KR820001356B1 - Process for preparation of benzo(c)quinolines - Google Patents

Abstract

Title compds. (I; R1 = H, benzyl, benzoyl, C1-5 alkanoyl; R4 = H, C1-6 alkyl; R5 = H, methyl, ethyl; R6 = carbobenzyloxy, formyl, C2-5 alkanoyl, C1-6 alkyl; Y1 = III, IV, V; R1 = H, C1-5 alkanoyl), useful as analgesics, were prepd. from II. Thus, 812 mg d,1-trans-5,6,6a ,7,10,10a -hexahydro-1-acetoxy-6β-methyl-3(2-heptyloxy)benzo[c quinolin-9(8H)-one was dissolved in 2.5 ml pyridine, and reacted with 421 mg benzoyl chloride for 2 hr in 5 ml chloroform to give d,1-trans-5,6 ,6a,7,10,10a -hexahydro-1-acetoxy-3-(2-heptyloxy)-5-benzoyl-6β-methylbenzo[c quinolin-9(8H)-one.

Description

[Name of invention]

Method for preparing benzo [C] quinoline

Detailed description of the invention

The present invention provides several novel benzo [C] quinolines, especially 1,9-dihydroxyoctahydrobenzo [C, useful as CNS agents, in particular analgesics and sedatives, hepatic depressants in mammals, including humans, glaucoma agents, and diuretics. ] Quinoline, 1-hydroxyhexahydrobenzo [C] quinolin-9 (8H) -one, and 1-hydroxytetrahydrobenzo [C] quinoline and the like and derivatives and intermediates thereof, and methods for preparing these compounds It is about.

The above-mentioned active compounds and intermediate products include compounds represented by the following structural formulas.

Where A is

Also in the compounds where A is (III '), ketals and thioketals containing 2-4 carbon atoms in the ketal group and pharmacologically acceptable acid addition salts of compounds in which A is (I') or (II ') And —0-alkylene-0- is an alkylenedioxy containing 2-4 carbon atoms, some of which may be described by the formulas (I) to (VII) shown below.

Another acceptable command of the compounds represented by the formulas (I)-(IV) is to replace "benzo [C] quinoline" with "phenanthridine". Thus, d, 1-trans-5,6,6aβ, 7,8,9,10,10aα-octahydro-6β-methyl-3 (5-phenyl-2-pentyloxy) benzo [C] quinoline is d, 1-trans-5,6,6aβ, 7,8,9,10,10aα-octahydro-1-acetoxy-9β-hydroxy-6β-methyl-3 (5-phenyl-2-pentyloxy) phenanthtri Become Dean.

There are numerous painkillers available today, but new and improved drugs are still being worked on, indicating that there are no drugs that are useful in relieving a wide range of pain and have minimal side effects. Aspirin, the most widely used drug, is known to be effective in eliminating extreme pain and to exhibit a number of undesirable side effects. More potent analgesics, d-propoxyphene, codeine and morphine, are addictive. Thus, the need for improved and strong analgesics is obvious.

There are a variety of painkillers known in the art. 9-nor-9β-hydroxyhexahydrocannabinol and other cannabinoid structure compounds such as Δ ⁸ -tetrahydro cannabinol (Δ ⁸ -THC) and its main metabolite 11-hydroxy-Δ ⁸ Analgesic properties such as THC are well known. Various 1-hydroxy-3-alkyl-6H-dibenzo- [b, d] pyrines and intermediates thereof with substituents such as oxo, hydrocarbyl, hydroxy, chloro, hydrocarbylide at position 9; Also well known.

It is also known that various tetrahydro-6,6,9-trialkyl-6H-dibenzo [b, d] pyran derivatives having a ω-dialkylamino alkoxy group at the 1 position are useful as a psychotherapeutic agent. 1,9-dihydroxyhexa hydrodibenzo [b, d] pyran and several 1-acyl derivatives thereof having an alkyl or alkylene group at position 3 are used as a relaxant, psychotherapeutic, sedative and analgesic agent. It is also known that hexahydro-9H-dibenzo [b, d] pyrin-9-temperature corresponding to the previous step used for preparation has the same utility as the 9-hydroxy compound. 3-alkoxy substituted dibenzo [b, d] pyranes have been known to have antiarthritis, anti-inflammatory and central nervous effects. The pentyl group at position 3 of 7,8,9,10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo [b, d] pyrin-1-ol is alkoxy (butoxy, It is also known that substitution with pentyloxy, hexyloxy and octyloxy) will result in biological inactivation. Hexyloxy derivatives show weak anesthesia at a dose of 10-20 mg / kg, while other ethers do not show any action at 20 mg / kg.

3-substituent of 7,8,9,10-tetrahydro-3-substituted-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1-ol is -OCH (CH ₃ ) C ₅ Comparing the case of H ₁₁ -CH ₂ CH (CH ₂ ) C ₅ H ₁₁ or -CH (CH ₂ ) C ₅ H ₁₁ , a compound containing an ether side chain has an alkyl side chain having an oxygen atom in the middle. It is also known that CNS is 50% less effective than commercial compounds attached directly to aromatic rings, and that oxygen is five times more effective than compounds substituted with methylene. 7,8,9,10-tetrahydro-1-hydroxy-5,6,6,9-tetramethyl-3-n-pentylphenanthridine called Δ ^6a (10a) -tetrahydric cannabinol 5- interest cognate of is known to be completely inactive in animal pharmacology. 5-I Δ ^6a (10a) -tetrahydro cannabinol of 7,8,9,10-tetrahydro-1-hydroxy-6,6,9-triketyl-3-n-pentylphenanthridine The pharmacological effect of is also known. It is also known that major structural changes in tetrahydrocannabinol molecules dramatically reduce their effectiveness as analgesics. In cannabinoids, the relationship between structure and effect is generalized. The presence of a dimethyl group in the pyran ring is critical to the effect of the cannabinoids, and the substitution of O in the pyran ring for N eliminates the effect.

Several benzo [C] quinolines, namely 1,9-dihydroxy octahydro-6H-benzo [C] quinoline (I), 1-hydroxy hexahydro-6H-benzo [C] -quinoline-9 (8H) -ON (II) and 1-hydroxy-tetrahydroquinoline (IV) are CNS agents, in particular, effective as analgesics and sedatives, narcotic and non-addictive strainers, glaucoma and diuretics. Was found by. Also various derivatives and intermediates of these compounds have been identified. The above compounds and their derivatives are represented by the formulas (I), (II) and (IV). Compounds of formulas (III) and (IV) are pre-step products of compounds of formulas (II) and (I).

Wherein R is selected from hydroxy, alkanoyloxy having 1-5 carbon atoms, hydroxymethyl and the like.

R ₁ is selected from hydrogen, benzyl, benzoyl, alkanoyl having 1-5 carbon atoms, -CO- (CH ₂ ) _P -NR ₂ R ₃ , and the like, where P takes a number from 0-4 and R ₂ and R ₃ are individually selected from hydrogen and alkyl having 1-4 carbon atoms, wherein R ₂ and R ₃ and the nitrogen to which they are attached together form a ring of 5 or 6 heteroatoms and form piperidino, Pyrrolodino, morpholino and N-alkylpiperazino having 1-4 carbon atoms in the alkyl group and the like.

R ₄ is selected from hydrogen, alkyl having 1-6 carbon atoms,-(CH ₂ ) _Z -C ₆ H ₅ , wherein Z is 1-4.

R ₅ is selected from hydrogen, methyl and ethyl.

R ₆ is hydrogen,-(CH ₂ ) _y -carabalkoxy (where the alkoxy group has 1-4 carbon atoms and y is 0-4), carbobenzyloxy, formyl, alkanoyl having 2-5 carbon atoms , Alkyl having 1-6 carbon atoms,-(CH ₂ ) _X -C ₆ H ₅ , wherein X is 1-4, -CO (CH ₂ ) _x-1 -C ₆ H ₅ , and the like.

R ₀ is selected from oxo, methylene, alkylene dioxy having 2-4 carbon atoms and the like.

R 'is selected from R and R ₀ .

Z is alkylene having 1-9 carbon atoms and-(alk ₁ ) _m -X- (alk ₂ ) _A- (where alk ₁ and alk ₂ are each alkylene having 1-9 carbon atoms, alk ₁ and The sum of the carbon atoms contained in alk ₂ is not more than nine, m and n are each 0 or 1, and X is selected from O, S, SO and SO ₂ ).

(여기서 W₁은 수소, 플루오로 및 클로로 등으로부터 선택됨), 및

(여기서 W₂는 수소 및

으로부터 선택되고, a는 1-5이며 b는 0-5이고, a와 b의 합은 5가 넘지 않음)등으로부터 선택된다.W is hydrogen, methyl, pyridyl, piperidyl,

Wherein W ₁ is selected from hydrogen, fluoro and chloro, etc., and

Where W ₂ is hydrogen and

And a is 1-5, b is 0-5, and the sum of a and b does not exceed 5).

Ketals of the compounds of formulas (II) (III) and (IV) have 2-4 carbon atoms in the ketal group.

The present invention also includes pharmacologically acceptable acid addition salts of the formulas (I) and (II). Such representative salts include mineral salts such as hydrochloride, bromate, sulfate, nitrate and phosphate, citrate, acetate, sulfosalicylate, tartarate, glycolate, malonate, maleate, fumarate, 2-hydroxy-3- Naphthoates, pamolates, salicylates, stearates, phthalates, succinates, gluconates, mandelates, lactates, methanesulfonates, and the like.

Compounds of formulas (I), (II) and (III) have asymmetric centers at the 6a and / or 10a positions. There may also be other asymmetric centers at the 3-position substituent (-Z-W) and at the 5, 6 and 9 positions. 9β-type diastereomeric isomers are better than 9α-type isomers because of their greater biological activity. For the same reason, the trans (6a, 10a) diastereoisomer of the compound of formula (I) is better than the cis (6a, 10a) diastereoisomer.

In the compound of formula II, the cis-diastereomeric isomer is better because one of R ₄ and R ₅ is other than hydrogen, and the biological activity is greater. In the compound of formula IV, an asymmetric center is present at the 9 and 3 substituents. Among the enantiomeric isomers of a given compound, the isomers of the given compounds are generally more active than the other isomers and racemates, and the better enantiomer isomers are determined as follows. 1-enan of 6aβ, 7,8,9,10,10aα-octahydro-1-acetoxy-9β-hydroxy-6β-methyl-3- (5-phenyl-2-pentyloxy) benzo [C] quinoline Tiomers have better analgesic effects than d-enantiomers and racemates.

For convenience, the structural formulas represent racemic compounds. However, the above structural formulas should be considered to include all racemic variants, diastereomeric isomeric mixtures, pure enantiomer isomers and diastereomeric isomers thereof of the compounds of the present invention.

Effects of racemic mixtures, diastereomer mixtures, pure enantiomers, diastereomers thereof, and the like are determined by the following biological evaluation.

In addition, various intermediate products useful for preparing the compounds of the formulas (I), (II), (III) and (IV) have the following formulas.

here

R ₄ , R ₅ , R ₆ and ZW are as described above,

R ₇ is selected from hydrogen and formyl,

Y ₁ is selected from hydrogen and hydroxy protecting groups, especially methyl, ethyl or benzyl and the like.

In intermediates (V), (VI) and (iii), an asymmetric center may be present at the substituents at positions 2 and 7 (-Z-W) and may also be present at other positions such as 1-position substituents. Positions 2 and 7 of the formulas (V)-(iii) correspond to positions 6 and 3 of the compounds of formulas (I), (II), (III) and (IV).

Compounds of structural formulas (I) and (II) that have greater biological activity than other compounds are:

R and R ₀ are as described above.

R ₁ is hydrogen or alkanoyl.

R ₅ is hydrogen, methyl or ethyl.

R ₄ and R ₆ are each hydrogen or alkyl.

Z and W are as follows.

As a compound of the formula (I), it is better that R is hydroxy and has a trans form in the compound. As a better compound of formula (II), R ₀ is oxo.

Particularly preferred as compounds of the structural formulas (I) and (II) are the following cases:

R and hydroxy (only for formula (I))

R ₁ is hydrogen or acetyl.

R ₅ is hydrogen.

R ₄ is methyl or propyl.

R ₆ is hydrogen, methyl or ethyl.

When Z is alkylene of 2-5 carbon atoms, W is phenyl or 4-pyridyl.

If Z is-(alk ₁ ) _m -0- (alk ₂ ) _n- , where m is 0, n is 1 and (alk ₂ ) n is alkylene of 4-9 carbon atoms, w is hydrogen or phenyl.

If Z is alkylene of 5-9 carbon atoms, W is hydrogen.

Also preferred among the intermediates of the formulas (III), (IV), (V), (VI) and (iii) are intermediate products used to prepare the preferred compounds of the formulas (I) and (II).

Compounds in which R ₆ is other than hydrogen, alkyl and-(CH ₂ ) _x -C ₆ H ₅ as compounds of formulas (I) and (II) are R ₆ valent hydrogen as compounds of formulas (I) and (II). , An alkyl, or an intermediate that produces-(CH ₂ ) _x -C ₆ H ₅ .

The compound of the present invention of formula (V) is capable of easily reproducing hydroxy groups by the easy removal of 3-hydroxy from suitably substituted anilines such as 3-hydroxy-5- (ZW-substituted) -aniline or derivatives thereof. It is manufactured from what is protected by the existing group Y ₁ . Suitable protecting groups are groups which can be removed under conditions which do not interfere with the next reaction of the 3- (protected hydroxy) -5-substituted aniline and do not cause undesirable reactions at the compound or elsewhere prepared therefrom. Representative protecting groups (Y ₁ ) include methyl, ethyl, benzyl, substituted benzyl (where the substituents are, for example, alkyl of 1-4 carbon atoms), halo (C1, Br, F, 1), and alkoxy of 1-4 carbon atoms, and the like. .

The importance of the protecting group is such that the precise chemical structure of the protecting group is not critical to the present invention since the functions as described above can be performed.

Selecting and confirming suitable protectors is readily available to those skilled in the art. The suitability and effects of any of the hydroxy protecting groups are determined by use in this aforementioned reaction sequence. Therefore, such groups should be easily removable to regenerate the hydroxyl group. Methyl groups are good as protective alkyl groups because they are easily removed by treatment with pyridine hydrochloride. Benzyl groups are also good protecting groups, which are removed by catalytic hydrogenolysis or acid hydrolysis.

When Z is-(alk ₁ ) _m -X- (alk ₂ ) _n- , it is preferred that Y ₁ is a benzyl or substituted benzyl group, which can be removed later without applying a phase to the Z group.

The protective aniline derivative is converted into a compound of formula (VII) by a known method described later.

The summarized reaction sequence for preparing the representative compound of formula (V) from the compound wherein -ZW- is OCH ₃ in 3- (protectivehydroxy) -5- (ZW-substituted) aniline is shown in the following flowchart A It is.

In process diagram A above, R ₀ is alkyl of 1-6 carbon atoms. R ₅ is represented by hydrogen for purposes of illustration in the overall process diagram. However, R ₅ may be hydrogen, methyl, or ethyl in the course of (i) → (i) or (i) → (V-B).

The 5-substituted group of formula (VII) may be a -ZW group desired for the compound of formula (II) or (I) or a group which can be easily converted to this group. When Z in the -ZW group is-(alk ₁ ) _m -X- (alk ₂ ) _n- , where X is 0 or S and m and n are each 0, the 5-substituent is-when W is hydrogen. XH (such as OH or SH) or a protective -XH group of the formula -XY _1- (Y ₁ is as described above). When -ZW is-(alk ₁ ) _m -X- (alk ₂ ) _n -W, where m is 1, n is 0 and W is hydrogen, the 5-substituent is-(alk ₁ ) _m -XH do.

The -XH group is advantageously protected in the manner described above.

The 3-hydroxy-5-substituted aniline described above is in the form of a derivative in which the 3-hydroxy group (and, if present, the 5-hydroxy group) is protected by the above-mentioned method, in the presence of acetic acid alkyl β-ketoester For example, it is preferable to react with alkylacetoacetate, thereby producing a satisfactory reaction, so that the corresponding β-[(3-protected hydroxy) -5-substituted anilino] -β- (R ₄ ) -acrylate (IX) Is prepared. This reaction is usually carried out in a reaction incombustible solvent such as benzene or toluene, between 50 ° C. and the reflux temperature of the solvent, under conditions in which the by-products can remove moisture. Benzene and toluene are useful solvents when the reaction is carried out at reflux temperature because it can azeotropically remove the byproduct moisture. Other solvents capable of azeotropically removing water may be used, and other water removal methods such as molecular sieves may also be used.

Good protecting groups for the 3-hydroxy-5-substituted aniline reactants include methyl, ethyl and benzyl groups, and these ethers are readily prepared and the yields of the compounds of formulas (VII) and (VII) are satisfactory and convenient. Is removed.

In particular, alkyl β-ketoesters having an alkyl group of 1-6 carbon atoms are usually used in excess so that the aniline reactant is converted to the corresponding alkyl β-anilino-β- (R ₄ ) -acrylate in maximum. 10-20% excess alkyl β-ketoester is usually sufficient to achieve a satisfactory conversion. The use of acetic acid in catalytic amounts facilitates the reaction.

Alkyl-β-anilino-β- (R ₄ ) -acrylate (X) is prepared by the corresponding alkyl-3-[(3-protected hydroxy) -5, for example by sodium borohydride-acetic acid and catalytic hydrogenation. -Substituted anilino] -3- (R ₄ ) -propionate (X). Platinum dioxide is a preferred catalyst because it allows this reaction to be carried out at low pressures, for example at pressures of 50 p.si or less. When the hydrogen pressure is in the range of atmospheric pressure to superatmospheric pressure, such as 200 p.si, noble metals such as platinum, palladium, rhodium and the like may be used as catalysts with or without an auxiliary support. In addition to these heterogeneous catalysts, it is also possible to use homogeneous catalysts such as Wilkinson catalysts, ie tris (triphenylphosphine) chlorodium (I).

Of course, if the protecting group is benzyl or substituted benzyl, these groups are removed by catalytic hydrogenation. For this reason, methyl or ethyl groups are preferred as protecting groups for the 3- and / or 5-hydroxy groups of the reactants of formula (VII).

The compound of formula _IV can also be prepared directly by reacting the compound of formula _IV with alkyl 3,3-R ₄ R ₅ -acrylate in acetic acid. This reaction can be carried out by reacting equimolar amounts of alkyl 3,3-R ₄ R ₅ -acrylate and di-substituted aniline in 0.1-2 equivalents of glacial acetic acid at a temperature of 0 ° C reflux temperature.

Compounds of formula (V-B) can be prepared directly by condensing an equimolar amount of the compound of formula (V) with a suitable substituted acrylic acid (R ₄ R ₅ C = CH-COOH) in pyridine hydrochloride at 150 ° -200 ° C. have.

When both R ₄ and R ₅ are alkyl groups, the compound of formula ( _IV ) and alkyl R ₄ R ₅ acrylate are treated with mercury acetate in a reaction inert solvent such as tetrahydrofuran and then reduced with sodium borohydride. If it becomes, it becomes a compound of a structural formula.

By treating 3,5- (unprotected hydroxy) -aniline hydrochloride with an excess of alkyl acetoacetate, such as ethyl acetoacetate, in the presence of sodium cyanoborohydride in a solvent such as methanol, the compound of formula Direct conversion to the compound of iii).

Alkyl 3-anilino-3- (R ₄ ) -propionate is a suitable cyclizing agent such as polyphosphoric acid (PPA), hydrogen bromide-acetic acid, sulfuric acid, fuming sulfuric acid, hydrogen fluoride, trifluoroacetic acid, phosphoric acid Formic acid, other known cyclizing agents, etc. are used to form 2- (R ₄ ) -quinolin-4-one (structural formulas (VA) and (VB), which are corresponding ring-shaped compounds.

In one modification of this conversion, the alkyl 3-anilino-3- (R ₄ ) -propionate can be converted to the corresponding acid, for example by saponification of the ester, and then acidified after acidification.

The ether protecting or blocking group of 3- (and 5-) hydroxy can be removed when cyclization occurs by using bromic acid in acetic acid as the cyclizing agent and blocking agent. A 48% aqueous solution of bromic acid is commonly used because it satisfies cyclization and blocking breakage. This reaction is carried out at high temperature, preferably at reflux temperature.

However, when Z is-(alk ₁ ) _m -X- (alk ₂ ) _n- , a cyclizing agent such as polyphosphoric acid or trifluoroacetic acid should be used to avoid cleavage of the bond of ether or thioether.

The protecting group can also be removed after the cyclization reaction. Bromic acid-acetic acid is also good as a blocking agent in this stage. This reaction is carried out as described above.

Other reagents such as iodide, pyridine hydrochloride or bromate can be used to remove protective ether groups such as methyl and ethyl groups. If the protecting group is a benzyl or substituted benzyl group, it can be removed by catalytic hydrogenolysis. Suitable catalysts include palladium or platinum, especially those coated with carbon. In addition, these protecting groups can be removed by solvolysis using trifluoroacetic acid. If -Z-W contains sulfur, of course, benzyl removal by acid rather than catalytic benzyl removal is used.

The method of converting the compound of formula (VII) to the compound of formula (V), which is satisfactory in yield and can be carried out under relatively mild conditions, reacts the compound of formula (IV) with a suitable alkyl or benzyl chloroformate. In this way, the N-carab alkoxy group is converted into an N-carabalkoxy derivative having 2-5 carbon atoms. The N-carabalkoxy or carbobenzyloxy derivatives of formula (VIII) are then cyclized to polyphosphoric acid to form N-carabalkoxy or carbobenzyloxy derivatives of the corresponding compound of formula (V). The N-substituted derivatives of the compounds of formula (V) are hydrolyzed as desired, and the corresponding 3-[(N-substituted) -3- (protected hydroxy) -5-substituted anilino] -3 prior to cyclization It can be made from-(R ₄ ) -propionic acid. Polyphosphoric acid generally results in maximum cyclization and is therefore a preferred cyclizing agent.

The compound of formula (V) wherein the hydroxy group is protected and the nitrogen atom is substituted with carbalkoxy becomes a compound of formula (V-A) when treated with bromic acid-acetic acid. If the hydroxy protecting group is benzyl or substituted benzyl, the hydroxyl group is regenerated by catalytic hydrogenolysis. If a carb alkoxy group is present at the nitrogen atom it is not changed by this reaction. This may be removed later by treatment with bromic acid-acetic acid or any of a variety of acids or bases as desired. Treatment of the benzyl protecting group with trifluoroacetic acid removes any N-carab alkoxy groups present.

The -ZW substituent of the compound of formula (V) is -XH (X = 0 or S), and the -ZW substituent is -X- (alk ₂ ) _n -W in the compound of formula (II) or (I), X is O, S, SO or SO ₂ , and W is as described above), at this point in the overall reaction sequence, the -XH group is conveniently and advantageously represented by -X- (alk ₂ ) _n -W. You can switch. Thus, the 7-XH group of formula (V-B), such as -OH, is Williamson reacted with a suitable bromate [Br- (alk ₂ ) _n -W], mesylate, or tosylate to -O- (alk ₂ ) _n -W Convert to structural formula (VC).

Similarly, even when the -ZW group of the formula (V) is-(alk ₁ ) -XH, this is-(alk ₁ ) _m -X- (alk ₂ ) _n -W where n is 0 or 1 and W is other than hydrogen. Can be carried out by the Williamson reaction at this stage of the reaction process.

In this good way of preventing nitrogen from quantizing, it is possible to use various groups, such as groups belonging to the definition of R ₆ , in place of carabalkoxy or carbobenzyloxy.

If no R ₆ group is already present in the formulas (VA), (VB) or (VC), prior to the formation of the hydroxymethylene derivative (formula (VI)), C1-R ₆ or Br— By reacting with the R ₆ reactant, the R ₆ groups can be introduced. Of course, the structural formula The compounds of (Ⅰ) or (Ⅱ) Structure in products like the acyl group R _6, such as acetyl group, the reaction sequence (Figure B) (Ⅱ) at the next point in time to form a (wherein R ₆ is hydrogen), The acyl group R ₆ can be introduced by acylating with a suitable acyl halide by known methods.

Compounds of formula (V) and also of formulas (VA), (VB) and (VC) are converted to compounds of formulas (II) and (I) where R ₅ is hydrogen by the following reaction sequence (flow chart B) do.

The quinoline of formula (V) is converted to the hydroxymethylene derivative of formula (VI) by reaction with ethyl formate and sodium hydride. This reaction is a formylation reaction, in which bis-formylated derivative (VI) is produced in good yield. Treatment of the bis-formylated derivative with methyl vinyl ketone results in a mixture of the corresponding mono-N-formylated Michael adduct and the 1,3-bis-formylated Michael adduct. These two products are conveniently separated by column chromatography on silica gel.

The conversion of the compound of formula (VII) to the compound of formula (III) is carried out by aldol condensation of the mono-N-formyl compound of formula (VII). Aldol condensation of the 1,3-bis-formylated Michael adduct produces a spiro-annealed product (III-A) as a main product. However, the compound of formula (VII-A) can be converted to the compound of formula (VII) by treatment with 1 equivalent of potassium carbonate in methanol.

In addition to spiro-annealed products, small amounts of the desired compounds of the formulas (III) and (V) are also produced.

Enones of formula (III) are converted to compounds of formula (II) by Birch reduction. Both cis- and trans-isomers are produced. This reduction is conveniently carried out by using lithium as the metal. Sodium or potassium can also be used. This reaction is carried out at a temperature from about -35 ° C to about -80 ° C. The reason why birch reduction is good is that the desired trans-ketone of formula (II) is produced as the main product because of its stereoselective ability.

When cis-diastereo is the main product, catalytic reduction on noble metals is preferred.

The hydroxyketone of formula (II) (R ₀ is oxo and R ₁ is hydrogen) and the dihydroxy compound of formula (I) (R = OR ₁ = OH) appear rather unstable. If left untreated, these compounds oxidize to become purple or red. These colored by-products also form when the hydroxyketone undergoes sodium borohydride reduction. To prevent the formation of colored byproducts, the 1-hydroxyl group (OR ₁ ) may be acylated, in particular acetylated, with acetic anhydride in pyridine and also form acid addition salts such as hydrochlorides. Acetyl derivatives are stable even in the next reaction even if left unchecked.

The colored by-products have a quinoidoid structure, and it is thought that the 1-hydroxy group (OR ₁ ) is oxidized to oxo, and a second oxo group is introduced at the 2-or 4-position. This by-product itself is also effective as a CNS agent, in particular analgesics, sedatives and hepatolytic agents, and is therefore used at the same dosage level in the same way as the compounds of formulas (I) and (II).

When the 9-oxo group of the compound of the formula (II) and the acetylated derivative of the formula (II) are reduced by the metal hydride reduction method for the reasons of the above-mentioned stability, a structural formula in which the hydroxyl group is present as the acetylated derivative in the 1-position Obtain the compound of (I). At this stage, sodium borohydride is preferred as the reducing agent, which not only gives the desired product a satisfactory yield, but also maintains the acetoxy key in the 1-position and also hydroxyl solvents (methol, ethanol, water). This is because they react slowly with so that they can be used as a solvent. Temperatures of about 0 ° C.-30 ° C. are usually used. In order to increase the selectivity of the reduction, it can be used at low temperatures, such as about -70 ° C. High temperatures cause sodium borohydride to react with hydroxyl solvents and also cause deacetylation. If high temperatures are desired or required for a given reduction, use isopropyl alcohol or dimethyl ether of diethylene glycol as solvent. Preferred reducing agent is potassium tri-sec-butyl borohydride, which assists in stereo selective formation of 9α-hydroxy groups. This reduction is carried out in anhydrous tetrahydrofuran at a temperature of about −50 ° C. or less using an equimolar amount of 9-oxo compound and a reducing agent.

Reducing agents such as lithium borohydride or lithium aluminum hydride require anhydrous conditions and non-hydroxyl solvents such as 1,2-dimethoxyethane, tetrahydrofuran, ether, dimethyl ether of ethylene glycol and the like.

More preferably, the compound of formula (III), in particular when the 1-hydroxy group is protected by ester or benzyl ether, is converted to the compound of formula (I) by catalytic hydrogenation. A convenient way is to catalytically hydrogenate on palladium, such as palladium on carbon or other supported or unsupported precious metal.

The acetylated derivative of formula (I) thus produced is converted to the corresponding hydroxy derivative by cleaving the acetyl group in a conventional manner.

9-α- and 9-β-hydroxy compounds, which are isomers having the structure (I), are produced in this reduction step. The keto compounds of formulas (II)-(IV) are suitably alkylene glycols or alkyls of 2-4 carbon atoms in the presence of dehydrating agents such as P-toluenesulfonic acid or other acids such as oxalic acid or adipic acid used for ketalization Treatment with lene dithiol yields the corresponding ketal or thioketal.

The compound of formula (I) wherein R is hydroxy methyl is prepared by reacting the corresponding 9-oxo compound of formula (II) with methylenetriphenylphosphorane or other suitable methylide. This reaction is carried out under relatively mild conditions to yield the corresponding 9-methylene compound.

Hydrogenboration-oxidation of the 9-methylene compound is then carried out to give a hydroxymethyl derivative. Borane in tetrahydrofuran is preferred in this hydrogen boration step because borane is commercially available and gives the desired hydroxymethyl compound in satisfactory yield. This reaction is usually carried out in tetrahydrofuran or diethylene glycol dimethylether. The borane product is oxidized directly with alkaline hydrogen peroxide without separation to form a hydroxymethyl compound.

The compounds of the structural formulas (I) and (II) include those in which each of R ₄ and R ₅ are alkyl, and the following process is also produced in the order of C.

The first step in this sequence is the above-mentioned enone (process B) in the presence of an equivalent amount of P-toluenesulfonic acid or other acid commonly used to azeotropically remove water in benzene to form a ketal as described above. Is converted to the corresponding ketal by reaction with a suitable alkylene glycol (such as ethylene glycol) to obtain a mixture of the two ketals, ie, the formula (II-A) is in reduced form and is represented by the formula (II- B) is in oxidized form.

To assist in the formation of Structural Formula (IV-A), additives such as air, pd / c, sulfur or 2,3-dichloro-5,6-dicyanobenzoquinone are added to the reaction mixture. Removing the oxidant from the reaction mixture or adding a reducing agent to the reaction mixture aids in the formation of formula (II-A).

Deketalization of the compounds of formulas (II-A) and (IV-A) affords the compounds of formulas (II) and (IV). These latter compounds are converted to the compounds of the formulas (I) and (IV) by the method of Process B.

The reduced compounds of formula (II-A) are oxidized (dehydrogenated) with various oxidants, including iodine, to obtain compounds of formula (IV-A).

Heterogeneous aromatic compounds of formula IV-A are readily added to organometallic reagents to form azomethine bonds. Organolithium reagents such as methyl and ethyllithium react with the formula (IV-A) to produce an additive of formula (III-B). The additive thus formed is oxidized, for example, with an oxidizing agent, such as air, to become aromatic to give a compound substituted at the 6-position in the formula (VI-B). Further reaction of the compound of formula (VI-B) with the 6-position substituted with an organic lithium reagent yields the 6,6-disubstituted product of formula (II-B).

The addition of the second group (R ₅ ) to the 6-position is readily carried out by quaternizing and activating the azomethine bond, especially when R ₅ is greater than methyl. This activation causes the compound of formula (III-B) to react with an alkyl halide (eg methyl iodide or ethyl) or an aralkyl halide, preferably an aralkyl bromide such as benzyl bromide [C ₆ H ₅ (CH ₂ ) _x B] to obtain a compound of the formula (III-C) substituted with the 5-position.

This activated compound readily reacts with excess organolithium or Grignard reagents to yield a trisubstituted compound of formula II-B.

Hydrolysis of the ketals of Structural Formulas (II-B) and (III-C) yields the corresponding enones, which are converted to the compounds of Structural Formulas (II) and (I) in the manner described above. Of course, when R ₆ of the compound of formula (III) or (III-C) is benzyl, the benzyl group is cleaved even if the enone is reduced to lithium-ammonia.

The process for further introducing an alkyl group at the 6-position in the final production of the compounds of formulas (I) and (II) is shown in process diagram D.

The 6-oxohexahydrobenzo [C] quinoline of formulas (VI-C) and (IV-E) can be used to prepare compounds of formulas (IV-A) and (IV-D) at high temperature, such as at about 200 ° -200 ° C. Prepared by reaction with sodium or potassium hydroxide. By quaternizing the nitrogen of formula (IV-A) by reacting formula (IV-A) with methyl or ethyl iodide, benzyl bromide, or other aralkyl halides, the reaction with sodium hydroxide or potassium is further enhanced. It can be carried out under mild conditions. The intermediate additive is easily oxidized with a mild oxidizing agent containing air to produce an oxo compound of formula (IV-E), which is substituted with a substituent (methyl, ethyl, aralkyl) on the nitrogen atom as a result of quaternization. ).

Another method is to treat the structural formula (IV-A) with peracids such as m-chloroperbenzoic acid and peracetic acid to form the corresponding N-oxides, which are then reacted with acetic anhydride and rearranged. (IV-C) is obtained. Other known methods may be used to convert the N-oxide to lactam.

Treatment of a compound of formula (IV-C) or (IV-E) with an excess of suitable Grignard reagents, such as methyl or ethyl magnesium bromide, results in the corresponding 6,6-dialkyl compound of formula (II-B). Get

3-hydroxy-5- (ZW-substituted) aniline is prepared by Bucherer reaction of the corresponding 5- (ZW-substituted) resorcinol, i.e. with aqueous ammonium sulfite or bisulfite. .

This reaction is carried out in a pressure vessel at high temperature, for example at about 150 ° -230 ° C. The aniline product is separated by acidifying the cooled reaction mixture and extracting the acid mixture, for example with ethyl acetate. The acid solution is neutralized and extracted with a suitable solvent such as chloroform to recover the aniline product.

The aniline product can also be separated by extracting the cold reaction mixture and subjecting the crude product to column chromatography.

5- (Z-W-substituted) resorcinol is prepared from 3,5-dihydrocybenzoin acid. In this process, hydroxy esterified (eg methyl, ethyl or benzyl ether) 3,5-dihydroxybenzoic acid or amide 3,5- [di (protected hydroxy)]-benzoic acid Make it angry.

The overall reaction sequence is summarized in process diagram E.

The starting material 3,5-dihydroxy benzoic acid of formula (XI) is a compound of formula (XI), wherein Y ₂ is an alkoxy group, preferably methoxy or ethoxy, or an amino group and Y ₁ is a hydroxy protecting group Switch).

The diprotected benzoic acid of formula (XII) is converted to the compound of formula (XIV) by known methods. One method hydrolyzes the structural formula (XII) to form the corresponding acid (Y ₂ = OH) or lithium salt, which is reacted with a suitable alkyllithium to produce an alkyl disubstituted phenylketone (Y ₂ = alkyl). When methyl lithium is used, the resulting acetophenone derivatives are treated with Grignard reagent (W-Z'-MgBr). The intermediate product is hydrolyzed to the corresponding alcohol, which is then hydrogenated to replace the hydroxy group with hydrogen. This method is particularly effective for compounds where Z is alkylene.

The ether group is destroyed in an appropriate manner. That is, treatment with pyridine hydrogen chloride (Y ₁ = methyl) or catalytic hydrogenolysis (Y ₁ = benzyl) or with acids such as trifluoroacetic acid, hydrochloric acid, bromic acid or sulfuric acid. If ZW contains sulfur, it is, of course, decanted benzylation.

In another method of converting a compound of formula (XII) to a compound of formula (XIV), the ketone (Y ₂ = alkyl) of formula (XII) is converted to the appropriate triphenylphosphonium bromide in the presence of a base (such as sodium hydride). React with a derivative [(C ₆ H ₅ ) ₃ P ⁺ -ZW] -Br. The reaction proceeds through alkenes, which are then catalytically hydrogenated to the corresponding alkanes (ZW) which are then blocked and converted to dihydroxy compounds of formula (XIV). Of course, in the case of benzyl in which -Z- is (alk ₁ ) _m -X- (alk ₂ ) _n and Y ₁ , benzyl ether is cleaved as a result of catalytic hydrogenation.

The conversion of the compound of the formula (XII) to the compound of the formula (XIV) may be carried out in the order of XII → XIII → XIV.

In this case, deprotected benzamide (XII) (Y ₂ = NH ₂ ) is reacted with a suitable Grignard reagent (BrMg-Z'-W) to give ketone (XIII) (Z '= Z miters 1CH ₂ group). And react again with methyl- or ethyl-magnesium halide to make the corresponding carbinol. Dehydration of the carbinol with, for example, P-toluene sulfonic acid yields the corresponding alkene, which is catalytically hydrogenated (pd / c) to make alkanes (XIV). The ether group is blocked (converted to hydroxy) as described above.

When Z is alkylene, it is preferable that Y ₁ is alkyl or benzyl of 1-4 carbon atoms. The function of the Y ₁ group is to protect the hydroxy group during the next reaction. The significance of the Y ₁ group is not its structure, but rather its specific function, ie the protection of the hydroxyl group. Selection and identification of suitable protecting groups can be performed by any person skilled in the art. The suitability and effect of certain groups as hydroxy protecting groups is determined by using such groups in the reaction sequence described above. Therefore, such protecting groups should be such that they can be easily removed again to recover the hydroxyl group. Methyl is easily removed by treatment with pyridine hydrogen chloride and thus is a protective alkyl group. When the benzyl group is used as a protecting group, it is removed by catalytic hydrogenolysis or acid hydrolysis.

When Z is-(alk ₁ ) _m -X- (alk ₂ ) _n- , it is preferable that Y ₁ is a benzyl or substituted benzyl group, since these groups can be removed later without damaging the Z group. to be.

Compounds of formula (VII-A) can also be prepared from 3-amino-5-hydroxybenzoic acid by the method of Process F.

-ZW is alkylene-W or-(alk ₁ ) _m -X- (alk ₂ ) _n -W, wherein-(alk ₁ ), (alk ₂ ), W and n are as described above and X ' The compound of structural formula (VII-A) which is this O or S can be obtained by the procedure of process chart F. FIG.

The first step in the sequence (Wittig reaction) is to select the appropriate reactants to give the opportunity to produce compounds with straight or branched alkylene groups. The amino group is protected by acetylation in a conventional manner.

In the above example, when R "is methyl or ethyl, it causes to form a compound having alkyl substitution at the carbon atom (α) adjacent to the phenyl group. Substituting the methyl or ethyl group at the β-carbon atom of another position, such as an alkylene group, This is done by selecting the appropriate carboalkoxy alkylidene triphenylphosphorane, ie (C ₆ H ₅ ) ₃ P = C (R ")-COOC ₂ H ₅ . The unsaturated ester thus produced is reacted with lithium aluminum hydride and reduced to the corresponding saturated alcohol. The presence of small amounts of aluminum chloride can promote this reaction. If Y ₁ is other than benzyl (eg methyl), the alcohol is produced by catalytic reduction of unsaturated esters with palladium-carbon and treatment of the saturated esters thus produced with lithium aluminum hydride. The alcohol is converted to the corresponding tosylate or mesylate, the tosylate or mesylate is alkylated with an alkali metal salt of the appropriate HX '-(alk ₂ ) _n -W reactant, and finally the protecting group (Y ₁ ) is removed. The desired compound of structural formula (VII-A) is obtained.

When X 'is sulfur, the protecting group Y ₁ is methyl.

One variation of the foregoing sequence is that the alcohol is brominated instead of converted to tosylate or mesylate. Tribrominated phosphoric acid is a convenient brominating agent. The bromo derivative is reacted with the appropriate HX '-(alk ₂ ) _n -W in the presence of a suitable base (Williamson reaction).

Bromo compounds are also important intermediates which act in this sequence to increase the length of the chain of the alkylene group, thus obtaining compounds in which Z is -alkylene-W. In this method, bromo derivatives are treated with triphenylphosphine to give the corresponding triphenyl bromide. Reaction of triphenyl phosphorous bromide with a suitable aldehyde or ketone in the presence of a base such as sodium hydride or n-butyllithium yields an unsaturated derivative which is then catalytically hydrogenated to the corresponding saturated compound.

In the above modification, the protecting group Y ₁ to be selected differs depending on the specific order to be performed. When using the vertical sequence on the right, benzyl is the preferred protecting group for reasons in the catalytic hydrogenation step. When using the left vertical sequence, methyl is the preferred protecting group because methyl is conveniently removed by treatment with acid.

Compounds of formula (II) wherein -ZW is-(alk ₁ ) _m -X- (alk ₂ ) _n -W and X is -SO- or -SO _2- , oxidize the corresponding compound wherein X is-S- Obtained by application. Hydrogen peroxide is a convenient oxidant to oxidize thioether to sulfoxide. Oxidation of thioethers with the corresponding sulfones is conveniently carried out using peracids such as perbenzoic acid, perphthalic acid or m-chloroperbenzophosphoric acid. In particular, m-chloro and benzoic acid are very useful peracids because they can easily remove the by-product m-chlorobenzoic acid.

Esters of the compounds of formula (II)-(IV) wherein R ₁ is alkanoyl or -CO- (CH ₂ ) p-NR ₂ R ₃ are dicyclohexylcarbodiimide of the compounds of formula (II)-(IV). Easily prepared by reacting with a suitable alkanophosphoric acid or acid of the structural formula HOOC- (CH ₂ ) p-NR ₂ R ₃ in the presence of a condensing agent such as: These esters may also be prepared by reacting compounds of formulas (II)-(IV) with a suitable alkanophosphate chloride or anhydride such as acetyl chloride or acetic anhydride in the presence of a base such as pyridine.

Esters of the compounds of formula (I) in which each of the R and R ₁ groups are esterified are prepared by acylating in the manner described above.

Compounds acylated only with 9-hydroxy groups are prepared by mild hydrolysis of the corresponding 1,9-diacyl derivatives, in which case the hydrolysis of the acyl groups of phenol is very easy.

Compounds of the structural formula (I) in which only 1-hydroxy group is esterified are obtained by borohydride reduction of the ketone of the corresponding structural formula (II) in which the 1-position is esterified. The compound of formula (I) thus produced has 1-acyl-9-hydroxy substitution or 1-hydroxy-9-acyl substitution, which is further acylated with other acylating agents to give esters in 1-position and 9-position The diesterated compound of structural formula (I) from which a group differs is obtained.

The presence of a base in the ester group (OR ₁ ) of the compound of the present invention makes it possible to form an acid addition salt containing the base.

When a basic ester is prepared by condensing a suitable amino acid hydrogen chloride (or other acid addition salt) with a suitable compound of formulas (I)-(IV) in the presence of a condensing agent, the hydrogen chloride of the basic ester is produced. Careful neutralization gives free bases. This free base can be converted to other acid addition salts by known methods.

As will be appreciated by those skilled in the art, acid addition salts may form with nitrogen in the benzo [C] quinoline system.

Such salts are prepared by conventional methods. Basic esters can form mono- or di-acid addition salts because of their basicity.

The analgesic properties of the compounds of the present invention measure the ability of a compound to inhibit thermal stimulation (e.g., touching the tail of a mouse with a hot object) or chemical stimulation (e.g., stimulating a mouse from stimulation of phenylbenzoquinone). Method). The above and other tests are described below.

Test using thermal stimulation

a) Analgesic test in which the mouse is placed on a hot plate.

Apply controlled thermal stimulation to the paws of mice on a 1/8 inch thick aluminum plate. Place an infrared heat lamp with a 250-watt reflector under the bottom of the aluminum dish. A thermostat connected to the thermometer on the dish surface maintains the temperature of the heat lamp at a constant temperature of 57 ° C. Each mouse is dropped into a glass cylinder (6.5 inches in diameter) placed on this hot plate and timed from when the mouse's foot touches the plate. At 0.5 and 2 hours after treatment with the test compound, the mice are first shaken by one or both of the hind paws. 10 seconds did not wobble. MPE ₅₀ = 4-5.6 mg / kg (sc) of morphine.

b) Analgesic testing of the mouse's tail

Highly regulated heat is applied to the tail of the mouse. Place each mouse in a cozy metal cylinder with its tail at one end.

The arrangement of the cylinders allows the mouse's tail to lie flat on a hidden heat lamp. At the beginning of the test, peel off the aluminum plate covering the lamp so that the light is focused through the gap at the tip of the mouse tail.

At the same time time is measured. Observe sudden clashes of tails. Untreated mice typically respond within 3-4 seconds after exposure to the lamp. Treated mice respond in 10 seconds. Each mouse is tested 0.5 and 2 hours after treatment with morphine and test compounds. MPE ₅₀ = 3.2-5.6 mg / kg (sc) of morphine.

Test Using Chemical Response Stimulation

Suppress Written from Stimulation of Phenylbenzoquinone

Groups of 5 mice were pretreated subcutaneously or orally with saline, morphine, codeine or test compound. After 20 minutes for subcutaneous treatment or 50 minutes after oral treatment, each group is irradiated with phenylbenzoquinone. This injection is known to cause abdominal contractions. Start 5 minutes after the injection and watch for 5 minutes to see if the mouse is wobbled. Identify the MPE ₅₀ of the pretreatment drug that is subject to wobble.

The results of the test are reported as the maximum possible effect in% MPE. The% MPE for each group is compared statistically with the% MPE for standard and pretreatment drug controls. % MPE is calculated as follows.

The table below shows the analgesic effects as MPE ₅₀ , which is the dosage observed in a test given half of the maximum possible analgesic effects.

The compounds of the present invention are effective analgesics in oral and topical administration and are conveniently administered in the form of compositions. Such compositions include a pharmacological carrier selected based on the route of administration and standard medical practice.

For example, it may be administered in the form of tablets, pills, powders, or particles containing ingredients such as powder, milk sugar, certain forms of clay, and the like. It may be administered in capsules with the same or equivalent ingredients. It may also be administered in the form of oral suspensions, solutions, emulsions, syrups and elixirs, including sweeteners and colorings.

When orally administering a therapeutic agent of the invention, tablets or capsules containing about 0.01-100 mg are suitable for most applications.

The best dosage for an individual patient will be determined by the doctor, and the dosage will vary depending on age, weight, individual patient's response, and the route of administration. In general, however, the first dose used as an analgesic for adults is 0.01-500 mg per day, which can be taken once or in portions. In many cases, it is not necessary to exceed 100 mg per day. A good oral dosage range is 0.01-300 mg per day, with a more preferred range of 0.10-50 mg per day. Good local dosages range from about 0.01-100 mg per day and less preferred ranges are about 0.01-20 mg per day. The method as described above determines the analgesic effects on the various compounds of the present invention and several conventional compounds. The following abbreviations are used in the table below.

PBQ = Wriggling due to Phenylbenzoquinone TF = Touching Tail HP = Hot Dish

TABLE 1

TABLE 2

The effect of a compound as a relaxant is determined by its ability to lower the blood pressure of these strained rats and dogs when orally administered to mice and dogs by the aforementioned dosages of these compounds.

The effect of the compound as a sedative is manifested in a decrease in autonomic nervous system when orally administered to rats at a dosage of about 0.01-50 mg / kg. The daily dosage range for mammals is about 0.01-100 mg.

The use of these compounds as glaucoma agents is thought to be due to their ability to reduce intraocular pressure. Their effect on intraocular pressure is determined by testing in dogs. Test drugs are injected into the dog's eye in the form of a solution or administered systematically over several periods of time. The eye is then anesthetized with 2 drops of 1/2% tetracaine hydrogen chloride. After such local anesthesia, after several minutes, the intraocular pressure is measured by Shiotz's mechanical tension meter, the fluorescein dye is dosed, and the intraocular pressure is measured by Holberg's manual tension meter. Test drugs are conveniently used in the following solutions:

Test solution (1 mg), ethanol (0.05 ml), splatter 80 (polyoxyalkylene derivative of sorbitan-mono-ullate) (50 mg) and brine (to make 1 ml total); Or a more concentrated solution in which the components are present in the proportions of 10 mg, 0.10 ml, 100 mg and 1 ml, respectively, in a concentration of about 0.01 mg / kg-10 mg / kg when used in humans.

The effect of these compounds as diuretics is determined by testing in mice. The dosage range for this use is the same as described above for the effect as an analgesic.

The present invention also provides pharmacological compositions comprising unit dosage forms, which compositions are important for analgesics and other uses. Dosage forms can be made one or several times to achieve an effective daily dosage for a particular application.

The compounds of the present invention can be formulated for oral or topical administration in solid or liquid form. A capsule comprising a drug of the present invention, such as a compound of formula (I) or (II), contains 1 part by weight of a drug mixed with 9 parts by weight of a carrier, i.e. starch or milk sugar and each capsule contains 100 parts by weight of this mixture. Prepared by placing in gelatin capsules. Tablets comprising Structural Formula (I) or (II) are prepared by appropriately mixing the drug with the usual ingredients used in the manufacture of the tablets, such as starch binders and lubricants, so that each tablet contains 0.01-100 mg of medicine.

These drugs, in particular suspensions and solutions of compounds in which R ₁ is hydroxy in the formulas (I) and (II), are usually prepared immediately before use, because of problems with the stability of the drug (eg oxidation) and suspensions or solutions This is to avoid problems (sedimentation) related to storage. Compositions suitable for this use are generally compositions in dry solid form, which compositions are readjusted for injection.

Example 1

d, l-trans-5,6,6aβ, 7,10,10aα-hexahydro-1-acetoxy-3- (2-heptyloxy) -5-benzoyl-6β-betaylbenzo [C] quinoline-9 ( 8H) -on

In 2.5 ml of pyridine d, l-trans-5,6,6aβ, 7,10,10aα-hexahydro-1-acetoxy-6β-methyl-3 (2-heptyloxy) benzo [C] quinoline-9 ( While stirring the solution containing 8H) -one (812 mg), 421 mg of benzoyl chloride in 5 ml of chloroform is added. After 2 hours the reaction mixture is poured onto ice and extracted twice with ether. The combined ether extracts were washed with water and sodium bicarbonate, dried (MgSO ₄ ) and filtered, and concentrated and determined from ether / petroleum ether, d, l-trans-5,6,6aβ, 7,10,10aα- Hexahydro-1-acetoxy-3- (2-heptyloxy) -5-benzoyl-6β-betaylbenzo [C] quinolin-9 (8H) -one is produced. Melting point = 108 ° -110 ° C m / e-491 (m ⁺ )

Repeating the above method using acetyl chloride instead of benzoyl chloride and using the appropriate benzo [C] quinoline yields the following compounds.

d, l-trans-5,6,6aβ, 7,10,10aα-hexahydro-1-acetoxy-3- (2-heptyloxy) -5-acetyl-6β-methylbenzo [C] quinoline-9 ( 8H) -on m / e-433 (m ⁺ )

Example 2

d, l-trans-5,6,6aβ, 7,10,10aα-hexahydro-1-acetoxy-5-methyl-6β-methyl-3- (2-heptyloxy) methylbenzo [C] quinoline-9 (8H) -on

387 mg of d, l-trans-5,6,6aβ, 7,10,10aα-hexahydro-1-acetoxy-6β-3- (2-heptyloxy) benzo [C] quinoline-9 in 3 ml of acetonitrile The solution containing (8H) -one is cooled to 15 ° C. and stirred while adding 0.5 ml of 37% aqueous formaldehyde solution and again adding 100 mg of sodium cyanoborohydride. Acetic acid is added to maintain neutral pH until thin layer chromatography indicates that no starting material remains, indicating that the reaction is complete. The product is separated by the following method.

Ice water and ether are added to the reaction mixture, the ether layer is removed and the aqueous phase is extracted again with ether. The combined ether layers are dried and evaporated to produce the desired d, l-trans-5,6,6aβ, 7,10,10aα-hexahydro-1-acetoxy-5-methyl-6β-methyl-3- (3-heptyl Roxy) -benzo [C] quinolin-9 (8H) -one is produced as oil.

N-CH₃에 대하여 2.85ppm에서 특성적 흡수를 나타낸다. ¹ H NMR (60 MHz, CDCL ₃ )

Characteristic absorption is shown at 2.85 ppm with respect to N-CH ₃ .

In the same manner, the following compounds are prepared from suitable reactants.

d, l-trans-5,6,6aβ, 7,10,10aα-hexahydro-1-acetoxy-3- (2-heptyloxy) -5-acetyl-6β-methylbenzo [C] quinoline-9 ( 8H) -one, oil

d, l-trans-5,6,6aβ, 7,10,10aα-octahydro-1,9-diacetoxy-5-methyl-6β-methyl-3- (2-heptyloxy) benzo [C] quinoline , Oil

m / e-445 (m ⁺ )

The following compounds are likewise prepared.

1) obtained with HC1 salt

Analysis: for C ₂₈ H ₃₅ O ₄ N · HC1

Calculated Value: C, 69.19, H, 7.47, N, 2.88%

Found: C, 68.72, H, 7.18, N, 2.74%

2) Analysis: for C ₂₈ H ₃₅ O ₄ N

Calculated Value: C, 74.80, H, 7.85, N, 3.12%

Found: C, 74.66, H, 8.05, N, 2.66%

Melting point as HC1 salt = 69 ° -75 ° C

3) Analysis: for C ₂₇ H ₃₃ O ₄ N

Calculated Value: C, 74.45, H, 7.64, N, 3.22%

Found: C, 73.89, H, 7.51, N, 3.04%

Example 3

d, l-trans-5,6,6aβ, 7,8,9,10,10aα-octahydro-1,9-dihydroxy-5-ethyl-6β-methyl-3- (2-heptylhydroxy) benzo [C] quinoline

In a solution of 100 mg of lithium aluminum hydride dissolved in 5 ml of anhydrous tetrahydrofuran (cooled in an ice bath), 90 mg of d, l-trans-5,6,6aβ, 7,8 in 3 ml of tetrahydrofuran A drop of 9,10,10aα-octahydro-1,9-dihydroxy-5-acetyl-6β-methyl-3- (2-heptyloxy) benzo [C] quinoline was added dropwise. The reaction mixture is heated to reflux for 1 hour and then allowed to cool to room temperature. After addition of an equivalent amount of water, 3N potassium hydroxide is added again, the resulting precipitate is filtered, and the filtrate is concentrated in vacuo to produce the desired N-ethyl derivative as oil.

m / e-375 (m ⁺ )

Example 4

d, l-trans-5,6,6aβ, 7,8,9,10,10aα-octahydro-1-acetoxy-9-hydroxy-5-methyl-3- (5-phenyl-2-pentyloxy ) Benzo [C] quinoline

D, l-trans-5,6,6aβ, 7,10,10aα-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) benzo [C] quinoline- in acetonitrile (15 ml) Formaldehyde (1.1 ml of 37% aqueous solution) was added to a solution of 9 (8H) -one at room temperature, followed by sodium cyanoborohydride (0.262 g). Acetic acid is added to the reaction mixture in the required amount and the reaction mixture is stirred for 1 hour while maintaining the neutral pH. Sodium cyanoboroidide (0.262 g) and methanol (15 ml) were further added to the reaction mixture, acidified to pH 3, stirred for 2 hours, and concentrated under reduced pressure to yield oil. The oil is diluted with water (50 ml), adjusted to pH 9-10 with aqueous sodium hydroxide solution, and the alkaline mixture is extracted with ether (3 x 200 ml). The combined ether extracts are washed with brine, dried (MgSO ₄ ) and concentrated under reduced pressure to give a clear oil. This oil is dissolved in 50% ether-hexane and placed in a silica gel column. This column is first eluted with 50% tel-hexane and again eluted with 60%, 70% and 75% ether-hexane. Eluent is detected by thin layer chromatography (Ethelle 10, Hexane 1). The primary collected product was d, l-trans-5,6,6aβ, 7,10,10aα-hexahydro-1-acetoxy-5-methyl-3- (5-phenyl-2-pentyloxy) benzo [ C] quinolin-9- (8H) -one (0.12 g).

m / e-435 (m ⁺ )

Analysis: for C ₂₇ H ₃₃ O ₄ N

Calculated Value: C, 74.45, H, 7.64, N, 3.22%

Found: C, 74.06, H, 7.77, N, 3.31%

The secondary product is 9α-hydroxy diastereo and isomer of the title compound (25 mg).

m / e-437 (m ⁺ )

Analysis: for C ₂₇ H ₃₅ O ₄ N

Calculated Value: C, 74.11, H, 8.06, N, 3.20%

Found: C, 73.96, H, 8.34, N, 3.00%

The tertiary product is 9α-hydroxy diastereo and isomer of the title compound (0.7 g).

m / e-437 (m ⁺ )

Analysis: for C ₂₇ H ₃₅ O ₄ N

Calculated Value: C, 74.11, H, 8.06, N, 3.20%

Found: C, 73.56, H, 8.86, N, 3.21%

Similarly, d, l-trans-5,6,6aβ, 7,10,10aα-hexahydro-1-acetoxy-3- (2-heptyloxy) benzo [C] quinolin-9- (8H) -one Treatment with sodium cyanoborohydride yields the following product.

d, l-trans-5,6,6aβ, 7,10,10aα-hexahydro-1-acetoxy-5-methyl-3- (2-heptyloxy) benzo [C] quinoline-9- (8H)- Whole oil

m / e-387 (m ⁺ )

IR (CHC1 ₃ ): 5.80 (ketone C = O), 5.65 (ester C = O), μ

Analysis: for C ₂₃ H ₃₃ O ₄ N

Calculated Value: C, 71.29, H, 8.58, N, 3.61%

Found: C, 70.78, H, 8.71, N, 3.27%

d, l-trans-5,6,6aβ, 7,10,10aα-octahydro-1-acetoxy-9β-hydroxy-5-methyl-3- (2-heptyloxy) benzo [C] quinoline, oil

m / e-389 (m ⁺ )

IR (CHC1 ₃ ): 2.80 (ketone OH), 5.70 (ester C = O), μ

Analysis: for C ₂₃ H ₃₅ O ₄ N

Calculated Value: C, 70.92, H, 9.06, N, 3.60%

Found: C, 70.56, H, 8.95, N, 3.56%

And d, l-trans-5,6,6aβ, 7,10,10aα-hexahydro-1-acetoxy-6β-methyl-3- (5-phenyl-2-pentyloxy) benzo [C] quinoline-9 -(8H) -one is converted to the following compound.

d, l-trans-5,6,6aβ, 7,10,10aα-hexahydro-1-acetoxy-5-methyl-6β-methyl-3- (5-phenyl-2-pentyloxy) benzo [C] Quinolin-9- (8H) -one

d, l-trans-5,6,6aβ, 7,8,9,10,10aα-octahydro-1-acetoxy-9β-hydroxy-5-methyl-6β-methyl-3- (5-phenyl- 2-pentyloxy) benzo [C] quinoline, melting point 163-165 ° C. (separated into hydrogen chloride)

Example 5

d, l-trans-5,6,6aβ, 7,10,10aα-hexahydro-1-acetoxy-5-isobutyryl-3- (5-phenyl-2-pentyloxy) benzo [C] quinoline- 9- (8H) -on

D, l-trans-5,6,6aβ, 7,10,10aα-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy in which 1.07 mmol) in anhydrous pyridine (1.5 ml) was dissolved ) Benzo [C] quinolin-9- (8H) -one (450 mg, 1.07 mmol) was dissolved in isobutyryl chloride (114 mg, 1.07 mmol) in chloroform (20 ml) while stirring at 0 ° C. under nitrogen atmosphere. Slowly add the solution. The reaction mixture is stirred for 5 hours and then poured into ice water (50 ml). The chloroform layer is separated and the aqueous layer is extracted with chloroform (2 x 20 ml). The combined chloroform extracts were washed sequentially with 10% hydrochloric acid (2 × 10 ml) and brine (1 × 10 ml) and dried (MgSO ₄ ). Concentration of the chloroform solution in vacuo yields a yellow oil which is left to solid. Trituration of this solid with hexane yields a white crystalline solid which is recovered by filtration and dried (400 mg). Melting point = 128 ° -129 ° C

Concentration of the hexane filtrate yields 121 mg of oil.

Example 6

d, l-trans-5,6,6aβ, 7,8,9,10,10α-octahydro-1-acetoxy-9β-hydroxy-5-isobutyryl-3- (5-phenyl-2- Pentyloxy) benzo [C] quinoline

D, l-trans-5,6,6aβ, 7,10,10aα-hexahydro-1-acetoxy-5-isobutyryl-3- (5-phenyl-2-pentyloxy) in pure ethanol (20 ml) Sodium borohydride (38 mg, 1.0 mmol) was slowly added to a solution of benzo [C] quinolin-9- (8H) -one (26-mg, 0.529 mmol) in a nitrogen atmosphere at 5 ° -10 ° C. The reaction mixture is stirred for 1 hour and then acidified with 10% hydrochloric acid. Ethanol is removed by concentration under reduced pressure. To the remaining solution was added water (10 ml) and extracted with ethyl acetate (2 x 50 mg). The combined extracts were washed with brine and dried (MgSO ₄ ). Concentration in vacuo gave the title compound as an amorphous solid (213 mg). This is used without further purification.

Example 7

d, l-trans-5,6,6aβ, 7,8,9,10,10aα-octahydro-1,9β-diacetoxy-5-isobutyryl-3- (5-phenyl-2-pentyloxy ) Benzo [C] quinoline

Slurry containing lithium aluminum hydride (100 mg, 2.6 mmol) in tetrahydrofuran (5 ml) d, l-trans-5,6,6aβ, 7,8,9,10,10aα in tetrahydrofuran (5 ml) -A solution of octahydro-1-acetoxy-9β-hydroxy-5-isobutyryl-3- (5-phenyl-2-pentyloxy) benzo [C] quinoline (213 mg, 0.432 mmol) was dissolved at room temperature. It is added under nitrogen atmosphere. After stirring the mixture halfway, water (0.1 ml), 15% sodium hydroxide solution (0.1 ml) and water (0.3 ml) are added. Next, the mixture was filtered under nitrogen, and the filtrate was washed with tetrahydrofuran (2 x 5 ml). Concentration of the filtrate and washings together produces a reddish oil (0.714 g).

The oil is dissolved in pyridine (1 ml) under nitrogen and the solution is cooled to 0 ° C. Acetic anhydride (1 ml) is added while stirring the pyridine solution, and the reaction mixture is stirred at 0 ° C for 30 minutes. It is poured into water (25 ml) and extracted with ethyl acetate (3 x 25 ml). The combined extracts were washed with brine, dried (MgSO ₄ ) and concentrated to give brown oil (184 mg).

Nitrogen is suddenly flowed into the oil and chromatographed on silica gel (40 g) using benzene ether (9: 1) as eluent. Collect 10 ml aliquots. Concentration of the fractions 2-10 together yielded oil (109 mg).

m / e-521 (m ⁺ )

Analysis: for C ₃₂ H ₄₃ O ₄ N

Calculated Value: C, 73.67, H, 8.31, N, 2.68%

Found: C, 74.33, H, 8.89, N, 2.23%

: 7.22(s,5H, 방향성), 6.05(d,1H,방향성), 5.90(d,1H,방향성), 4.90(bs,1H), 4.30(bs,1H), 3.10(d, 2H,N-CH₂), 2.90(d,2H,N-CH₂), 2.70(bs,2H), 2.40 및 2.15(s,6H,2-CH₃-COO-), 1.85(bs,2H,H₇및 H₈), 1.5(m), 1.05(d,6H,

), 1.0-3.0(가변성, 나머지 프로톤)1 H NMR (60 MHz)

: 7.22 (s, 5H, directional), 6.05 (d, 1H, directional), 5.90 (d, 1H, directional), 4.90 (bs, 1H), 4.30 (bs, 1H), 3.10 (d, 2H, N- CH ₂ ), 2.90 (d, 2H, N-CH ₂ ), 2.70 (bs, 2H), 2.40 and 2.15 (s, 6H, 2-CH ₃ -COO-), 1.85 (bs, 2H, H ₇ and H ₈ ), 1.5 (m), 1.05 (d, 6H,

), 1.0-3.0 (variable, rest protons)

Claims (1)

Reacting a compound of the following structure with formaldehyde or alkyl or acyl halide or phenyl substituted alkyl or acyl halide to introduce an R ₆ group or subsequently reacting the resulting product with an alkali metal complex hydride to obtain a compound wherein R ₆ is alkyl or benzyl Characterized by

How to prepare a compound of the following structural formula

In the above formula

R 'is hydrogen or alkanoyl of 1-5 carbon atoms R ₁ is hydrogen, benzyl, benzoyl, alkanoyl of 1-5 carbon atoms or —CO— (CH ₂ ) _P —NR ₂ R ₃ , wherein p is an integer of 0 or 1-4; R ₂ and R ₃ are hydrogen or alkyl having 1-4 carbon atoms or R ₂ and R ₃ together with the nitrogen to which they are attached form a 5- or 6-membered heterocycle ring, wherein the ring is piperidino, Pyrrolo, pyrrolidino, morpholino, or N-alkylpiperazino having 1-4 carbon atoms in the alkyl group; R ₄ is hydrogen, alkyl of 1-6 carbon atoms or-(CH ₂ ) _Z -C ₆ H ₅ , wherein z is an integer from 1-4; R ₅ is hydrogen, methyl or ethyl; R ₆ is-(CH ₂ ) _Y -carabalkoxy having 1-4 carbon atoms in the alkoxy group, where y is an integer of 0 or 1-4, carbobenzyloxy, formyl, alkoxy having 2-5 carbon atoms Noyl, alkyl of 1-6 carbon atoms,-(CH ₂ ) _x C ₆ H _5, wherein x is an integer from 1-4 or -CO (CH ₂ ) _X-1 C ₆ H ₅ ; Z is an alkylene of 1-9 carbon atoms or-(alk ₁ ) _m -X- (alk ₂ ) _n- , _where the sum of the carbon atoms in (alk ₁ ) and (alk ₂ ) is 9 or less and m and n are 0 Or 1 and X is O, S, SO or SO ₂ ; W is hydrogen, methyl, piperidyl,

or

Wherein W ₁ is hydrogen, fluoro or chloro and W ₂ is hydrogen or

A is an integer from 1-5, b is an integer from 0 or 1-5, but the sum of a and b is 5 or less.