AU609068B2 - Compounds useful as intermediates for the production of substituted 1-pyridlyoxy-3-indolyalkylamino-2-propanols - Google Patents

Description

or oilier witness required 6' a PHILLIPS ORMONDE AND FITZPATRICK 80 558/87 Patent and Trade Mark Attorneys 357 Collins Street NXtf.-brurae. Aiistralia r

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AUSTRALIA

Patents Act COMPLETE SPECIFICAT IION

(ORIGINAL)

Class Int. Class Application Number: Lodged: 8

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9 *9 p 8* 8 9 84 4' 99

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I, Ii 609068 Complete Specification Lodged: Accepted: Published: Priority oo I Related Art: APPLICANT'S REF.: DIV. B OF 18952/83 Name(s) of Applicant(s): BRISTOL-MYERS COMPANY Address(es) of Applicant(s): Actual Inventor(s): 345 Park Avenue, New York, New York 10054, United States of Amnerica William E. Kreighbaum.

Address for Service is: PHILLIPS, ORMONDE AND FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne, Australia, 3000 Complete Specification for the invention entitled: COMPOUNDS USEFUL AS INTERM4EDIATES FOR THE PRODUCTION OF SUBSTITUTED 1-PYRIDYLOXY- 3-INDOLYLALKYLAMINO- 2-PROPANOLS The following statement is a full description of this invention, including the best method of performing it known to applicant(s):I P19/3/4 I I i COMPOUNDS USEFUL AS INTERMEDIATES rO:. THE PRODUCTION OF SUBSTITUTED 1-PYRIDYLOXY-3-INDOLYLALKYLAMINO-2-PROPANOLS *o B O 00 o s o~ a* o q O D 0q* O00 0 0* o go 0 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 with drug bio-affecting and body-treating processes employing these compounds.

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 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; chemically, 1-(isopropylamino)-3-(l-naphthyloxy)-2-propanol.

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

-lai ~i 1 i IICU~I- IUi-~~-ll 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) 0 as o o 0 4 0 03 00B0 o 0 e o o 0s 0) o0 o oo 0 oooo00 S0 9 9 Ba O 000o 0 09 0 8 C 6 49 wherein R is alkyl, phenalkyl, phenoxyalkyl; R is H, C-L, with L 0 being alkyl or aryl; R 2 is H, CN, CF 3 OH, C-L, C1, NO F, pyrrolyl, oxadiazolyl.

The series of Baldwin patents, assigned to Merck Co., Inc., 10 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; 4,144,343, March 13, 1979; 4,145,425, March 20, 1979; 4,151,284, April 24, 1979; 4,210,653, July 1, 1980; 4,259,327, March 31, 1981; 4,263,307, April 21, 1981; 4,279,913, July 21, 1981; and 4,329,351, May 11, 1982.

A preferred compound of this series, 2-[3-(tert.-butylamino)- 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

I

c i r.

F

i -2administration at high doses (cf: Journal of Medicinal. Chemistry, 22/11, 1284-1290 (1979)).

CN

Q MK-761 N \C(CH 3) 3 H C1

OH

A series of indol- 3-yl- ter t. butylaminopropanols with antihypertensive properties was described in: Kreighbaum, et al., S. 5 U.S. Patent No. 4,234,595 patented November 18, 1980; U.S. Patent No.

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

0 0 0 3 0-Ar-Xn N J-"R~

R

0 0 (2) 0 N 0-Ar-Het M N R 2

OH

(3) A preferred comprtnd if the series represented by structure is designated MJ 13105, also known as bucindolol, and is currently undergoing evaluation clinically as an antihypertensive agent.

CN

H

N 0- N OH

H

MJ 13105 The present invention resides in a compound having the formula: x

Y

0 S-G

D

o0 and the acid addition salts thereof, wherein 0 *0 X is selected from the group consisting of -CHO, -CN, -CF -CONR R b or -CO R c with Ra and R b 3 o a2 )0«0 being independently chosen from hydrogen or Rc and wherein R can be lower alkyl (C 1 to C aryl, or aryl-lower alkyl; SY represents a second substituent on the pyridine ring and is hydrogen, halogen, lower (C 1 to C 4 0. alkoxy, aryl-lower alkoxy, hydroxy, or -O-alkyl wherein alkyl is C -C 6 alkyl; r A0co\ c 0 xc(16vo4zoc no're^Koy the iAndolyalkylaminprey side chain is coupled at the pyridine 2- or 4- position; D is hydrogen or phenyl and preferably is phenyl; G is the radical '1 2 C A4

B

wherein R 1

R

2 A and B are independently chosen from hydrogen or lower alkyl; -4- -4- C represents a substituent in the benzo ring of indole and is selected from hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy; and the indolyl system is attached by its 2- or 3- position.

Further, the present invention also resides in a process for preparing the compound of claim 1, said process comprising: coupling a 9-substituted pyridine of formula IV 0 10 0

N

00 a 0 (IV) wherein X and Y are as defined in claim 1 and wherein 9 is 00 hydroxyl or halogen, with a W-substituted propanol or incipient propanol intermediate of formula IIA a w 0 N-G IIA

D

wherein D is hydrogen or phenyl and preferably phenyl; wherein G is the radical 1 2 A C

RI

B

JC -4a- 1 2 wherein R R A and B are independently chosen from hydrogen or lower alkyl; C represents a substituent in the benzo ring of indole and is selected from hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy; and wherein W is halogen and preferably chloride when 9 is hydroxyl and wherein W is hydroxyl when B is halogen.

The compounds of the present invention are useful as intermediates for producing compounds, as described in parent application 18592/83, 0 09I concerning a series of vasodilating agents having a range of beta- 000 adrenergic blocking potency and possessing the general formula I and the pharmaceutically acceptable acid addition salts thereof.

a* 00 0o x 2A y Rl R2 Ac 0'.

I H oq

OR

B

o4* 0 4(I) 6 In the foregoing structural formula, X is CHO, CN, CI 3 CONR R or t t 20 CO 2 Rc with Ra and R being independently chosen from hydrogen or R i 2

S

l and RC being lower alkyl, aryl, or arylalkyl; Y is hydrogen, halogen, alkoxy, aralkyloxy, or hydroxyl; R is hydrogen of with L Sbeing selected from alkyl, aryl, substituted a:ryl, or arylalkyl; R 2 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).

General Process b D4 bog* 4Hydrolysis (IV) OR (II) 4

H

2

NG

(IIC)

1 *0 99 o *o 0 9, 990 9 9i 01 0 0 f0 9a 9 91 0 In the foregoing general process, D is hydrogen, or preferably, phenylj

I

1

R

G is the radical Z is hydroxyl or halogen, preferably chloride; W is 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 9 preparation of l-(substituted amino)-3-(hetaryloxy)-2-propanols as represented by the patents and publications cited in "Background of the Invention". The process involves reaction of the appropriately substituted pyridine with either 1) a yljmethanol (or methyl halide) of Formula IIA, or 2) an indolylalkyl- 4 aminopropanediol (or halcpropanol) of Formula IIB, or 3) glycidol of Formula IIC.

15 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 concentration at temperatures of from about 20-100 C. The product of 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 11 of a reaction inert organic solvent with an amine of the formula H 2

NG

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 .0 products of parent application 18592/83.

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

0 00 oo 00 O @0 0Q 0 00 00l *o e *i 00 Reaction 1 S X N Y halo HO/

OR

base

(IV)

(IIB)

1 2 In the foregoing scheme, Y, R, R

I

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 -8- 0 9* o 09 00 4 990 9 0 09 9 000 9 9009 0 9 0009 0 le 0 0 9 0 9~ Of 0 0 9 000 &0 49 4 0 10 I000 9 9 091 09 .9 1 0# 0-9

I

I 0 0 0 90 0 0 1 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: 0L Reaction 2 R A x BJ R 2 tOMe M R A OOR NyR B

I

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 -9- 3-chloro-1,2-propanediol in refluxing alcohol containing sodium carbonate. This process is illustrated by reaction equation 3.

Reaction 3

R

1

R

2

A

R H0 _'Cl H2NC

OH

R 2 RA C Base

C

Alcohoi

HO"(

(Ill)

(IIB)

6 0 0 00 0 3 0 O 0D 0 0 .ooo 5 o a0 0 o o eg 0 0 0 10

T

1 2 In reaction scheme 3, R R 2 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 chluride, benzoyl chloride, para-methoxybenzoyl cloride, or anhydride, e.g. acetic anhydride, and the like. The reaction is illustrated by the following equation shown below as Reaction 4: Reaction 4 X 1 2 R R 0 R-C-C1 or

-O

t" 2 0 1 X R 1 2

OR

B

The indolylalkylamines (III) are described in the aforementioned Kreighbaum, et al. patents and Journal of Medicinal Chemistry i 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 l,4B application, and their methods of preparation will appear more fully Sr from a consideration of the following examples and appended claims which are given for the purpose of illustration only and are not to be .9.9 construed as limiting the invention in sphere or scope. In the following 4 .9 examples and appended claims which are given for the purpose of illustration only and are not to be construed as limiting the invention i 9 in sphere or scope. In the following examples, used to illustrate the foregoing synthetic processes, temperatures are expressed in degrees Celsius and melting points are uncorrected. The nuclear magnetic shifts in the H NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature (of Sfatoms of a particular functional type in the molecule. The nature of the shifts as to mpltiplicity is reported as broad singlet (bs), singlet multiplet(m), or doublet -11- II I i I Abbreviations employed are DMSO-d 6 (deuterodimethylsulfoxide), CDC1 3 (deuterochloroform) and are otherwise conventional. The infrared (IR) spectral descriptions include only absorption wave numbers -1 (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 EXAMPLE 1 6 4 6 D 3-(21Amin-2-methylpropyl)-6-methoxyindole (R R Me, Aand B H, C 6-MeO) *o0 To 15.2 mL of a chilled 25% aqueous solution of dimethyl- Samine the following were added sequentially with stirring and continued cooling: 16.9 mL of acetic acid, 7.2 mL of 37% formaldehyde, 27 mL 15 of 95% ethanol. The resulting stirred solution was kept at 0 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 300 over a period of one-half hour and then held at 300 with stirring for 3 hrs. The reaction mixture was then chilled to 10-150 614 20 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 -12- The following statement is a full description of this invention, including the best method of performing it known to applicant(s): P19/3/84 1 1 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 (MgSO4), 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.

a Ci 10 The nitropropylindole compound and activated Raney nickel h 0 (4.2 g) were combined in 80 mL 95% ethanol and heated to reflux.

a 9" Heating was halted as a solution comprised of 85% hydrazine hydrate 4 (7.8 g) in 8 mL 95% ethanol was added dropwise. The reaction mixture 4, was then heated at reflux for 2 hrs, cooled to room temperature and filtered. The filtrate was concentrated to a residual oil which r t slowly solidified and was recrystallized from ethyl acetate-isopropyl tt, ether to give 4.2 g of product, m.p. 125-128.

EXAMPLE 2 2- (-Amio-2-methylpropyl)indole ?O (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 This ether solution was treated with 80 mL of dimethylamine in mL of Et20. The ethereal reaction mixture was concentrated to dryness and the tesidue crystallized in isopropyl alcohol. The solid -13- 1 1 1 r l product, m.p. 181-183o 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 0 00 was taken up in absolute ethanol and treated with a slight excess of 0 o dimethyl sulfate. The resulting alcoholic solution was stirred at room temperature for 4 hrs and then concentrated in vacuo to dryness giving as residue the trimethylamine quaternary salt.

o 00 The crude quaternary salt product (3.0 g, 0.01 mole) was combined with NaOH (2.0 g pellets, 0.05 mole) and 2-nitropropane S. 15 (15 mL) and the mixture was heated at reflux under a nitrogen atmosphere for 1 hr. The resultant dark thick mixture was cooled, diluted with 0000 0000 water, acidified with acetic acid to a pH of approximately 6 and then extracted with Et20. These Et20 extracts were combined, washed with water, dried (MgSO4) and concentrated to a dark residue which was 00000 20 chromatographed on a silica column and diluted with methylene chloride.

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. 102-103o 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. 130-133o Additional examples of indolealkylamines are displayed in Table 1.

-14- «1 1 an theL mitr a etda elx ne irgnamshr Table 1 Indolealkylamines

R

1 H 2

N

B

09000 2 Example RR A B- C 0OI 0 0*05 4 Me Me 2-Me H

H

00 9 069,: 5 Me Me 2-H H 6 Me Me 2-H H O 997 H Me 2-H H

H

@08 H Me 2-Me Me 99.10 9 H Me 3-Me Xe 9 10 Me Me 2-H H 6-OWe 11 Me H 2-Et H 4-Cl $see 12 Me H 2-H H B. Compounds of Formula II EXAMPLE 13 3-[[2-(3-Indolyl)-1,1-dimethylethyl] amino]-l,2-propanediol Hydrate (IIB) A mixture of a,a-dimethyl-8-(3-indolyl)ethanamine (10.0 g, 0.05 mole), Na 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 a oo" evaporated to a volume of 100 mL. The solution deposited a white solid 0 ff0 o a which was recrystallized from EtOAc to give 7.7 g m.p. 112-114 C.

0 Bo oo. The material crystallized with one-fifth mole of water.

o0° Using other intermediates of Formula III in this or a similar procedure readily gives a variety of Formula IIB intermediates.

-16a 0 ooo 0 o 0 0 16o -16-

Claims (3)

1. A compound having the formula: 0 -G and the acid addition salts thereof, wherein 0X is selected from the group consisting of -CHO, -CN, -CF 3 -CONR aR b, or CO Rc ,with R a and R b 0010 being independently chosen from hydrogen or RC and wherein Rc can be lower alkyl (C 1 to C 4 0 44 aryl# or aryl-lower alkyl; Y represents a second substituent on the pyridine 0400ring and is hydrogen, halogen, lower (C 1 to C 4 alkoxy, aryl-lower alkoxy, hydroxy, or -0_-alkyl wherein alkyl is C 1 -C 6 alkyl; teindalv1a kvla7 cysd bi is coupled at the pyridine

2- or 4- position; D is hydrogen or phenyl ran preferabl1y is phany' G is the radical R 1>e2 A B wherein R 1 R 2 A and B are independently chosen from hydrogen or -~~lower alkyl; -17- i C represents a substituent in the benzo ring of indole and is selected from hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy; and the indolyl system is attached by its 2- or 3- position. 2, A process for preparing the compound of Claim 1, said process comprising: 0 0 coupling a B-substituted pyridine of formula IV (Iv) wherein X and Y are as defined in claim 1 and wherein 9 is hydroxyl or halogen, with a W-substituted propanol or incipient propanol o a intermediate of formula IIA 6 1 0 N-G IIA D wherein D is hydrogen or phenyl &ndpr fer blypheyl. R R 2 A .18 N8 L 0 0 intermediate of formula iA -18- f -19- 1 2 wherein R R A and B are independently chosen from hydrogen or lower alkyl; c represents a substituent in the benzo ring of indole and is selected from hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy; and wherein W is halogen when is hydroxyl and wherein W is hydroxyl when is halogen.

3. A process as claimed in claim 2 wherein D is phenyl and W is chloride. DATED: 17 August, 1990 PHILLIPS ORMONDE FITZPATRICK t tg Attorneys for: BRISTOL-MYERS COMPANY it ttI I t i ttft t tt t t IS C I WDP 4956N