rr

U.S. DEFARTMENT OF COMMERCENational Technical Information Service

AD-A023 974

NAPHTHYRIDINE ANTIMALARIAL AGENTS

I EXXON RESEARCH AND ENGINEERING COMPANY

JUNE 1975

r131010

AD_

EXXON/GRU.10BJJB.75F

NAPHTHYRIDINEANTIMALARIAL

AGENTS

FINAL TECHNICAL REPORTfor

April 1, 1973 -June 30, 1975

byJOHN F. PILOT

EUGENE L. STOGRYN

(201-474-2015)

JUNE, 1975

Sponsored By

UN fED STATES ARMY MEOICAL RESEARCH AND OEVELOPMENT COMMANDWASHINGTON, D.C. 20314

CONTRACT NO. DADA 17-73-C-3079

Exxon Research & Engineering Company, Government Research Laboratory, Linden, N. J. 07036

|E)5ONI

DISTRIBUTION STATEMENT Approved forpublic release; distribution unlimited.

REPRODUCED BY

NATIONAL TECHNICALINFORMATION SERVICE

U. S. DEPARTMENT OF COMMERCESPRINGFIELD, VA. 22161

EXXON/GRU. lOBJJB. 75F

NAPHTHYRIDINE ANTnIALARIAL AGENTS

Final Technical Report

for

April 1, 1973 - June 30, 1975

by

John F. PilotEugene L. Stogryn(201-474-2015)

June, 1975

Supported by

U.S. Army Medical Research and Development CommandWashington, D.C. 20314

Contract No. DADAI7-73-C-3079

Exxon Research and Engineering CompanyGovernment Research Laboratory t -

Linden, New Jersey 07036

Approved for public release; distribution unlimited........... ..............

By

• "+ ++,,+,+; d:J V'T , -r

+ • , ,.ve

UnclassifiedISECUP4T1 CLASSrIFICATIn4 or T41S PAr rnxbl *te l.te,dj

REPORT-DOCUMENTATION PAGE fEFORE COMsLETIP FOM

1. L ORI MUMUBF.R 2. GOVT ACCESSION MO . tECSPIENT'S CATALOG NUMSu*m

4. TITLE (aibesu"S|is) S. TYPE Or REPORT & PEIOD COVEREDFinal Report

Naphthyridine Antimalarial Agents April 1, 1973-June 30, 197!£. PERFORiNNOOC. REPORT NUMBER

_EON/GRU. ," -J.mB. 75F7. AUTHOR(s) S. CONTRACT OR GRANT NUMBER s)

John F. Pilot-Euguene L. Stogryn Contract DADA 17-73-C-3079

9, PERFORMING ORGANIZATION NAME AND ADDRESS W0. PROGRAM ELEMENT. PROJECT. TASKAREA & WORK< UXT NUMBERSExxon Research and Engineering CompanyGovernment Research LaboratoryP.O. Box 8. Linden. New Jersey 07036

If. CONTROLLING OrriCe NAME AND ADDAESS 12. EPO'4T DATE

U.S. Army Medical Research and June, 1975Development Command 23. NUMBER OF PAGES

Washington, D.C. 20314 m __ 914. ONITORING AGENCY NAME S AODRESS(It dIler.9t Ir Confotallng Dlle) 15. SECURII Y CLASS. (of this report)

Unclassified15s. DOCLASSIFICATIONIDOWAIGRADING

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IS. DISTRIBUTION STATEMENT (of this Repotl)

Approved for pulic release; distribution unlimited.

17. E4STRIUUTIMN STATEMENT (of the abstract ontitodin Block 20. II different from Report)

IS. SUPPLEMENTARY NOTES

None

I9. KEY WORDS (Continue o reser ,rde if nocesse ," end Identify by block number)

Antimalarial

Naphthyridine

120. A13STRACT (Cont,jup, on rovsraeo side it nocseps~ty and Idents(y by lblack number)

Interest in the 4-amino-l,5-naphthyridines as potentialprophylactic eztimalarial agents has been generated by the structuralsimilarity of this ring system to both the 4- and 8-alm-"oquinoline&.In our synthetic studies during this program, we sought to expand uponthe derivatives of 4-amino-l,5-naphthyridine which are currently availablein an effort to secure an optimal prophylactic antimalarial drug.Accordingly, as a result of bur synthetic efforts, a total of 26

DD 1473 TO.-ON OF I IIOV 65 IS OBSOLETE Unclassified

4: ECURITY CLASSIFICATION OF THIS PAGE ,.,n is Entered)

- nclassifiedStCUfRt|Y CLASSIFICATION4 OF TIS PAGEMN'N D&84 ,.Irsnd)

naphthyridine target and 145 naphthyridine intermediates and miscellaneousprecursors have been prepared and submitted for biological testing.

The synthetic studies during the first year of our program wasconcerned mainly with the formation of three classes of target structures:2-alkoxy, 6-alkoxy, and 2,6-dialkoxy-4-amino-l,5-er-phthyridine. Signi-ficant accomplishments included: new synthetic technzques for thepreparation of 6-alkoxy-4-amn.o-l, 5-naphthyridines Pnd for the introductionof the pantaquAfe sidechain into alkoxy-l,5-naphthyridines.

"he brunt of the second years program was the formation of 2-merho-4-amino-l, 5-naphthyridine derivatives, isosteric to primaquire-, pentaqu-I'me,and pamaquin. In addition, both the 6-methyl (alkoxy) and the 8-methylfunctionalities were desired because ot their known activity enhancementin the related 8-amino quinolines. Accordingly, the requisite 6- and8-substituted-2, 4-dichloro-l,5-naphtlhyridines were synthesized.

The termin&l phase of the niphthyridin a program yieldedauthentic 4-amino-l-methyl-napithyridn-2*ene d+-tvatives and a 2-6-dialkoxy4-dmiro-l, 5mphthyridine.

While antimalarial testing has not yet been completed, resultsobtained for must of the target drugs submitted to WRAIR have disclosedno significavt prophylactic activity iut the lower dosage range (1.0 and3.0 mg/kg). However, one of the target structures, 2-ihydroxy-4-(5-isopropyl-aminopentylaaino)-l,5-naphthyridine, has now pr,ven to be curative in theRhesus monkeyr infected with sporozoites of the R strain of P.cynomolgiat a dosage level of 10.0 mg/kg. In the P.berghei/mouse, curativescreen to date, the targets showed only marginal activity and the sixty-four variously substituted intermediates or precursors, no activity.

4Unclassified

SECURITY CLASSIFICATION OF THIS PAGE(IWh*n Dora Enterod)

[4

TABLE OF CONTENTS

Page

1. SU MARY ..................................................... . . 1

2. INTRODUCTIOl . 2

3. NAPHTHYRIDINE TARGETS SUBMITTED 4/1/73-6/30/75 ................... 4

4. SYNTHESIS ........................................................ 9

4.1 4-Amino-i-methyl-naphthyridin-2-ones ........................ 94.2 4.-Awino-2, 6-Dialkoxy-1,5-Naphthyridine ...................... 154.3 Primaquine Sidechain ........................................ 15

5. EXPERIMENTAL ..................................................... 16

5.1 6-.i-Butoxy-4-(4-diethylamino-l-methylbutylamino)-2-methoxy-1,5-naphthyridine di-o-resorcylate [NT-24] .......... 16

5.2 4-(5-Isopropylaminopentylamino)-l-ncthyl-1,5-naphthyridin-2-one 0-resorcylate [NT-25] .................... 16

5.3 4-(5-Isopropylminopentylamino)-l-methyl-6-(2,2,2-trifluoroethoxy)- 1,5-naphthyridin-2-one0-resorcylate [NT-26] ....................................... 16

5.4 4-Cliloro-2-hydroxy-6-(2,2,2-trifluoroethoxy)-1,5-naphthyridine [NI-731 ..................................... 17

5.5 4-Chloro-l-methyl-6-(2,2,2-trifluoroethoxy)-,5-naphthridin-2-one [NI-74] ................................. 17

5.6 5-Bromo-2-pentanone [NP-701 ................................. 175.7 l-Phthalamido-4-pentanone [NP-71] ........................... 17

6. REFERENCES ....................................................... 18

7. APPENDICES ....................................................... 19

7.1 Naphthyridine Intermediates (NI-73-74) ...................... 197.2 Naphthyridine Intermediates (NI-i through NI-41) ............ 197.3 Naphthyridine Frecursors (NP-70-71) ......................... 327.4 Naphthyridi-e Precursors (NP-1-69) .......................... 327.5 Biological Activity Data .................................... 447.6 Program Organization and Personnel ......................... 457.7 Distribution Statement ...................................... 45

I

I. SUMMARY

Interest in the 4-amino-l,5-naphthyridines as potentialprophylactie antimalarial agents has been generated by the structuralsimilaritv of this ring system to both the 4- and 8-aminoquinolines.In our vynthetic studies during t~ii program, we sought to expand uponthe derivatives of 4-amino-l,5-naphthyridine which are currently availablein an effort to secure an optimal prophylactic antimalarial drug.Accordingly, as a result of our synthetic efforts, a total of 26naphthyridine target and 145 naphthyridine intermediates and miscellaneousprecursors have been prepared and submitted for biological testing.

The synthetic studies during the first year of our program wasconcerned mainly with the formation of three classes of target structures:2-alkoxy, 6-alkoxy, and 2,6-dialkoxy-4-anino-!,5-naphthyridine. Signi-ficant accomplishments included: new synthetic techniques for thepreparation of 6-alkoxy-4-ami.:o-l, 5-nap.I yridines and for the introductionof the pentaquine sidechain into alkoxy-l,5-naphthyridines.

The brunt of the second years program was the formation of 2-methoxy-4-aino-!,5-naphthyridine derivatives, isosteric to primaquine, pentaquine,and pamaquin. In addition, both the 6-methyl (alkoxy) and the 8-methylfunctionalities were desired because of their known activity enhancementin the related 8-amiro quinolines. Accordingly, the requisite 6- and8-suostituted-2,4-dichloro-l, 5-naphthyridines were synthesized.

The terminal phase of the naphthyridine program yieldedauthentic 4-amino-l-methyl-naphthyridin-2-one derivatives and a 2-6-dialkoxy-4-amino-l,5-naphthyridine.

While antimalarial testing has not yet been completed, resu]ts

obtained for most of the target drugs submitted to WRAIR have disclosed

no significant prophylactic activity in the lower dosage range (1.0 and

3.0 mg/kg). However, one of the target structures, 2-hydroxy-4-(5-isopropyl-aminopentylanno)-l,5-naphthyridine, has now proven to be curative in theRhesus monkey infected with sporozoites of the B strain of P.cynomolgi

at a dosage level of 10.0 mg/kg. In the Pberghei/mouse, curativescreen to date, the targets showed only marginal activity and the sixty-

four variously substituted intermediates or precursors, no activity.

I.

-2-

2. INTRODUCTION

The drugs presently available for the treatment of malaria suffer

from two serious deficiencies. First, no single agent is suitable for all

purposes. Secondly, drug resistant strains of the parasite have evolved inthe early 1960's. Clearly, further developments in drug design ±st lead toagents which possess pharmacologic and chemotherapeutic properties which aresuperior to those presently available. The goals of new synthetic effortsmusL be directed toward the development of agents which exhibit broad activityagainst all. life cycles of the parasite. In addition, they should possesshigh potency, low toxicity, and a long duration of activity. Ideally, aprophylactic drug is sought for the recently encountered drug resistant strainsof the malaria parasite.

With all of the above in mind, it is our contention that certain4-amino-1,5-naphthyridines,

NH-R

8 1

should possess the desired prophlactic chaxscte:'i-tL k-s. Quinine, a classicexample of a specific chemotheraupeucic agent, incorporates a quinoline ringas a basic structurae fragment. The quinoline nucleus has, therefore, servedas a template for biochemists in the design of a wice array of candidateantimalarial drugs. Of the many substitaent vAriatior-s effected upon thequinoline nucleus, the 4-amino and 8-amino substituted analogs have e. nibitedthe greatest activity (1). In general, the 4-aminoquinolines, e.g., chloro-quine, zLe schinzoDtocidal agents which act at the asexual e-vthrocytic lifecycle of the malaria parasite. By contrast, the 8-aminoqu'.noll:es,-as typi-fied by pamaquine, are gametocytocidal drugs which act against the u tcondaryexoe.y'hroc-ytic stages and thereby destroy the sexual forms of the humanmalai:ia arasite (2). Derivatives of the 4-amino-l,5-naphthyridines should,therefore, -Ahibit an enhanced antimalarial activity, since they are iso-steres of both the 4- and 8-aminoquinolines. This supposition has beenconfirv d by aa early report in the literature that 4-04-diethylamino-l-methylbu ylamino) -1,5-naphthyridine,

P13NHCHCH 2CH2CH 2NEt 2

-3-

was found to exhibit an antimalarial activity comparable to quinine itself(3,4). Moreover, recent reports iri the literature have disclosed signifi-cant antimalarial activity for the 4-amino-l,5-naphthyridinzs which aresubst--_=ited with alkoxy groups in '-th the 2- and 6-positions (2,5). Inour research, we sought to expand upon the derivatives of 4-amino-l,5-naphthyridine currently- available in an effort to produce an optim drug.The rasults of our synthetic studies for this year are-fully discussed inthe text of this report.

The results of our previous synthetic studies are described intwo annual reports (6,7). The compounds are designated and reportedtherein as follows:

NT NI NP Report Reference

1-19 1-41 1-43 620-23 42-72 44-69 7

The structure of those compounds is shown within this report in pages4 to 8 for the NT series; pages 19 to 23, N! series; and pages 32-43,NP series.

- -4T-

-4-

3. NAPHTEYRIDINE TARGETS SUBMITTED 4/1/73 - 6/30/75

The chemical structures and our code designation for compoundsprPpared and submtted to WRAIR for biological testing are shown below.Where available, zhe Walter Reed bottle numbers appear in j erentheses belowour code. Structures not detailed in this report have beet. referenced.

Naphthyridine Targets (NT-24-26)

Structure Code No.

CH 0'I

n-BuONHCHCH2CH2CH2NEt CO

NT-24

(BE 83502)

0I,

NRCH2CH2CR CH2 C 2NHCH (CH3)2 CO

NT-25

CH3 OH

0NHCH2CH2CH2CH2 CH2NHCH(CH3)2

CF3CH2 ON0

NT-26N' O

CH3 OH

I5

Naphthyridine Targets (NT-I through NT-19p

Structure Code No.

CK3

hCH(CH2) NEtN 23 2

CH3(CH2) 30

(BD 26404)

CH3

IHCH(CH2 ) 3 NEt 2N

CF C'OR' 3 2 J T-2

(BD 26413)

S NH (CU 2 ) 5(CCF (C0 3 )2

C3 (- 2) 30 "

NT--3

(BD 26422)

6F (C' 2 ) 5 NL-(CH3 ) 2

N. NT-4

,' . y -. 3 (BD 54711) ]3

NT-5(BD 54120)

'3

-~ N NT-6

(BD 54739)

OH

-6-

ORH (BD 54748 1C

N

CF~c~O~NT-8OR (BD 54757)

N N (CEh 2 ) 5 MHC (CR 3)2 CO

CF NT-9I 2 (BD 54766)N

N0

NH(C 2 ) NCH H 3 )2 coaf

CF 3 C2 0 ~ 2 I 11 T10N 2 (BD 54775)

ORi

NK

010

COH

CR3 - N ~r ~NT-11

N (BE 10983)N

C -7-

0N 2con

CH 3C 2 0 N MCEY HHC-3 O NT-14-2 (BE 10992)

CH3

H N 'd(CH2) 3N(CH2CR3 j 2

d NT-15

! / (BE 11006)N-

CU3' 0NHCH2 N(CH CH3C23 2 32 COif

CH 2 OH NT-16H 22 (BE 11015)

OH

20OH

COCH3CH3 NT-17

(BE 11024)NCH3

mHCH(CH2 ) 3N (CH2 CH3 )

cH 3 cHo NT-18(BE 13493)

N

C3 0N NC(C"2 ) 3 (C 2 CH3 )z CO

CHCH0 NOil NT-19

2 (BE 13500)

OH

-8-

Naphthyridine Targets (QNT-20 through NT-23) 7

0Structure Code Number

COPOCR3

CH N ' H OH NT-203 " - .%, 2 J .1/2 12 9 (BE 17286)

N -.. NHCH(CH2 ) 3 N(CH 2c( 3 ) 2

0atocIR3 90H

C3CH2O N-C 3 .2 NT-21

I. (BE 17295)1' CH (CR2 ) 3N (CR2CH3)2

OH

CF, 3 0NIRCHcCH RC'i N(CH2 CF. OI';INICtC2CI 2U 2N (C2 C3 )2 C0t

CH 3 "YOH ?1T-22 (BE 67286)

s OCR3 OH

0'I

.3N I HNT-23

C2C2 2H 0C1H2 HN 2 (BE 67295);I? JHCH IGICH CH N CI{(CH) 2 O

__9_-

4. SYNTHESIS

The synthetic efforts in the 4-am no-1,5-nphthridine class of

antimalarials during the 3-month ,xtension period have been directed toward,

* a 4-amino-l-methyl-naphthyridin-2-one

* a 2, 6-diakoxy-4-amino-l, 5-naphthyridine

* a .,5-naphthyridine with the primaquine sidechain

Biological rationale for these target derivati es are adequately describedand referenced in our previous Annual Reports.

7

4.1 4-Amino-l-methyl-naphthyridin-2-ones

The synthetic entry into this class of potential antimalarials hasbeen realized according to the sequence depicted in Scheme 1. The infraredspectrum of NT-25, as the P-resorcylate, is shown in Figure 1.

Scheme 1

+

H3 0 Me2SO4

OH0

Me

H N(CH 2 NHi -Pr

CH2CH2CH2CH2CH21%HCR (Cf!3)2

Me

NT-25

o 10 o

co< 0

I ~ ~ ~ ~ .I- .4IA a

0 _0

~u 8-NV.11 OS4J

ii

The above sequence of reactions was noted to be also applicableto the synthesis of more complex naphthyridinones. The structure of this

k target naphthyridinone, NT-26, is given belowt. The spectrum of NT-26 isshown in Figure 2.

2F CO 0

CH3 O O

NT-26

Concownmitant with this mode of naphthyridinone synthesis attempts weremade to effect an N ---> 0 methyl migration of NI-70. This approach wasbased on Cheng's2 report that methyl migration may have occurred duringthe preparation of NI-70 in acid media.

N NC(CH2)3 Nt 1*ICH(CH 2) 3NEt 2N

0 0QOMe0

NI-70 Me

Although N-IO migrations in nitrogen heterocycles, including naphthridinessystems, are well documented thermolysis of NI-70, neat, in the presenceof p-toluenesulfonic acid, or novaldiamine hydrochloride at temperaturesup to 230°C were unrewlarding.

- 12 -0 00 000 C

6 CN4 C' ItLO "ON.

,.. .,II

... ... . . C

00 1

2-H4

ccl

0-0

if

o~~ Ij -) "IK

4 '4JII00 000000P NV4 4S4

C) 0 0 o80 C

. .. . . .

I. St l .li ... a a

.i St.$

CO I C i . .

17-J

-77-,0 1 fil ... -1 1 1 to

. . .. oil....1.4 1. of0 ... i I s 11 11 ....

0 , - so. ,. f ll .to 1 ,0-

00i .. a 0 0 0 0 0 .H.:: 17I ~ ~ ~ C i~ H 'of ilooi .. .. i". ."

DNVS~iOS9

- 4

00

'VQ

00

0 00

UL

o c

% 0%

ItI

E0 I

4.3 V4

tLn

.$2'- 0H~ -4

0C0 o 0 0 0

3NVIOSbV'

r

4.2 4-Amino-2,6-Dialkoxy-.- Naphthyridine

Previous efforts to introduce a basic dtamino side chain atthe 4 -position of 2,6-disubstituted naphthyridinea were plagved by accompanyingloss of halide and alkoxy. Recently w- fnund that aminolysis under lessrigorous conditions than previously employed permitted introdoxtion of theamino sideChain at the 4-position without the accompanying loss of alkoxygroup(s). The specific target structure having 2- and 6-position alkoxygroups is NT-24. The spectrum of NT-24, as the free base is given inFigure 3. This target compound was submitted for testing purposes asthe di-p-resorcylate.

,CH3 'I

n-BUO - NH-CHCH2CH2Cb2NEt2 CH

N OCH 3 zyOH

NT-24

4.3 Primaquine Sidechain

•The classical approach to introduction of the Primaquine sidechain,namely alkylation of the 8-amino quinoline, has been previously noted byus to be inoperative with 4-aminonaphthyridine7. The failure of this alkylationstep is explicable in terms of the poor nurleophilic character of the 4-amino function resulting from the stroag electron witlkdrawing effect ofthe naphthyridine ring nitrogen. Since aminolysis of 4-chloro naphthyridinesis a viable route attempts to pr ro.*e a terminally blocked 1,4-diaminopentane (primaquine sidechain) were made. To our knowledge such an inter-mediate is unknown. The route devised to produce the desired intermzdiateis shown in Scheme 2.

Scheme 2

0 0HBr

CH3 -CCH2CH2CH20H -- .------ , CH3 CCH2 CH2CH2Br

K phthalamide

0 0

H2 N-C(CH2 ) 3 -N NH4OAc CH(CH2)2 N-- NaBH3 CN C3(H)N /

SII I

0 0

The first two stepk. occur in good yield giving isolable and characterizableproducts. The reductive aumination,8 under a variety of conditions, failed.Although spectral data indicated loss of the keto function and the appearanceof the primary amino group no single material could be inolatel by chromato-graphic or other techniques.

-16-

5. EXPEPRMENTAL

5.1 6-n-Butoxy-4- (4-diethylamino- l-methylbutylamino)-2-methoxy-l.5-nap -ine di-a-°resorcvlate [VT-24]

A mixtu,.e of 3.7 g of 6-butoxy-4-chloro-2-methoxy-1,5-naphthyridine,20 g of 4-diethyamito-l-methylbutyl amine, and 1.42g of K2 CO3 were heatedat 1400 for 2.5 lays. The cooled reaction was treated with 50 ml of 5NNaOH, extracted with ether and dried. The ether and excess amine wereremoved at reduced pressure and the dark amber residue chromatographedthrough neutral alumina (activity grade 1). The starting naphthyridineeluted with chloroform; NT-24 (free base) appeared in acetone and THFeluates.

The free base of NT-24 was reacted with three equivalents ofO-resorcylic acid in ether, filtered and washed with large volumes of ether.NT-24, mp = 80-3' was isolated as a white solid.

Anal calcd for C3 6H48N4010 : 7C, 62.07; 7%H, 6.90; N, 8.05. Found:7, 62.21; 7.1,, 7.13; U, 8.27.

5.2 4-(5-Isopropylaminopentylamino)-l-methyl-l 5-naphthyridin-2-one 8-resorcylate [NT-25]

A mixture of 1.3g of 4-chloro-l-methyl-l,5-naph:'.;ridin-2-one(NI-62), 5 g of 5-isopropylamino pentylamine, and 0.3g of copper-bronze wasstirred at 175' for 20 hrs. After removal of excess amine, at reduced pressurethe rebidue was dissolved in water made strongly alkaline, and exriactedwith ether. The dried ether solution was charcoal tr'ated, concentratedand added to 2g of O-resorcylic acid in a minimum ot ether. The precipitatedproduct was filtered (very hydroscopic at this stage), quickly washed withlarge volumes of ether, and vacuum dried. Recrystallization from methavolyielded ig of NT-25, mp - 194-60.

Anal calcd for C24H3 2N405 : %C, 63.16; M.H, 7.02; N 12.23. Found:%C 62.87; .H, 6.74; *IN, 12.07.

5.3 4-(5-Isopropylaminopentylamino)-l-methyl-6-(2,2,2-trifluoroethoxy)-1,5-naphthyridin-2-one 8 resorcylate [NT-26]

4-Chloro-l-methyl-6-(2,2,2-trifluoroethoxy)-l,5-naphthyridin-2-one was converted to NT-26 in the manner described for the preparationof NT-25. The product was isolated as an off-white powder mp = 200-1' (MeOH).

Anal calcd for C2 6H3 3F3N406: % C, 56.32; % H, 5.96; % N,10.11: Found: % C, 56.51; % H, 5.35; % N, 10.04

- 17 -

5.4 4-Chloro-2-hydroxy-6-(2,2,2-trifluoroethoxy)-l,5-naphthyridine [NI-73)

2, 4-Dichloro-6- (2,2, 2-trifluoroethoxy)-l, 5-nephthyridine wasconverted to the title compound in 25% via the procedure reported for thepreparation of NI-17. Mp = 233-5' (EtOH-H20).

5.5 4-Chloro-l-methyl-6-(2,2,2-trifluoroethoxy)-l,5-naphthridin-2-one [NI-74]

Methylation of NI-73 was effected in the manner detailed forNI-62 in 40% yield. Mp = 139-140* (heptane).

Anal calcd for CIIH8 CIF3 N202. % C, 45.20; M1, 2.74; UN, 9.59:

Found: 7C 45.28; 7U1, 2.97; N, 9.85

5.6 5-Bromo-2-pentanone [NP-70]

To a cooled solution of 100 ml of conceatrated H2SO4 and 200 ml

of 48% HBr was added, dropwise, 100.5 g of 5-hydroxy-2-pentanone. Afterstirring at ambient temperature overnight the reaction was extracted with

ether and the ether backwashed with dilute NaHC03 , dried, and distilled.

The titl3d compound was isolated in 71% yield, b15 mm = 78-80* (lit, 9

b16 = 83-5-).

5.7 l-Phthalamido-4-pentanone [NP-71]

Potassium phthalamide (305 g) and 137 g of 5-bronio-2-pentanone

were stirred and heated, at reflux, in 825 ml of dimetbylformamide for 4 hours.

The cooled reaction was diluted with three volumes of water and extractedwith 3 x 500 ml of benzene. The benzene was evaporated and the residuerecrystallized from MeOH/H20. Mp 73-74' (b13 rmm = 169-173').

Anal calcd for CI3Hl3N2 03 : % C, 67.50; % H, 5.62; % N, 6.06.

Found: % C, 67.52, % H. 5.84; % N, 6.00.

-18

6. REFERENCES

I. P.E. Thomspon and L.M. Werbel, "Antimalarial Agents, Chemistry and

Pharmacology", Academic Press, New York, N.Y. (1972).

2. D.J. Mcf(austland and C.C.Cheng, J. Heterocyci. Chem., 1, 467 (1970).

3. F.Y. Wiselogle, "A Survey of Antimalarin! Drugs", J.W. Edwards, AnnArbor, Michigan, Vol. II, Pt. 2, p. 1365 (1946).

4. J.T. Adams, C.K. Bradsher, D.S. Breslow, S.T. Amore, and C.R. Hauser,J. Am. Chem. Soc., 6, 1317 (1946).

5. A.A. Goldberg, R.S. Theobold and W. Williamson, J. Chem. Soc., 2357

(1954).

6. "Naphthyridine Antimalarial AgenL,", Exxon Annual Technical Report",by John Pilot, Exxon Research and Engineering Co., GRU.5.BJJB.74,April 1, 1973-March 31, 1974.

7. "Naphthyridine Antimalarial Agents", Exxon Annual Technical Report",by John Pilot, Exxon Research and Engineering Co., GRU.9.BJJB.75,April 1, 1974-March 31, 1975.

8. R.F. Borch, M.D. Bernstein, H.D. Durst, J. Am. Chem. Soc., 93, 2897

(1971).

9. Ya. M. Slobodin and I.U. Shokhor, Chem. Abst. 46:7059h.

10. T. S. Osdene, P. B. Russeil, and L. Rane, J. Med. Chem., 10 431 (1967).

19

7. APPENDICES

7.1 Naphthyridie intermediates (NI-73-74)

Structure Code No.

:1

CF8 CR2 O, 9

1 'NI-73

N OR

Cl

NI-74

N0

7.2 Naphthyridine Intermediates (NI-i through NI-*4) 6

Structure Code No.

0OH 0,N 1

C3 -N NI-I

N (BD 26431)N

OH

CH 3 0 .NI-2

COCH2CH3 (BD 26440)

0

0OH

N COCH CH3 2 NI-3

(BD 26459)N

- 20 -

OH 0

-j; ' t 23C - (::-) 0 TJ/] V COC'!Ct

NI-4(BD 26468)

- NI-5S c c(BD 26477)

O.i 0

C N coci CH2 2NI-6 (BD 26486)

N

ou 0

COH

I NI-7

(BD 26495)

Cc HO O

3 .2)3 NI-8

J (BD 26502)N

OH 0

CF3 CH2 0 IZ 'COH NI-9

I~ HO( x2

(BD 26511)N

OH

3 (2 30 I-10

(BD 26520)

- 21 -

OH

CF3C2I, NI-I3 2 N(BD 26539)

Cl

CH3(CH2)30 NI-12

(BD 26548)

Cl

CF 3 C20 NI-13

(BD 26557)

OHN

NI-14(BD 26566)

NOHN

ClN

NI-15

C1 (BD 26575)

ClN

, NI-16

(BD 26584)0CH

c1

N NI-17(BD 54560)

N OH

- 22 -

NNI-18

(BD 54579)OCR CF

N 2 3

cNI-19OCH 2 Cl (BD 54588)

OH ,,CHCHCOCH2CH3

C3C 2 u I NI-20

. -k. (BD 54597)VN

OH 0N3 20 1/2 H2 NI-21

QCO1 (BD 54604)

OH 0N "

c 1

C 1 t N) NI-23

(BD 54622)

- 23 -

NHr2N

a3 (C H 2 ) 30 NNI-244(BD 54631)

N

0OH 0

c C0(i2C 3 NI-25

(BE 10778)

OH 0

110 . OCH2 CH 3 NI-26

(BE 10787)

OH 0

Cl COH NI-27

(BE 10796)

Cl

CH3 04! -C-23

(BE 10803)

Ci

CH CH2 2NI-29

(BE 10803)

-24-

NH(CH ) 5NHCH(,PCH3 )2

NI-30(BE 10821)

N(CH 2 )5 NHCR (CR 3 )2 0

Nil (CR2,) 5NHC!R(CH1) COILH ~NI-3i

.2 H 2 0 (BE 10830)7N.NH(CH )?MIH(C11 3 )2

CH3NHCH(CH2 3 N(C 2 H31

'T NI-32

" N (BE 10849)

~(HCH(C ) 3P(CH2CR3)2

CR3 ~3 0t

* NHcCH) ( CH H2 3 ) COIL7)(HC3 NI-33

7 OHI C 2 (BE 10858)

N NHCI(CH 2 3 (HC{)

CH3

NI-34(BE 10867)

N OCR 3

NH2' HclNI-35

CH 3 (H 2)3(BE 10876)

-25-

Ou

CH30 NI-36(BE 13322)

OH

Cl

CH 3 0 NNI-37

, ,(BE 13331)

Cl

N nl NI-38

(BE 13340)

Cl

N".-39

(BE 13359)

0

cl

NI-40

'N OCH2 C (BE 13368)

OH 0

CH 0 COCH2CH NI-412~ 2 3 (BE 13377)

-26-

Naphthyridine intermediates (NI-42 throuh NI-~72) 7

Code Numnber

OC!{3 I4

C'::,30N (BE 17133)

Cl

5:,."L NI -43CcC- (BE 17142)

N

0

Cl

N N N4-44CC62 ) 30 (SE 17151)

0

ClN 111-45

CF Can,2-<: (BE 1716)

Cl

0 Ni-46CE-.C NH23 (BE 17179)

Ncl

- 27 -

Structure Code Number

OH 0

CH 20 COH e 1/2 H20 NI-47

(BE 17188)

C-.3CH20~rjt~Z.(~117NI-48

(E-Z 17197)

NH-Z

CF3 022 0--NI-49

N (BE 17204)

OH

I 1NI-50

N1 OH (E43757)

Cl

N

II N-5iN c Cl (BE 43866)

NY

r-28-

Structure Code Number

Cl

CR NI-52

(BE 43875)SOCR

3

OCH3

CH3 7 NI-53I 1I (BE 43884)

OH 0

CH. CC2C3 NI-541(BE 43893)

N

OR 0

CH. N (EE 43900)N-

OH

CH 3C NI-56

(BE 43919)

N

NH -T cotI NI-57R 3 5 -' " I

-. 9 ~(BE 43919)N4

--29 -i

nfl -

Structure Code Number, ' 0 C H 3

3

NI-58c1 (BE 43937)

clNCF3CH2- ",r ,

NI-59OCH3 (BE 43946)

cl

NNNI-60

NH2 (BE 43955)

o-jN

SNI-61 (BE 43964)

clN

N 0

I (BE 43973)CH3

- 30 -

Structur- Code Number

NHCH2CH CHCH2 CH2NCH(C3)

N~C2C 2 2 22 32

) INI-63N CH2 CH2 CH2 CH2CH 2 NHCH (CH3 ) 2 (BE 57333)

CH

NICH C2 C 2 CH2 N (CH 22 CH3 ) 2

Q NI-64

NH3 N.C HCH2 CH2 CH2 N(CH2 CH3 ) 2 (BE 57342)

CH3

CH 0

N CH1 H Cl CH 12N(CH2 CH3 ) 2 OR

3C2 23 NI-65[:AN -;-tNHHCH2 C 2 C 2 (CH2CH )2(BE 57351)

CH3

cl

NI-66

N N- (BE 57360)

0

0

CR3 NCOCH 2 CI 3CI3 NI-67

(BE 57379)

CH 3

Cl

CH3CH 2 C! 2CH2 NI-68

Cl (BE 47388)

- 31 -

Structure Code Number

OCR3

cifCHCHCH

NI-69O 5H3 c(BE 57397)

CH

N iqCHCH2 CH2 CH2 "(C" 2 CH3) 2

OCI NI70

N'

3 (BE 57404)

Cl

NI-71

(BE 80207)

0

ClNC CHCH2 CH2H- 2O 2 y NI-72

(BE 80216)N -N CHR3

- 32 -

7.3 Naphthyridine Precursors (NP-70-71)

0'ICH3CCH2CH2CH2Br NP-70

0oo

CH3CCH2CH2CH2-N Jo NP-71

it

0

7.4 Naphthyridine Precursors (NP-1 through NP-43)6

CH30 "NP-i

(BD 26593)NO2

CH3 (CH2 ) 3 0 NP-2(BD 26600)

S(HNP-33(2) 970 1NO2 (BD 26619)

- NO 2

N

C 3Ci 2 .O NP-4(BD 26623)

oNO,

C, CH2O NP-5

2(BD

26637)

-33-

NCH3 (CH2 )3 0 l/31 2HC1 NP-6

(BD 26646)NH22

CH (CH 2HCI NP-7NH 2 (BD 26655)

N

CF CH20 NP-8(BD 26664)

NH2

cl Cy 0H20".-A' NP-9

, . (B D 2 6 6 7 3 )

L3H 0 NP-10= 2C (BD 26682)lvuCH=C.COCH

2CH 3)2

CH3 (CH2 )30 NP-1

(BD 26691)NHCH=C4COCH 2CH 3)2

CF CII2 0 NP-123210 (BD 26708)

NHCH=C4COCH2CH3)2

ci C H) P- 13

to0 (BD 26717)" ITHCH=CCOCH 2CH 3) 2

-34-

0Is

N C

NH NP-14c / (BD 26726)

I,

0

C-0 NP-15

N 2Cu (BD 26735)

COH NP-16

(BD 26744)N~2

01I

N COCH2CH3/ NP-17

N, (BD 26753)

Nci 3C120-ci NP-18

/N (BD 54640)

NNP-19

20 (BD 54588)

NCH-POC1 2 CH 3 )2

- 35 -

NCH 3 (CH 2) 9 0_-/<,

K 0 NP-20

NHCI=C-C2 CU3 )2 (BD 54668)

NC3 NP-21

NO (BD 54677)2

NN1C1 NP-22

NO 2 CH3 (BD 54686)2

HO CH3 NP-23

(BD 54695)NO2

Cl , N_ CU3 NP-24

(BD 54702)NO2

Ncl NP-25

(BE 10885)

2

-36-

C 0 NP-26NHCI= C(COCH 2 CH 3) 2(BE 10894)

0It NP-27

CHc3OCH=CuCOCH3 ) 2 (BE 10901)

NCH 300 NP-28

. - N H) (BE 10910 )

N..-NHCH-C-(COCH 3 ) 2

CH 0- CH3 NP-29CH3 c (BE 10929)

r NO2

0if

C 3 N COHCH3°/ NP-30

NH 2 (BE 10938)

0

ONCOCH3 NP-3 1

COCH 3 (BE 10947)

00t oN "O

a C CH -32

H ° 3 (BE 10956)

03

-37-

3 3JI3 NP-33NHCCH (BE 13386)

it 30

0

CH36 A COII3 NP-34

NHCCH (BE 13395)of 30

0

o

C 3 NP-35

COCH. (BE 13402)

o 30

0,N CO 3NP-36

COCH 3 (BE 13411)0

0C 30 " COHt

'NP-37

C O -I (BE 13420)if 20

0

3 -H NP-38/l (BE 13439)

i00

- 38 -

0

cif N NP-39Cu (BE 13448)

2

0N

CH30 " COCH 2CI3 NP-40H2 ~(BE 13457)

C 0NP-4120 (BE 13466)

-QNO2

2 N,. 2 (BE 13475)

CHN0 NP-430 (BE 13493)

NHCH=C-(COQI 2CH3 ) 2

- 39 -

Naphthyridine Precursors (N?-44 through hP-69)7

Structure Code Number

0t2

C' fCoH NP44

COR (BE 17213)

O

0

CNH2 NP-45C E 1CN4 (BE 17222)

0

0

CE3 -H NP-46

(BE 17231)I,

0

0'I

CCOH N-47

(BE 17240)NH 2

0'3

CH3 COCH2 CH3(BE 17259)

2

- 40 -

Structure Code Number

0

3 4N-4O(BE 17268)

0

0CH3 cf NHl

NP-50

COH (BE 17277)Ii

0

NCH 3 No NP-51

(BE 43982)

NCH 0 NP-52

'T.0 %COCH 2 CH3" CH(BE 43991)

CH NP-53

I (BE 44005)

lo CNH

- 41 -

Structure Code Niurber

CH 3 NP-54

U NH 2 (BE 44014)

N3 0 Ni-55CH HH-*CCHC")

H=CJCO CH 2 CH3)2 (BE 44023)

NTi NO2 NP-56

2 J NP-56

O2 (BE 57413)3

NTh N~-*

O2 __ (BE 57422)

C' 3

Ho - N-53

I (BE- 57431)CO 2

-42 -

Structure Code Number

NP-59CO2

(BE 57440)"c3

CH 3 0" 1 NP-60

NO2 (BE 57459)

3

CH3

3 0NP-61

2 (BE 57463)

CH 3

CH3 T 0 Nr-62

N \HCH=C(COCH 2 CH3 ) 2 (BE 57477)

CH 3

OHAN

IN-63(BE 57466)

CH3

- 43 -

Structure

Code Number

0It

COl

NP-64COH (BE 57495)91

CH3 o

K 1 NP-65Y2 (BE 57502)

CH3

0 I NT-66(BE 57511)

CH 3

0It

N c NP-67, C(BE 80172)

CH3 i

C3 0

0NH NP-68

CH i(BE 80181)CH3 0

COH

NP-69

, 3 2 (BE 80190)CtR3

-44-

7.5 Biological Activity Data

Test results in the Rhesus monkey Lnfected with sporozoites of theB strain of P. cynomolgi have been obtained for most of the target drugs whichhave been submitted to WRAIR. In general, no significant prophylactic activityhas been observed in the Rhesus monkey in the lower dosage range (I mg/kg).However, one target compound, 2-hydroxy-4- (5-isopropylaminopentylamino)-1,5-naphthyridine (NT-7), continues to afford protection after more than seventydays at a dosage level of 10 mg/kg.

INR (CH2 ) 5Nt CH(CHt3 ) 2

I (NT-7)~H

While biologic testing data are not yet complete in the P..berghei/mouse

curative screen (10), we have included below a summary of the activity data

received to date.

Compound Activity (T-C)Code No-. 1RAIR No. 12mg 20 40 80 160 320 640

NT-2 BD 26413 0.2 0.2 1.2 2.8 5.2 9.2

NT-4 BD 54711 0.1 0.3 0.9(2)

NT-5 DD 54720 0.1 0.1 0.1

NT-6 BD 54739 0.1 0.1 0.3

NT-8 BD 54757 0.3 0.3 2.9 3.7 5.9 7.9(2)

NT-9 BD 54 766 0.1 0.5 2.1 4.1 6.9 8.9

NT-10 BD 54775 0.1 0.1 0.3

NT-13 BE 10983 0.5 0.7 1.7 3.7 4.5 0.0(5)

INT- 4 BE 10992 0.3 0.0(5) 0.0(5)

NT-15 BE 11006 0.1 0.3 0.3 0.5 2.5 5.3

NT-17 BE llOz4 0.3 0.4(1) 0.0(5)

NT-19 BE 13500 0.3 0.5 0.0(5)

NT-20 BE 17286 0.3 0.5 0.0(5)

NT-21 BE 17295 0.3 0.7 1.1

In addition NP-18 through NP-50 and NI-17 through NI-49 (excluding NI-26

and NI-33) have also been tested in the therapeutic screen at dosage levels of

40, 160 and 640 mg/kg. None of these precursors and intermediates exhibited a

T-C in excess of 1.0 day at any dosage level.