FI78291C - FOR EXAMINATION OF THERAPEUTIC FRAME THERAPEUTIC 1-PHENOXY-3-HYDROXY-INDOLYL-ALKYLAMINO-3-PROPANOLER. - Google Patents

Description

1 78291

This invention relates to the preparation of heterocyclic compounds of the indole series having an amino substituent. The compounds are therapeutically useful, especially as antihypertensive agents.

Many groups of compounds classified as 3- (aryloxy) -2-hydroxy-10 propylamines are well known in the art. Most of the compounds belonging to these groups of compounds have been mentioned to be useful in the treatment of cardiovascular diseases, in particular they have beta-adrenergic receptor blocking activity. Many compounds in this general class also have some degree of vasodilatory activity, due in some cases to the inherent alpha-adrenergic receptor blocking activity. Various other cardiovascular effects, or the absence thereof, combine to make these compounds useful as antihypertensive agents. The prior art is mostly concerned with the property of these groups of compounds as beta-adrenergic blocking agents. The prototype of such structures is propanolol; chemically expressed 1- (isopropylamino) -3- (1-naphthyloxy) -2-propan-25-ol. Propanolol and certain similar naphthyloxypropanolamines are the subject of the invention in U.S. Patent No. 3,337,628, issued August 22, 1967. Subsequently, numerous patents have been granted covering a series of compounds representing structurally modified 3- (aryloxy) -2 -hydroksipropyyliamiineja.

A series of indol-3-yl-tert-butylaminopropanols (1,2) with antihypertensive properties have been described in the literature: Kreighbaum et al., U.S. Patent No. 4,234,595, issued November 18-35, 1980. ; U.S. Patent No. 4,314,943, patented 9.

2,789,291, February 1982; and Journal of Medicinal Chemistry 23: 3, 285-289 (1980).

-'- öcihr- ·· ** (1) R1 15 <»In these above structural formulas, the symbol may be hydrogen, halogen, lower alkyl or alkoxy, but not hydroxyl.

One preferred compound in the series of structural formula (I) is termed MJ 13105 and is also known as busindole in the United States and is currently being tested clinically as an antihypertensive agent.

CN

B

MJ 13105 30 -

With respect to the present compounds, it is interesting that the major metabolic pathway of MJ 13105 involves 6-hydroxylation of the indole ring. This was confirmed by comparing metabolic isolates with the corresponding synthetically prepared 6-hydroxyindolyl compound of this invention.

U.S. Patent No. 3,789,291, filed September 3, 1982, describes a series of vasodilators having beta-adrenergic blocking properties and having the structural formula (3).

I 0H N (3)

10 - B

Although C in the above structural formula (3) may be hydroxyl among other substituents, this series is generally distinguishable from the present invention in that the compounds of structure (3) are pyridinyloxypropanolamines.

The present invention relates to a process for the preparation of therapeutically useful 1-phenoxy-3-hydroxyindolylalkylamino-3-propanols of formula (I) and their acid addition salts.

': CHY \ ph XX

; / X- [X-r5 | O-J ^ p

| 0H CN

25 H (1> 5 in which R is hydrogen or 5-fluoro, and the hydroxyl substituent group is in the 4-, 5-, 6- or 7-ring position of the indole.

The compounds of the present invention are useful as antihypertensive agents in part due to their combination of adrenergic receptor blockade and vasodilatory effects.

For medical use, pharmaceutically acceptable acid addition salts are preferred, i.e. salts in which the anion is substantially non-toxic and does not affect the pharmacological activity of the organic cation of the compounds. Acid addition salts are obtained either by reacting an organic base of formula I with an organic or inorganic acid, preferably in solution, or by any of the standard methods described in detail in the literature and available to one skilled in the art. Examples of useful organic acids include carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, esithionic acid, succinic acid, pamoic acid, cyclamic acid, pavalinic acid and the like; useful inorganic acids include hydrohalic acids such as HCl, HBr, HJ; sulfuric acid, phosphoric acid and the like.

It is also to be understood that the compounds of the present invention encompass all optically isomeric forms, i.e., mixtures of enantiomers, e.g., racemic modifications, as well as individual enantiomers. These individual enantiomers are generally designated by the direction of optical rotation by (+) and (-), (1) and (p), or a combination of these symbols. The symbols (L) and (D) and the symbols (S) and (R), denoting left and right, respectively, indicate the absolute space configuration of the enantiomers.

When no isomer-25 is labeled, the compound is a racemic modification.

Optical isomers of compounds belonging to the aryloxypropanolamine class can be most commonly obtained by one of four basic methods.

These are 1) fractional recrystallization of chiral acid salt derivatives; 2) derivatization with a chiral organic reagent, partitioning and regeneration of the parent compound in optically active form; 3) synthesis of the private optical isomer using chiral intermediates; and 4) column x-ray chromatography using chiral stationary phases. The applications of these different methods are well known to those skilled in the art.

5 78291

The compounds of the present invention are prepared according to the invention by a) coupling of methoxylated indole alkylamine (III) I (III)

B

5 10 R-substituted phenoxyepoxide (IV),

5 r "^ CN

R (O) 15 (IV) by heating compounds (III) and (IV) together either undiluted or in the presence of a reaction-inert organic solvent to form intermediate (II)

20 CN

»HpT ^ ch ^ / ch3 ^ 0H (IT) 25 where k is as defined above; after which the methoxy group of intermediate (II) is cleaved under appropriate conditions into a hydroxyl group, preferably by reacting intermediate (II) with boron tribromide in methylene chloride solution to give a compound of formula (I); and thereafter, if it is desired to prepare a pharmaceutically acceptable acid addition salt of the compound of formula (I), the compound of formula (I) thus obtained is converted into a salt by a standard method.

6 78291

According to the invention, the appropriate methoxylated indolalkylamine (III) is coupled with an R 1 -substituted phenoxy epoxide intermediate (IV). The synthetic methodology for performing the coupling is analogous to the synthetic method used to prepare busindolol (cf. Kreighbaum et al. U.S. Patent Nos. 4,234,595 and 4,314,943 and J. Med. Chem. 23: 3, 285 This is followed by an additional step in which the methoxylated indole analog (II) is converted to the desired product (I) by cleavage of the methoxy group with boron tribromide in methylene chloride solution Other synthetic methods for preparing hydroxylated products, e.g., benzyloxy precursors, include hydrogenol precursors. well known and can also be applied in the modifiable method.

Coupling of the epoxy ether intermediate (IV) with the indolylalkylamine (III) to give the intermediate (II) is performed simply by heating the epoxy ether either undiluted or in the presence of a reaction-inert organic solvent with a suitable indolylalkylamine. No catalyst or condensing agent is usually required. Suitable solvents are 95% ethanol, but other reaction-inert organic liquids in which the reagents are soluble may be used. These may include, but are not limited to, benzene, tetrahydrofuran, dibutyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, etc. Suitable reaction temperatures are in the range of about 60-200 ° C.

The required reaction intermediates III and IV can be obtained by several methods. Phenoxyepoxide intermediate 5. . routes (IV) can be obtained by alkylation of the appropriate R-substituted cyanophenol (V) with epichlorohydrin, as in Scheme 1; or using epibromohydrin, K 2 CO 3 and dimethylformamide.

7 78291

Scheme 1 • * -oC -0C4 (v) row

Although several cyanophenols (V) are commercially available, they can also be conveniently prepared from readily available phenols by the synthesis shown in Scheme 2.

Diagram 2 15 * 5-CX. »- θΓ - ^ - ÖC *"

NaOH OH OH

AC2 °: 'f r5-OCm (V) This reaction sequence shows the formylation of a substantially R1-substituted phenol under Reimer-Tiemann conditions to give a salicylaldehyde derivative which is converted via the oxime intermediate to the desired salicylonitrile (V).

β 78291

Typical synthetic methods for the preparation of intermediate indolylalkylamines of structure III are available in the aforementioned Kreighbaum et al. in patents and in J. Med. Chem.

Finally, it is interesting that the 6-hydroxyindolyl compound of the formula I (2- [2-hydroxy-3 -? - [2- (6-hydroxy-1H-indol-3-yl) -1,1-dimethylethyl] amino] propoxy] benzonitrile), which structurally corresponds to busindolol (R 1, R 2, R 2 are hydrogen and R 2, R 2 are methyl) was used to confirm the identity of the major metabolite of busindolol. It is known that 6-hydroxylation is perhaps more important than 5-hydroxylation in the metabolism of tryptamine derivatives (cf. Jepson, et al., Biochim. Biophys. Acta., 62, 91 (1962); Jaccarini 15 and Jepson Biochim. Biophys Acta., 156, 347 (1968) This information suggested the possibility that 6-hydroxylation of busindolol may be an important metabolic pathway, confirmed by showing that this 6-hydroxyindolyl compound 20 of the present invention is consistent with mass spectral and gas chromatographic analysis. with the corresponding major hydroxy metabolite of busindolol.

Biological testing of the compounds of formula I in animals shows that they have biological properties which make them useful as antihypertensive agents. In addition to the antihypertensive activity demonstrated in animal experiments, these compounds also have vasodilatory properties, together with varying degrees of adrenergic alpha- and beta-receptor blocking properties and inherent sympathetic irritant activity.

78291

Preferred compounds have a particularly desirable combination of the above effects, as well as pharmacological effects that promote these effects, or the absence thereof, making them particularly suitable for specific cardiovascular indications, e.g., for use as antihypertensive agents. The utility of the compounds of formula I can be demonstrated in a variety of animal models involving the antagonism of isopterenol in an anesthetized dog treated intravenously (adrenergic beta-receptor activity), intrinsically hypertensive or DOCA-induced hypertensive hypertensive angiotensin-maintained nerve-node-blocked rat model (vasodilating effect), and the anesthetized rat model (alpha-adrenergic blockade), as well as in various other animal laboratory models (cf. Deitchman et al., Journal Pharmacological Methods 3, 311). 1980).

Examples are two typical compounds of formula I 2 - [/ 2-hydroxy-3 - [[Z'2- (6-hydroxy-1H-indol-3-yl) -1,1-dimethylethyl] amino] propoxy] benzonitrile and 2- [2-hydroxy -3-Z "ε 2- (5-Hydroxy-1H-indol-3-yl) -1,1-dimethylethylamino / propoxy / benzonitrile produces a mean decrease in systolic blood pressure of greater than 20 mm Hg in rats in antihypertensive experiments when the drug was administered orally at a dose of 30 mg / kg. An intravenous dose of 3 mg / kg of these compounds produced a reduction of more than 20% in mean state 30 blood pressure (determined 30 minutes after dosing) in a vasodilation test.

V. Biological Evaluation: The following biological assay was used to evaluate the antihypertensive profile of the compounds of formula I: 1 ° 78291

Rats (Wistar species, males) were anesthetized by intraperitoneal administration of a combination of urethane and chloralase. After falling asleep, chloroisondamine was injected into the peritoneal cavity to effect nerve node blockade. A connecting tube was connected to the femoral artery to monitor blood pressure and heart rate, and a connecting tube was connected to the two femoral veins for administration of the compounds. A Kurk tube was placed in the trachea and the rats were allowed to breathe freely. Animals 10 were stimulated before and after intravenous administration of the test compound with gradual doses of phenylephrine, and changes in blood pressure were recorded. The results were plotted to obtain dose-response curves, and the dose amount of phenylephrine required to induce a 50 mm increase in blood pressure of 15 Hg (ED 2 q) was interpolated from the curves. Dose changes were calculated by dividing the ED 2 g after drug administration by the ED 1 g before drug administration.

By the same method, the 20 C & blocking effect of structurally related compounds known from the prior art was also investigated. In these known compounds, the indole moiety of the compounds is either unsubstituted or contains a non-hydroxy substituent.

The results were as follows: ;; "30 Test compound R o6 blockade (dose change_ 1H (comparison 5 + 0 2 5-OMe (compare 8.1 + 1.7 3 5-OH 12 + 1 25 4 6-OMe (comparison) 5.9 +0.7 5 6-OH 23 + 1 11 78291

The results show that the compounds of the present invention having a hydroxy substituent on the indole moiety are about 2 to 4 times more effective as O 6 blockers than the known compounds. The compounds of the invention are thus more preferred than the known compounds as antihypertensive agents.

The dosage of the compounds of formula (I) will vary depending on the subject and the mode of administration chosen, with about 0.1 μg to 100 mg / kg body weight of the compound of formula I or a pharmaceutically acceptable acid addition salt thereof providing the desired therapeutic effect. The preferred range for an effective dose would be about 0.1 to 0.5 mg / kg when administered intravenously and about 0.5 to 5 mg / kg when administered orally.

The compounds of the present invention may be used in accordance with conventional pharmaceutical practice to provide pharmaceutical compositions in unit dosage form, such as tablets, capsules, powders, granules, emulsions, suspensions. Solid preparations contain the active ingredient in admixture with non-toxic pharmaceutical excipients such as inert diluents, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants, for example, corn, starch or alginic acid; binders such as starch, gelatin or acacia; and lubricants, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known methods to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Liquid preparations suitable for parenteral administration include solutions, suspensions or emulsions of the compounds of formula I35. Aqueous suspensions of the pharmaceutical dosage forms of the compounds of formula I contain the active ingredient 12 78291 in admixture with one or more non-toxic pharmaceutical excipients which are known to be suitable in the preparation of aqueous suspensions. Suitable excipients are, for example, suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia. Suitable spreading or wetting agents are naturally occurring phosphatides, for example lecithin and polyoxyethylene stearate.

Anhydrous suspensions may be formulated by suspending the active ingredient in an edible oil, for example olive oil, sesame oil or coconut oil, or in a mineral oil, for example liquid paraffin. Suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents commonly used in pharmaceutical compositions may also be used, such as saccharin, sodium cyclamate, sugar, and burnt sugar. The compositions may also contain other absorbents, stabilizers, wetting agents and buffers.

In the following examples, which are intended to illustrate the above synthetic methods, temperatures are reported in degrees Celsius and melting points are uncorrected. Nuclear Magnetic Resonance Spectrum (NMR) data refer to chemical changes ("E") expressed in parts per million against tetramethylsilane (TMS) used as a reference standard. The relative range, which indicates different shifts in NMR spectral results, corresponds to the number of hydrogen atoms of a given functional type. The nature of the transitions in terms of multiplicity is indicated by the terms broad singlet (bs), singlet (s), multiplet (m) or doublet (d) The abbreviations used are DMSO (deuterodimethylsulfoxide), i3 78291 (CDCl 3) (deuterochloroform) and abbreviations are otherwise conventional Infrared (IR) data include only absorption wave numbers (cm *) with functional group identification IR assays were performed using potassium-5 bromide (KBr) as diluent Elemental analyzes are expressed as weight percent.

Synthesis of intermediates A. Intermediates of formula III: General methods 10 Example 1

Methoxy-indol-3-yl-tert-butylamine To 15.2 ml of a cooled 25% aqueous solution of dimethylamine add the following substances successively with stirring and cooling: 16.9 ml of acetic acid, 7.2 ml of 37% formaldehyde and 27 ml of 95% ethanol. The resulting stirred solution is maintained at 0-5 ° C in a cooling bath while 10.0 g (0.07 moles) of the appropriate methoxyindole is added portionwise. This mixture is stirred and warmed gradually to 30 ° over a period of 20 half-hour and then kept at 30 ° C with stirring for 3 hours. The reaction mixture is then cooled to 10-15 ° C and acidified with 170 ml of 2N HCl. This acidic mixture can be decolorized (Dargo G-60), filtered, basified using 245 ml of 20% NaOH solution while cooling and stirring. The resulting brown oily precipitate is extracted with ether and the extracts are washed with water, dried (MgSO 4) and concentrated by evaporation to a brown oily residue (14 g). The residue is recrystallized, e.g. from isopropyl ether and hexane, to give the desired methoxygramine, usually as a tan solid.

A mixture of 7.7 g (0.04 mol) of the appropriate methoxygramine, 26.5 g (0.3 mol) of 2-nitropropane 35 and 1.7 g of NaOH (as pellets, 0.04 mol) is heated to 14 ° C. 78291 using a reflux condenser under a nitrogen atmosphere for 3-5 hours. The reaction mixture is then cooled to room temperature, acidified with 10% acetic acid and extracted with ether. The ether extracts are washed with water, dried (MgSO 4) and concentrated to dryness in vacuo. Recrystallization of the residue from, for example, a mixture of isopropyl alcohol and water gives 3- (2-methyl-2-nitropropyl) methoxyindole.

This nitropropylindole compound and 4.2 g of activated Raney nickel are mixed in 80 ml of 95% ethanol and heated to reflux. The heating is stopped when a solution containing 7.8 g of 85% hydrazine hydrate in 8 ml of 95% ethanol is added dropwise to the vessel. The reaction mixture is then heated to reflux for 2 hours, cooled to room temperature and filtered. The filtrate is concentrated by evaporation to leave an oily residue which can be recrystallized, e.g. from ethyl acetate-isopropyl ether, to give the desired methoxyindol-3-yl t-butylamine product.

Example 1a 6-Methoxy-indol-3-yl-tert-butylamine

A mixture of 0.9 g of 6-methoxygramine (0.004 mol; prepared from 6-methoxyindole by the method of Example 1), 3.0 g (0.034 mol) of 2-nitropropane and 0.19 g (0.005 mol) NaOH pellets, was stirred at reflux under an oil bath under a nitrogen atmosphere for 2 hours while dimethylamine flowed out through the condenser. The resulting mixture was cooled to 25 °, treated with a solution of 0.47 ml of glacial acetic acid in 4.1 ml of water, and extracted with ether. The ether extract was washed with three portions of water, dried (MgSO 4) and evaporated to dryness. The residual brown oil was crystallized by trituration and cooling with a small amount of isopropyl ether. The solid was filtered off, washed with cold isopropyl ether and air dried to give 0.6 g of a tan solid which was recrystallized from a mixture of isopropyl alcohol and water to give 0.52 g (46%) of 3- (2-methyl). -2-nitropropyl) -6-methoxyindole, m.p. 98-99 ° C.

A slurry of 8.0 g (0.032 moles) of the nitro compound prepared above, 80 mL of 95% ethanol, and 4.2 g of Raney nickel (washed with water and 95% ethanol) was heated to reflux with stirring. a paddle stirrer. External heating was stopped and a solution of 7.8 g of 85% hydrazine hydrate in 8 ml of 95% ethanol was added dropwise to the vessel at a rate sufficient to maintain slow reflux.

After the addition, the mixture was reheated to reflux for 2 hours and then cooled to 25 ° C. After filtration and evaporation of the filtrate to dryness, a crude syrup was obtained which was chromatographed on a silica gel column eluting with CH 2 Cl 2 -CH 3 OH-concentrated NH 4 OH (90: 10: 1). The resulting tan solid (2.9 g, mp 125-128 ° C) was recrystallized from ethyl acetate-isopropyl ether to give 1.27 g (18%) of 6-methoxyindol-3-yl tert-one. butylamine, m.p. 125-128 °.

25 Example 2

Methoxyindol-2-yl-tert-butylamine 12 14 (R, R = H, R, R = Me) In this general method, a solution containing 0.06 moles of the appropriate methoxyindole-2-carboxylic acid is stirred. and 2.0 g (0.17 mol) of thionyl chloride in 130 ml of anhydrous ether, for 12-18 hours at room temperature under a nitrogen atmosphere. The reaction mixture is filtered and the filtrate is concentrated by evaporation to an oily residue which is taken up in 150 g of any anhydrous ether. This ether solution is treated with 80 ml of dimethylamine in 90 ml of ether. The reaction mixture containing ether is evaporated to dryness and the residue is crystallized from isopropyl alcohol. The solid is filtered off to give the product in 30-40% yield of methoxy-indole-2-carboxylamide.

Methoxyindol-2-ylcarboxamide is dissolved in 100 ml of THF and this solution is added dropwise under a nitrogen atmosphere to a stirred suspension containing 3 g of lithium aluminum hydride in 50 ml of THF. After refluxing for 2 hours, the reaction mixture is cooled and quenched with a small amount of water and dilute NaOH solution. The mixture is filtered and the filtrate is concentrated by evaporation to leave an oil which is taken up in absolute ethanol and treated with dimethyl sulphate using a small excess. The resulting alcoholic solution is stirred at room temperature for 4 hours and then concentrated to dryness in vacuo to give a residue of the quaternary salt of trimethylamine.

0.01 moles of crude quaternary salt product are mixed with 2.0 g (0.05 moles) of NaOH pellets and 15 ml of 2-nitropropane and the mixture is heated under reflux under a nitrogen atmosphere for 1 hour. The resulting dark thick mixture is cooled, diluted with water, acidified with acetic acid to a pH of about 6 and then extracted with ether. These ether extracts are combined, washed with water, dried (MgSO 4) and concentrated by evaporation to a dark residue which is chromatographed on a silica column and diluted with methylene chloride. After the methylene chloride used as solvent is evaporated off and the crude substance is recrystallized from an aqueous mixture of isopropyl alcohol, methoxyindole is obtained, which is substituted in the 2-position by a 2-methyl-2-nitropropyl moiety.

Reduction of this nitro product with Raney nickel and 177,7291 hydrazine according to the procedure used in Example 1 above affords the desired methoxyindol-2-yl-tert-butylamine.

Example 3 5-Methylation of methoxyindolylalkylamines: 3- (2-amino-2-methylpropyl) -1-methylmethoxyindole 13 4 2 (R, R, R = Me, R = H) In this general method 7 g (0.11 moles) 10 85% KOH is ground in a mortar and transferred rapidly to a 25 ml Erien-* Meyer flask purged with nitrogen gas. 55 ml of DMSO are added and the mixture is stirred for 5 minutes. Additions of methoxyindolyl-tert-butylamine (0.27 moles) and iodomethane (3.78 g, 0.03 moles or other suitable alkylating agent) are each followed by stirring for 45 minutes, after which the suspension is cooled in 300 ml of water. . Extraction of the mixture with ethyl acetate, followed by washing of the extracts with water and saturated brine, gives a clear solution which is dried (MgSO 4) and evaporated in vacuo to an oily product. This free base can be used as an intermediate without further purification. The identification of the product can usually be performed by changing the oily base to the hydrochloride salt to give a crystalline product.

Example 4

Methoxyindol-2-ylethylamine In this method, which is essentially the same as that described by Bhat and Siddappa in J. Chem. Soc. (C), 1971, 178-81; reducing various methoxyindole-2-carboxylate esters (commercially available or prepared according to literature methods) to the corresponding 2-hydroxymethylindole derivative by reduction with lithium aluminum-35 hydride in ether. The conversion to indole-2-carbaldehyde is carried out by dissolving 4 g of 2-hydroxyacetylmethoxymethole in 250 ml of dichloromethane and adding 10 g of activated manganese dioxide, after which the reaction mixture is stirred at room temperature for 20-30 hours. The reaction is monitored by TLC to monitor the disappearance of the starting 2-hydroxymethylindole spot. If necessary, add fresh amounts of manganese dioxide (2-3 g). The reaction mixture is filtered and the remaining manganese dioxide is washed repeatedly with a small amount of fresh dichloromethane. The combined filtrate is evaporated to dryness to give crude methoxyindole-2-carbaldehyde as a pale yellow solid which is then recrystallized.

5 g of methoxyindole-2-carbaldehyde, 8 ml of nitromethane and 1 g of ammonium acetate are heated under reflux for 1/2 hour. The reaction mixture is cooled and the dark red crystals which separate are collected, washed thoroughly with water, dried and crystallized from ethanol. The nitrovinylmethoxyindole thus prepared is then reduced to the desired methoxyindol-2-yl-ethylamine by treatment with lithium aluminum hydride in anhydrous ether. The reduction mixture is gently heated to reflux for 10 hours, after which the excess lithium aluminum hydride is decomposed. After filtration, the filtrate is concentrated by evaporation in a vacuum to give a residue which is crystallized from a suitable solution to give the desired methoxyindol-2-ylethylamine.

Example 5

Methoxyindol-2-ylpropylamine By modifying the procedure of Example 4, 1 g of the appropriate methoxyindole-2-carbaldehyde in 0.5 ml of nitroethane is treated with 4 drops of benzylamine, after which the mixture is heated under reflux for 1 hour. After standing, dark red crystals separate from the cold reaction mixture, which can be collected, washed with a small amount of ether, dried and crystallized from ethanol. The nitropropenyl indoles thus prepared are reduced with lithium aluminum hydride as described in Example 4 above. The solid products are crystallized and the liquids are identified as benzoyl derivatives.

5 Example 6

Methoxy-indol-3-ylethylamine

Compare: Young, J. Chem. Soc. 1958, 3493-96; this synthesis starts from methoxyindole-3-aldehydes, which are either commercially available or can be prepared by methods described in the literature. Using the procedure set forth in Example 4 above, the appropriate methoxyindole-3-carbaldehyde is condensed with nitromethane using ammonium acetate as a catalyst. After standing, dark red crystals of small batches separate from the cooled solution, which can be recrystallized from benzene or methanol to give 3-nitrobinylmethoxyindole, which is reduced with lithium aluminum hydride as above to give the desired methoxyindol-2-ylethylamine.

20 Example 7

Methoxyindol-3-ylpropylamine 5 g of the selected methoxyindole-3-carbaldehyde, 10 ml of nitroethane and 1 g of ammonium acetate are heated in a steam bath for 1/2 hour with occasional shaking.

After cooling, the crystals are collected, washed with hot water (2 x 50 ml) and crystallized from methanol. The resulting 3- (2-nitropropenyl) methoxyindole is reduced to the desired 3- (2-aminopropyl) methoxyindole by treatment with lithium aluminum hydride as detailed in the previous methods.

B. Intermediates of formula IV Example 8 2 - [(2,3-epoxy) propoxy] benzonitrile A solution of 25.0 g (0.21 moles) of 2-cyano-35 phenol, 117 g (0.26 moles) of epichlorohydrin and 10 drops of piperidine, stirred and heated at 115-120 ° in an oil bath for 2 hours. The reaction mixture was then concentrated by evaporation (90 ° / 30 torr) to remove unreacted epichlorohydrin. The residue was diluted with toluene and evaporated to dryness twice to facilitate removal of the last traces of volatile material. The residual oil was dissolved in 263 ml of tetrahydrofuran and this solution was stirred between 40-50 ° for 1 hour with 263 ml of 1N NaOH. The organic layer was separated and concentrated by evaporation to an oil which was combined with the aqueous phase. The mixture was extracted (Cl 2 Cl 2) and the extract was dried (MgSO 4) and concentrated by evaporation to give 36.6 g (100%) of an oil which slowly crystallized as a waxy solid. This intermediate can be used in the preparation of products of formula I without further purification.

Example 9 2- (2,3-Epoxy) propoxy] -4-methoxybenzonitrile The required 5-methoxysalicylaldehyde can be obtained from 4-methoxyphenol by the method of Reimer-Tiemann 20, which is well described in the literature, see e.g., Kappe et al., Arch . Pharm. 308/5, 339 (1975). A solution of 0.005 mol of starting salicylaldehyde in 6 ml of pyridine and 6 ml of absolute ethanol is treated with 0.4 g (0.02 mol) of hydroxylamine hydrochloride and refluxed for 4 hours. The mixture is concentrated by evaporation in vacuo to a gray syrup which is mixed with 50 ml of H 2 O and the suspension is decanted. After adding 10 ml of 10 ° C to the remaining glass and cooling the mixture to 5 °, filtration gives about 1.2 g of crude solid which is taken up in 25 ml of 50% ethyl ether isopropyl ether. The ether solution is filtered, dried (MgSO 4), treated with Dargo G-60 and Celite, filtered and concentrated by evaporation in vacuo to a waxy solid. Recrystallization from ethyl ether- 21 78291

Skelly from B gives the corresponding benzaldehyde oxime.

A mixture of 0.002 moles of oxime and 1.02 g (0.01 moles) of acetic anhydride is heated under reflux for 30 minutes and then cooled to 25 °. 50 ml of water are added, followed by dropwise addition of 20% NaOH to pH 10. The resulting suspension is stirred at 25 ° C for 20 hours to hydrolyze all of the acetate ester of the desired phenol derivative. The pH is adjusted to approximately 2 using 6N HCl and the resulting mixture is extracted with 40 ml of ethyl acetate to give an organic layer which is separated, dried (MgSO 4) and evaporated at 65 ° C to 70 torr to give a tan syrup which still contains mainly acetate ester. The syrup is then hydrolyzed in a mixture of 7 ml of methanol, 7 ml of water and 0.1 g of NaOH pellets at 25 ° for 3 hours and then the methanol is removed at 60 ° at 70 torr. Dilution of the aqueous residue with 0.5 N HCl affords a precipitate which can be recrystallized from isopropyl ether and dried to give the desired benzonitrile intermediate.

A mixture of 0.015 moles of 2-hydroxy-5-methoxybenzonitrile, 4.2 g (0.03 moles) of finely ground anhydrous potassium carbonate and 140 ml of DMF; stirred at 50 ° for 15 minutes. 2.8 g (31 0.02 mol) of epipromohydrin were added in one portion and stirring was continued for 3 days. The reaction mixture was poured into one liter of saturated brine, and the resulting suspension was stirred at 0-5 ° for 3 hours. Filtration of the mixture and washing of the filter cake with water gave, after air drying, a crude intermediate which could be used without further purification.

The use of other substituted 2-cyanophenols in the modifications of the above methods provides correspondingly other intermediate compounds of formula IV which can be used in the synthesis of the various compounds of formula I of this invention.

78291 22

Synthesis of products

Example 10

Most common method: 2- [2-hydroxy-3 - [(hydroxyindolyl) alkylamino] propoxy] benzonitrile 5 The selected methoxyindolylalkylamine (III) is mixed with an equimolar or slightly excess amount of the selected epoxypropoxybenzonitrile (IV) and the combination is carried out either -cooler using a solution of the reactants for about 18-24 hours or by heating the undiluted mixture at a temperature of about 120-130 ° C for about 1/2-2 hours. Ethanol and toluene are usually selected as the reaction medium when heated to reflux using a solution of compounds III and IV. In some cases, it is advantageous to monitor the progress of the reaction by TLC by adding more IV epoxide until the indolylamine III has disappeared. After the reaction, the mixture is concentrated by evaporation to dryness and the residue is either washed and used crude in the next step or the intermediate methoxy product can be purified by crystallization and recrystallization as either a base or a suitable acid addition salt.

The methoxyindolyl product is dissolved in methylene chloride and stirred under a nitrogen atmosphere at 0-10 ° while a dropwise addition of a multiple of 1 N boron tribromide in methylene chloride is added dropwise. After the addition, the reaction mixture is stirred at room temperature for about 6-8 hours. Excess boron tribromide is decomposed by cooling the reaction mixture and adding an excess of water. The crude hydrobromide salt product of formula I can be further processed by many conventional means, such as recrystallization, basification and purification, conversion to a base and subsequent conversion to a different acid addition salt, and so on.

li 23 7 8 2 91

The modifications necessary for the application of this method to the preparation of the specific compounds of formula I will be apparent to those skilled in the art of chemistry.

Example 11 2- [2-Hydroxy-3-yl] -2- (6-hydroxy-1H-indol-3-yl) -1,1-dimethylethyl / amino / propoxy / benzonitrile A solution containing 2.6 g of 6-methoxyindol-3-yl-t-butylamine (0.012 mol; prepared according to Example 10a), 2.1 g of 2- (2,3-epoxy) propoxy] benzonitrile (0.012 mol) prepared in Example 8 ) and 100 ml of absolute ethanol, was heated while stirring under reflux for 20 hours. Additional epoxide (0.21 g) was added and refluxing was continued for 4 hours, after which the mixture was concentrated by evaporation to dryness and the residue was triturated in isopropyl alcohol to initiate crystallization. The product was collected by filtration, washed with cold isopropyl alcohol and air dried to give 4.0 g (85%) of methoxy product (II), m.p. 145-146 °, which was used directly in the next step.

A solution of the methoxyindole product prepared above (1.5 g, 0.004 mol) in 225 ml of methylene chloride was stirred under a nitrogen atmosphere between 5-10 ° C while 15.3 ml (0.015 mol) of 1-boron tribromide in methylene chloride was added dropwise. After the addition, the ice bath was removed and the reaction mixture was stirred at 25 ° for 6 hours before being cooled to between 5-10 ° and 47.5 ml of ϊ ^ Ο was added dropwise. The resulting mixture was decanted and the remaining resinous solid was rinsed with two portions of 1 x 0. Dissolution of this crude hydrobromide salt in 50 mL of hot 1 O 0 was followed by treatment with Darco G-60, filtration, cooling (25 °) and basification (pH 8) with concentrated NH 4 OH to give 1.2 g. a tan amorphous solid which was chromatographed (silica gel 60, 230-400 mesh, 24 78291 EM reagents) under medium pressure using chloroform-methanol-concentrated NH 4 OH (90: 10: 1). The product thus obtained was crystallized from a small amount of 95% ethanol to give, by gradual addition of 0.1.0 g (71%) of the desired 6-hydroxyindole product (I) as a tan solid, m.p. 90-94 °. Analysis: Calculated for C 22 H 25 N 3 O 3 * 1/3 ^ 0: C, 68.56; H, 6.67; N, 10.90; H 2 O, 1.54.

Found: C, 68.69; H, 6.68; N, 10.68; 1 ^ 0, 1.80. NMR (DMSO-d 6): 0.98 (6, s); 2.70 (4, m); 3.30 (2, bs); 3.83 (1.1 m); 4.11 (2, d / 5.8 Hz); 5.00 (l, bs); 6.65 (3, m); 7.20 (3, m); 7.60 (2, m); 8.71 (1.1 bs); 10.35 (l, bs).

IR (KBr): 760, 800, 1260, 1290, 1450, 1495, 1600, 1630, 2230 and 3300 cm-1.

Example 12 2- [2-Hydroxy-3- [2- (5-hydroxy-1H-indol-3-yl) -1,1-dimethylethyl] amino] propoxy / benzonitrile A solution of 2.7 g of -methoxy-indol-3-yl-t-butylamine (0.0125 moles; prepared from 5-methoxy-20-indole using the procedure described in Example 1), 2.2 g (0.0125 moles) of 2-f (2,3- epoxy) propoxy / benzonitrile and 20 mL of acetone, was heated at reflux for 1/2 hour. The acetone used as solvents was then allowed to boil off and the oily residue was heated undiluted at 100 ° for 2 hours. 20 ml of isopropyl alcohol were added and the reaction mixture was heated under reflux for 4 hours, then cooled to room temperature, diluted with 50 ml of ether and triturated to give a white powder 30 which crystallized to 4.7 g (96%), m.p.

119-124 °; TLC (9: 1 CHCl 3 -methanol) shows one spot,

Rf 0.25. This crude m-ethoxy product can be used directly in the next step or can be purified by conversion to the HCl salt. Conversion to the HCl salt by treatment of the acetonitrile solution with ethanolic HCl gives the crude product which is recrystallized from a mixture of butanone and 95% ethanol (20: 1) to give an off-white powder. mp. 164-166 °.

Analysis: Calculated for C 23 H 27 N 3 O 3 * HCl: δ C 64.25; H 6.56; N 9.77

Found: C, 64.14; H 6.54; N 9.68.

Using the method described in Example 11 above for cleavage of the methoxy group with boron tribromide, but using the 5-methoxyindole-10 intermediate (II) prepared above, the desired 5-hydroxyindole product (I) is obtained in the form of its hydrobromide salt. The pure hydrobromide salt is beige in color, m.p. 219-221 °.

Analysis: Calculated for C 22 H 25 N 3 O 3 * HBr: C, 57.40; H 5.70; N 9.13 Found: C, 56.90; H 5.67; N 9.45.

NMR (DMSO-d 6): 1.32 (6, s); 3.08 (2, m); 3.36 (2, m); 4.30 (3, m); 5.90 (l, bs); 7.10 (6, m); 7.71 (2, m); 8.55 (3, bs); 10.95 (l, bs).

IR (KBr): 750, 800, 1265, 1290, 1455, 1495, 1580, 2000, 2230 and 3300 cm-1.

Starting from the appropriate methoxyindole alkylamines (III) and epoxypropoxybenzonitriles (IV), further examples of products of formula I can be synthesized using essentially the same methods as described above with only minor modifications known to those skilled in the art. Some other products of formula I that can be synthesized by these methods are shown in Table I.

26,782 91

Table 1 (1) “i o« »« c sign -OH R Rz RJ r * r5

13 A- H 2-H Me Me H

14 7- H 2-H Me Me H

15 A- Me 2-H Me Me H

16 5- Me 2-H Me Me 5-F

17 6- Me 2-H Me Me 5-OH

18 7- Me 2-H Me Me H

19 A— Me 3-H H Me H

20 5- Me 3-H H Me 5-F

21 6- Me 3-H H Me H

22 7- Me 3-H H H A-Me

23 A- H 2-Me H Me H

2A 5- H 2-Me H H H

25 6- H 2-Me Me Me H

26 7- H 2-Me Me Me H

27 A- H 3-Me H H 5-OH

28 5- H 3-Me H Me 5-F

29 6- H 3-Me H Me H

30 7- H 3-Me H H 5-Br 31 A- H 2-H H Me 5-Me 32 5- H 2-H H Me A-Cl

33 6- H 2-H H Me H

3A 7- H 2-H H Me A-OH

Claims (6)

2? 78291 A process for the preparation of therapeutically useful 1-phenoxy-3-hydroxyindolyl-alkyl-5-amino-3-propanols of the formula (I) and their acid addition salts, CH, CH3 ho -ίο R CN (I) in which hydrogen or 5-fluoro is present and the hydroxyl substituent group is a 4-, 5-, 6- or 7-ring mass of indole, characterized in that methoxylated indole alkylamine (III) is added CH ~ / CH3 £ :) (III) • -5 R-substituted phenoxyepoxide (IV), 25 * 5-oo (IV) by heating compounds (III) and (IV) together either undiluted or with a reaction-inert organic solvent. in the presence of intermediate (II) 28 782 91 CN r5 — fo I Cl3 “3 1 (II) H 5 wherein R is as defined above; after which the methoxy group in intermediate (II) is converted into a hydroxyl group under suitable conditions, preferably by reacting intermediate (II) with boron tribromide in methylene chloride solution to give a compound of formula (I); and thereafter, if it is desired to prepare a pharmaceutically acceptable acid addition salt of the compound of formula (I), the compound of formula (I) thus obtained is converted into a salt by a standard method. Process according to Claim 1, characterized in that 2- [2-hydroxy-3- [7,2- (6-hydroxy-1H-indol-3-yl) -1,1-dimethylethyl] amino] propoxy] benzonitrile is prepared. Process according to Claim 1, characterized in that 2- [2-hydroxy-3-Z *? 2- (5-hydroxy-1H-indol-3-yl) -1,1-dimethylethyl] amino] propoxy is prepared. , 7bentsonitriili. 29 7 8 2 91 A process for the preparation of a therapeutically active compound with 1-phenoxy-S-hydroxy-indolyl-alkylamino-S- or 5-fluoro, and hydroxyl substituents are indolensate 4-, 5-, 6- or 7-ring, 15 turns are not methoxyated with indole-alkylamine (III) ch3 ch3 20 f ), 30 genomics upstream of the derivatives (III) and (IV) are used in the form of the reaction or in the reaction of the reaction-inert organic solvents for the product (II),