AU567112B2 - Substituted 1-pyridyloxy-3-indolylalkylamino-2-propanols - Google Patents

Description

appbicltionlin ser "~LLJV 4 "Convention"

0 0 AUSTRAI0 1859283 in M Patent wU

Delete one OR9~S NDARD/

Insert FULL I/We BRISTOL-MYERSCOPN0-s name(s) of applicant(s)

Insert FULL Of 345 Park Avenue, New York,~ w~~ address(es) of United States of America applicant(s)

Delete one 567112 hereby apply for the grant of a StandarMiet TWENTY DOLLA, Patent for an inver-tion entitled (f0 Insert TITLE of invention "SUBS TIT _KY le O2- PROPANOLS"

Insert "complete" which is described in the accompanying (g) complete specification. or "provisional" or "petty patent"

(Note: The following applies only to Convention applications) Details of basic application(s)

:::?lnsert number, S.~utry and Filing Date filinp date for he/or each 0 basic application 3 September 1982 0

~PHILLIPS ORMONDE AND FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne, Australia 3000 Sigaueo LODGED AT SUB-OFFICE 3 1 AUG 1983 1983 *0@ Melbourne Dated 26 August, Insrtodate sa f sinn ()PHILLIPS ORMONDE AND FITZPATRICK (k) Attorneys for. aplalizatio Note: N BRISTOL-MYERS C or (othr wcitnes credat requi

PHILLIPS ORMONDE AND FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne, Australia P17/2/83

I AUSTRALIA 8359 2193 Patents Act DECLARATION FOR A PATENT APPLICATION V INSTRUCTIONS Insert "Convention" if applicable In support of the Conivention a-plication made by Insert FULL name(s) BRISTOL-MYERS COMPANY of applicant(s)

"of addition*' If applicable Insert (hereinafter called "applicantN for a patent for an Insert TITLE of invention invention entitled 5UBSTITUTED 1-PYRIDYLOXY-3-INDOLYLALKYLAMINO-2- PRO PAN OL S

Insert FULL name(s) AND address(es) of l/Wkle) Isaac Jarkovsky, Assistant General Counsel Patents declaorant(s) (See headnote*) of the Applicant Company, of 345 Park Avenue, New York, New York, United States of America. do solemnly and sincerely declare as follows: 1. 1 am,1/e are the applicantC(). (or,_in the case of an application by a body corporate) 1. 1 am! We-e. authorized to make this declaration on behalf of the applicant(s. 2. 1 ttn,'te-ftI' the aetuial in;'zratzr~s) of t :ivtynie. (or, where the applicant(s) is/are not the actual inventor(s')) Insert FULL name(s) AND address(es) of 2. f) William E. Kreighbaum of 2501 St. George Road, Evansville, actual inventor(s) Indiana 47711, a citizen of the United States of America

(It)Rdtle how appli- *calt(s) derive(s) is/am the actual inventor(N of the invention and the facts upon which the applicarit(T) .g(T'e from actual is/afoe entitled to make the* application are as follows: *(See headnote" 8y virtue of an assignment between Applicant and inventor 0 of dated August 31, 1982 The said Applicant is the assignee of the said invention. 6 a.

(Note: Paragraphs 3 and 4 apply only to Convention applications) Insert country. filing date, and 3. The basic applicatioi*N for patent or similar protection on which the application is based haric applicant(s) is/-are i&!ntifed by country, filing date, and basic applicat2k as follows: for the/or EACH basic application (h Uni ted States September 3, 1982 William E. Kreighbaum 09 of America

4. The basic applicationtN referred to in paragraph 3 hereof was/Awefe the first application(s) made in a Convention country in respect of the invention the subject of the application.

(k)Insect PLACE of signing Declared at Wk New York DATE of Dated (1 8 August, .1983 *signing S.0 (in) BRISTOL- YERS CMA 461 =inaue(s) of ecaat(s)

Note: No legalization or other witness required To: The eommissioner of Patents stiatgneraI iet-atents P18/7/8 1 PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne, Australia I UART. T.Y1.-

(12) PATENT ABRIDGEMENT (11) Document No. AU-B-18592/83 (19) AUSTRALIAN PATENT OFFICE (10) Acceptance No. 567112

(51)4 International Patent Classification C07D 401/12 C07D 209/16 C07D 405/12 C07D 413/14 (21) Application No. 18592/83 (22) Application Date 31.08.83 Priority Data (31) Number (32) Date (33) Country 414748 03.09.82 US UNITED STATES OF AMERICA (43) Publication date 08.03.84 (44) Publication Date of Accepted Application 12.11.87 (71) Applicant BRISTOL MYERS CO. (72) Inventor WILLIAM E. KREIGHBAUM (74) Attorney or Agent PHILLIPS,ORMONDE FITZPATRICK (54) Title SUBSTITUTED 1-PYRIDYLOXY-3-INDOLYLALKYLAMINO-2-PROPANOLS

(57) COMPOUNDS USEFUL AS ANTIHYPERTENSIVE, VASODILATORS. AND/OR BETA ADRENERGIC BLOCKING AGENTS. Claim 1. A compound having the formula

Y R R A C H OR B

and the acid addition salts thereof wherein

X is selected from the group consisting of -CHO, -CN,

-CF3, -CONRaRb, or -CO2RC with Ra and Rb being independently

chosen from hydrogen or Rc and wherein Rc can be lower

alkyl (C1 to C 4 aryl, or aryl-lower alkyl;

Y represents a second substitutent on the pyridine ring

and is hydrogen, halogen, lower 6C1 to C4 alkoxy,

aryl-lower alkoxy, hydroxy, or -C-0-alkyl wherein

i l

i

(11) AU-B-18592/83 -2- 567112

alkyl is C -C6alkyl;

the indolylalkylaminopropoxy side chain is coupled at the pyridine

2- or 4- position; 0 I, R is hydrogen or -C-L with L being selected from C1 to

alkyl, phenyl, or phenalkyl; 1 2 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

the indolyl system is attached by its 2- or 3- position.

a :i

AUST7RALI[A

Patents Act 71 1 561 COMPLETE SPECIFICATION (ORIGINqAL)

Class Int. Class Application Number: L )dged:

Complete Specification Lodged: Accepted: Published: This document contains Ube Priority: amendments made under Section 49,

Related Art: and bs cc:nmct for printinj.

0 ~0 APPLICANT'S REF.: MJ-556 S 0. 0000 Name(s) of Applicant(s): *0 S BRISTOL-MYERS COMPANY 00 0 .00 0 00 0 0 @0 Address(es) of Applicant(s): 345 Park Avenue, New York, New York, S 000000 0 Un1ited States of America

Actual Inventor(s): William E. Kreighbaum.

*g @0 0 S 0 00 00 S 00 Address for Service is: PHILLIPS, ORMONDE FITZPATRICK 00 0S Patent and Trade Mark Attorneys 0 00 367. Collins Street. Melbourne, Australia, 3000

.0004 Complete Specification for the invention entitled: S 00 0' a "~SUBS TITUTED*- 1-PYRI DYLOXY- 3-INDO'LYLALKYLAMINO- 2-PROPANOLS" 3 9

The following statement is a ful desciiption of this invention, including t best method of performing it "Own to *applicant(s):

V P190/11/77

MJ 556

SUBSTITUTED 1-PYRIDYLOXY-3- INDOLYLALKYLAMINO-2-PROPANOLS, PREPARATION, AND USE THEREOF

The present invention is concerned with heterocylic 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;

So chemically, l-(isopropylamino)-3-(l-naphthyloxy)-2-propanol. Propranolol

Sand some related naphthyloxy propanolamines are the subject of U.S. 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.

o

SS S S

la

I I

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)

2 R

O0HR L OR

(1) 0 1 wherein R is alkyl, phenalkyl, phenoxyalkyl; R is H, C-L, with L 0 2 I being alkyl or aryl; R is H, CN, CF3, OH, C-L, Cl, NO F, pyrrolyl,

oxadiazolyl. e

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; :,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,

15 May 11, 1982.

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

2-hydroxypropoxy]-3-cyanopyridine, also known as MK-761, haj undergone

considerable further study as described in: Sweet, et al., The *00« 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

1 2.

I

administration a' high doses (cf: Journal of Medicinal Chemistry,

22/11, 1284-1290 (1979)).

CN Q CN MK-761

o0-HC(CH3) 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.

4,314,943 patented February 9, 1982; and Journal of Medicinal

Chemistry, 23:3, 285-289 (1980).

3 N- 0 O-Ar-Xn a.g N R2 OH

(2) (2) R

H @0

3 N O-Ar-Het 2 -O N /\R OH R1

(3)

A preferred 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. C

N H H OH

MJ 13105

3

This invention concerns a series of vasodilating agents

having a range of beta-adrenergic blocking potency and possessing the

general formula I and the pharmaceutically acceptable acid addition

salts thereof. X

YR A C N1 OR

e 0(I)

5 In the foregoing structural formula, X is CHO, CN, CF3 CONR R or *c a b c CO2 R with R and R being independently chosen from hydrogen or Rc

and R c being lower alkyl, aryl, or arylalkyl; Y is hydrogen, halogen,

alkoxy, aralkyloxy, or hydroxyl; R is hydrogen of C-L with L 1 being selected from alkyl, aryl, substituted aryl, or arylalkyl; R

10 R A and B are independently selected from hydrogen or alkyl; and C

can be halogen, hydrogen, hydroxy, alkyl or alkoxy. Compounds of

the invention 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.

15 The compounds of the invention have the foregoing

structural formula and the acid addition salts thereof. In b structural Formula I, X can be -CHO, -CN, -CF 3 -CONRaR or -CO 2Rc.

Ra and Rb are independently chosen from hydrogen or Rc which can be

lower alkyl (Cl to C4 aryl; or aryl-lower alkyl, aryl being preferably

<C

T- I

phenyl. It is also 1/p-rrrc.d that X be attached to the 3- position

in the pyridine ring system. Y represents a second substituent on

the pyridine ring and may be hydrogen, halogen, lower (C1 -C 4 )alkoxy, O It aryl-lower alkoxy hydroxy, or -C-0-alkyl wherein alkyl is CI-C 6

alkyl. The entire pyridinyl group is coupled to the indolylalkyl-

aminopropoxy side chain at the pyridine 2- position. R is hydrogen

or [C-L with L being selected from C 1-C 1 0 alkyl, phenyl, substituted 1 2 phenyl, or phenalkyl. 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. The indole moiety itself is preferably

coupled to the main side chain through its 3- position.

For medicinal use, the pharmaceutically acceptable acid

addition salts, those salts in which the anion does not contribute

15 significantly to toxicity or pharmacological activity of the organic

cation, are preferred. The acid addition salts are obtained either

by reaction of an organic base of structure I with an organic or

inorganic'acid, preferrably by contact in solution, or by any of the 6 standard methods detailed in the literature and available to any

pract:itioner skilled in the art. Examples of useful organic acids

are carboxylic acids such as maleic acid, acetic acid, tartaric acid,

propionic acid, fumaric acid, isethionic acid, succinic acid, pamoic

acid, cyclamic acid, pivalic acid, and the like; useful inorganic

acids are hydrohalide acids such as HC1, HBr, HI; sulfuric acid;

phosphoric acid; and the like.

It is also to be understood that the compounds of the

present invention include all the optical isomer forms, that is,

mixtures of enantiomers, racemic modification as well as the

-c L' 1_1 Itr

k

individual enantiomers. These individual enantiomers are commonly

designated according to the optical rotation they effect, by and

and or combinations of these symbols. The symbols (L)

and and the symbols and which stand for sinister and

rectus respectively, designate an absolute spatial configuration of

the enantiomer. Where no isomer designation is given for a compound,

the compound is the racemic modification.

Biological testing of the subject compounds of Formula I in

aniamls demonstrates that they possess potent vasodilating properties

along with varying degrees of adrenergic betareceptor blocking

properties and intrinsic sympathomimetic activity. Preferred members

have a particularly desirable combination of the foregoing actions,

and ancillary pharmacological effects, or a lack thereof, which

particularly suits them for specific cardiovascular indications, e.g.

15 use as antihypertensives. The utility of the compounds of Formula I *o

can be demonstrated in various animal models including antagonism of

isoproterenol in the anesthetized dog treated intravenously (adrenergic

betareceptor action), the spontaneous hypertensive and DOCA salt

r~c hypertensive rat (antihypertensive action), angiotensin-maintained

20 ganglion-blocked rat model (vasodilator action), and in various other

animal and laboratory models (cf: Deitchman, et al., Journal a 0-

Pharmacological Methods, 3, 311321, (1980)). No evidence of terato-

genicity or mutagenicity has been found to be associated with the

compounds of formula I.

25 For use as antihypertensives, vasodilators, and/or beta-

adrenergic blocking agents, therapeutic processes of this invention

comprise systemic administration, by both oral and parenteral routes,

D X_

of an effective, nontoxic amount of a compound of Formula I or a

pharmaceutically acceptable acid addition salt thereof. An effective

amount is construed to mean a dose which exerts the desired pharma-

cological activity, such as those stated hereinabove, vithout undue

toxic side effects when administered to a mammal in need of such

treatment. Dosage will vary, according to the subject and route of

administration selected, with an expected range of about 0.1 mcg to

100 mg/kg body weight of a compound of Formula I or a pharmaceutically

acceptable acid addition salt thereof generally providing the desired

therapeutic effect.

The compounds of the present invention 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 S

0 -G D SA H2NGolsis

0e (IV) (IIB) ((IV)

(IIC)

-7-

i

I I JII

In the foregoing general process, D is hydrogen, or preferably, phenyl;

G is the radical A Z is hydroxyl or halogen, preferably

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

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

yl]methanol (or methyl halide) of Formula IIA, or 2) an indolylalkyl-

aminopropanediol (or halopropanol) of Formula IIB, or 3) glycidol of o0

Formula IIC.

15 The intermediate from reaction of-IV and Ia -is Converted to

the product I by hydrolysis under acidic conditions. This hydrolysis

Sis accomplished with dilute mineral acid of from 0.1N to 1N concen-

tration at temperatures of from about 20-100 0 C. The product of

Formula I can be recovered as the free base by neutralization of the

20 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

S* conventional means such as recrystallization.

The conversion of the epoxide intermediate resulting from

25 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

Sn- 8- of a reaction inert organic solvent with an amine of the formula H 2NG 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, dimethoxy ethane, ethylene glycol, etc.

Suitable reaction temperatures are from about 60-200°0C.

The single step process pathway involves the reaction of IV

with liB and this is the preferred pathway for synthesis of the

1LO products of this invention.

This process is illustrated by the following specific

reaction equiation which shows the preferred synthetic method of the

above as Reaction 1.

Reaction 1

bas )Y 1 2AX SX Y halo

N (IV) (IIB)

In the foregoing scheme, X, Y, R, R I R2 A, B, and C are as defined,

in Formula I. Essentially this process involves heating the selected

substituted halopyridine with the appropriate indolylalkylamino-

propanol intermediate (liB) 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

~n

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

20-800 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:

LO Reaction 2

X 1 RA X 1 qM' Ole BBr Y R A 2 4 nXOH OR OR B T B .3 3 S 3 *3

0O 3 Other synthetic methods resulting in conversion to hydroxylated S Be 0 3*3 0 products, e.g. such as hydrogenolysis of benzyloxy precursors, are a.

well known to the chemical practitioner and may also be applied in 00

these cases.

Requisite halopyridines are available commerc!.ally or may

*0 *O be prepared using standard methods for their preparation reported in .i

00 the literature. Preparation of related trisubstituted pyridines is 33

3* disclosed in U.S. 4,329,351, issued May 11, 1982 to Baldwin, et al.. O S and which is hereby incorporated by reference in its entirety.

The intermediate indolylalkylaminopropanols (IIB; R H), S *630S* a preferred synthetic intermediates, are conveniently prepared by

*0 S reacting an appropriately substituted indolylalkylamine (III) with

I

3-chloro-l,2-propanediol in ref luxing alcohol containing sodium

carbonate. This process is illustrated by reaction equation 3.

Reaction 3

R1.R2A C HO Cl HN 0 Base

OH (III) (IIB)

In reaction scheme 3, R 1 2 R B, and C are es defined in Formula I.

Formula I products of the -j,.:asent invention wherein R is

other than hydrogen are conveniently p-zepared 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: see*&: S. a

Reaction 4

R 1 R2 0 Ix R- C-Cl 1 X RR 2 5* 3. B S or a. S S. it 2 OR 56 5 0 B *0

000005 The indclylalkylamines (III) are described in -the afore- S

S S mentioned Kreighbaum, et al. patents and Journal of~ Medicinal Chemistry article, which art hereby incorporated hy reference, as well as certain references cited therein. Although these referenced procedures are applicable to the preparation of cthe. indolylalkylamine intermediates not specifically disclosed therein but which are required as inte mediates for the present invention, representative syntheses of

Formula III compounds are given hereinbelow for further exemplification.

The compounds of the present invention can be formulated

according to conventional pharmaceutical practice to provide pharma-

ceutical compositions of unit dosage form comprising, for example,

tablets, capsules, powders, granules, emulsions, suspensions, and the

like. The solid preparations contain the active ingredient in

admixture with non-toxic pharmaceutical excipients such as inert

diluents, for example, calcium carbonate, sodium carbonate, lactose,

calcium phosphate or sodium phosphate; granulating and disintegrating

agents, for example, maize, starch, or alginic acid; binding agents,

for example, starch, gelatin or acacia; and lubricating agents, for

example, magnesium stearate, stearic acid or talc. The tablets may

be uncoated or they may be coated by known techniques so as to defy

disintegration and absorption in the gastrointestinal tract and o thereby provide a sustained action over a longer period.

Liquid preparations suitable for parenteral administration

include solutions, suspensions, or emulsions of the compounds of

Formula I. The aqueous suspensions of the pharmaceutical dosage

forms of the compounds of Formula I contain the active ingredient in 25 admixture with one or more non-toxic pharmaceutical excipients known

to be suitable in manufacture of aqueous suspensions. Suitable

excipients are, for example, suspending agents such as sodium carboxy-

S methylcellulose, methylcellulose, hydroxypropyl methylcellulose,

12 J I sodium alginate, polyvinyl pyrrolidone, gum tragecanth, and gum acacia. Suitable disbursing or wetting agents are naturally occuring phosphatides, for example, lecithin, polyoxyethylene stearate.

Non-aqueous suspensions may be formulated by suspending the

active ingredient in a vegetable oil, for example, olive oil, sesame

oil, or coconut oil, or in a mineral oil, for example, liquid paraffin.

The suspensions may contain a thickening agent such as beeswax, hard

paraffin, or cetyl alcohol. Sweetening and flavoring agents generally

used in pharmaceutical compositions may also be included such as

saccharin, sodium cyclamate, sugar and caramel to provide a palatable

oral preparation. The compositions may also contain other absorbing

agents, stabilizing agents, wetting agents and buffers.

The compounds which constitute this invention, their methods

15 of. preparation and their biologic actions will appear more fully from

a consideration of the following examples and appended claims which are

Z. 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 Cels.- and melting poits are uncorrected.

The nuclear magnetic resonance (NNR,.n '"ectral,haracteristics refer I to chemical shifts (6 expressed as parts per illion (ppm) versus S

tetramethylsilane (TMS) as reference standard. The relative area

reported for the various 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 the shifts as to multiplicity is reported as broad singlet bs), singlet- multiplet or doublet'(d). broad singlet singlet multiplet or doublet

Abbreviations employed are DMSO-d 6 (deuterodimethylsulfoxide), CDC13

(deuterochloroform) and are otherw' e c'..ventional. The infrared

(IR) spectral descriptions include only absorption wave numbers

(cm having functional group identification value. The IR deter-

minations were employed using potassium bromide (KBr) as diluent.

The elemental analyses are reported as percent by weight.

Synthesis of Intermediates

A. Intermediates of Formula III

EXAMPLE 1

3-(2 1AminQ- 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 dimethyl-

amine 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 0° 0 to.-5 with a cooling bath while 6-methoxyindole (10.0 g, 0.07 mole)

e. 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 10-15°

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 (MgSO4 and concentrated to a brown oily residue (14 The 25 residue was recrystallized from isopropylether and hexane to yield

9 g of 6-methoxygramine as a tan solid, m.p. 88-900.

*e eee

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 (MgSO 4 and concentrated in vacuo to a residue.

Recrystallization of the residue from isopropyl alcohol-water gave

7.6 g 2 of 3-( -methyl-2-nitropropyl)-6-methoxyindole as a tan

solid, m.p. 98-100°.

The nitropropylindole compound and activated Raney nickel

(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

slowly solidified and was recrystallized from ethyl acetate-isopropyl

ether to give 4.2 g of product, m.p. 125-128°. S.C. EXAMPLE 2 e 2- (-Amio- 2-methylpropyl) indole 20 (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

25 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

90 mL of Et 0. The ethereal reaction mixture was concentrated to

dryness and the tesidue crystallized in isopropyl alcohol. The solid Ce e O C q was isolated by filtration to give 4.0 g of the 2-indolylamide product, m.p. 181-1830.

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

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.

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

(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 S water, acidified with acetic acid to a pH of approximately 6 and then *0 extracted with Et 0. These Et 0 extracts were combined, washed with 2 2 6

Swater, dried (MgSO 4 and concentrated to a dark residue which was o0 chromatographed on a silica column and diluted with methylene chloride.

Removal of the methylene chloride and recrystallization of the crude

0 m material from isopropyl alcohol-water gave 0.4 g of 2-(2-methyl-2-

iitropropyl)indole as a cream colored solid, m.p. 102-1030. o*

Reduction of this nitro product with Raney nickel and 25 hydrazine according to the procedure used in Example 1 above yields

the desired indolalkylamine as a white solid, m.p. 130-133°. **see: •Additional examples of indolealkylamines are displayed in

Table 1.

oi

A process for preparing a compound having the 16.

formula

Table 1

Indolealkylamines

HNN 2 B

(III)

Example R1R 2A B C

3 Me H 3-H Me H

4 Me Me 2-Me H H

Me Me 2-H H

6 Me Me 2-H H

7 H Me 2-H H H

8 H Me 2-Me Me

9 H Me 3-Me Me

Me Me 2-H H 6-O,,e

S.ii Me H 2-Et H 4-Cl

12 Me H 2-H H 7-OMe

-"17

B. Intermediates of Formula II

EXAMPLE 13

3-[[2-(3-Indolyl)-l,l-dimethylethyl] amino]-l,2-propanediol Hydrate (IIB)

A mixture of a,a-dimethyl-B-(3-indolyl)ethanamine (10.0 g,

0.05 mole), Na2 CO3 (11.3 g, 0.11 mole), 3-chloro-l,2-propanediol

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 7.7 g m.p.

112-114 0 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.

Synthesis of Products

EXAMPLE 14

2-[2-Hydroxy-3-[[2-(1H-indol-3-yl)-l,l-dimethyl ethyl]amino]propoxy]-3-pyridineca bonitrile Hydrochloride (Y H. X CN, R H. R and R Me, A, B, and C H) 0

20 .3-[[2-(3-Indolyl)-l,l-dimethylethyl]amino]-l,2-propanediol *o 0

(47.3 g, 0.18 mole) and sodium hydride (7.6 g of 57% dispersion in 0

oil, 0.18 mole) were stirred in 2.5 liters of toluene and heated at

700 for 3 hrs under a nitrogen atmosphere. The mixture was then 0* *e SO 0 allowed to cool to room temperature while being stirred and 18-crown-6 0 5 0 ether (0.5 anhyd. powdered K2 C03 (62.1 g of powder, 0.45 mole) *0

S B and 2-chloro-3-cyanopyridine (25.0 g, 0.18 mole) were added sequentially 6

to the stirring mixture and then the whole was stirred for an additional

42 hrs. Concentration to dryness gave a residue which was partitioned 0 between hot H20 and EtOAc. After cooling to room temperature, the aqueous layer was separated, washed with additional EtOAc and this wash combined with the original EtOAc layer. The EtOAc was dried

(MgSO4 and concentrated hot to -about half volume. Upon cooling, a

solid precipitated and was isolated by filtration to give approximately

41 g of the crude product base.

Conversion of the base into the hydrochloride salt is

accomplished by treating an isopropyl alcohol solution of the base

with ethanolic HC1. Recrystallization of the crude hydrochloride

salt from absolute ethanol gives a white solid, m.p. 181-183.

Anal. Calcd. for C2 1 H24 N4 02 HC1: C, 62.92; H, 6.29;

N, 13.98. Found: C, 62.85; H, 6.29; N, 14.04.

NMR (DMSO-d6 1.30 3.20 3.99 m);

6.02 d [4.0 7.30 8.31 dd 7.6 Hz]);

8.51 dd 5.6 8.82 bs); 9.32 11.27 (l,bs).

IR (Kbr): 750, 1110, 1310, 1440, 1460, 1580, 1588, 2230, -1 0O B S S 2790, 2980, and 3400 cm SS

Preparation of the Cyclamate Salt

*s 5 555 5 The cyclamate salt may be prepared by treating the crude q

base synthesized above (2 g crude base) with cyclamic acid (1 g) in 00

50 mL methanol. The methanol solution was warmed, filtered and the

filtrate concentrated in vacuo to give a residue which was crystallized

in 10 mL acetonitrile. Recrystallization of the crude salt from 0* @5 0 *0 methanol-acetonitrile gave 2.0 g of white solid, m.p. 172-174 5 0

Anal. Calcd. for C21H24N 0 2C6H13NO3S: C, 59.65; H, 6.87;\ 00 S 0@ 25 N, 12.89. Found: C, 59.74; H, 5X 12.82.

0

0 *7

19

I

g

EXAMPLE

2-Hydroxy-3-[ (lH-indol-3-yl)-l,1- dimethylethyl ]amino 1propoxy 1-3-pyridinecarbonitrile

Using the procedure of Example 14 and utilizing

indolyl)-l,l-dimethylethyl ]amino 2-propanediol (10.4 g, 0.04

mole); sodium hydride (1.7 g, 0.04 mole), 550 mL toluene, 4-chloro-3-

cyanopyridine (5.5 g, 0.04 mole), Cf: Wieland and Biener, Chem.

Berichte., 96, pages 268-274 (1963)); 18-crown-6 ether (0.11,g) and

anhydrous powdered K2 C03 (13.7 g, 0.1 mole), a gunmrpv material (15 g)

was obtained. The gum was chromatographed on a silica column eluting

with methylene chloride (90 parts), methanol (10 parts) and ammnonium

hydroxide (1 pait) to give 2 fractions. The second fraction to be

eluted gave 6.8 g of gum which was crystallized in ethyl acetate to

give 5 g of solid, m.p. 124-126 Recrystallization of this material

from ethyl acetate gave 4.2 g of white solid, m.p. 126-128.

Anal. Calcd. for C21H 24N 40 2:C, 69.21; H, 6.64; N, 15.38.

Found: C, 69.42; H, 6.75; N, 15.65. 0

00 NMR (DMSO-d6 1.00 1.55 2.75 mn); S. 0

O 0 3.90 mn); 4.27 in); 5.10 7.25 in); 8.64 d [6.0 Hz]); 00

0 20 8.78 10.82 (l,bs).

IR 745, 1010. 1190, 1290, 1315, 1455, 1495, 1520,

1590, 2225, 2970, and 3400 cm 5* OS 6S 0 0

50 S. S 0e

OS 0 00

S 0055*0

S* 00 0

I

EXAMPLE 16

2-[2-Hydroxy-3-[[2-(lH-indol-3- l)-1,1- dimethylethyl]amino]propoxy]-3-pyridinecarboxamide

Using a procedure similar to that outlined in Example 4.

above, 3- [2-(3-indolyl)-1,-dimethylethylethyl]amino]-l,2-propanediol

(10.5 g, 0.04 mole), sodium hydride (1.7 g, 0.04 mole), 400 mL

toluene, 2-chloronicotinamide (5.6 g, 0.04 mole), 18-crown-6 ether

(0.11 g) and anhydrous powdered K 2 CO3 (13.8 g, 0.1 mole) were reacted

to give 17 g of residual gum. The gum was chromatographed on a

silica column eluting with methylene chloride (90 parts), methanol

parts) and ammonium hydroxide (1 part). The product-containing

fractions were combined and concentrated to a residue which was

crystallized in ethyl acetate to give 5.2 g of material, m.p. 68-72

Recrystallization from ethyl acetate and drying in a vacuum oven

afforded 4 g of white solid, m.p. 131-1330.

Anal. Calcd. for C2126 N40: C, 65.95; H, 6.86; N, 14.65. 21 26 4 3 Found: C, 65.80; H, 6.85; N, 14.31. We

NMR (DMSO-d 1.03 2.77 3.95 m); 6

4.46 7.20 7.81 bs); 8.30 d [6.1 Hz]);

20 10.85 (l,bs).

IR (KBr): 740, 780, 1100, 1235, 1430, 1460, 1585, 1670, -1 2970, 3330, and 3470 cm 00 0 EXAMPLE 17 0* Conversion of Methoxy Products to Hydroxy Products General Procedure

Dissolve the methoxy product in methylene chloride and stir

under a nitrogen atmosphere while keeping chilled with an ice bath.

Add dropwise 3 equivalents of boron tribromide in methylene chloride S solution. Following addition, remove the ice ath and aow the solution. Following addition, remove the ice bath and allow the

L I

reaction mixture to stir at room temperature for 6-8 hrs. Again,

chill the reaction mixture with an ice bath and decompose excess

reagent by adding excess H20 dropwise, causing a gummy material to

precipitate. The supernatant is decanted from the gummy material

which is rinsed with two portions of water. The gum is dissolved in

hot water, treated with activated charcoal (Darco), filtered, the

filtrate chilled and made basic with ammonium hydroxide to a pH of

approximately 8. The resultant precipitate is filtered, washed with

water, dried and further purified by column chromatography on silica

gel, eluting with CHC1 3 (90 parts) methanol (10 parts) NH4OH

(1 part). Concentration of product-containing fractions gives a

residue which is recrystallized from ethanol-water to give pure

hydroxy product.

Starting with the appropriate pyridine and indolylalkyl-

15 amine, additional examples of Formula I products may be synthesized

using substantially the same procedures as outlined hereinabove.

Some additional products of Formula I which may be synthesized are

R R A c 00***o shown in Table 2. G in the formulae represents the LA C

B group as determined by the intermediate III selected

20 (cf: examples 1-12). 0* 0 S0 *00 a 0

0*000* *0

-i j

Table 2

Example Formula Example Formula

0 CNe 2

18

0 0 11 F MN

N NG 01!

Cl CN

OH OCCH it 3 CONH 2 CONH 0 HOn *0 S S. 0* NG .ee OH N 0 NG S S S. S

SS OH 0 6 @00 S 3 CHO b. S S OS

S 600555 NN S

OCCH of 3

S. 00 S S o 0

05 5 S. S OCEt 0 S0 5 55 0 a. ~CF3 N 0O,-y'-NG OCPh S 11

0 0 0e 0@ 5 S S

Biological Evaluation

These biological tests were used to gauge the cardiovascular

profile of a number of the compounds of Formula I as vasodilators

with a range of beta-adrenergic blocking activity.

EXAMPLE 31

The efficacy of antihypertensive agents other than adrenergic

beta-receptor blocking agents is commonly estimated in the spontaneous

hypertensive rat. Blood pressure values are determined for test

animals prior to and 24 hours after oral doses of 50 mg/kg of test

compounds; the observed percentage change in heart rate is noted as

well. A fall -in blood pressure in the range of 19-24 mmHg is considered

"questionable". "Active" and "inactive" designations are decreases

greater and less than that range.

EXAMPLE 32

15 The angiotensin-maintained ganglion-blocked rat model is

utilized as a screening test for estimation of the vasodilator

component of activity. Percentage changes in blood pressure in

anesthetized rats 30 minutes after intravenous dosing are determined.

The intravenous dosing is done with test compound at 3 mg/kg.

Borderline activity is defined as a 15-20% decrease in blood pressure

measured 30 minutes after dosing. "Active" and "inactive" designations

are increases greater and less than that range.

EXAMPLE 33 e *e Diastolic blood pressure and heart rate responses to a fixei

challenge dose of isoproterenol are obtained before and

after graded doses of test compound administered intravenously over a

S* 3-min interval to anesthetized dogs. A branch of a femoral artery'and,

vein are cannulated to record blood pressure and to administer the

i:

I IL ii II__

drugs which are dissolved in saline. The vagi were sectioned bilaterally

in the mid-cervical region of the neck and the dogs are ventilated

mechanically (Harvard respirator) with room air a rate of

and a stroke volume of 20 mL/kg. Heart rate is monitored with a

cardiotachometer triggered by the pressure pulse. All measurements

are recorded on a Beckman R-612 recorder. The drug effect is expressed

in terms of a cumulative dose (microgram/kg) causing 50% inhibition of

isoproterenol response.

The following abbreviations used herein have the following

meanings: Ph stands for a phenyl group, Pr stands for a propyl group, Me stands for methyl group, and Et stands for an ethyl group.

Additionally, an accepted convention in modern organic

chemistry has been used throughout. For alkyl structures, in a shorthand form, joined line sigments substitute for explicit

notation of C and H groups. Thus, for example, formula I

can also be written:

CH CH

CH N CH 2 I H SOR *N33 B

0

I rL3

Claims (1)

1. I Ir

   The claims defining the invention are as follows:

   XEKXYaHIX2Cx:

   1. A compound having the formula

   R1 R2 R

   OR B

   and the acid addition salts thereof wherein I

   X is selected from the group consisting of -CHO, -CN,

   -CF3, -CONRaRb, or -CO RC with Ra and Rb 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 substitutent on the pyridine ring

   and is hydrogen, halogen, lower Cl 1 to C4 alkoxy,

   aryl-lower alkoxy, hydroxy, or -C-0-alkyl wherein

   10 alkyl is C -C alkyl; 6

   the indolylalkylaminopropoxy side chain is coupled at the pyridine

   2- or 4- position; If R is hydrogen or -C-L with L being selected from C1 to

   C1 0 alkyl, phenyl, or phenalkyl;

   o, 1 15 1 2 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 the indolyl system s attached by its 2- or 3- position the indolyl system is attached by its 2- or 3- position.

   -s p~r a j-C

   2. A compound of claim 1 wherein the indolylalkylamino-

   propoxy side chain is coupled to the pyridine 2-position.

   3. A compound of claim 1 wherein the indolyl ring 's

   attached at its 3-position.

   4. A compound of claim 2 or claim 3 wherein X is cyano 1 2 or amido; Y is hydrogen; R is hydrogen; R and R are lower alkyl;

   A and B are hydrogen; and C is halogen, hydrogen, hydroxy, alkyl,

   or alkoxy.

   A compound of claim 1, which is 2-[2-hydroxy-3-

   [[2-(1H-indol-3-yl)-1,1-dimethylethyl]aminohpropoxy]-3-pyridine-

   carbonitrile or a pharmaceutically acceptable acid addition salt thereof. 6. The cyclamic acid addition salt of the compound of

   claim

   7. The HC1 acid addition salt of the compound of Claim 9*

   A compound of claim 1,-Whih is 4-[2-hydroxy-3-[[2-

   (lH-indol-3-yl),1-dimtylthyllaminopino]6y--yidncro 8. A compound of claim l,which is 4-[12-hydroxy-3-[[2- nitrile or a pharmaceutically acceptale acid addition salt thereof. (1H-indol-3-yl)1,1-dimethylethyl]aminopropxy]-3-pridinecarbo- *R

   9. A compound of claim l,-which is 2-[2-hydroxy-3-[[2- nitrile or a pharmaceutically acceptable acid addition salt thereof. (lH-indol-3-yl) 1-dimethylethyl] aminolpropoxy]-3-pyridinecarbox- a.bidz..or-.a pharmaceutically'acceptable acid addition salt thereof.

   A method of exerting a vasodilating effect in a 9

   S* mammalian host, wherein said method comprises administring to a mammal having a condition in which ther-apeutic-.benefit .is

   derived from vasodilatation a non-toxic effective-vasodilating

   -dose.of a compound as claimed in claim 1.

   11. A method of treating hypertension, said method com-

   prising administering to a mammalian host having hypertension a

   non-toxic antihypertensive effective dose of a compound claimed in claim 1. 12. A pharmaceutical composition in dosage unit form suitable

   for systemic administration to a mammalian host, said composition comprising

   a pharmaceutical carrier and an amount of a Formula I compound

   according to claim 1 to provide an effective non-toxic dose of from

   0.1 mcg to 100mg/kg body weight of said host.

   13. A pharmaceutical composition of claim 12 wherein the

   Formula I compound is 2-[2-hydroxy-3-[[2-(H-indol-3-yl)-l,1-

   dimethylethyl]amino]propoxy]-3-pyridinecarbonitrile or a pharma-

   ceutically acceptable acid addition salt thereof.

   S, 14. A pharmaceutical composition of claim 12 wherein the Formula I compound is 4-[2-hydroxy-3-[[2-(lH-indol-3-yl)-l,1-

   dimethylethyl]amino]propoxy]-3-pyridinecarbonitrile or a pharma- c ceutically acceptable acid addition salt thereof.

   A pharmaceutical composition of claim 12 wherein the

   Formula I compound is 2-[2-hydroxy-3-[[2-(1H-indol-3-yl)-l,l-

   dimethylethyl]amino]propoxy]-3-pyridinecarboxamide or a pharma- S ceutically acceptable acid addition salt thereof.

   S*

   cS 0

   16. A process for preparing a compound having the

   formula

   OR B

   and the acid addition salts thereof, wherein X is selected from the group consisting of -CHO, -CN,

   -CF 3 -CONRaR, or -CO 2 R c with Ra and R b being

   independently chosen from hydrogen or Rc and wherein

   Rc can be lower alkyl (C1 to C4), aryl, or aryl-

   lower alkyl;

   Y represents a second substitutent on the pyridine 0.. I ring and is hydrogen, halogen, lower (C1 to C .1 4 alkoxy, aryl-lower alkoxy, hydroxy, or

   -C-O-alkyl wherein alkyl is C -C 6 alkyl; 1

   the indolylalkylaminopropoxy side chain is coupled at the pyridine

   2- or 4- position;

   R is hydrogen or -L with L being selected from C 1 to C 1 0 alkyl, phenyl, or phenalkyl; 1 2 R R A and B are independently chosen from hydrogen or lower alkyl;

   C represents a substituent in the benzo ring of indole 0. and is selected from hydrogen, halogen, lower alkyl,.

   lower alkoxy, or hydroxy; and

   the indolyl system is attached by its 2- or 3- position, 0

   said process comprising:

   coupling a B-substituted pyridine of formula IV

   (IV)

   S hTPi n x and Y are as defined above and wherein P is hydroxyl or

   II R II IIIC L.

   halogen, with a W-substituted propanol or incipient propanol

   intermediate II selected from the group consisting of IIA, IIB,

   and IIC:

   IIA 0 N-G

   Y

   NH W N-G IIB

   OR

   O W0 IIC

   wherein D is hydrogen or phenyl and preferably phenyl;

   wherein G is the radical S* R1 R2 A

   *eO I BI B

   R2 g 1 wherein R A, B, and C are as defined above;

   wherein W is halogen and preferably chloride when 8 is hydroxyl

   and wherein W is hydroxyl when is halogen; and i) when compound IIA is reacted with compound IV,

   then converting the product thereof by hydrolysis

   under acidic conditions to said compound I;

   ii) when compound IIC is reacted with compound IV,

   an epoxy ether is formed and including a further

   step of heating said epoxy ether either neat or

   in the presence of a reaction inert organic

   solvent with an amine of the fornula H 2 NG, wherein

   G is as defined above, so as to form said compound I.

   IF ;1 i I

   A -ocess according to Claim 16, wherein said compound

   IIB is used, wherein W is hydroxyl, wherein Z is halogen, and said coupling in step comprises heating compound IV with

   compound IIB in the presence of a base, all in an inert organic

   liquid under mild conditions.

   18. A process according to Claim 16, wherein said

   hydrolysis under acidic conditions employs dilute mineral acid

   of from 0.1N to IN concentration and temperatures within the

   range from about 20-100 C and including also the step of

   recovering either the product of Formula I as the free base

   of neutralization of the hydrolysis mixture and collecting the

   precipitate or the acid addition salts thereof by evaporating

   the hydrolysis mixture or by reacting the free base with acid.

   19. A process according to Claim 16, wherein said Y

   and/or C in said Formula I products are/is hydroxy, said process

   comprising the process according to Claim 16 wherein said

   **oo compound IIB is used and including also the step of cleaving

   the corresponding methoxy precursor by the reaction as shown in

   Reaction 2: S

   Reaction 2

   X 11 2 °t •eBBr R A 2 N OH OR 2 S2 OR B I **B B zo A compound according to claim 1 substantially as hereinbefore described with reference to any one of the examples. A process according to claim 16 substantially as hereinbefore described with reference to any one of the examples.

   DATED: 26 August, 1983

   PHILLIPS ORMONDE AND FITZPATRICK Attorneys for: BRISTOL-MYERS COMPANY 0

   0e

   6a

   *00

   *0 0

   00

   0

   32

   7~RAZ,