JPH0587503B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to heterocyclic carbon compounds of the indole series having amino substituents, and methods for affecting and treating living organisms with drugs using these compounds. A large amount of prior art exists for many series of compounds classified as 3-(aryloxy)-2-hydroxypropylamines. Most of these series have been shown to have utility as useful agents in the treatment of cardiovascular disease, particularly beta-adrenergic receptor blocking activity. It appears that the effects, or lack thereof, of various other cardiovascular drugs, in combination, make some of these compounds useful as antihypertensive agents. However, most of the prior art concerns the beta-adrenergic blocker properties of these series of compounds. The prototype for this type of structure is propranolol; chemically it is 1-(isopropylamino)-3-(1-naphthyloxy)-
2-propanol. Propranolol and certain related naphthyloxypropanolamines are disclosed in U.S. Pat.
This is the object of No. 3337628. The structure has been modified 3
A number of generic patents have been granted covering the family of compounds that are -(aryloxy)-2-hydroxypropylamines. A series of indol-3-yl-tertiary butylaminopropanols with antihypertensive properties have been described in the following literature: Kreichbaum et al., U.S. Pat.
No. 4234595 (granted November 18, 1980); U.S. Patent No. 4314943 (granted February 9, 1982); and
Journal of Medicinal Chemistry , 23:3,
285–289 (1980). [C] [C] In these above structural formulas, the symbol R ³ is hydrogen,
It can be halogen, lower alkyl or alkoxy, but not hydroxyl. A preferred compound of the structural formula (1) series is designated MJ13105, also known by its American Adopted Name as bucindolol, and is currently undergoing clinical evaluation as an antihypertensive agent. It is of interest for the compounds of the present invention that the main metabolic pathway for MJ13105 involves 6-hydroxylation of the indole ring. This was confirmed by comparing the metabolic isolates with the corresponding synthetically available 6-hydroxyindolyl compounds of the invention. Attention is also drawn to applicant's co-pending U.S. Pat. (3) Discloses a series of vasodilators having: In the above structural formula (3), C is, among other substituents,
This series is generally distinguished from the present invention in that the compounds of structure (3) are pyridinyloxypropanolamines. The present invention includes compounds of formula () and acid addition salts of these substances. embedded image In the above structural formula, the symbols R ¹ to ^{R 5} have the following meanings. R ¹ and R ² are each hydrogen, R ³ and
Each R ⁴ can independently be C _1-4 alkyl and R ⁵ can be hydrogen. For preferred compounds, R ¹ is H, R ² is 2-H, R ³ and R ⁴ are methyl, and R ⁵ is hydrogen. The compounds of the present invention are useful as antihypertensive agents, in part due to their combination of adrenergic receptor blocking and vasodilatory activity. The present invention includes compounds having the above structural formula () and acid addition salts thereof. In the structural formula,
R ¹ , R ² , R ³ and R ⁴ can be hydrogen or alkyl having 1 to 4 carbon atoms.
R ¹ and R ² are each hydrogen, while R ³ and R ⁴ are each independently selected and both alkyl.
R ⁵ is hydrogen. Indolyl type is 2- or 3-
-position, and the hydroxyl substituent is the indole ring 4-, 5-, 6-
Or occupy the 7th place. For preferred compounds, R ¹ is hydrogen, R ² is 2-hydrogen (the indole moiety is coupled to the main side chain at its 3-position), and R ³ and R ⁴ are methyl. , and R ⁵ is hydrogen. For pharmaceutical applications, pharmaceutically usable acid addition salts, salts whose anions do not contribute significantly to the toxicity or pharmacological activity of their organic cations, are preferred. Acid addition salts can be prepared by reaction of an organic base of the structure with an organic or inorganic acid (preferably by contacting in solution) or according to standards detailed in the literature and available to those skilled in the art. Obtained by any of the following methods. Examples of useful organic acids are maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid,
Carboxylic acids such as pamoic acid, cyclamic acid, habalic acid, etc.; useful inorganic acids include HCl,
Hydrohalic acids such as HBr and HI; sulfuric acid; phosphoric acid, etc. It is also to be understood that the compounds of the invention encompass all optical isomeric forms, ie mixtures of enantiomers, such as racemic modifications, as well as individual enantiomers. These enantiomers are commonly designated according to their optical rotation by (+) and (-), (l) and (d), or combinations of these symbols. Symbols (L) and (D) and symbols (S) and (R)
[These are the abbreviations for sinister and rectus, respectively] indicating the absolute spatial configuration of the enantiomer. If there is no indication of isomerism for a compound, the compound is a racemic modification. The individual optical isomers of the aryloxypropanolamine class of compounds, of which the compounds of the present invention are members, have been obtained by one of four basic methods. These are: 1) fractional recrystallization of chiral salt derivatives; 2) derivatization, resolution and regeneration of the raw compound in optically active form with chiral organic reagents; 3) single use of chiral intermediates. synthesis of optical isomers; and 4) column chromatography utilizing chiral stationary phases. The application of these various methods is well known to those skilled in the art. Biological testing of representative subject compounds of the formula in animals clearly shows that they possess biological properties that make them useful as antihypertensive agents. Besides the antihypertensive activity that can be demonstrated in animals, the compounds of the invention also have
It also has vasodilatory properties as well as varying degrees of adrenergic alpha- and beta-receptor blocking and endogenous sympathomimetic activity. A more detailed description of the specific pharmacological tests used and the criteria used to determine appropriate biological activity is included in the Biological Evaluation section. Preferred representative members have the above-mentioned effects, as well as ancillary pharmacological effects,
or they have a particularly desirable combination of deficiencies, which makes them suitable for use in certain cardiovascular indications, for example as antihypertensive agents. The use of compounds of the formula as indicated above is to antagonize isoproterenol (adrenergic beta-
receptor action), spontaneous hypertension and DOCA salt hypertensive rats (antihypertensive effect), angiotensin-maintained ganglion blockade rat model (vasodilator effect),
as well as in a variety of animal laboratory models, including the anesthetized rat model (alpha-adrenergic blockade) (Deichman et al.
Journal Pharmacological Methods , 3, 311
~321 (1980)). As an example, two representative compounds of the formula; 2-
[2-hydroxy-3-[[2-(6-hydroxy-
1 H -indol-3-yl)-1,1-dimethylethyl]amino]propoxy]benzonitrile and 2-[2-hydroxy-3-[[2-(5-hydroxy-1 H -indol-3-yl) )-1,1
-Dimethylethyl]amino]propoxy]benzonitrile caused an average reduction in systolic blood pressure of rats of more than 20 mgHg in one or both of the antihypertensive tests when administered at a dose of 30 mg/Kg id. Intravenous administration of 3 mg/Kg of these compounds reduced mean arterial blood pressure (after administration) in a vasodilatory test.
(measured at 30 minutes) resulted in a decrease of more than 20%. For use as antihypertensive agents, vasodilators, and/or adrenergic blockers, the therapeutic methods of the invention include an effective, non-toxic amount of a compound of formula or a pharmaceutically usable acid addition salt thereof. , consisting of systemic administration by both oral and non-oral routes. By effective amount is meant a dose that, when administered to a mammal in need of treatment, will exhibit the desired pharmacological activity, such as those described above, without undesirable toxic side effects. The dosage will vary depending on the subject and the route of administration chosen, and will be approximately
An expected range of 0.1 mcg to 100 mg of a compound of formula or a pharmaceutically acceptable acid addition salt thereof will generally provide the desired therapeutic effect. Preferred ranges of effective doses are about 0.1-0.5 mg/Kg for intravenous administration and about 0.5-5 mg/Kg for oral administration. The compounds of the invention can be prepared by convenient general methods. This method is shown in diagram 1 below.
Outlined in Throughout this application, Me is the abbreviation for the methyl group and Ac is the abbreviation for the _acetate ion, _C2H3O ^- ₂ . embedded image R ¹ to R ⁵ are as defined above. The method involves coupling a suitable methoxylated indole alkylamine () with an ^R5 -substituted phenoxyepoxide intermediate ().
The synthetic methodology required to reach this point in the production of the product of formula is analogous to that used to produce bucindolol. US Pat. Nos. 4,234,595 and 4,314,943 to Kreichbaum et al. and J. Med ．
Chem. , 23:3, 285-289 (1980), which are included in the references in their entirety. However, an additional step is required since the resulting methoxylated indole analog () is converted to the desired () product by cleavage of the methoxy group using boron tribromide in methylene chloride solution. Other synthetic methods that produce hydroxylated products, such as hydrolysis of benzyloxy precursors, are well known to chemists and are suitable for use in alternative methods. Coupling of the epoxy ether intermediate () with indolylalkylamine () to obtain the epoxy ether intermediate () is illustrated with the epoxy ether neat or in the presence of a reactive inert organic solvent with a suitable indolylalkylamine. This is easily carried out by heating. Usually no catalyst or condensing agent is required. A suitable solvent is 95% ethanol, but other reaction-inert organic liquids in which the reactants are soluble can also be used. These include, but are not limited to, benzene, tetrahydrofuran, dibutyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, and the like. A suitable reaction temperature is 60-200°C. The required reaction intermediates and can be obtained by several methods, including but not limited to: Phenoxyepoxy compound intermediate () is
by epichloro as shown in Scheme 2; or in difficult cases, by epibromohydrin;
Suitable R ⁵ -substituted cyanophenols () by using K ₂ CO ₃ and dimethylformamide
can be obtained by alkylation of Although many cyanophenols are commercially available, they can also be successfully prepared from readily available phenols by the synthesis outlined in Scheme 3. [Formula] [Formula] This reaction example essentially follows Reimer-Tiemann conditions to formylate an R ³ -substituted phenol to obtain a salicylaldehyde derivative, which is then converted to the desired salicylaldehyde derivative via an oxime intermediate. Including converting to nitrile (). It should be noted that when a product of the formula where R ⁵ is hydroxyl is desired, intermediates where R ⁵ is methoxy will be used in Scheme 1. For intermediate indolylalkylamines of structure, typical synthetic procedures for their preparation are described in the Kreichbaum et al. patents cited above and in J. et al.
Med. Chem ． It is obtained in the paper and is used as a reference. These referenced procedures apply to other indolylalkylamine intermediates that may be desired but are not specifically disclosed therein, but include representative syntheses of compounds of formula , are shown below to further illustrate the intermediates required for this invention. Finally, structurally bucindolol (R ¹ , R ² ,
R ⁵ is hydrogen and R ³ , R ⁴ are methyl)
6-hydroxyindolyl compound (2-[2-hydroxy-3-[[2-(6-hydroxy-1 H -indol-3-yl)-1,1
It is interesting to note that the immobilization of the major metabolite of bucindolol was confirmed using dimethylethyl[amino]propoxy]benzonitrile). It is known that 6-hydroxylation is probably more important than 5-hydroxylation in the metabolism of tryptamine (Diepson et al.
Biochim. Biophys . Acta , 62, 91 (1962); Jacchukarin and Jiepson, Biochim . Biophys .
Acta, 156, 347 (1968)). This knowledge suggested the possibility that 6-hydroxylation of bucindolol might be an important metabolic pathway. This is confirmed by clearly showing that the 6-hydroxyindolyl compounds of the present invention match the corresponding major hydroxy metabolites of bucinediol in mass spectra and gas chromatography retention times. In this regard, another aspect of the invention provides that (2-[2-hydroxy-3-[[2-(6-hydroxy-1 H -indol-3-yl) -1,1-dimethylethyl]amino]propoxy]benzonitrile.The compounds of the invention may be formulated according to conventional formulation techniques to form, for example, tablets, capsules, powders, granules, etc.
Pharmaceutical compositions can be obtained in unit dosage forms consisting of emulsions, suspensions, and the like. Solid formulations contain inert fillers, such as calcium carbonate, sodium carbonate,
Lactose, calcium phosphate or sodium phosphate: granulating and disintegrating agent, such as corn, starch, or alginic acid; binding agent, active ingredient mixed with non-toxic pharmaceutical excipients such as magnesium stearate, stearic acid or talc. Contains. The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby obtaining a long-lasting action. Solutions suitable for parenteral administration include solutions, suspensions, or emulsions of the compound of formula. Aqueous suspensions of pharmaceutical dosage forms of compounds of the formula include the active ingredient in admixture with one or more non-toxic pharmaceutical excipients known to be suitable for the manufacture of aqueous suspensions. Contains. Suitable excipients are suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia. Suitable dispersing or wetting agents are natural phosphatides such as lecithin, polyethylene stearate. Non-aqueous suspensions may be in vegetable oils, such as olive oil, sesame oil, or coconut oil, or in mineral oil.
For example, they can be formulated by suspending the active ingredient in liquid paraffin. Suspending agents may contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. Sweetening and flavoring agents commonly used in pharmaceutical compositions, such as saccharin, sodium miclamate, sugar and caramel, can be included to provide a palatable preparation. The composition can also contain other absorbent, stabilizing, wetting agents, and buffering agents. The compounds constituting the invention, their preparation and their biological action will become clearer in more detail from the discussion of the following examples. The examples are presented for illustrative purposes only and are not intended to limit the scope of the invention. used to illustrate the above synthetic method,
In the following examples, temperatures are expressed in degrees Celsius and melting points are uncorrected. Nuclear magnetic resonance (NMR) spectral characteristics indicate chemical shifts in parts per million (ppm) relative to tetramethylsilane (TMS) as a reference standard. The relative areas reported for various shifts in the H NMR spectral data correspond to the number of hydrogen atoms of a particular functional type in the molecule. The type of shift in multiplicity is reported as broad singlet (bs), singlet (s), multiplet (m), or doublet (d). The abbreviations used are:
DMSO-d ₆ (deuterodimethyl sulfoxide),
CDCl ₃ (deuterochloroform) and other commonly used drugs. Descriptions of infrared (IR) spectra include only absorption wavenumbers (cm ^-1 ) with sensory identification numbers. IR determinations were performed using potassium bromide (KBr) as a diluent. Elemental analysis is
Reported as weight percent. Synthesis of intermediates A Intermediates of formula: General operating example 1 Methoxyindol-3-yl-tertiary-butylamine To 15.2 ml of a cooled 25% aqueous solution of dimethylamine is added successively, with stirring and continuous cooling:
Acetic acid 16.9ml, 37% Formaldehyde 7.2ml, 95%
27ml of ethanol. The resulting aqueous solution is kept at 0 DEG to -5 DEG with stirring in a cooling bath, while the appropriate methoxyindole (10.0 g, 0.07 mol) is added in small portions.
The mixture was stirred and gradually heated to 30° for 0.5 h.
and then kept under stirring at 30° for 3 hours. The reaction mixture is then cooled to 10-15° and acidified with 170 ml of 2N HCl. This acidic mixture is used for decolorization (Darco G-
60), filtered and the solution can be made basic using 245 ml of 20% NaOH (under cooling and stirring).
The resulting brown oily precipitate was extracted with ether, and the extract was washed with water, dried (MgSO ₄ ), and concentrated to give a brown oily residue (14 g). The residue is recrystallized, for example from isopropanol ether and hexane, to give the desired methoxygramine, usually as a brown solid. appropriate methoxygramine (7.7 g, 0.04 mol),
2-nitropropane (26.5 g, 0.3 mole), and
A mixture of NaOH (1.7 g pellets, 0.04 mole) is refluxed under nitrogen for 3-5 hours. The reaction mixture is then cooled to room temperature, acidified with 10% acetic acid and extracted with ether. The ether extract was washed with water, dried (MgSO ₄ ), and concentrated in vacuo to give a residue. for example,
Recrystallize the residue from isopropyl alcohol-water to give 3-(2-methyl-2-nitropropyl)
Obtain methoxyindole. This nitropropylindole compound and Raney nickel (4.2 g) were mixed in 80 ml of 95% ethanol and heated to reflux. 85% in 8 ml of 95% ethanol
Heating is stopped while a solution consisting of hydrated hydrazine (7.8 g) is added dropwise. The reaction mixture is then heated to reflux for 2 hours, cooled to room temperature and filtered. Concentrate the liquid to obtain an oily residue. This can be recrystallized, for example from ethyl acetate-isopropyl ether, to yield the desired methoxyindol-3-yl- t -butylamine product. Example 1a 6-Methoxyindol-3-yl-tertiary butylamine 6-methoxygramine (0.9 g, 0.004 mol; prepared from 6-methoxyindole by the procedure of Example 1), 2-nitropropane 3.0 g (0.034 mol) and 0.19 g (0.005 mol) of NaOH pellets is stirred at reflux in an oil bath under a stream of nitrogen for 2 hours, and the dimethylamine exits through the condenser. the resulting mixture
Cool to 25°, treat with a solution of 0.47 ml of glacial acetic acid in 4.1 ml of water and extract with ether. 3 ether extract
Wash twice with water, dry (MgSO ₄ ), and evaporate to dryness. The residual brown oil crystallizes upon cooling by rubbing in a small amount of isopropyl ether. The solid was isolated by filtration, washed with cold isopropyl ether, and air dried to give 0.6 g of a brown solid, which was recrystallized from isopropyl alcohol-water and 3-(2-methyl-2
-nitropropyl)-6-methoxyindole,
mp 98-99°C, yielding 0.52 g (46%). 8.0 g (0.32 mol) of the nitro compound prepared above,
95% ethanol 80ml and Raney nickel 4.2g
The slurry (washed with water and 95% ethanol) is heated to reflux with paddle stirring. Stop external heating, 95%
A solution of 7.8 g of 85% hydrated hydrazine in 8 ml of ethanol is added at a rate that maintains a gentle reflux. After the addition, the mixture is reheated to reflux for 2 hours and then cooled to 25°C. The solution was concentrated to dryness to give a crude syrup, which was chromatographed on a silica gel column with _{CH2Cl2 - CH3OH} -concentrated _NH4OH .
Elute with (90:10:1). The brown solid thus obtained (2.9 g, mp 125-128°C) was recrystallized from ethyl acetate-isopropyl ether to give 6-methoxyindol-3-yl-tert-butylamine,
mp125-128°, yielding 1.27g (18%). Example 2 Methoxyindol-2-yl-tert-butylamine (R ¹ , R ² = H, R ³ , R ⁴ = Me) In this general procedure, 130 ml of dry ether
methoxyindole-2-carboxylic acid (0.06 mol) and thionyl chloride (2.0 g, 0.17 mol)
The solution was stirred at room temperature under nitrogen for 18 hours. The reaction mixture is filtered and the liquid is concentrated to give an oily residue, which is taken up in 150 ml of dry ether.
This ethereal solution is treated with 80 ml of dimethylamine in 90 ml of ether. The ether reaction mixture is concentrated to dryness and the residue is crystallized in isopropyl alcohol. Isolate the solid by filtration to obtain a 30-40% yield of methoxyindole-3-carboxamide product. Dissolve methoxyindol-2-ylcarboxamide in 100 ml of THF, and add this solution to 50 ml of THF.
A suspension of 3 g of lithium aluminum hydride in ml is added dropwise under stirring under a stream of nitrogen. After heating to reflux for 2 hours, the reaction mixture was cooled and added with a small amount of water and diluted
Decompose with NaOH solution. Strain this mixture
The liquid is concentrated to give a residual oil, which is taken up in pure ethanol and treated with a slight excess of dimethyl sulfate. The resulting alcoholic solution is stirred at room temperature for 4 hours and then concentrated to dryness in vacuo to yield the trimethylamine quaternary salt as a residue. This crude quaternary salt product (0.01 mol) was mixed with NaOH (2.0
g pellets, 0.05 mol) and 2-nitropropane (15 ml) and the mixture was heated to reflux under nitrogen for 1 hour. The resulting dark thick mixture is cooled, diluted with water, brought to a pH of about 6 with acetic acid, and then extracted with ether. Combine these ether extracts, wash with water,
Dry (MgSO ₄ ) and concentrate to give a dark residue, which is chromatographed on a silica column and diluted with methylene chloride. The methylene chloride solvent is removed and the crude material is recrystallized from isopropyl alcohol to yield the methoxyindole substituted at the 2-position with a 2-methyl-2-nitropropyl moiety. Reduction of this nitro product with Raney nickel and hydrazine following the procedure used in Example 1 above provides the desired methoxyindol-2-yl-tertiary butylamine. Example 3 1-Methylation of methoxyindolylalkylamine: 3-(2-amino-2-methylpropyl)
-1-Methyl-methoxyindole (R ¹ , R ³ , R ⁴ = Me, R ² = H) In this general method, 7 g (0.11 mol) of 85% KOH is ground in a mortar and immediately placed in a 25 ml Erlenmeyer flask purged with nitrogen. Move to. DMSO (55ml) is added and the mixture is stirred for 5 minutes. Methoxyindolyl-tert-butylamine (0.27 mol) and iodomethane (3.78 g, 0.03 mol, or any other suitable alkylating agent) were added and stirred for 45 minutes each, then the suspension was dissolved in 300 ml of water. Cool quickly. The mixture is extracted with ethyl acetate and the extract is then washed with water and brine to give a clear solution, dried (MgSO ₄ ) and evaporated in vacuo to give an oil. This free base can be used as an intermediate without further purification. Properties are usually investigated by converting the oil base to the hydrochloride salt to obtain a crystalline product. Example 4 Methoxyindole-2-ylethylamine Essentially Burt and Sidatsupa, J .; Chem ．
Soc. (C), 1971, 178-81, various methoxyindoles-2-
The corresponding 2-hydroxymethylindole derivatives are obtained by reducing the carboxylate esters (commercially available or prepared by literature methods) with lithium aluminum hydride in ether. For conversion to indole-2-carbaldehyde, 2-hydroxymethyl-methoxyindole (4 g) was added to dichloromethane (250 ml).
Activated manganese dioxide (10 g) was added and the reaction mixture was heated at room temperature for 20-30 min.
This is done by stirring for a period of time. The reaction is
Followed by TLC by monitoring the disappearance of a spot of starting material 2-hydroxymethylindole. If necessary, additional manganese dioxide (2-3 g) can be added. The reaction mixture is filtered and the remaining manganese dioxide is washed repeatedly with a small amount of fresh dichloromethane. The combined liquids were evaporated to dryness to yield crude methoxyindole-2-carbaldehyde as a pale yellow solid, which was then recrystallized. Methoxyindole-2-carbaldehyde (5 g), nitromethane (8 ml) and ammonium acetate (1 g) are heated under reflux for 1/2 hour. The reaction mixture is cooled and the dark red crystals that separate are collected, washed thoroughly with water, dried and crystallized from ethanol.
The nitrovinylmethoxyindole thus prepared is then reduced to the desired methoxyindol-2-ylethylamine by treatment with lithium aluminum hydride in dry ether.
The reduction mixture is heated gently to reflux for 10 hours, then the excess lithium aluminum hydride is decomposed. After filtration, the liquid was concentrated in vacuo to obtain a residue,
This is crystallized from a suitable solvent to obtain the desired methoxyindol-2-ylethylamine. Example 5 Methoxyindole-2-isopropylamine The procedure of Example 1 was modified and nitromethane (0.5 ml)
Treat appropriate methoxyindole-2-carbaldehyde (1 g) with 4 drops of benzylamine;
The mixture is then heated to reflux for 1 hour. Dark red crystals precipitate when the cold reaction mixture is allowed to stand; these are collected, washed with a little ether, dried, and crystallized from ethanol. The nitropropylindole thus prepared is reduced with lithium aluminum hydride as described above in Example 4. The solid product is crystallized and the liquid has the properties of benzyl derivatives. Example 6 Methoxyindole-3-ylethylamine Young, J. Chem ． Soc ． , 1958, 3493-96; the synthesis starts from methoxyindole-3-aldehyde, which is either commercially available or prepared from literature methods. Using the procedure outlined in Example 4 above, the appropriate methoxyindole-3-carbaldehyde is condensed with nitromethane using ammonium acetate as catalyst. If you leave it alone,
The cold solvent gradually precipitated dark red crystals, which were recrystallized from benzene or methanol to give 3-nitrovinyl-methoxyindole, which was reduced with lithium aluminum hydride as above to give the desired methoxyindole-2- Obtain ylethylamine. Example 7 Methoxyindol-3-ylpropylamine Selected methoxyindole-3-carbaldehyde (5 g), nitroethane (10 ml), and ammonium acetate (1 g) are dissolved in 1/
Heat on a steam bath for 2 hours. Cool, collect crystals,
Wash with hot water (2 x 50 ml) and crystallize from methanol. The resulting 3-(2-nitropropenyl)
- methoxyindole to form the desired 3-(2-aminopropyl) by treatment with lithium aluminum hydride as detailed in the procedure above.
- Obtain methoxyethanol. Intermediate example of formula 8 2-[(2,3-epoxy)propoxy]benzonitrile 2-cyanophenol (25.0 g, 0.21 mol),
A solution of epichlorohydrin (117 g, 0.26 mol) as well as piperidine (10 drops) is heated in an oil bath at 115-120° for 2 hours. The reaction mixture is then concentrated (90°/30 torr) to remove unreacted chlorohydrin. The residue was diluted with toluene and concentrated to dryness (2
times) to help remove the last traces of volatiles. Dissolve the remaining oil in 263ml of tetrahydrofuran,
This solution is stirred with 263 ml of 1N NaOH at 40-50° for 1 hour. The organic layer is separated and concentrated to give an oil, which is combined with the aqueous phase. The mixture was extracted (CH ₂ Cl ₂ ) and the extract was dried (MgSO ₄ ) and concentrated to give 36.6 g (100%) of an oil that slowly crystallized to a waxy solid. This intermediate product can be used in the preparation of products of formula without further purification. Example 9 2-[(2,3-epoxy)propoxy]4-methoxybenzonitrile The required 5-methoxysalicyaldehyde can be found in the literature (e.g. Kap et al., Arch . Pharm ., 308/
5, 339 (1975)) from 4-methoxyphenol by the Reimer-Tiemann procedure described by J.D. 5, 339 (1975). Starting salicylaldehyde in 6 ml of pyridine and 6 ml of pure ethanol.
The 0.005 mol solution is treated with 0.4 g (0.02 mol) of hydroxylamine hydrochloride and heated under reflux for 4 hours. The mixture is concentrated in vacuo to give a gray syrup, which is stirred with 50 ml of H ₂ O and the suspension is decanted. 10 ml of H ₂ O was added to the remaining glass and then cooled to 5°, yielding about 1.2 g of crude solid upon filtration, which was dissolved in 50% ethyl ether.
Take up in isopropyl ether. The ether solution was filtered, dried (MgSO ₄ ), treated with Dalco G-60 and Celite, filtered and concentrated in vacuo to give a waxy solid.
Recrystallization from ethyl ether-Skelly B gives the corresponding benzaldehyde oxime. 0.002 mol of this oxime and 1.02 g of acetic anhydride
(0.01 mol) was heated to reflux for 30 min, then
Cool to 25°. Add water (50ml), then 20
% NaOH was added dropwise to bring the pH to 10. The resulting suspension is stirred at 25° for 20 hours to hydrolyze the acetate ester of the desired phenol derivative. 6N
The pH was adjusted to approximately 2 using HCl and the resulting mixture was extracted with 40 ml of ethyl acetate to obtain the organic layer, which was separated, dried (MgSO ₄ ) and evaporated at 65°/70 Torr to give a syrup. get. It consists primarily of acetate ester. 3 at 25° in a mixture of 7 ml methanol, 7 ml water and 0.1 g NaOH pellets.
Further hydrolyze the syrup and then 60°/70
Remove methanol in toll. Dilute the aqueous residue with 0.5 N HCl to obtain a precipitate. This can be recrystallized from isopropyl ether and dried to yield the desired benzonitrile intermediate. 0.015 mol of this 2-hydroxy-5-methoxybenzonitrile, 4.2 g (0.03
mol) and 140 ml of DMF at 50°
Stir for a minute. Epibromohydrin (2.8g i.e.
0.02 mol) was added all at once and stirring continued for 3 days. Pour the reaction mixture into 1 liter of brine,
The resulting suspension was stirred at 0-5° for 3 days. The mixture was filtered, the filter cake was washed with water, and air dried to give the crude intermediate compound, which could be used without further purification. Similarly, the above procedure may be modified and other substituted cyanophenols may be used to obtain intermediate compounds of other formulas used in the synthesis of compounds of various formulas of the present invention. Product Synthesis Example 10 General procedure: 2-[2-Hydroxy-3-[(hydroxyindolyl)alkylamino]propoxy]benzonitrile The selected methoxyindolylalkylamine () is added in equimolar or slightly excess amounts. Mix with the selected epoxypropoxybenzonitrile () and reflux the solution of reactants for about 18-24 hours, or reflux the neat mixture at a temperature of about 120-130°.
Coupling is done by heating for ~2 hours. Ethanol and toluene are the solvents of choice for coupling by refluxing solutions of and. In some cases it may be advantageous to follow the reaction by TLC and add more epoxide until all the indoleamine has disappeared. Following the reaction, the mixture is concentrated to dryness and the residue is washed with water and used crude in the next step. Alternatively, the intermediate methoxy product can be purified by crystallization-recrystallization as a base or appropriate acid addition salt. A solution of the methoxyindolyl product () in methylene chloride is stirred at 0 DEG to 10 DEG under a stream of nitrogen while a several-fold excess of 1 N boron tribromide in methylene chloride is added dropwise. After the addition, the reaction mixture is stirred at room temperature for 6-8 hours. The reaction mixture is cooled and excess boron tribromide is destroyed by adding excess water dropwise. This crude hydrobromide salt of the product of formula can be recrystallized, converted to base and purified,
Purification can be accomplished by several conventional methods such as conversion to a base followed by conversion to another acid addition salt. Modifications necessary to adapt this procedure to the preparation of particular compounds of formula are readily available to those of ordinary skill in the chemical arts. Example 11 2-[2-hydroxy-3-[[2-(6-methoxy-1 H -indol-3-yl)-1,1-
Dimethyl]amino]propoxy]benzonitrile 6-methoxyindol-3-yl- t -butylamine (2.6 g, 0.012 mol; prepared in Example 1a), 2
-[(2,3-epoxy)propoxy]benzonitrile (2.1 g, 0.012 mol; prepared in Example 8) and 100 ml of pure ethanol were stirred and refluxed for 20 hours. Further epoxide (0.21 g) was added and refluxing was continued for 4 hours, after which the mixture was concentrated to dryness and the residue was crystallized by triturating in isopropyl alcohol.
The product was collected by filtration, washed with cold isopropyl alcohol, and air-dried to yield the methoxy product.
mp145-146°, 4.0 g (85%) was obtained, 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 at 5-10° under a stream of nitrogen while 15.3 ml (0.015 mol) of 1 M boron tribromide in methylene chloride was added.
was added dropwise. Following the addition, the ice bath was removed and the reaction mixture was stirred at 25° for 6 hours, then at 5-10°.
The mixture was cooled to 500 mL and 47.5 ml of H ₂ O was added dropwise. The resulting mixture was decanted and the remaining gummy solid was washed twice with H ₂ O. The crude hydrobromide salt was dissolved in 50 ml of hot H ₂ O, then treated with Dalco G-60, filtered, cooled (25°) and basified (PH 8) with concentrated NH ₄ OH to give a brown solid. 1.2 g was obtained, which was chromatographed on a medium pressure system using chloroform-methanol-conc. _NH4OH (90:10:1) (silica gel 60, 230
~240 mesh, EM reagent). The product thus obtained was crystallized from a small amount of ethanol and stepwise addition of _H2O gave the desired 6-methoxyindole product () as a brown solid, mp90
Obtained as ~94°. Analysis Calculated value as C ₂₂ H ₂₅ N ₃ O ₃・1/3H ₂ O:
C, 68.56; H, 6.67; N, 10.90; _H2O , 1.54.
Experimental value: C, 68.69; H, 6.68; N, 10.68; H ₂
O, 1.80. NMR (DMSO-d ₆ ): 0.98 (6, s); 2.70 (4,
m); 3.30 (2, bs); 3.83 (1, m); 4.11 (2, d
[5.8Hz]); 5.00 (1, bs); 6.65 (3, m); 7.20
(3, m); 7.60 (2, m); 8.71 (1, bs); 10.35
(1, bs). IR (KBr): 760, 800, 1260, 1290, 1450,
1495, 1600, 1630, 2230, and 3300cm ^-1 . Example 12 2-[2-hydroxy-3-[[2-(5-hydroxy-1 H -indol-3-yl)-1,1
-dimethylethyl]amino]propoxy]benzonitrile 5-methoxyindol-3-yl- t -butylamine (2.7 g, 0.0125 mol; prepared from 5-methoxyindole using the procedure shown in Example 1), 2- A solution of [(2,3-epoxy)propoxy]benzonitrile (2.2 g, 0.0125 mol) and 20 ml of acetone was refluxed for 1/2 hour. The acetone solvent was then boiled off and the oily residue was heated neat at 100° for 2 hours. Isopropyl alcohol (20 ml) was added and the reaction solution was refluxed for 4 hours, followed by cooling to room temperature and adding 50 ml of ether.
white powder, 4.7g using a stirring rod, diluted with
(96%), scraped out mp119~124°; TLC
(9:1 CHCl ₃ -methanol) shows a single spot, Rf 0.25. This crude methoxy product can be used directly in the next step or purified by converting to the HCl salt. Conversion of the acetonitrile solution to the HCl salt by treatment with ethanolic HCl yields the crude product, which is recrystallized from butanone-95% ethanol (20:1) to yield an off-white powder, mp 164-166°. . Analysis Calculated value as C ₂₂ H ₂₇ N ₃ O ₃・HCl: C,
64.25; H, 6.56; N, 9.77. Experimental value: C,
64.14; H, 6.54; N, 9.68. Using the procedure shown above in Example 11 for the boron tribromide cleavage of the methoxy group, the 5-
The methoxyindole intermediate product can be used to obtain the desired 5-hydroxyindole product () in the form of the hydrobromide salt. Pure hydrobromide is a beige powder, mp219-221°. Analysis Calculated value as C ₂₂ H ₂₅ N ₃ O ₃・HBr: C,
57.40; H, 5.70; N, 9.13. Experimental value: 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 (1,
bs); 7.10 (6, m); 7.71 (2, m); 8.55 (3,
bs); 10.95 (1, bs). IR (KBr): 750, 800, 1265, 1290, 1455,
1495, 1580, 1600, 2230 and 3300 cm ^-1 . Starting with the appropriate methoxyindole alkylamine () and epoxypropoxybenzonitrile (), using substantially the same procedures as outlined above, with minor modifications that can be readily performed by one skilled in the chemical arts. Further example products of formula can be synthesized. Some additional formula products that can be synthesized by these techniques are shown in Table 1. Biological Evaluation These biological tests were used to determine the antihypertensive properties of selected formula compounds. Example 35 The efficacy of antihypertensive agents other than adrenergic beta-receptor blockers is commonly evaluated in spontaneously hypertensive rats. Blood pressure values are measured on the test animals before and 2 and 4 hours after oral administration of 30-100 mg/Kg of the test compound. Heart rate is measured in conjunction with each pressure measurement. 15-20mm 2 or 4 hours after single administration
A decrease in blood pressure in the Hg range is considered "questionable."
"Active" and "inactive" are reductions greater or less than the respective ranges. Example 36 Another test useful for determining the effectiveness of antihypertensive agents uses DOCA salt hypertensive rats. These hypertensive rats are created as follows: male Sprague-Dawley rats weighing approximately 90 g are individually caged and allowed free access to food and water for a 5-day pretreatment period, followed by drinking water. Replace with 1% saline. 10 times in rats during a 3-week treatment period.
Inject 10 mg of DOCA (deoxycorticosterone acetate) subcutaneously in 0.2 ml of suspension medium (0.25% Tween 80 and 0.125% CMC in normal saline). After the final injection, the 1% saline is replaced with distilled water and the animals are ready for use after one week. The test is performed by selecting non-fasted animals with elevated systolic blood pressure (>160 mmHg). 30-100 mg of test compound/
Blood pressure values are measured before and 4 hours after the oral administration of Kg. Animals are placed in metabolic cages without food or water for the duration of the study and urine is collected for 4 hours. Heart rate and body weight will be measured along with each blood pressure measurement. A decrease in blood pressure 4 hours after administration in the range of 15-20 mmHg is considered "questionable." Reductions greater and less than this range are designated as "active" and "inactive." Example 37 Angiotensin-supporting ganglion blockade in rats:
It is utilized as a screen for the evaluation of active direct vasodilator components. Measure the percent change in blood pressure in anesthetized rats 30 minutes after intravenous administration.
A tranquil injection is carried out with 3 mg/Kg of test compound. Borderline activity is defined as an approximately 10% reduction in blood pressure 30 minutes after administration. "Active" and "inactive" are greater or lesser increases. Example 38 Diastolic blood pressure and heart rate for a fixed challenge dose of isoproterol are measured before and 15 minutes after intravenously administering graded doses of test compound to anesthetized dogs at 3 minute intervals. Femoral motion and stillness 1
A cannula is inserted into the limb to record blood pressure and administer drugs dissolved in saline. The vagus nerve is cut in the mid-cervical region of the neck, and the dog is ventilated mechanically (Harvard Respiratory) with room air at a rate of 20 breaths per minute and a pumping volume of 20 ml/Kg. Heart rate is monitored using a cardiocacometer induced by internal heartbeats. All measurements are recorded on a Beckman R-612 recorder. The effect of the drug is
It is expressed as the cumulative dose (micrograms/Kg) that causes a 50% inhibition of the isoproterenol response. Example 39 A rat is anesthetized using a combination of urethane and Coralase in a quiet environment. After induction of anesthesia, chlorisondamine is injected intraperitoneally to produce ganglion blockade. Blood pressure and heart rate were monitored by inserting a cannula into the femoral arm, and compounds were administered by inserting cannulae into the two femoral arms. Intubate into the trachea,
The rat was allowed to breathe spontaneously. Animals were challenged with phenylephrine before and 15 minutes after intravenous administration of test compound, and changes in blood pressure were recorded. Plot the data to obtain a dose-response curve and
The dose of phenylephrine required to induce Hg (ED ₅₀ ) was interpolated from this curve. after medication
Calculate the dose shift by dividing the _ED50 by the pre-dose _ED50 .

Claims (1)

[Claims] 1 Formula: where R ¹ and R ² are each hydrogen; R ³ and R ⁴ are each independently C _1-4 alkyl; R ⁵ is hydrogen; The enoxypropanol aminoalkyl side chain is attached to the indole ring at the 2- or 3-position and the hydroxyl substituent is attached to the indole ring 4-,
A compound having: occupying the 5-, 6- or 7-position or an acid addition salt thereof. 2. A compound according to claim 1, wherein the indole ring is attached to the phenoxypropanol aminoalkyl side chain at its 3-position. 3. The compound according to claim 1, wherein R ³ and R ⁴ are methyl. 4. The compound according to claim 1, wherein the hydroxy substituent occupies the 6-position of the indole ring. 5 2-[2-hydroxy-3-[[2-(6-hydroxy-1 H -indol-3-yl)-1,1
-dimethylethyl]amino]propoxy]benzonitrile. 6 2-[2-hydroxy-3-[[2-(5-hydroxy-1 H -indol-3-yl)-1,1
-dimethylethyl]amino]propoxy]benzonitrile. 7 Formula: (wherein R ¹ and R ² are each hydrogen; R ³ and R ⁴ are each independently C _1-4 alkyl; R ⁵ is hydrogen; phenoxypropanol aminoalkyl The side chain is attached to the indole ring at the 2- or 3-position and the hydroxyl substituent is attached to the indole ring 4-,
occupies the 5-, 6-, or 7-position) or an acid addition salt thereof, in which a methoxylated indole alkylamine [formula] (wherein R ¹ , R ² , R ³ and R ⁴ are as defined above) and (R ⁵ -substituted phenoxy epoxide) [Formula] (wherein R ⁵ is as defined above) )
by heating and coupling with to produce the intermediate [where R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above]; then b Reacting the intermediate under appropriate conditions to cleave the methoxy group to a hydroxyl group, thus producing a compound of formula; and then c optionally if a pharmaceutically usable acid addition salt of formula is desired. A process for preparing a compound of formula or an acid addition salt thereof, characterized in that the product of step (b) is converted into said salt by standard techniques. 8. Claim 7, wherein step (b) comprises reacting the intermediate with boron tribromide in methylene chloride under reaction conditions to produce a compound of formula
The method described in section.