AU609067B2

AU609067B2 - Compounds useful as intermediates for the production of substituted 1-pyridyloxy-3-indolyalkylamino-2- propanols

Info

Publication number: AU609067B2
Application number: AU80557/87A
Authority: AU
Inventors: William E. Kreighbaum
Original assignee: Bristol Myers Co
Current assignee: Bristol Myers Co
Priority date: 1982-09-03
Filing date: 1987-10-30
Publication date: 1991-04-26
Anticipated expiration: 2003-08-31
Also published as: NO833128L; AU8055787A; ES8604930A1; IL69618A0; GR79061B; GB2126230A; FI833102A0; FI79709B; LU84986A1; ES8507537A1; DE3331612A1; AU613589B2; YU44940B; SE8304751L; SE8802265L; GB8323641D0; ES525243A0; IE832063L; ZA836469B; GB2126230B

Description

PHILLIPS ORMONDE AND FITZPATRICK Patent and Trade Mark Attorneys 367 Co]llln Street Mebourne, Australia 80557/87

AUSTRALIA

Patents Act COMPLETE SPEgSIgQA

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: 'Published: S Priority Related Art: t1 1 Related Art: his documnt contains the amendments made under Se, ction 49 and is correct for Sprinting. t t Name(s) of Applicant(s): APPLICANT'S REF.: DIV. A OF 18952/83 BRISTOL-MYERS COMPANY 11 tt Address(es) of Applicant(s): Actual Inventor(s): Address for Service is: 345 Park Avenue, New York, New York 10054, United States of America William E. Kreighbaum PHILLIPS, ORMONDE AND FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne, Australia, 3000 Complete Specification for the invention entitled: COMPOUNDS USEFUL AS INTERMEDIATES FOR THE PRODUCTION OF SUBSTITUTED 1-PYRIDYLOXY-3-INDOLYALKYLAMINO-2-PROPANOLS The following statement is a full description of this invention, including the best method of performing it known to applicant(s): P19/3/84 m fi COMPOUNDS USEFUL AS INTERMEDIATES OR THE PRODUCTION OF SUBSTITUTED 1-PYRIDYLOXY-3-INDOLYLALKYLAMINO-2-PROPANOLS The present application is a divisional application from Australian patent application number 18592/83, the entire disclosure of which is incorporated herein by reference.

The present invention is concerned with compounds that may be used as intermediates during the process of producing heterocyclic carbon compounds of the indole series having an amino substituent, and 0 with drug bio-affecting and body-treating processes employing these o o a compounds.

r o 44,, A rather large body of prior art exists relating to compounds of 3-(aryloxy)-2-hydroxypropylamine series which have beta-adrenergic receptor blocking activity and/or vasodilating properties and are 15 useful in treatment of cardiovascular diseases. Much of this prior art concerns the beta-adrenergic blocking agent class of these series of compounds. The prototype for these structures is propranolol; S chemically, 1-(isopropylamino)-3-(l-naphthyloxy)-2-propanol.

Propranolol and some related naphthylc'xy propanolamines are the subject of U.S. Patent No. 3,337,628 issued August 22, 1967. Numerous 4 4 subsequent patents have been granted covering carbocyclic ethers in which other aromatic rings or heterocyclic systems replaced the naphthyloxy group of propranolol.

-la- A series of patents has been granted to J. J. Baldwin disclosing the employment of the pyridinyloxy group in this fashion.

These compounds and their salts-are disclosed and claimed as useful antihypertensive agents. These patents, which are listed below, generally disclose the following generic structure (1)

R

2 0Qo-y HR

OR

1 QO. 00 06 (1) 0 0 O0/9 0 0 00 1 o wherein R is alkyl, phenalkyl, phenoxyalkyl; Ris H, C-L, with L 0 bon* 2 It 0000 0 0 being alkyl or aryl; R is H, CN, CF 3 OH, C-L, Cl, NO 2 F, pyrrolyl, oxadiazolyl.

The series of Baldwin patents, assigned to Merck Co., Inc., comprise the following: 4,000,282, December 28, 1976; 4,060,601, November 29, 1977; 4,091,104, May 23, 1978; 4,092,419, May 30, 1978; 0 4,144,343, March 13, 1979; 4,145,425, March 20, 1979; 4,151,284, a 600006 April 24, 1979; 4,210,653, July 1, 1980; 4,259,327, March 31, 1981; 0000 ooo 4,263,307, April 21, 1981; 4,279,913, July 21, 1981; and 4,329,351, @0 15 May 11, 1982.

A preferred compound of this series, 2-[3-(tert.-butylamino)- A 2-hydroxypropoxy]-3-cyanopyridine, also known as MK-761, has undergone considerable further study as described in: Sweet, et al., The Journal of Pharmacology and Experimental Therapeutics, 211/1, 195-296 (1979); Sweet, et al., Clinical and Experimental Hypertension, 1(4), 449-471 (1979); and Vickers, et al., Drug Metabolism and Disposition, 8/3, 163-167 (1980). Acute studies in man were terminated, however, when MK-761 was found to be teratogenic in rabbits after chronic -2- -4 B. Compounds of Formula II EXAMPLE 13 administration at high doses (cf: Journal of Medicinal Chemistry, 22/11, 1284-1290 (1979)).

CN

Q MX-761 SO'Y NC(CH 3 HC1

OH

A series of indol-3-yl-tert.butylaminopropanols with antihypertensive properties was described in: Kreighbaum, et al., U.S. Patent No. 4,234,595 patented November 18, 1980; U.S. Patent No.

S' 4,314,943 patented February 9, 1982; and Journal of Medicinal Chemistry, 23:3, 285-289 (1980).

I trt t 11 W t 3- O-Ar-Xn ml '1

R

(2) BR3 N/ 0-Ar-Het SN R OH '1

*R

o(3) A preferr,: compound of the series represented by structure is designated MJ 13105, also known as bucindolol, and is currently undergoing evaluation clinically as an antihypertensive agent.

CN

N0 N HcOH

H

MJ 13105 -3- -'4 4 4 4* a4 4 4 4 0t

SI.

0 I to t a 0 8 48 4 The present invention resides in a compound having the formula: and the acid addition salts thereof, wherein X is selected from the group consisting of -CHO, -CN, -CF 3 -CONR R or -CO2R with R and R being independently c c chosen from hydrogen or R and wherein R can be lower alkyl

(C

1 to C 4 aryl, or aryl-lower alkyl; Y represents a second substituent on the pyridine ring and is hydrogen, halogen, lower (C 1 to C 4 alkoxy, aryl-lower alkoxy, hydroxy, or -C-O-alkyl wherein alkyl is C -C 6 alkyl; efoWYK1eAOy and the indolylalkylamincprpoeiy side chain is coupled at the pyridine 2- or 4- position.

Further, the present invention also resides in a process for preparing the compound of claim 1, said process comprising: coupling a S-substituted pyridine of formula IV

(IV)

wherein X and Y are as defined in claim 1 and wherein B is hydroxyl or halogen, with a W-substituted propanol or incipient propanol intermediate of formula IIC W0 4 THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:- 1. A compound having the formula: wherein W is halogen and preferably chloride when B is hydroxyl and wherein W is hydroxyl when 8 is halogen.

The compounds of the present invention are useful as intermediates for producing compounds, as described in parent application 18592/83, concerning a series of vasodilating agents having a range of betaadrenergic blocking potency and possessing the general formula I and the pharmaceutically acceptable acid addition salts thereof.

x

R

2 A Y R R C OR NO

~B

In the foregoing structural formula, X is CHO, CN, CF 3 CONR b or RC wtRa an Rb 'CO R with R and R being independently chosen from hydrogen or R and R being lower alkyl, aryl, or arylalkyl; Y is hydrogen, halogen, r'i S. alkoxy, aralkyloxy, or hydroxyl; R is hydrogen of LC-LJ with L being selected from alkyl, aryl, substituted aryl, or arylalkyl; R

I

R A and B are independently selected from hydrogen or alkyl; and C can be halogen, hydrogen, hydroxy, alkyl or alkoxy. Compounds of the parent application 18592/83 have X in the 3-position of the pyridine ring and the indolylalkylaminopropoxy side chain is attached to the 2-position of the pyridine nucleus.

The compounds of the parent application 18592/83 can be prepared by a convenient general process. This process involves the coupling of a Z-substituted pyridine (IV) with a suitable W-substituted propanol or incipient propanol intermediate (II).

J

General Process 0 N-G

(IIA)

H

W N-G

(IV)

Hydolysis a 00 0 6 4 0 PP o..

o 0

OR

(IIB)

2 NG w0

(TIC)

U

1L~ In the foregoing general process, D is hydrogen, or preferably, phenyl; G is the radical Z is hydroxyl or halogen, preferably

B

chloride; Wis halogen, preferably chloride, when Z is hydroxyl and is hydroxyl when Z is halogen. Generally, the hydroxyl-bearing reactant is initially converted to the oxide anion with a strong base prior to reaction with the halogen-bearing intermediate.

This process employs methods known in the prior art for the 0 0 S preparation of l-(substituted amino)-3-(hetaryloxy)-2-propanols as a.

0o" represented by the patents and publications cited in "Background of the Invention". The process involves reaction of the appropriately A o substituted pyridine with either 1) a yl]methanol (or methyl halide) of Formula IIA, or 2) an indolylalkylaminopropanediol (or halopropanol) of Formula IIB, or 3) glycidol of Formula IIC.

*5 The intermediate from reaction of IV and IIa is converted to the product I by hydrolysis under acidic conditions. This hydrolysis is accomplished with dilute mineral acid of from 0.1N to IN concen- *o tration at temperatures of from about 20-100 C. The product of p Formula I can be recovered as the free base by neutralization of the hydrolysis mixture and collecting the precipitate. Acid addition salts may be obtained by evaporating the hydrolysis mixture or by reaction of the free base with acid. Purification is accomplished by conventional means such as recrystallization.

The conversion of the epoxide intermediate resulting from the reaction of IV with IIC into the product of Formula I is carried out simply by heating the epoxy ether either neat or in the presence of a reaction inert organic solvent with an amine of the formula H2NG as shown. No catalyst or condensation agent is required. Suitable solvents include 95% ethanol but other reaction-inert organic liquids in which the reactants are soluble may be employed. These include but are not limited to benzene, tetrahydrofuran, dibutylether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, etc.

Suitable reaction temperatures are from about 60-200 0

C.

The single step process pathway involves the reaction of IV with IIB and this is the preferred pathway for synthesis of the .10 products of parent application 18592/83.

This process is illustrated by the following specific tr reaction equation which shows the preferred synthetic method of the above as Reaction 1.

Reaction 1 1 2 C Y halo HON b

Y

as

A

N

B

OR

B

(IV) (IIB)

(I)

1 2 In the foregoing scheme, R, R, R, A, B, and C are as defined in Formula I. Essentially this process involves heating the selected substituted halopyridine with the appropriate indolylalkylaminopropanol intermediate (IIB) in the presence of a base, all in an inert organic liquid under mild conditions. Standard strong bases such as potassium t-butoxide, potassium hydroxide, or sodium hydride may be employed but the sodium hydride is preferred. Similarly, any of a number of inert organic liquids may be chosen as the reaction

I

medium or the cyanopyridine and indolylalkylaminopropanol may be reacted neat in the presence of the base. Suitable solvents include but are not limited to benzene, "toluene, tetrahydrofuran, dibutylether, dimethoxyethane, etc. Suitable reaction temperatures are from about 20-80 C. Addition of a suitable crown ether, such as 18-crown-6 ether, aids the reaction process.

Formula I products in which Y and/or C are hydroxy, are prepared by cleavage of the corresponding methoxy precursor as shown in Reaction 2: Reaction 2 M ee R OA OR

B

Other synthetic methods resulting in conversion to hydroxylated products, e.g. such as hydrogenolysis of benzyloxy precursors, are well known to the chemical practitioner and may also be applied in these cases.

Requisite halopyridines are available commercially or may be prepared using standard methods for their preparation reported in the literature. Preparation of related trisubstituted pyridines is disclosed in U.S. 4,329,351, issued May 11, 1982 to Baldwin, et al..

and which is hereby incorporated by reference in its entirety.

The intermediate indolylalkylaminopropanols (IIB; R H), preferred synthetic intermediates, are conveniently prepared by reacting an appropriately substituted indolylalkylamine (III) with S-9- 3-chloro-l,2-propanediol in refluxing alcohol containing sodium carbonate. This process is illustrated by reaction equation 3.

Reaction 3

R

1 R 2 HO '"C1 H 2

Q

OH

1 R 2 RA C Base V

OH

(III)

(IIB)

4f a .44 4 j4 44 4 *4

I*

41 4 S S S- t I I' 1 2 In reaction scheme 3, R R A, B, and C are as defined in Formula I.

Formula I products of the present invention wherein R is other than hydrogen are conveniently prepared by treating the corresponding Formula I product wherein R is hydrogen with an appropriate acylating agent such as an acyl halide, e.g. undecanoyl chloride, pivaloyl chloride, benzoyl chloride, para-methoxybenzoyl chloride, or anhydride, e.g. acetic anhydride, and the like. The reaction is illustrated by the following equation shown below as Reaction 4: Reaction 4 e f. X 1 2 R R 0 R-C-C1 or (R-C O-0 2 0 X R 1 R2

OR

B

The indolylalkylamines (III) are described in the aforementioned Kreighbaum, et al. patents and Journal of Medicinal Chemistry article, which are hereby incorporated by reference, as well as certain references cited therein. Although these referenced procedures are applicable to the preparation of other indolylalkylamine intermediates not specifically disclosed therein but which are required as intermediates for the present invention, representative syntheses of Formula III compounds are given hereinbelow for further exemplification.

Compounds useful as intermediates for compounds as described in parent application 18592/83, including compounds of the present 10 application, and their methods of preparation will appear more fully from a consideration of the following examples and appended claims which uare given for the purpose of illustration only and are not to be construed as limiting the invention in sphere or scope. In the following examples and appended claims which are given for the purpose of illustration only and are not to be construed as limiting the invention in sphere or scope. In the following examples, used to illustrate the foregoing synthetic processes, temperatures are expressed in degrees 'It Celsius and melting points are uncorrected. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts 0 (6 expressed as parts per million (ppm) versus tetramethylsilane (TMS) S, as reference standard. The relative area reported for the various shifts in the H NMR spectral data corresponds to the number of hydrogen Satoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad ianglet (bs), singlet multiplet(m), or doublet -11- K Abbreviations employed are DMSO-d 6 (deuterodimethylsulfoxide), CDC 3 (deuterochloroform) and are otherwise conventional. The infrared (IR) spectral descriptions include only absorption wave numbers (cm having functional group identification value. The IR determinations were employed using potassium bromide (KBr) as diluent.

The elemental analyses are reported as percent by weight.

A. Compounds of Formula III EXAIPLE 1 3-(2 1 AminQ-2-methylpropyl)-6-methoxyindole S(R R Me, A and B H, C 6-MeO) To 15.2 mL of a chilled 25% aqueous solution of dimethylamine the following were added sequentially with stirring and continued cooling: 16.9 mL of acetic acid, 7.2 mL of 37% formaldehyde, 27 mL of 95% ethanol. The resulting stirred solution was kept at 00 with a cooling bath while 6-methoxyindole (10.0 g, 0.07 mole) was added in portions. This mixture was stirred and gradually warmed to 30° over a period of one-half hour and then held at 300 with stirring for 3 hrs. The reaction mixture was then chilled to 10-15 and acidified with 170 mL of 2N HC1. This acidic mixture was decolorized (Darco G-60), filtered and the filtrate made basic using 245 mL of NaOH while being cooled and stirred. A resulting brown oily precipitate was ether extracted, and the extracts were water-washed, dried (MgSO 4 and concentrated to a brown oily residue (14 The residue was recrystallized from isopropylether and hexane to yield 9 g of 6-methoxygramine as a tan solid, m.p. 88-90°.

-12i A mixture comprised of the 6-methoxygramine (7.7 g, 0.04 mole), 2-nitropropane (26.5 g, 0.3 mole), and NaOH (1.7 g pellets, 0.04 mole) was refluxed under a nitrogen atmosphere for 3-5 hrs. The reaction mixture was cooled to room temperature, acidified with acetic acid and extracted with ether. The ether extracts were water-washed, dried (MgS4), and concentrated in vacuo to a residue.

Recrystallization of the residue from isopropyl alcohol-water gave 7.6 g of 3-(2-methyl-2-nitropropyl)-6-methoxyindole as a tan solid, m.p. 98-100°.

The nitropropylindole compound and activated Raney nickel c (4.2 g) were combined in 80 mL 95% ethanol and heated to reflux.

Heating was halted as a solution comprised of 85% hydrazine hydrate (7.8 g) in 8 mL 95% ethanol was added dropwise. The reaction mixture was then heated at reflux for 2 hrs, cooled to room temperature and filtered. The filtrate was concentrated to a residual oil which S slowly solidified and was recrystallized from ethyl acetate-isopropyl ether to give 4.2 g of product, m.p. 125-128 Cr t EXAMPLE 2 r -Amio-2-methylpropyl)indole (R R Me, A, B, and C H) A solution comprising indole-2-carboxylic acid (10.0 g, 0.06 mole) and thionyl chloride (20.0 g, 0.17 mole) in 130 mL of dry Et 2 0 was stirred for 12-18 hrs at room temperature under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated to an oily residue which was taken up in 150 mL of dry Et 2 0. This ether solution was treated with 80 mL of dimethylamine in mL of Et20. The ethereal reaction mixture was concentrated to dryness and the residue crystallized in isopropyl alcohol. The solid -13was isolated by filtration to give 4.0 g of the 2-indolylamide product, m.p. 181-183°.

The amide was dissolved in 100 mL THF and this solution was added dropwise to a stirred suspension comprised of 3 g lithium aluminum hydride in 50 mL of THF under a nitrogen atmosphere. After heat at reflux for 2 hr, the reaction mixture was cooled and decomposed with a small amount of water and dilute NaOH solution. This mixture was filtered and the filtrate concentrated to a residual oil which was taken up in absolute ethanol and treated with a slight excess of 9 SO0 dimethyl sulfate. The resulting alcoholic solution was stirred at 0 0 room temperature for 4 hrs and then concentrated in vacuo to dryness moo. 0 giving as residue the trimethylamine quaternary salt.

6 ft *O'Q0 0 0 The crude quaternary salt product (3.0 g, 0.01 mole) was So 6* combined with NaOH (2.0 g pellets, 0.05 mole) and 2-nitropropane (15 mL) and the mixture was heated at reflux under a nitrogen atmosphere 0 0* for 1 hr. The resultant dark thick mixture was cooled, diluted with water, acidified with acetic acid to a pH of approximately 6 and then *09 extracted with Et 2 0. These Et 2 0 extracts were combined, washed with 0,0> «4 0 4 water, dried (MgSO 4 and concentrated to a dark residue which was chromatographed on a silica column and diluted with methylene chloride.

S° Removal of the methylene chloride and recrystallization of the crude material from isopropyl alcohol-water gave 0.4 g of 2-(2-methyl-2nitropropyl)indole as a cream colored solid, m.p. 102-103 Reduction of this nitro product with Raney nickel and hydrazine according to the procedure used in Example 1 above yields the desired indolalkylamine as a white solid, m.p. 130-133 Additional examples of indolealkylamines are displayed in Table 1.

-14- Table 1.

Indolealkylamines

B

(III)

t ce rt.C V, t f C! C

C

c C VOC C Example 3 4 5 6 7 8 9 10 11 12 Me Me Me Me He

H

Me Me Me

H

Me Me Me Me Me Me Me

H

A

3-H 2-Me 2-H 2-H 2-H 2-Me 3-Me 2-H 2-Et 2-H

B_

Me

H

Me Me

H

C

H

6-OWe 4-Cl 7-OMe n -i B. Compounds of Formula II EXAMPLE 13 3-[[2-(3-Indolyl)-1,l-dimethylethyl] amino]-1,2-propanediol Hydrate (IIB) A mixture of a,a-dimethyl-8-(3-indolyl)ethanamine (10.0 g, 0.05 mole), Na 2

CO

3 (11:3 g, 0:11 mole), 3-chloro-l,2-propanediol (7.0 g, 0.06 mole) and EtOH (250 mL) was stirred overnight at reflux. After cooling, the mixture was filtered and concentrated in vacuo. The residue was dissolved in EtOAc, decolorized (Darco G-60), and evaporated to a volume of 100 mL. The solution deposited a white solid which was recrystallized from EtOAc to give g m.p. 112-114 C.

The material crystallized with one-fifth mole of water.

Using other intermediates of Formula III in this or a similar procedure readily gives a variety of Formula IIB intermediates.

C

C C r C 4

CCT

C'

C ec '7 CC iiC

C.

C

'7~i '74 -16- I A

Claims

1. A compound having the formula: O 1110 r C t; 0 I t t C C I; ajL and the acid addition salts thereof, wherein X is selected from the group consisting of -CHO, -CN, aCONRab c a b -CF 3 -CONRaR b or -CO 2 R with R and R being independently chosen from hydrogen or Rc and wherein Rc can be lower alkyl (C 1 to C 4 aryl, or aryl-lower alkyl; Y represents a second substituent on the pyridine ring and is hydrogen, halogen, lower (C 1 to C 4 alkoxy, aryl-lower alkoxy, hydroxy, or -0-alkyl wherein alkyl is C-C6 alkyl; and the indly llk lminpre y- side chain is coupled at the pyridine 2- or 4- position.

2. A process for preparing the compound of claim 1, said process comprising: coupling a a-substituted pyridine of formula IV (IV) -17- -18- wherein X and Y are as defined in claim 1 and wherein E is hydroxyl or halogen, with a W-substituted propanol or incipient propanol intermediate of formula IIC 0O IIC wherein W is halogen when e is hydroxyl and wherein W is hydroxyl when is halogen.

3. A process according to claim 2, wherein the halogen is chloride. DATED: 17 August, 1990 PHILLIPS ORMONDE FITZPATRICK Attorneys for: BRISTOL-MYERS COMPANY ,r 0." oa WDP 4961N