JPS5965087A - Substituted 1-pyridyloxy-3-indolylalkylamino-2-propanol, ma-nufacture and use - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to indole-based heterocyclic carbon compounds having amine substituents and methods of clinical and biological treatment using drugs using these compounds. 3-(aryloxy)-2 with beta-adrenoceptor-blocking activity and/or vasodilatory properties and useful in the treatment of cardiovascular cramps.
- There are many conventional techniques regarding hydroxypropylamine compounds. Much of this prior art relates to the development of beta-adrenergic blocking agents in these classes of compounds. The standard for these structures is propranolol,
Chemically it is 1-(isopropylamino)-3-(1-naphthyloxycou-2-propanol. Propranolol and some related naphthyloxypropanol amines are described in U.S. Pat. (Published on August 22nd). Numerous subsequent revisions have included the "UM line" describing carbocyclic ethers in which the 7-tyloxy group of propranolol has been replaced with other aromatic ring-spanning heterocyclic ring systems. It was done.

A series of patents issued to J. J. Baldvrin disclose the use of pyridinyloxy groups in this type. These compounds and their salts have been described as useful anti-hyperdepressants. These patents (shown below) generally disclose the following general structure (1).

2 (1) [R in the formula is alkyl, phenalkyl, phenoxyalkyl; RIF1H, CL (L is alkyl or aryl); R2 is H, CN, CF3, OH,
C-L, C.I.

NO2, F, pyrrolyl, oxadiazolyl〕0
The above Bal transferred to Merck & Co.
dwin's patent series includes: U.S. Pat. No. 4,000.282 (issued December 28, 1976);
; Same No. 4.060,601 (issued November 29, 1977): Same No. 4.091,104 (May 2, 1978)
Issued on the 3rd]; Same No. 4゜092.419 (May 1978
Published on the 30th of the month; No. 4゜14a, 54s-+4 (19
Issued March 13, 1979]; No. 4.145,425 (
Issued on March 20, 1979); No. 4,151,284
No. 4,210,6 (issued on April 24, 1979)
No. 53 (issued July 1, 1980); No. 4.259.
No. 327 (issued March 51, 1981); No. 4, 26
No. 5,507 (issued April 21, 1981);
No. 279,913 (issued July 21, 1981); and No. 4.329.551 (issued May 11, 1982).

A preferred compound of this series, 2-[3-(tert-butylamino]-2-hydroxypropoxy]-3-cyanopyridine (also known as MK-761), is described in The Journal by S Sweet et al.
l of Pharmacology and Exp.
erimental The, rapeutics,
211/1.195-296 (1979); S
Weet et al.'s C11nicaland Experi
mental Hypertension, 1 (
4), 449-471 (1979); and Vieke
Drag Metabolism and Dis of r et al.
position, 8/3.163-167 (
1980). However, research on the burning period in humans is
It was terminated when it was discovered that MK-761 caused malformations in rabbits upon long-term administration at high doses (Jo
urnalof Medicinal Chemist
ry, 22/11.1284-1290 (19
79)).

OHMK-761 A series of indol-3-yl-tertiary butylamitubrobanols (having formulas (2) and (3) below) with antihypertensive properties are disclosed in U.S. Pat. No. 4,254 by Kreighbaum et al. , No. 595 (published on November 18, 1980)
; U.S. Patent No. 4,314°943 (February 9, 1982)
): and Journal of Medicine
al Chemistry, 23: 3.285-
289 (1980) K.

(3) A preferred compound of the series represented by structural formula (2) is named MJ13105 (bueindolo
The present invention describes a series of vasodilators and pharmaceutical agents with a range of beta-adrenergic blocking abilities and having the general formula: It relates to acceptable acid addition salts thereof.

(1) In the above general formula, X is CHO%CH snow OH, CN
.

CF3, C0NR"Rb, '!fcI/'i C0z
Re (R') is selected from hydrogen or Re, and R is lower alkyl, aryl, or arylalkyl; Y is hydrogen, halogen, acyloxy, alkoxy, aralkyloxy, aryloxy,
or hydroxy: R is hydrogen or I: is (C-L) and L is selected from alkyl, aryl, substituted aryl, or arylalkyl;
1, R2, A and B are independently selected from hydrogen or argyl, and C can be halogen, hydrogen, hydroxy, alkyl or alkoxy. Preferred compounds have an X in the 3-position of the pyridine ring and an indolylalkylaminopropoxy side chain attached to the 2-position of the pyridine nucleus.

The present invention includes compounds having the above structural formula (2) and acid addition salts thereof. In structural formula (1), X is -C
H0l-CN, -CFs, -CONR'Rb,'tfc
is -CO2Re ib5. R' and nb are selected independently from hydrogen or r, and r is lower alkyl (Cs-C
4), riichiru, or aryl-lower alkyl,!
However, aryl is preferably phenyl.

Also preferred are those in which X is bonded to the 3-position of the pyridine ring system. Y represents the second substituent of the pyridine ring, and is hydrogen, halogen, low Wj (('+~C4) alkoxy, aryl lower alkoxy, hydroxy, or -C-O-alkyl (alkyl is C1-C6 alkyl)). The entire pyridinyl group is attached to the indolylalkylaminopropoxy side chain at the 2-position of the pyridine. R is hydrogen or (C-L) and L is CI""CIOalkyl, phenyl, Selected from substituted phenyl or phenalkyl.R1% R'' % A% and BFi independently selected from hydrogen or lower alkyl. , or hydroxy.The indole moiety itself is preferably attached to the main side chain through its 3-position.

For pharmaceutical uses, pharmaceutically acceptable acid addition salts in which the anion does not particularly contribute to the toxicity or pharmacological activity of the organic cation are preferred. Acid addition salts can be prepared by reaction of an organic base of structural formula Depending on the thing,
Five gills. Examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, conolilic acid, pamoic acid, shiframic acid, hybaric acid, etc.; useful inorganic acids are hydro Halides such as HCI, HBr, HCl; sulfuric acid; phosphoric acid, etc.

It is also to be understood that the compounds of the present invention encompass all optical isomers or enantiomer mixtures, such as dicemic forms as well as individual enantiomers. These individual enantiomers are (+) and (-), (
t) and (d) or a combination of these symbols. The symbols representing left and right, respectively (
Q and (6) and the symbols (S) and (river refer to the absolute spatial configuration of the enantiomers. If no isomeric designation is given for a compound, the compound is racemic.

Physiological tests in animals of the subject compounds of formula (1) demonstrate that they have vasodilatory properties with varying degrees of adrenergic beta receptor blocking and intrinsic harmonic mimetic activity. Preferred compounds have particularly desirable combinations of the above actions and supplementary pharmacological effects or lack thereof, which make them particularly suitable for use in certain cardiovascular conditions, such as as antihypertensive agents.

The usefulness of the compound of formula (1) is the antagonism of isoproterenol (adrenergic beta receptor action) in intravenously injected anesthetized rats, and the antagonism of isoproterenol (antihypertensive action) in spontaneously hypertensive and DOCA salt hypertensive rats. action),
Journal of the antagonism (vasodilator effect) of inproterenol in an angiotensin-retaining ganglion murine model and the antagonism of isoproterenol in various other animal and experimental models (Deitchman C).
lPharmacological Methods
, Sat., 311321 (1980)). No evidence of teratogenesis or mutations was found associated with compounds of formula (1).

For use as antihypertensive agents, vasodilators, and/or beta-adrenergic blockers, the therapeutic methods of the present invention provide oral and non-toxic administration of a compound of formula (1) or a pharmaceutically acceptable salt thereof. It consists of administration to body tissues by both oral and oral routes. An effective amount is taken to mean a dosage which, when administered to a mammal in need of treatment, exerts the desired pharmacological activity as described above without undesirable toxic side effects. Although it varies depending on the recipient subject and the route of administration, it is approximately 1L1 per 1Kf body weight.
A compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof in the expected range of mCg to 100 cm will provide the desired therapeutic effect.

The compounds of the present invention may be prepared by a convenient general method, which involves combining a z-substituted pyridine (IV) with a suitable W-substituted propator or initial propator intermediate (It).
It includes the combination with.

General Method In the above general method, D is hydrogen or preferably 7 edroxy or halogen, preferably chlorine; W is 2
When is hydroxy, halogen is preferably chlorine, and 2
When is I.logen, it is hydroxy. Generally, the hydroxy group-containing reagent is first converted to the oxide anion with a strong base before reacting with the halogen-containing intermediate.

This method is a method known in the prior art for the preparation of 1-(substituted amino)-3-(hetaryloxy)-2-propanol as set out in the patents and literature cited in the Background of the Invention above. use. This method consists of a suitably substituted pyridine of formula (IIA) [
3-(indolylalkyl]oxazolidin-5-yl]methanol (or methyl halide), or 2
) indolylalkylaminopropatur (or halopropatol) of formula (IIB), or 3) indolylalkylaminopropatur of formula (IIB);
The intermediate from the reaction of 0 (IV) with (IIA), including reaction with either glycidol, IC), is converted to product (1) by hydrolysis under acidic conditions.

This hydrolysis occurs at temperatures of about 20-100°C.
This is accomplished using dilute mineral acids at N to 1N concentrations. The compound of formula (1) may be recovered as the free base by neutralization of the hydrolysis mixture and collection of the precipitate. Acid salts are obtained by evaporating the hydrolysis mixture or by reacting the free base with the acid. Purification is accomplished by conventional means such as recrystallization. The conversion of the epoxide intermediate obtained from the reaction of (IV) and (IIC) to the product of formula (1) is carried out by converting the epoxy ether neat or in the presence of an organic solvent inert to the reaction as described above. Formula H shown in the reaction formula of
, NG by simply heating with the amine. 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 liquids include, but are not limited to, benzene, tetrahydrofuran, dibutyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, etc. Suitable reaction temperatures are about 60 to 200°C for a single step. Process route 1d<N) includes the reaction with (IIB), which is the preferred route for the synthesis of the products of the invention.

This method is illustrated by the following specific reaction formula showing the above-mentioned preferred synthesis method as reaction (1) below.
(TIB) B In the above reaction formula, X%Y, R, R1, R2, A%B1 and C are represented by the formula (
This is defined in υ. Essentially, this method involves heating a (substituted) lopyridine with the appropriate indolylalkylaminopropatol intermediate in the presence of a base, all in an inert organic solvent, under miscible conditions. do. Potassium-t-butoxide,
Standard strong bases such as potassium hydroxide, salt or sodium hydride may be used, but sodium hydride is preferred.

Similarly, any of a number of inert organic liquids may be used as the reaction medium, including reacting the cyanopyridine and indolylalkylaminopropatol neat in the presence of a base. Suitable solvents include benzene,
These include, but are not limited to, toluene, tetrahydrofuran, dibutyl ether, dimethoxyethane, and the like. The preferred reaction temperature is about 20-80°C. The addition of a suitable crown ether, such as 18-crown-6-ether, aids the reaction process.

Y and /i 7'c are formula (1) where C is hydroxy
The methoxy precursor corresponding to the product of is subjected to the following reaction (2)
It is manufactured by splitting FA as shown in the figure.

Reaction (2) Conversion to Hydroxylated Products Other synthetic methods leading to hydrolysis of benzyloxy precursors, for example 6D, are well known to those skilled in the art and may be used in these cases.

The required halopyridines are commercially available and can be prepared using standard preparation methods described in the literature. The production of related 3-substituted pyridines is B
U.S. Patent No. 4.329.551 (1) to Aldwin et al.
(Published May 11, 1982), which is incorporated herein by reference in its entirety.

A preferred synthetic intermediate, the intermediate indolylalkylaminopropatool (IIB; R=H), is prepared by converting the appropriate substituted indolylalkylamine (J to 3-chloro-1,2-propanediol in a refluxing alcohol containing sodium carbonate). This method is shown by the following reaction formula (3).

Reaction (3) <m)M (11B)B In the reaction formula of reaction (3) above, R1, R", A,
B and C are defined by formula (1).

Products of formula (T) of the present invention, in which R is other than hydrogen, can be converted from the corresponding products of formula (υ), in which R is hydrogen, to acyl halides such as undecanoyl chloride, piparoyl chloride,
They may be conveniently prepared by treatment with a suitable acylating agent such as benzoyl chloride, para-methoxybenzoyl chloride; or an acid anhydride such as acetic acid. This reaction is explained by the reaction formula shown in reaction (4) below.

Reaction (4) Indolylalkylamine (1) is prepared by the above Kreigh
Baum et al. patent and Journal of Med
It is described in icinal chemistry,
I am including this here along with the references introduced there. Although these methods are not specifically described in these references but can be applied to the production of other indolylalkylamine intermediates necessary as intermediates for the present invention, the formula (A representative method of synthesizing the compound of the present invention is described below.) The compound of the present invention can be formulated in accordance with common pharmaceutical practices to form into tablets, capsules, powders, granules, emulsions, suspensions, etc. Solid formulations from which unit dosage pharmaceutical compositions can be made include non-toxic pharmaceutical excipients, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate;
Contains the active ingredient in admixture with a granulating and disintegrating agent such as corn flour, starch or alginic acid; a binder such as starch, gelatin or acacia; and a binder such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by well known techniques to prevent disintegration and absorption in the gastrointestinal system and provide a sustained action over a longer period of time.

Liquid formulations suitable for parenteral administration include solutions, suspensions, or emulsions of compounds of formula (1). Aqueous suspensions of pharmaceutical dosage forms of compounds of formula (1) contain the active ingredient in admixture with one or more non-toxic excipients known to be suitable for the manufacture of aqueous suspensions. including. Suitable excipients include, for example, sodium-carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone,
suspending agents such as gum trajecans, and gum acacia. Suitable dispersing or wetting agents are naturally occurring phosphatides such as pectin, polyoxystyrene stearate.

Non-aqueous suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as olive oil, sesame oil, or coconut oil, or in a mineral oil, such as liquid paraffin. Sweetening agents and flavoring agents commonly used in pharmaceutical compositions, such as saccharin, sodium cyframate, sugar and caramel, can also be included to provide a palatable oral formulation. Agents, wetting agents, and buffering agents may also be included.

The compounds constituting the invention, their preparation and their biological effects will become clearer from the following examples.

However, these examples are for illustrative purposes only and should not be construed as limiting the invention in form or scope. In the following examples to illustrate the above synthetic methods, temperatures are expressed in degrees Celsius and melting points (m, h) are uncorrected. Nuclear magnetic resonance (NMR)
) Spectral characteristics are chemical shifts expressed as ppm (parts per million) relative to tetramethylsilane (TMS) as a reference material.The relative areas reported for various shifts in H-NMR spectral data are corresponds to the number of hydrogen atoms of a particular functional type in the molecule.The nature of the shift in terms of multiplicity is the broad singlet (b
s), singlet (a), multiplet) (rn
), or dupletsu) (d). The abbreviations used are DMSO-ds (deuterium dimethyl sulfoxide), CDCl5 (deuterium chloroform)
, and the others are commonly used. The description of the infrared (IR) spectrum is the absorption wave number (3-”) with the functional group identification value.
Contains only. An IR measurement using potassium bromide (KBr) as a diluent was employed.

Elemental analysis is reported as weight percent.

Synthesis of intermediates A0 Intermediates of formula (III) Example 1 3-(2-amino-2-methylglobyl)-6-medoxiindole and the following components were added one after another with continued cooling: 1
&9- of acetic acid, 7.2 ml of 37% polyaldehyde,
27-95 ethanol. The resulting stirred solution was kept at 0 to -5°C in a cooling bath, and then 6-medoxiindole (10, Of) was added.

0.07 mol] was added in portions. The mixture was stirred and gradually warmed to 30°C (hours) and then kept at so'c for 30 minutes with stirring.The reaction mixture was then rapidly cooled to 10-15°C and 170 m
- Acidified with MCI. This acidic mixture was decolorized (Dulco G-60), the P solution was cooled and stirred, and then made basic using 245-20% NaOH, and the resulting brown oily precipitate was extracted with ether. The extract was washed with water, dried over Mg5Od and concentrated to give a brown oily residue (141F). The residue was recrystallized from isopropyl ether and hexane to give 99 (65%) of 6-
Medoxygramine was obtained as a tan solid. Melting point 88~
90℃.

6-Medoxygramine (7,7f, 104 mol), 2-
A mixture consisting of nitrobroba y (26,5f, rl, 5moh) and Na0H (1,7f pellets), [L (14 mol) was refluxed under nitrogen atmosphere for 3-5 hours. The reaction mixture was cooled to room temperature, acidified with 10% acetic acid, extracted with ether, and the ether extract was washed with water and dried.
g SO4) and concentrated in vacuo to give a residue. Recrystallization of the residue from alcohol-water 7.6t (80%) 3
-(2-Methyl-2-nitropropyl)-6-medoxiindole was obtained as a tan solid. Melting point 98-100
'c.

The nitropropylindole and activated Raney nickel (4,2f) were placed in 95% ethanol 8o-
Heat to reflux. Heating was discontinued and a solution of 85 thihydrazine hydrate (7,89) in 95% ethanol 8- was added dropwise. The reaction mixture was then heated under reflux for 2 hours, cooled to room temperature and filtered. The P solution was concentrated to obtain a residual oil.

This was gradually acidified and recrystallized from ethyl acetate isopropyl ether to give the product 4.22.

Melting point 125-128°C.

Example 2 Indole-2-carboxylic acid (1 (10t, ao6 mok) and f-onyl chloride (20,
Of.

0.17 mol) in a room source under a nitrogen atmosphere.
Stirred for 2-18 hours. The reaction mixture was filtered once, and the residue was concentrated to obtain a residual liquid, which was dried with Et, 0 to 150
I took it during d. Add this ether solution to 90-Et20
The ether reaction mixture treated with dimethylapane 80 was filtered to dryness and the residue was recrystallized in isopropyl alcohol. The solids were separated by filtration at 4.0 f (3
4%) of 2-indolylamide product was obtained. Melting point 18
1-183℃.

This amide was dissolved in 10-THF and the solution was
〇- Lithium aluminum hydride in THF 3
The mixture was added to the force-stirred suspension under a nitrogen atmosphere from t. After heating under reflux for 2 hours, the reaction mixture was cooled and decomposed with a little water and dilute NaOH solution. The mixture was filtered and one part was concentrated to give a residual oil, which was taken up in absolute ethanol and treated with excess dimethyl sulfate.The resulting alcoholic solution was stirred at room temperature for 4 hours; It was then concentrated to dryness in vacuo to obtain trimethylamine quaternary salt as a residue.

The crude quaternary salt product (309% 0.01 mol) was dissolved in NaOH
(2,01F, Pelletz), 0.05 mol) and 2-nitrofuropane (15 m) and the mixture was heated at reflux under nitrogen atmosphere for 1 hour. The resulting dark thick mixture was cooled, diluted with water, acidified with acetic acid to pH ˜6, and then extracted with Et,0. These ether extracts were combined, washed with water, dried (MgSO4) and concentrated to give a dark residue. This was chromatographed on a silica column and diluted with methylene chloride. The methylene chloride was removed and the crude product was dissolved in isopropyl alcohol.
2- (2-methyl-2-
Nitropropyl) indole was obtained as a cream-colored solid. Melting point: 102-103°C.

The nitro product was reduced with nickel silane and hydrazine according to the method used in Example 1 above to provide the desired indole alkylamine as a white solid. Melting point 13
0-135℃.

Additional examples of indole alkyl amines are shown in Table 1.

Table 1 Indole Alkylamine Examples RI R2A B C4
11,-1-1,-1++Mari,Yu,---Akebono 3
Me H3-I (Me H4Me
Me 2-Me HH5Me Me
2-HH5-Br6 Me Me
2-HH5-OMe7 HMe 2-H
HH 8HMe 2-Me Me 5-OP
r9 HMe 3-Me Me
5-Br10 Me Me 2-1i
H6-OMell Me H2-Et
! (4-C112Me H2-HH7-OMe B0 Intermediate Example 13 of formula (It)
5? , 10.11 mol], 3-chloro-1,2-propanediol (7, (1°0.06 mol)) and EtOH (
250 mg) was stirred under reflux overnight.

After cooling, the mixture was filtered and concentrated in vacuo. Et the remaining liquid
Dissolve in OAc and decolorize (Darco G-60) for 10
Evaporated to 〇-volume. A white solid precipitated from the solution, which was recrystallized from EtOAc to 7.7F (
55 L) of product was obtained. Melting point 112-114°C. This material crystallized with 7 moles of water.

Using other intermediates of formula (III) in this or similar methods, various intermediates of formula (It) were obtained.

Product Synthesis Example 14 C=H) 3-([2-(j-indolyl)-1,1-dimethylethyl]ami/)-1,2-propanediol (a
y, sf, CL18 mol) and sodium hydroxide (
57% dispersion in oil 7.6 f, 0.18 mol] to 2.5
Stir in toluene for 3 hours under nitrogen atmosphere.
heated to ℃. The mixture was then cooled to room temperature with stirring and 18-crown-6-ether (o,sr)
, in anhydrous powder form, (powder 62.11F, 0.45
mol) and 2-chloro-3-cyanopyridine (25,
Of.

118 mol] were added one after another to the above stirred mixture and the whole was then stirred for a further 42 hours. The residue was obtained by concentrating and drying. This was partitioned between hot H,O and EtOAc. After cooling to room temperature, separate the aqueous layer and add additional EtOA
This wash was combined with the original EtOAc layer. The EtOAc layer was dried (MgSO4) and concentrated to approximately 1 volume. cooling to precipitate the solid;
Separation by filtration yielded approximately 41 tons (62 tons) of crude product base.

The base was converted to the hydrochloride salt by treating a solution of the base in isopropyl alcohol with ethanolic MCI. Recrystallization of the crude hydrochloride from absolute ethanol gave a white solid. Melting point: 181-183°C.

Analysis: (Calculated value as 41H24NaOz・HCI: C, 62,92; H, 6,29; N, 1
598° Actual value: C, 62, 85: H, 6, 29:
N, 14.04°NMR (DMSO-ds):
1.30 (6, s): 3.20 (4, m): 3.
99(!1.m); 6.02(1,d(4,0H
z)); 7.5rJ(6,m); a31(1,
dd(2,o,7.6Hz));a51(1,dd[:
2.0, 5.6Hz]); 11L82 (1, bs)
; 9.32 (1, bs); 11.27 (1, ba)
.

IR (KBr): 750. 1110. 1310
．． 1440°1460, 1580. 158B
, 2250. 2790°2980, a
nd 3400 cm □Production of cyclamate salt The crude base synthesized as above (crude base of 2, f) was
The cyclamate salt was prepared by treatment with siframic acid (1f) in methanol of -. The methanol solution was warmed, filtered through ft'', and one solution was concentrated in vacuo to obtain a residue.
This was crystallized in 10-acetonitrile. 2 by recrystallization of the crude salt from methanol-acetonitrile
．． 0t of white solid was obtained. Melting point: 172-174°C.

Analysis: (41B34 N40!・C, H13Nf13S
As, calculated value: C, 59, 65; H, 6,
87; N, 12.89° Actual value: C, 59,
74; H, 6,77; N, 12.82° Example 15 Using the method of Example 14, 3-((2-(3-indolyl)-1,1-dimethylethylcoamino)-1, 2
-Propanediol (1α4f, 0.04 mol), aqueous sodium (1,7f, α04 mol], 5oon) toluene, 4-chloro-3-cyanopyridine (,5,5?,
0.04 mol) (Wieland and Bien
er, Chem, Berichte,, 96.
268-274 (1963)], 18-Crown-
6-ether (0,11?) and anhydrous 2COs (
13,7f, 0.1 mol) to form a gummy substance (15f
) was obtained. This gum was chromatographed on a silica column and eluted with methylene chloride (90 parts), methanol (10 parts) and ammonium hydroxide (1 part) to give two fractions. 2nd distillation 6
．． It gave 8t of gum which was crystallized in ethyl acetate to give 5t of solid, melting point 124-126°C. This material was recrystallized from ethyl acetate to give a white solid.

Melting point 126-128°C.

Analysis: Calculated value as C21H24N4011: C
, 69, 21; H, 6, 64", N, 1a38.)
Actual value: C, 69,42; H, 6,75; -N
, 15.65°NMR (DMSO-d6): 1.
00(6,s); 1.55(1,bl);2.75
(4, m); 590 (1, m); 4.27' (
2, m); 5.10 (1, bs): 7.25 (6,
m); 8.64 (1, d[:6.0Hz':l);
a78 (1, s): 10.82 (1, bs).

IR (KBr) Near 45. 1010. 1190.
1290°1315, 1455. 1495.
1520. 1590°2225, 2970
．． and 34000n, l example
16 Using a method similar to that described in Example 4, 3-((
2-(3-indolyl)-1,1-dimethylethylcoamino]-1,2-propanediol (1α52.0.
04 mol), sodium hydride (1,7f, α04 mol), 400-toluene, 2-chloronicotinamide (
5,6f, 0.04 mol), 18-crown-6-ether (α11t) and 2COs (11
89,0,16-vol) was reacted to give 17 residual gums. The kernel gum was chromatographed on a silica column, methylene chloride (90 parts), methanol (
10 parts) and ammonium hydroxide (1 part). Product-containing fractions were collected and concentrated to yield a residue. The residue was crystallized in ethyl acetate to yield 5.2 g of material, mp 68-72°C. Recrystallization from ethyl acetate and drying in a vacuum oven gave 4t of a white solid. Melting point 1
31-163℃0 Analysis: Calculated as C21H211N403 (ffl:
c, 65.9s; m, 6.86; N,
14.650 Actual value: C, 65, 80; H,
6,85; N, 14.31°NMR (DMSO-
d6): 1.03 (6, s); Z77 (4, m
); A95 (1, m); 4.46 (2, m);
7.20 (6, m) near, 81 (2, bs); 1l
L30(2,d[6,1Hz]);10.85(1,'
b@).

IR (KBr): 740. 780. 1100
．． 1235°1450, 1460. 15B5
．． 1670. 2970°3330, an
d 3470 on □Example 17 Conversion of methoxy product to hydroxy product - General method □ The methoxy product is dissolved in methylene chloride and stirred under a nitrogen atmosphere while keeping it cooled in a water bath. Three equivalents of porontribromide are added dropwise. After the addition, remove the water bath and stir the reaction mixture at room temperature for 6-8 hours. The reaction mixture is again cooled in a water bath and excess H,O is added dropwise to destroy excess reagents and precipitate a gummy material. Decant the supernatant from the gum and wash the gum with two portions of water. The gum is dissolved in hot water, treated with activated carbon (Darco), filtered, and the P solution is cooled and made basic to about 8 H with ammonium hydroxide. The resulting precipitate was filtered, washed with water, dried and further purified by column chromatography on silica gel, CHCl
5 (90 parts)-methanol (10 parts)-NH40H (
1 part). The product-containing fraction is concentrated to give a residue, which is recrystallized from ethanol-water to yield the pure hydroxy product.

Starting with the appropriate pyridine and indolylalkylamine, additional examples of products of formula (1) can be synthesized using substantially the same methods as described above.

Some additional products of formula (I) that can be synthesized are shown in Table 2.

G in these formulas is a selected intermediate (■) [Example 1~
12 Table 2 LA;t,;f13 Table 2 (Continued) 0.

Table 2 (Continued) Biological Evaluation These biological tests demonstrate that a large number of formula
It was used to evaluate the cardiovascular profile of the metal.

Example 31 The efficacy of antihypertensive agents other than adrenergic-beta receptor blockers is commonly estimated in naturally hypertensive rats.

The blood pressure of the test animals was measured before and 24 hours after oral administration of 150q/Kg body weight of the test compound. Observed changes in heart rate were also recorded. 19-24 m
A blood pressure drop in the H9 range is considered "questionable."

"Active" and "Inactive" ratings are greater than this range and less than this range.

Example 52 A murine model of angiotensin-sparing ganglion blockade is used as a putative screening test for active vasodilator components. Changes in blood pressure are measured 30 minutes after intravenous administration to anesthetized rats. Intravenous administration: 3w1g/kg body weight
with the test compound. Borderline activity occurs 30 minutes after administration. The ratings for "Active" and "Inactive" are greater than this range and less than this range.

Example 33 Cardiac diastolic blood pressure and heart rate responses to fixed test doses of isoproterenol before and 15 minutes after administration of equidistant doses of the test compound intravenously over 3 minutes under anesthesia. Can be seen. A cannula is inserted into the branch of the femoral artery and vein to record blood pressure and administer drugs dissolved in salt water. The vagi is divided bilaterally into the mid-cervical region of the neck and the dog is mechanically ventilated with room air at a rate of 20/min and a stroke volume of 20 cumbres (Barbard respirator). Monitor the heartbeat using a cardiac tachometer, which is displayed by pressure pulses. All measurements are recorded on a Peckman R-612 recorder. The effect of the drug is on the isoproterenol response.
It is expressed in terms of cumulative doses 11) (micrograms/Kq) resulting in an 8% inhibition.

Abbreviations used in the specification have the following meanings. ph represents a phenyl group, Pr represents a propyl group, Me
represents a methyl group, and Et represents an ethyl group0
Also, transformations acceptable in modern organic chemistry have been used in the specification. Regarding the structure of alkyl, in a simplified form, a segment of the bonding line was used as a substitute for representing the groups C and 1. Therefore, for example, equation (1) can also be written as follows.

Continuation of page 1

Claims (1)

[Claims] 1. The following formula (1) (1) [In the above formula, X is -CH0l-CN, -CF,
, -CONR'Rb, ttaha-CO2R' (R11
> YohiRbId independently selected from hydrogen or Re,
Re is lower alkyl (Ct~C,), aryl,! i or aryl lower alkyl; Y represents the second substituent on the pyridine ring;
Halogen, lower (Ct~c4) alkoxy, aryl-
Lower alkoxy1. hydroxy, or 1-C-0-alkyl (wherein the alkyl is C1-C6 alkyl); Hydrogen or 1 -C-L (L is selected from Ct to CIG alkyl, phenyl, or phenalkyl); R1, Rz
, A and B are independently selected from hydrogen or lower alkyl; C represents a substituent in the benzo term of indole;
selected from hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy; and the indolyl group is attached through its 2- or 5-position] and acid addition salts thereof. 2. The compound according to claim 1, wherein the indolylalkylaminopropoxy side chain is bonded to the 2-position of pyridine.3. 2. A compound according to claim 1, wherein the indolyl ring is attached at its 3-position. 4, X is cyano or amide; Y is hydrogen; R is hydrogen; Hl and R are lower alkyl; A and B are hydrogen; C is halogen;
4. A compound according to claim 2 or 3 which is hydrogen, hydroxy, alkyl, or alkoxy. 5.2-[2-hydroxy-3-[(2-(IH-indol-3-yl)-1,1-dimethylethyl]amino]propoxy]-3-pyridine-carbonitrile or a pharmaceutically acceptable thereof The compound according to claim 1, which is an acid addition salt. 6. The chemical food according to claim 5, wherein the acid addition salt is a shiframic acid addition salt. 2. The acid addition salt is a hydrochloric acid addition salt. The compound according to claim 5. a 4-[2-hydroxy-5-[[:2-(1-
indol-5-yl)-1,1-dimethylethyl]
Compound-1 according to claim 1, which is amino]propoxy]-3-pyridinecarbonitrile or a pharmaceutically acceptable acid addition salt thereof 9,2-[2-hydroxy-3-((2-( IH-indol-3-yl)-1,1-dimethylethyl]amino]furopoxy]-3-pyridinecarboxypamide or a pharmaceutically acceptable acid addition salt of the compound according to claim 1 0 10 , administering a non-toxic and effective vasodilatory dosage of a compound according to claim 1 to a mammal suffering from a condition that would benefit from treatment by vasodilation. 11. A method for treating hypertension, which comprises administering a non-toxic and effective vasodilator dosage of the compound of claim 1 into a mammal having hypertensive symptoms. 12. Pharmaceutical carrier and mammal per 1 KIi body weight n, 1 m
cg~1o. (1) [In the above formula, X is -CHO, -CN, -CF3
, -CONR'Rb, 1 fcu -CO2Re (R' and Rbti are independently selected from hydrogen or Re, Re
is selected from the group consisting of lower alkyl (CI-C4), aryl, aryl, or aryl-lower alkyl; C4) Alkoxyaryryl is lower alkoxy, hydroxy, or -0-alkyl, where the alkyl is C1-C6 alkyl; the indolylalkylaminopropoxy side chain is
R is hydrogen or 10-L (L is c
t-C+o alkyl, phenyl, or phenalkyl carae);
are independently selected from hydrogen and lower alkyl; C represents a substituent in the benzo ring of indole, selected from hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy↓ and indolyl is the 2- or 3-
They are joined by the − position]. 13, the compound of formula (1,1 is 2-[2-hydroxy-3
-((2-(1H-indol-3-yl) -1,1
-dimethylethylcoaminopropoxy]-5-pyridinecarbonitrile or a pharmaceutically acceptable acid addition salt thereof; 2-hydroxy-3-
[(2-(IH-indol-3-yl) -1,1-
13. The compound according to claim 12, which is dimethylethyl]amino]propoxy]-3-pyridinecarbonitrile or a pharmaceutically acceptable acid addition salt thereof. 15, the compound of formula (1) is 2-[2-hydroxy-5-
((2-(1!!-indole-3-yl) -1,1
-dimethylethyl]amino]propoxy]-3-pyridinecarbonitrile or a pharmaceutically acceptable acid addition salt thereof. 16th formula (1,) (1) [In the above formula, X is -CH0l-CN, -CF,
, -CONR'Rb, t7'cbarC0zRc(R'
ojhi Rbti independently selected from hydrogen or ue,
Bi is selected from the group consisting of lower alkyl (Ct-C4), aryl, or aryl-lower alkyl; alkoxy, aryl-lower alkoxy, hydroxy, or -C-O-alkyl (
The alkyl is C1-C6 alkyl] and the indolylalkylaminopropoxy side chain is bonded to the 2-0 or 3-position of the pyridine ring; R is hydrogen or -C-L
(selected from LijCl-wC1g alkyl, phenyl, or phenalkyl);
A and R are independently selected from hydrogen or low alkyl; C is selected from hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy; Part 2
bonded through the - or 3-position] and its acid addition salts, the method comprises:
a) 2-substituted pyridine (fV) of the following formula (M) [in the formula, X and Y are as defined above: z is hydroxy or halogen] by the following formula...A, JIB,
and ■ W-substituted propatool or initial propatool intermediate (II, 1) selected from the group consisting of ", R"s A% B and C are as defined above); W is halogen, preferably chlorine when 2 is hydroxy, and hydroxy when 2 is halogen]. coupling; and (b) when reacting compound (IIA) with compound C), converting the product of (a) into the compound of formula (I) above by hydrolysis under acidic conditions; I
When reacting IC) with compound (IV, 13), an epoxy ether is produced, and the epoxy ether is further reacted neat or in the presence of an organic solvent inert to the reaction with 2H, NG (G is as defined above). A method for producing a compound of the above formula (1), comprising a step of heating with an amine of (17) and amine of (1) to produce a compound of the above formula (1). 17. Compound in which W is hydroxy and 2 is halogen (I
IB) and the coupling of step (a) combines compound (mV) with compound (UB) in the presence of a base,
17. A method as claimed in claim 16, comprising heating all in an inert organic solvent under mild conditions. 1a Use a soaking degree of Q, IN to 1N and a temperature in the range of about 20 to 100 °C for hydrolysis under acidic conditions, and (a) neutralize the Calo-water Wt-Wx compound and collect the precipitate. or (b) recovering the acid addition salt by evaporation of the hydrolysis mixture or by reaction of the free #, jU groups with the acid. The method according to scope item 16. 19 Y and/or C in the product of formula (1) is hydroxy, using compound (IIB): and cleavage of the corresponding methoxy precursor by the reaction shown by the following reaction formula (2) 17. The method of claim 16, further comprising: Reaction formula (2) 2(L-order formula [In the above formula, X is -CH0l-CN, -CF3
, -CONR'Rb,'ifc is -CO2Re(R'e
and R are independently selected from hydrogen or R, and me is selected from the group consisting of lower alkyl (Cs-C4), aryl, or aryl-lower alkyl;
Y represents the second alkyl group of the pyridine ring, and is hydrogen, halogen, lower (C, -C4) alkoxy, aryl-lower alkoxy, hydroxy, or -C-alkyl (the alkyl is C1-Cs alkyl). The indolylalkylaminopropoxy side chain is bonded to the 2- or 4-position of the pyridine ring] and acid addition salts thereof.21. , -CF3
, -CONR'Rb,'1fcti, -CO*Rc(R
'OjhiRbU independently selected from hydrogen or Re, R
e is selected from the group consisting of lower alkyl (Cx-Ca), aryl, or aryl-lower alkyl, which can be sb; Y represents the second substituent on the pyridine ring, and alkoxy, ary-lower alkoxy, hydroxy, or -C-alkyl, where the alkyl is a C1-C6 alkyl; the indolylalkylaminopropoxy side chain is
D is hydrogen or phenyl, preferably phenyl; G
is a group of the following formula (wherein R"% R", A and B are independently selected from hydrogen or lower alkyl);
represents a substituent in the benzo ring of indole and is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy; and the indolyl system is bonded through its 2- or 3-position] and its acid addition salt. 22, the following formula [in the above formula, X is -CH0, -CN, -CF,
, -CONR''Rb, or -co, Rt'<
R11 and nb are independently selected from hydrogen or Re, Rc is lower alkyl (Cm-C4), aryl, tf
c can be aryl-lower alkyl; Y represents the second substituent on the pyridine ring, hydrogen, halogen, low M (Cl-C4) alkoxy, aryl-lower alkoxy, hydroxy; -C-alkyl (the alkyl is 01-c6 alkyl); the indolylalkylaminopropoxy side chain is the 2-
or bonded to the 4-position] A method for producing a compound having z-lig-pyridine (Vl) having the following formula (IV) [wherein X and Y are as defined above] 2 is hydroxy or halogen] of the following formula (IIA)
- Substituted propanol or initial propatool intermediate [wherein D is aqueous or phenyl, preferably phenyl; G is a group of the following formula (R', R2, A:I-; - and B are independently hydrogen or lower alkyl; C represents a substituent in the benzo ring of indole, selected from hydrogen, halogen, lower V>alkyl, lower alkoxy, or hydroxy]
and W is halogen-loving chlorine when 2 is hydroxy; and hydroxy when 2 is halogen. 23, the following formula [2 in the above formula, X is -CH0l-CN, -CF3
, - CONR'Rb, ttalfi -C02R
e(R'OyohiRbl1'1.Independent dihydrogen or lbit, selected, lte is lower alkyl (Ct~C4)
, aryl, or aryl-lower alkyl)
selected from the group consisting of is C1-C6 alkyl); the indolylalkylaminopropoxy side chain is attached to the 2- or 4-position of the pyridine ring; D is hydrogen or phenyl, preferably phenyl;
is a group of the following formula (R', R2, A and B in the formula are independently selected from hydrogen or lower alkyl); C represents a cylinder or substituent in the benzo term of indole, and hydrogen , halogen, lower alkyl, lower alkoxy, or hydroxy; and indolyl is the 2-i! or 3-
a Z-substituted pyridine having the following formula (IV), wherein X and Y are as defined above; 2 is hydroxy or halogen; ] in the following formula (lie)
-fU conversion property tool or initial property tool intermediate 1
\</([Ie) A method consisting of coupling with a halogen, preferably chlorine, when W#'iz in the formula is hydroxy, and hydroxy when 2 is a halogen. 24, the following formula (DB) OR (HB) [In the above formula, W is a halogen or hydroxy group; R is hydrogen or [-C-L:] (L is c
1~cIo alkyl, phenyl, 'bj4! X! phenyl or phenalkyl; represents hydrogen, halogen,
[lower alkyl, lower alkoxy, or hydroxy]]. 25th formula Cu1l) OR (IIB) [In the above formula, W is halogen or H hydroxy group, 9; R is water Lt:I (-C-L) (
Lt'lt Ct-Cto alkyl, phenyl, fl'
f-substituted phenyl, 1 straddle phenalkyl color gills)
and G is (wherein R', R'', A and B are independently selected from hydrogen or lower alkyl, and C represents the ht substituent in the benzo salt of indole, hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy)], the compound having the following formula (m) [in which A% B, R', R'', and 3-chloro-1,2-propanediol in refluxing alcohol and a base, preferably sodium carbonate.