reduced pressure, diluted with 30 cc of aqueous methanol, concèlitrated and mixed with 75 cc of water. This mixture was filtered and the filtrate was batchwise and then columnar treated with an excess of a sulfonic acid ion exchange resin (Hf form). Thus, 2- (8'-methoxy-1 ', 6'-methanocyclodecapentaen-3'-yl) -propanol-2-phosphate was obtained.

B e i 5 p i e 1 62 Examples 41 and 42 were made using 1, G-dichloromethanocyclodecapentaen-3-ylacetic acid and 1 1,6-difluoromethanocyclodecapentaen-3'-ylacetic acid acid repeated; the corresponding methyl ester was alkylated according to Example 9 and gave the methyl ester of 2- (1 ', 6'-dichloromethanocyclodecapentaen-3'-yl) propionic acid and the methyl ester of 2- (1 ', 6'-difluoromethanocyclodeca-pentaen-31-yl) -proplonic acid. The methyl ester thus obtained can by following the procedure of Example 44 to the free Acid to be hydrolyzed. The methyl esters can also be prepared according to the procedures of Example 36 or 58 to the corresponding alcohols, i.e. 2- (1 ', 6'-dichloromethanocyclodecapentaen-3'-yl) propanol and 2- (1 ', 6'-difluoromethano-cyclodecapentaen-3'-yl) -propanol are reduced; and the latter can be oxidized according to Example 5 to the corresponding aldehyde.

B e i 5 p i e 1 63 According to Example 42, 1,6-methano-8-methoxycyclodecapentaen-3-ylessisic acid was obtained converted into the corresponding methyl ester and this according to Example 43 to the methyl ester the 2- (8'-methoxy-1 ', 6'-methanocyclodecapentaen-3'-yl) propionic acid is alkylated. This according to Example 44 gives 2- (8'-methoxy-1 ', 5'-methanocyclodecapentaen-3'-yl) propionic acid.

Example 64 To a solution of 1 g of 2- (8'-methoxy-1 ', 6'-methanocyclodecapentaen-3'-yl) Propanol and 25 cc of benzene were added to 2 cc of 4'-methoxy-5 ', 6'-dihydro-2H-pyran. About 5 cc of the mixture was distilled off to remove moisture. then the remaining mixture was cooled to room temperature. To the cooled mixture 0.1 g of p-toluenesulfonic acid was added and the resulting mixture for 72 hours Maintained room temperature, then with aqueous 5% sodium carbonate solution and washed neutral with water, dried over sodium sulfate and evaporated; so the 4 "methoxytetrahydropyran-4" -yl ether was obtained from 2- (8'-methoxy-1 ', 6'-methanocyclodecapentaen-3'-yl) -propanel, which can be purified by chromatography.

Example 65 A mixture of 1 g of 8-acetoxy-1,6-methanocyclodecapentaen-3'-ylacetic acid and 4 cc of oxalyl chloride in benzene was under anhydrous conditions for 2 hours heated to reflux. The solution was evaporated in vacuo, taken up in benzene and again evaporated to give 8-acetoxy-1,6-methanocyclodecapentaen-3-ylacetic acid chloride, that after treatment with anhydrous ammonia 2- (6 '-acetoxy-1' 6 '-me, tbano-cyclodecapentaen-3' -y1) propionic acid amide.

To a cooled solution of 1 g of 2- (8'-acetoxy-1 ', 6'-methanocyclodecapentaen-3'-yl) propionic acid chloride and 75 cc of tetrahydrofuran was 1 molar equivalent of lithium tri-tert. butoxyal uminiumhydride was added and the mixture was allowed to stand at room temperature for about 12 hours left, diluted with water, concentrated under vacuum and again with water diluted. This mixture was extracted with ethyl acetate and the combined extracts dried and evaporated; 2- (8'-acetoxy-1 ', 6'-methanocyclodecapentaen-3'-yl) propanol was thus obtained. The aldehyde thus obtained was tri-tert-butoxyaluminum hydride with 1 molar equivalent in tetrahydrofuran to give 2- (8'-acetoxy-1 ', 6'-methanocyclodecapentaen-3'-yl) -oropanol reduced.

Claims (15)

P a t e n t e. n p r ü c h e 1.- Compounds of the following formulas (A) and in which R is hydrogen, lower alkyl, a lower monocyclic alkyl group, lower alkoxy or a lower carboxylic acyloxy group; R1 is hydrogen or lower alkyl; R² represents hydrogen, lower alkyl, together with R1 represents methyl or together with R1 and the carbon atom to which R1 and R² are bonded represents a lower monocyclic alkyl group; R3 is -CHO, -CH2-R4, -COOR5, -CON (R6) n or -CONHOH, where R4 is hydroxy or a hydrolyzable ester or ether thereof, R5 is hydrogen, lower alkyl or an alkali metal and each R6 is Is hydrogen or lower alkyl; and X is methylene, dichloromethylene or difluoromethylene. 2.- Compounds according to claim 1, characterized in that R -for Is hydrogen and R3 is -COOR5. 3.- Compounds according to claim 1, characterized in that R is for Is hydrogen, H1 is methyl and R 3 is -COOR5. 4.- Compounds according to claim 1, characterized in that R is for Methoxy and R3 is -COOR5. 5.- Compounds according to claim 1, characterized in that R is for Is methoxy, R1 is methyl and R3 is -CCOR5. 6.- Compounds of the formula A of claim 1, characterized in that that F is hydrogen, X is methylene, R1 is methyl and R3 is -COOR5, where R is hydrogen. 7.- Compounds of the formula A of claim 1, characterized in that dß fl denotes hydrogen, X denotes difluoromethylene, H1 denotes methyl and is -COOR5, where R5 is hydrogen. 8.- Compounds according to claim 1, characterized in that R3 for -CH2-R4, where R is hydroxy. 9.- Compounds of the formula A of claim 1, characterized in that that R3 is -CH2-R4, where R4 is hydroxy. 10. Compounds according to claim 9, characterized in that R is for Hydrogen and R is methyl. 11.- Compounds according to claim 9, characterized in that n is for Is methoxy and R1 is methyl. 12.- Compounds of the formula A of claim 1, characterized in that that is methoxy, X is methylene, R 1 is methyl and R3 is -COOR5, where R5 is hydrogen. 13.- Compounds of the formula A of claim 1, characterized in that that i denotes methoxy, x denotes difluoromethylene, R1 denotes methyl and R3 denotes -COOR5, where R5 is hydrogen. 14.- Compounds of the formula A of claim 1, characterized in that that R is methoxy, X is dichloromethylene, R1 is methyl and H3 is -COOR5, where R5 is hydrogen. 15. Medicinal product containing a compound according to claim 1 to 14.