NO762444L - - Google Patents

Description

Process for the preparation of 4α-aryl-trans-decahydro-isoquinolines with aliphatically unsaturated N-substituents"

The present invention relates to the discovery of a selected group of 4a-aryl-trans-decahydroisoquinolines which are usable as analgesics.

Boekelhéide and Schilling, J. Am. Chem. Soc. 7_2, 712

(1950), described the compound N-methyl-4α-phenyl-cis-decahydroisoquinoline (called "N-methyl-10-phenyldecahydroisoquinoline") and indicated that it had a low analgesic activity.

The present invention is the result of efforts to develop new compounds that are effective and safe as analgesics.

According to the invention, there are provided new compounds of formula I and their suitable pharmaceutical salts, processes for the production of these, pharmaceutical compositions containing them, and methods of using these to induce an analgesic effect in warm-b' silly animals.

where R-1 is -CH2X, where X is C- 2~ C6 alkenY1 or C2-Cg alkynyl, where m 5 1 or 2, R2 is divalent oxygen <R>3 is H, -OH, -OCH3, or F, R4 is -H , -OH, -OCH3,

provided that when R^ is F, R^ must.

be -H.

The multi-step process according to the invention for the preparation of the compounds of formula I also includes the preparation of compounds where the substituents on the isoquinoline nitrogen are different from those indicated above, as follows. like for example. ci_cg alkyl, phenethyl and cycloalkylmethyl.

Representative R 1 groups are allyl (-CH 2 CH=CH 2 ), 3,3- . dime.thylallyl [-CH2CH=CH3) 2] /, propargyl (-CH2C=CH), 2-hexenyl and 2-hexynyl.

Representative aryl groups are phenyl, 3-hydroxyphenyl, 3-merhydroxyphenyl, 4-methoxyphenyl, 2-acetoxyphenyl, 2,3-dihydroxy-phenyl, 3,4-dimethoxyphenyl, 3,4-diacetoxyphenyl, 3-hydroxy-4-methoxyphenyl and 2-methoxy- 3-acetoxyphenyl.

The 4α-<aryl-trans-decahydroisoquinlines of formula I include various stereochemical isomers derived from

substitution at the 6-position, and from optical asymmetry of the entire structure. When monovalent R 2 substituents at the 6^position

is different (f>£ks>when R2 is

), will consider space-

nings require the presence of axial and equatorial isomers. In the molecule as a whole, spatial considerations will require the presence

se of d and 1 optical isomers. These are normally present as racemic mixtures•which can be resolved by known methods (Eliel, Stereochemistry of Carbdn Compounds, McGraw-Hill, 1962, . p. 31).

Separation of d and 1 isomers can also be achieved by dissolving an intermediate product. For example, formation of optically active diastereomeric salts from, 2-cyano-3-phenyl-3-carboxymethyl-cyclohexane (obtained by hydrolysis of the corresponding ester) and

(+) or (-)-α-phenethylamine, after regeneration of the acid and transesterification, lead to d and l-2-cyaho-3-phenyl-3-carbethoxymethyl-cyclohexane which can be carried out through the synthesis chain forming optically active N- s'substituted-4a-aryl-trans-decahydroisoquinol i - ner.

Pharmaceutically suitable acid addition salts of these compounds include those prepared with physiologically acceptable acids known in the art, and such salts include hydrochloride, sulfate, phosphate, nitrate, citrate, maleate and the like.

The multi-step process according to the invention starts with 2-cyano-3-aryl-3-carbalkoxymethylcyclohexenes which can be obtained according to the methods described by Boekelheide and Schilling (loe eit.) with regard to 2-cyano-3-phenyl-3-carbethoxymethylcyclohexene ( see example 1>part A). Important steps in this process are the reaction of a 2-cyano-3-aryl-3-car-balkoxymethylcyclohexene with hydrogen chloride in a lower alkanol such as ethanol to form a 4a-aryl-1,3-diketo-1,2, 3,4,4a,5,6,7-octahydroisoquinoline (see example 1, part B) and the reaction of such diketooctahydroisoquinoline with benzyl bromide or mesyltate in the presence of sodium hydride to form a N-benzyl-4α-aryl-1,3-diketo-1,2,3,4,4α,5,6,7-octahydroisoquinoline (see Example 1, part C). The 1,3-diketo-1,2,3,4,4a,5,6,7-octa-hydroisoquinolines exhibit a structural arrangement of the fused rings that requires the formation of trans-decahydroisoquinoline structures when the 8,8a-double bond is converted to a single bond by reduction. A key step is the reaction of an N-benzyl-4α-aryl-trans-decahydroisoquinoline with an aryl, hydrocarbyl or chlorohydrocarbyl chloroformate, followed by hydrolysis to form a ,4α-aryl-trans-decahydroisoquinoline (see Example 1, part F). This type of tertiary amine cleavage is described in Fieser and Fieser, Reagents For Organic Synthesis, Vol. 2, pp. 318 - 319 (ref. Hobson and Mc.Cluskey, J.Chem. Soc. (C) 1967, 2015). The 4a-aryl-trans-decahydroisoquinolines can be easily reacted in the usual manner to form 4a-aryl-trans-decahydroisoquinolines in which the nitrogen atom carries the saturated or unsaturated groups as defined by R 8 in the following.

The choice of specific preparation steps following the immediate formation of a 1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline depends on the specific 4a-aryl-trans-decahydroisoquinoline derivative desired. The reaction sequence includes at least six steps, which can be illustrated as follows:

In the preceding formulas I through VII, R 5 is

R<6> is C1-C4 alkyl, R<7> is

<c>l"<c>6<alky>!/C3_6alkenylmethyl, C^-Cg haloalkyl or C6~C10ary!'

R 8 is C1-C6 alkyl,<C>3~C6alkenylmethyl, C3-C6alkynylmethyl,<phen>eth<y>l (-CH2-CH2C6H5), cycloalkylmethyl of the formula

-CH2CH <(CH2)where n is an integer in the range 2-5,

2-furanylmethyl

2-(2-furany1)e thyl 2-thienylmethyl or 2-(2-thienyl)ethyl

9 10

wherein R is hydrogen, fluoro or methoxyl, R is hydrogen or methoxyl, provided that when R 9 is F, R 10 is H.

In step A, reactant R OH is used, which is also the reaction medium usually in excess, but to ensure maximum yield it should be used in an amount of at least 1 mol per moles of cyanoester. Likewise, the HCl reactant can be used in excess, but to ensure maximum yield this should be present in an amount of at least 1 mol per moles of cyanoester. The reaction is carried out in a liquid vase under anhydrous conditions. The reaction temperature shall be in the range from 50 to 120° C. The reaction pressure is not critical, usually atmospheric pressure is appropriate, but must be in accordance with the indicated reaction temperature.

In step E, it is appropriate to carry out the hydrolysis of the urethane intermediate without isolating it, although isolation can be carried out if desired. In this step, any inert solvent can be used (e.g. ethylene chloride, diethyl ether etc). Temperatures in the range from -10 to +5o° C are suitable, and practical reaction times are in the range of 2 to 48 hours.

Representative R 7 groups in the chloroformate reagent in step E are ethyl, butyl, hexyl, vinyl, 3-butenyl, 2,2,2-trichloro-ethyl and phenyl..

In step F, the hydrocarbyl group of the hydrocarbyl bromide, iodide, or mesylate reactant corresponds to R Q , which may be saturated or unsaturated as previously indicated. The method is therefore not limited to the production of the unsaturated compounds ay formula I, but can also give products where the substituent on the nitrogen atom is saturated. Such hydrocarbyl bromides or iodides are readily available as indicated in the following table, and the mesylates can be readily prepared from the corresponding available alcohols by the method described by Crossland and Servis-, J. Org. Chem., 35 , 3195' (1970).

In the preparation of a 2-cyano-3-phenyl-3^carbalkoxy-methylcyclohexene, Boekelheide and Schilling have described a procedure starting with cyclohexanone as shown in the following:

These preliminary steps can be of help in the preparation of different equivalents defined by different values of Ar and R in general formula I by starting with suitable substituted cyclohexanones in step (a) and with suitable substituted arylmagnesium bromides. as intermediates in step (b). Thus, 4-methylcyclohexanone and . 4-methoxycyclohexanone, which are commercially available, are used as main starting materials for the preparation of compounds of formula I. wherein R<2> is

The compounds of formula I in which R 2 (R R in the process description) is can be converted into other compounds of formula I in which R 2 has values different from R 5. The following table (Table II) shows additional R 2 values and known methods for the preparation of these.

Likewise, the use of suitable substituted phenyl bromides in the preparation of the arylmagnesium bromide Grignard reagent for step (b) can lead to corresponding Ar groups (Ar1 in the process description) in the compound of formula I. The following table (Table III) shows substituted phenyl bromides from which the relevant Ar -groups are derived, with.substituent and R^ groups as defined above.

Compounds in which Ar<1> has methoxyl substituents (as in Table III) can serve as intermediates for compounds of formula I in which Ar has hydroxyl or acetoxyl substituents using methods for conversion of R groups to R 2 groups as shown in Table II.

In the following illustrative examples, all parts are by weight and temperatures are given unless otherwise indicated.

Example 1

N- ally1- 4a- phenyl- trans- decahydroisoquinline (R1=CH„CH=CH2/

A. 2-cyano-3-phenyl-3-carbethoxymethylcyclohexene 90 g (0.346 mol) 2-carbethoxymethyl-2-phenylcyclohexanone (Boekelheide et al., supra), 200 ml of hydrogen cyanide and 12 drops of a saturated aq. solution of potassium cyanide was stirred at 0° C. overnight. 15 drops of concentrated sulfuric acid were then added and excess hydrogen cyanide evaporated. The unclean cyanohydrin was taken up in ether and washed with cold 10% sulfuric acid solution and then dried with Na2SO4 and evaporated. The residual oil was dissolved in 1500 ml of pyridine and 100 ml of phosphorus oxychloride was added. The reaction mixture was stirred under nitrogen at reflux for 5 hours and then allowed to stand at 25° C. overnight. It was then carefully poured into a mixture of 2 liters of ice water and 400 ml of concentrated hydrochloric acid and extracted with ether. The ether extract was washed with dilute hydrochloric acid, water and brine, was then dried (Na 2 SO 4 ) and evaporated. The residual oil was distilled to give 45 g of a pale yellow liquid, bp -.135°C (0.20 mm), identified as 2-cyano-3-phenyl-3-carbethoxymethylcyclohexene.

NMR (CDCl 3 )(<2>): triplet. at 64, 71, 78 eps, 3H' (-OCH2CH3),

methylene envelope from 70-150 eps, approx. 6H,

in

singlet at 178 eps; 2H (-Q-CH2-CO2), quartet at 234, 242, 249, 256, 2H (-OCH2CH3),

triplet at 406, 419, 414, 1H

singlet at 436 eps, 5H (aromatic H). IR ( ): 4.50 y (C=N); 5.5 and 5.85 y (lactone purity); 5.75 y (-CO2-). (2). Peaks indicated in eps from tetramethylsilane (TMS). B. 4-phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydro isoquinoline 50 g of the product from part A dissolved in a minimal amount of absolute ethanol was added to 2.5 liters of absolute ethanol previously saturated with anhydrous hydrogen chloride. The solution was refluxed under nitrogen for 4 8 hours. It was then cooled and concentrated to approx. 300 ml on a rotary evaporator. On cooling, a white crystalline solid precipitated which was filtered, washed with cold ethanol and dried to give 25 g (56%) of 4a-phenyl-1,3-diketo-1,2,3,4,4a-5 ,6,7-octahydroisoquinoline, srri.p. 241 - 243° C.

Analysis: Calculated for C15H15N02: c 74.65, H 6.2u, N 5.81

Found: C 74.67, H 6.25, N 5.65

Analogously, various 1,3-diketo compounds (formula (2)) were prepared from corresponding 3-carbalkoxymethyl-2-cyanocyclohexenes (formula (1)) as indicated in the following table (Table IV) showing pairwise Ar - and R - substituent- . groups..

C. N-benzyl-4a-phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline ' ' 10 g (41.5 mmol) of the product from part B in 75 ml of dry dimethylformamide was added to 1.97 g of a 55% suspension of sodium hydride in mineral oil (45.1 mmol NaH) mixed with 50 ml of dimethylformamide, while maintaining the reaction mixture at 70°C under nitrogen. The mixture was heated to 80-100°C for 1 hour and then allowed to cool. 7.8 g (45'.6 mmol) of benzyl bromide in 25 ml of dimethylformamide were added dropwise. The mixture was then heated to 85° C. for 2 hours after which it was allowed to stand overnight at 25° C. The reaction mixture was poured into water and the resulting precipitate filtered. This crude product was chromatographed on "Silicar" eluting with 5:95 ether:benzene to give 3 g of N-benzyl-4a-phenyl-1,3-diketo-1,2,3,4,4a,5,6 ,7-octahydroisoquinoline.

IR: 5.85, 6.02 y (imide CO); 6.15 y (C=C)j 6.25, 6.32 y (Ar).

NMR: Multiplet at 50 - 150 eps (CH2).JAB quartet at 154 , 175,

201, 217 eps (CH 2 CO ); singlet at 289 eps (NCH20);.

multiplet at 400 - 450 eps (arH);

triplet at 440, 444, 448 eps (C=CH).

D'N- benzyl- 4a- phenyl- 1, 3- diketo- trans- decahydroisoquinoline

A mixture of 1.4 g (4.23 mmol) of the product from Part C, 100 mL of absolute ethanol, and 700 mg of 5% palladium-on-carbon was shaken under 2.81 kg/cm hydrogen for 18 hours. The catalyst was removed by filtration and the solvent evaporated from the filtrate to give N-benzyl-4a-phenyl-1,3-diketo-trans-decahydroisoquinoline, m.p. 130 - 133° C.

IR: 5.85, 6.0 y (imide CO); 6.25, 6.32 y (Ar).

NMR (CDCl 3 ):■ Complex multiplet from 50 to 200 eps (CH 2 );

singlet at 291 eps, (NCH2);

singlets at 424 and .427 eps (Ar-H) .

E. N-benzyl-4a-phenyl-trans-decahydroisoquinoline

4.0 g (12.0 mmol) of the product from part D in 15.0 ml of sodium-dried tetrahydrofuran was treated under nitrogen with 4.0 g of lithium aluminum hydride. The mixture was boiled under reflux. for 24 hours and then cooled and quenched under successive additions of 4.0 ml of water, 4.0 ml of 15% aqueous sodium hydroxide and 12 ml of water. The inorganic salts were filtered off and washed with ether, and the combined filtrates were dried (K 2 CO 3 ) and evaporated to a clear oil. The residual oil was evaporatively distilled, boiling point 160° C. (0.4 oil) to form N-benzyl-4a-phenyl-trans-decahydroisoquinoline.

NMR (CDCl3) : Complex multiplet at 60 - 170 eps from TMS

(methylene H, 15H);

singlet at 206 eps (2H,.N-CH2-O);

multiplets at 422 - 455 eps (10H, ArH).

F. 4a-phenyl-trans-decahydroisoquinoline

A solution of 2.5 g (8.2 mmol) of the product from part

E, 75 ml of methylene chloride and 2 g (18.8 mmol) of vinyl chloroformate (Kung, US Pat. 2,377,085) were stirred at 0° C. for 4 hours and then at 25° C. for 18 hours. Volatile material was removed under vacuum (15 mm) on a rotary evaporator. The residue was. dissolved in 150 ml of ethanol and then cooled to 0° C, and saturated with anhydrous hydrogen chloride. The solution was stirred at 0° C. for 4 hours

o

and then at 25 C for 18 hours. The solvent was removed under vacuum (rotary evaporator). The residue was dissolved in 1N hydrochloric acid and extracted with ether. The aqueous portion was basified with solid potassium hydroxide and extracted with ether. The ether was evaporated and the residue distilled, b.p. 105° C. (0.05 mm) to give 1.26 g of 4α-phenyl-trans-decahydroisoquinoline.

Analysis: Calculated for-C^H^N: . C 83.67, H 9.83

Found: C 83.12, H 10.16

NMR (CDCI3): Complex multiplet from 50 eps to 218-cps

(-CH2-/NH, 16H), complex multiplet from 420 - 456 eps (5H, Arll).

G. N-allyl-4a-phenyl-trans-decahydroisoquinoline

A mixture of 430 mg (2 mmol) of the product from Part F, 290 mg (2.4 mmol) allyl bromide, 165 mg (1.2 mmol) .11'. ^' potassium carbonate and 5 ml of absolute ethanol were stirred under nitrogen at 25°C for 48 hours. The volatile material was removed under vacuum (rotary evaporator) and the residue diluted with 5% potassium hydroxide, then extracted with ether to give 330 mg of an oil which was distilled, b.p. 120°C (9.15 mm) to form pure N-allyl-4a-phenyl-trans-decahydroisoquinoline.

IR: 6.0 8 y(C=C, 6 , 25, 6.3 2 y (Ar).

NMR (CDCl3): Complex multiplet from .50 - 1868 eps (15H, -CH2-), doublet at 172, 179 eps (2H, N-CH2), complex multiplet from 290 - 370 eps.

Analogously, various N-substituted 4α-aryl-trans-decahydroisoquinolines of formula (7) were prepared from corresponding 4α-aryl-trans-decahydroisoquinolines of formula (6) as indicated in the following table (Table V) showing Ar1, 5 8

The R and R -substituent groups in each product.

Dosage forms and their use

The analgesic agents according to the invention can be administered to relieve pain by any method that provides contact between the active agent and the area of action of the agent in the mammal's body. They may be administered by any conventional method available for use in connection with pharmaceutical preparations, either as individual therapeutic agents or in combination with therapeutic agents. They may be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen method of administration and standard pharmaceutical practice.

The dose administered will of course vary depending on known factors such as the pharmacodynamic properties of the particular agent, its mode of action and method of administration, age, health and weight of the recipient, the nature and degree of symptoms, the type of concomitant treatment, frequency of treatment and the desired effect. Generally, a daily dose of active ingredient can be 0.01 - 100 mg per kg body weight. Usually 0.1 to 50, and preferably 1 - 25 mg per kg per,, day given in divided doses 2-4 times per day or in a form that provides prolonged release, effective in achieving the desired results.

Dosage forms (compositions). suitable for internal administration contains from 25 mg to approx. 7 5 mg active ingredient per unit. In these pharmaceutical compositions, the active ingredient will usually be present in an amount of approx. 0.5 95% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or 1. liquid dosage forms, such as elixirs, syrups and suspensions; it can also be administered parenterally, in sterile liquid dosage forms or rectally in the form of suppositories.

Gelatin capsules contain the active ingredient and powdered carriers such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be manufactured as products that provide extended release to provide continuous release of medication over a period of several hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric-coated for selective breakdown in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain coloring and flavoring substances to increase the patient's confidence.

In general, water, a suitable oil, physiological saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenterals. solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, buffering agents. Antioxidizing agents such as sodium bisulphite, sodium sulphite or ascorbic acid either alone or in combination are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions may contain: preservatives, such as benzalkonium chloride, methyl or propyl paraben and chlorobutanol.

Suppositories contain the active ingredient in a suitable oily or water-soluble base. The oily class includes cocoa butter and fats with similar properties, the water-soluble class includes polyethylene glycols.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, E.W. Martin, a standard reference text in this field.

Suitable pharmaceutical dosage forms for administering the compounds according to the invention can be illustrated as follows:

Capsules

A large..number of unit capsules produced by filling

of standard two-part hard gelatin capsules each containing 50 mg of powdered active ingredient, 110 mg of lactose, 32 mg of talc and 8 mg of magnesium stearate.

Capsules

A mixture of active ingredient in soybean oil was prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 50 mg of active ingredient. The capsules were washed in petro-. leiimether and dried.

Pills

A large number of tablets were prepared according to usual methods so that the dosage unit is 50 mg of active ingredient, 7 mg of ethyl cellulose, 0.2 mg of colloidal silicon dioxide, 7 mg of magnesium stearate, 11 mg of microcrystalline cellulose, 11 mg of corn starch and 98.8 mg of lactose. Suitable coatings can be applied to improve taste or delay absorption.

Inj. isable forms

A parenteral composition suitable for administration by injection was prepared by stirring 1.5% by weight of active ingredient in 10% by volume of propylene glycol and water. The solution was sterilized by filtration.

Suspension

An aqueous suspension was prepared for oral administration such that each 5 ml contained 10 mg of finely divided active ingredient, 500 mg of acacia, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, USP, 5 mg of sodium saccharin and 0.025 ml of vanilla extract tincture.

Injectable forms

A parenteral composition suitable for administration by injection was prepared by dissolving 1% by weight of active ingredient in sodium chloride injection solution USP XV after which the pH of the solution was adjusted to between 6 and 7. The solution was sterilized by filtration.

A standard procedure for determining and comparing the analgesic activity of compounds in series and where there is good correlation with efficacy in humans is. the standard phenylquinone torsion test modified from Siegmund,. a. at., Proe. Soc. Exp. Biol. With. 95, 729 (1957). A test compound suspended in 1-% methylcellulose is given orally to fasted (17 - 21 hours) white female mice, 5-20 animals per double blind tests. Water (0.01% phenyl-p-benzoquinone) phenylquinone was injected intraperitoneally at 23 or 30 minutes later using 0.25 ml per mouse. Starting at 30 or 37 minutes after the oral administration of the test compound, the mouse was observed for 10 minutes for a characteristic stretching or writhing syndrome indicative of pain induced by phenylquinone. The effective analgesic dose for 50% of the mice (ED 50 ) was calculated by the method according to Weil, Biometrics 8, 249 (1952).

By this test method it was found that upon oral administration of N-allyl-4a-phenyl-trans-decahydroisoquinoline the ED^q was 89 mg/kg.

Claims (3)

1.. Procedure for the preparation of a compound of formula 9 in R is -H, F or -OCH-. and R is H or -OCH-, provided that when 9 10 R is F, R is equal to H, characterized by (a) a compound of the formula is contacted with a hydrocarbyl or chlorohydrocarbyl chloroformate at a temperature in the range of 0 - 25°C, and (b) the product of step (a) is hydrolyzed. 2. Process according to claim 1, characterized in that the hydrocarbyl chloroformate is vinyl chloroformate. 3. Process for preparing a compound of the formula hnvåor rR i 9 R e9r eFr , He, r F R e10llelr ik OCHH, ., koag rR, aker tH eerlleir sOCeHr.,, t fovrued tsaatt ten that connection of the formula where R 1 is C 1 -C 2 -alkyl, is brought into contact with an anhydrous alcohol of the formula R 60H.