CA2109186A1 - Aminocarbonyl (thiocarbonyl) and cyanoguanidine derivatives of quinoline and indoline - Google Patents

Abstract

Abstract AMINOCARBONYL (THIOCARBONYL) AND CYANOGUANIDINE
DERIVATIVES OF QUINOLINE AND INDOLINE
Novel compounds having potassium channel activating activity and useful, for example, as antiischemic agents are disclosed. These compounds have the general formula I

, wherein A is or a single bond to complete an indoline nucleus;

X is -O-, -S- or -NCN; and the R groups are as defined herein.

Description

" 2~0918~

-l- HA614a AMINQC~ON~I~OCARBONYL! A~D CYANOGUANI~INE
DERIVATIVE$ QF OUINOLINE~ AND I~OLINE

, In accordance with the present inwntion novd compounds having potassium channel ac~a~ng ac~vi~ and useful, for example, as an~ischemic agents are disclosed. These compounds have the general fonnula R~
~X

~A ~--R3 and phamlaceu~cally acceptaUe salts the~of wherein A is --~ or a single bond to complete an indolinc . R~ Rg nucleus;
X is -O-, -S- or-NCN;
Rl is aryl, arylalkyl, heterocyclo or (heterocyclo)all~l;
R2 is hydrogen, alkyl or arylal~l, or Rl and R2 takcn together forrn a 5- to 7-membercd sah~ated or unsah~ated ring, which may further include an aryl group fu~ed to 2 car~on atoms of such S- to 7-membaed ring;
R3, R4, R7 and R8 arc each indcpcndently hydrogcn, allyl or arylallcyl; or R3 and R4, or indcpcnden~y R7 ~nd Rg, tal~en toge~cr with -~` 21091~
HA614a the carbon atoms to which they are attached form a 5- to 7-membcred carbocyclic ring, with the proviso that when A is ~ , and R7 and Rg R~ R8 are other than hydrogen, then R3 and R4 are hydrogen, or when R7 and R8 are hydrogen then, R3 and R4 are other than hydrogen; . -RS is hydrogen, allyl, haloaL~cyl, alkenyl, al~ynyl, cycloalkyl, arylalkyl, (cycloalkyl)alkyl, -CN, -NO2, -COR, -COOR, -CONHR, -CON(R)2, -CF3. S-alkyl, -SOalkyl, ~SO2alkyl~--P(o~ )2~ ~.
Ib~

(~ CH2)n , halogen, amino, substituted anuno, -O-a~yl, - --OCF3,-OCH2CF3,-OCOalkyl,-OCONRalkyl,-NRCOall~yl, ~-NRCOC)alkyl or -NRCON(R)2 wherein R is hydrogen, allcyl, aryl, arylalkyl, cycloalkyl, (cycloallcyl)allcyl or haloallcyl;
R6 is hydrogen, aL~yl, halo, OH, -O-allcyl, an~ino, subs~d~uted - ~ ~ -arnino,-O-aLlyl,-OCOalkyl,-OCONRaLIcyl,-NRCOallcyl,-NRCOOa~yl or -NRCON(R)~; and - -n is an integer of 1, 2 or 3.

This imcntion relates to the novel compounds of fonnula I
which are useful as antiischcmic agents. ~ ;
Thc tcnn "alkyl" used in defining various symbols refers to straight or b~anched chain saturated hydrocarbon radicals having up to eight carbons, preferably from one to fivG carbons. Simila~ly, the tcnns "aLl~oxy" and "aL~ylthio" refer to such all~yl groups attached to an oxygen or sulfur.
2S The term "alkcnyl" refers to straight or branched chain hydrocarbon radicals having from two to cight carbons and at least one double bond, preftrably three to fivc carbons. The tcrm "alkynyl" refcrs to straight or blanched chain hydrocarbnn radicals having from h~o to eight carbons and at least one ~aiple bond, preferably th~ee to ~Ive carbons. ~ ~
-:

` 210918~

3 HA614a The term "cycloalkyl" refers to saturated carbocyclic rings of 3 to 7 carbon atoms with cyclopropyl, cyclopentyl and cyclohexyl being most preferred.
The te~m "halo" or "halogen" refers to chlorine, bron~ine, iodine 5 or fluorine.
Thc term "halo substitutcd alkyl" refers to such alkyl groups described above in which onc or more hydrogens have been replaced by chloro, bromo, iodo or fluoro groups such as chloromethyl, bromomethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trichloroethyl or 2,2,2-10 trifluoroethyl. Trifluorome~yl is prefe~
The term "aryl" Fefers to phcnyl, I-naphthyl, 2-naphthyl or mono substituted phenyl, 1-naphthyl, 2-naphthyl whercin said subs~tuent is al~yl of 1 to 4 carbons, (arnino)allcyl, (substitutcd amino)alkyl, alkylthio of 1 to 4 carbons, alkoxy of 1 to 4 carbons, halo, nitro, cyano, hydroxy, 15 amino, -NH-alkyl wherein alkyl is of 1 to 4 carbons, -N~allcyl)2 whcrein ~ Rg -O-CH
alkyl is of 1 to 4 carbons, -CF3, -O(haloalkyl), A~ Rg -S-CH2~
-- , (wherein Rg is hydrogen, alh,rl of l to 4 carbons, alkoxy of 1 to 4 carbons, allcylthio of 1 to 4 carbon, halo, hydroxy or-CF3), -~CH2~ycloalkyl9 -S-CH2~ycloalkyl, o~ -20 -alkyl(COORIo) (wherein Rlo is hydrogcn or alkyl), and di-subslituted phenyl, l-naph~hyl, 2-naphthyl wherein said subs~ucnts are methyl, methoxy, methylthio, halo, -CF3, nho, an~ino, ~ ;2, or -allcyl(COORIo)-Preferrod aryl groups include unsubstituted phcnyl and 25 monosubstituted phenyl whereul the subsdtuents aro nitro, halo, -CF3, all~yl, cyano, methoxy, or -alkyl(COORIob).
The tenn "hetcrocyclo" refers to fully saturatcd or unsaturatçd rings of S or 6 atoms containin~ one or two O and S atorns and/or onc to four N atoms provided ~at the total numbe~ of hete~ atoms in the nng is 30 4 or lcs. Thc hetero nng is a~ched by way of an a~railable atom.
Pref~red monocyclic hcterocyclic groups include 2- and 3-thienyl, 2- and -- 2109~8~
HA614a 3-furyl, 2-, 3- and 4-pyridyl, and imidazolyl. Thc term hetcrocyclo also includes bicyclic rings wherein the five or six membercd nng containing 0, S and N atoms as defined above is fused to a benzcne nng and the bicyclic ring is attached by way of an availablc carbon atom. Prefcrred S bicyclic hetero groups include 4, 5, 6, or 7-indolyl, 4, 5, 6, or 7-isoindolyl, 5, 6, 7 or 8~uinolinyl, 5, 6, 7 or 8-isoquinolinyl, 4, 5, 6, or 7-benzothiazolylt 4, 5, 6 or 7-bcnzoxazolyl, 4, 5, 6 or 7-bcnzimidawlyl, 4, 5, 6 or 7-benzodiazolyl, and 4, S, 6 or 7-bcnzofuranzanyl. ~ -The tcrm heterocyclo also includes such monocyclic and -10 bicyclic rings wherein an available carbon atom is substituted with a lower alkyl of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, lower a1koxy of 1 to 4 carbons, halo, nitro, keto, cyano, hydroxy, amino, -NH-al~yl wherein allcyl is of 1 to 4 carbons, -N(allyl)2 wherein alkyl is of 1 to 4 carbons, -CF3, or -OCHF2; or such monocyclic and bicyclic rings wherein two or three a~railable carbons are substituted with methyl, mcthoxy, ~ ~
methylthio, halo, -CF3, nitro, hydroxy, amino or -OCHF2. ~ ~-The term "subsdtuted amino" rcfers to a group of the forrnula -NZIZ2 whcrein Zl is hydrogcn, allcyl, cycloalkyl, aryl, arylalkyl, cycloal~ylalkyl and Z2 is alkyl, cycloallcyl, aryl, arylalkyl, cycloalkyl-20 allcyl or Zl and Z2 taken together with the nitrogen atom to which they areattachedare l-pyrrolidinyl, 1-piperidinyl, l-azepinyl,4mo~pholinyl, 4thiamorpholinyl, l-piperazinyL 4aLlcyl-l-piperazinyl, ~arylallcyl-l-piperazinyl, or 4diary1alkyl-1-piperazinyl, cach of which may bo optionally substituted with alkyl, alkoxy, alkylthio, halo, ~ifluoromcthyl 25 or hydroxy.
Thc compounds of fonnula I wherein X is oxygen can be prepared by trea~nent of a compound of the formula II -R~ C-(~NO2 with ~ compound of the formula ,~- - , , ~- . ., - , . . .

--` 2109~
HA6 14a III

~A~I--R3 in an organic solvent. such as dimcthylfonnamide, telrahydrofuran, S acetonitrilc or dichlommethane.
Compounds of formula I wherein R2 is hydrogen and X is oxygcn or sulfur can also bc prepared by reacting a compound of formula m with an isocyanate or isothiocyanate of the formula IV
RlN=C=X
where X is oxygen or sulfur.
Compounds of formula I wherein X is NCN can bc prepared by trca~nent of compounds of formula I wherein X is sulfur with cyanamidc in the pressncc of dicyclohexyl carbodiirnide or 1-(3-dirnethylamino-15 propyl~2-cthylcarbodiimide hydrochloride.
Compounds of fonnula I wherein X is NCN can also be prepared by treatment of an int~me~ate of formula V

~ NJ~ (~

wi~ a compound of fonnula m.
Compounds of formula I whcrein X is NCN can also bc preparod by first treating compounds of formula m with : ~
diphenylcyanoca~bonilT~idate ?~1 the presencc of an or~?anic basc such as : ~ :
pyndine or triethylamine, followed by reaction wi~ an amine of ?~o?~rnula 2S V~?
~2 R
opdonally in the presence of ~ne~ylalulr~inu~
-2109~86 - 6 - HA614a Compounds of formula II can be preparcd, for cxamplc, by treatment of a eompound of the formula VI with 4-nitrophcnyl- ~ ' chloroformatc.
Thc compounds of forrnula III whcre A is a single bond, Rs is S -CN and R3 and R4 aIe each hydrogen and R7 and R8 are as defined, can be prepared according to Scheme 1.

R~;~'CH3 Al~ ~CH3 NaO13r C~OH 2 AO~ HNO~

O O
02N~cb~R3 H~ Pd/C ~`Ob<~t 2) csUB NaN~

X N
o NOH
B~ 0H~Ha~ ~
~ R NaOAc ~L_¦~ R pyndil~e XII xm O ~==~ .
N ~ CH3 H H
8r~N~NC~C, N~
CH2C12 ~ J ~u~ N--- " L 11 3 -78-~ 0~C ~ ~ N~/200C ~
R~ R~ R~ R3 R4 xn xv XVI

"-` 210gl8~
HA614a . 7 Benzene or a subsdtuted derivative thereof is allcylated with an c~
unsaturated ketone in the presence of a Lewis acid (aluminum chloride, dn chloride etc.) to provide a compound of formula VII which upon oxidatdon with, for example sodium hypobromide, gives the acid of formula VIII.
5 The acid is converted to its chloride by treatment vith phosphorus oxychioride or thionyl chloride, which on treatment with a Lewis acid gives an indanone of formula IX. The aromatic ring is nitrated with fu~flg nitrie acid to give a compound of formula X whieh upon catalytie hydrogenatdon gives the amino compoond of formula XI. The amino 10 compound is converted to the bromide X~ via its diazonium salt, prepared by treatrnen~ with sodium nitrite and hydrobromic aeid. The Icetone XII is eonverted to its oxime XIII under standard conditions (hydroxylamine hydrochloride and sodium acetate). The oxime XIII is subjeeted to reductive Beekman rearrangement (diisobutylaluminum hydnde in an 15 organie solvent such as te~ahydrofuran, diethyl ether) via its tosylate XIV, prepared from xm by treatment with tosyl chloride in the prcsence of an organic base such pyridine or triethyl amine. The bromide in the resul~ng produet XV ean be replaeed with other groups sueh as nitdle (e.g, XV~
trifluoromethyl, ~alkyl, S-al~yl, alkenyl, allcynyl ete., by methods 20 deseribed in the literature.
Compounds of formula m wherein A is -CH2-, RS is -CN and ~-R3 and R4 are as defined, can be prepared aeeording to Seheme 2.
~h~ 2 G b KOCM~ ~R3 HN03 O~N~R~
~ e R4 Xvll xvm XIX
o O
~nC12 ~, ~R -1-) HBr~NaN~-Br~ R~
EtOH l~ ' 2.) CuBr ~R~
xx x~a :

2iO9~8~
HA614a NOH H
H~HCI~ ~ R~ DIBAIH ~ R3 NaOAc CH2C12 R~
EtOH, ~ 78--- 0-C
XXII xxm H

t'l!t`N ~ ~, NMP I 00 C R~
XXIV ::
The indanone XV~ is alkylatcd with an alkyl halide and a base such as ~ ~ -S potassium ter-butoxide to gn~e compound XVI~ which upon nitration (fuming nitric acid) provides XIX. The ni~o ~oup in XIX is changed to the bromide X~ via the same reaction sequcnce as descnbed for compounds X to XII in Scheme 1. llle rcducdve Bechnan realFangemcnt of oxime ~I proceeded undcr standar~ conditions (diisobu~laluminum 10 hydride in telrahydrofuran) to give bromo~trahydroquinoline X~II in good overall yield. The brominc in X~II can bc changed to o~er groups .
(e.g., CN, CF3, ~alkyl, S-allyl ctc.) under standard conditions, such as dlose shown for ~e prepara~on of compound X~V.
Compounds of formula m whertin A is a singlc bond. Rs is -CN alld R3 and R4 are as defined, can be p~pa~ed according to Scheme .
3.

H H
N-smmosuccinimide Br ~o~, Br Sul~
senzene~ hat dia~

xxv Xxvl ~ ~
:
M~
N ~O ~ :
Br~ ' Acelicanhyd~ r~ N~ro Sodiumhydride R~ ~R3 210~8~
HA614a Br N o Sodium hydroxide ~o Rod-AI
1~R3 aqueous me~lunol Tolucne x~x XXx M~
H ~o Br~O~N~ Triethylamine Br~N~ CuCN
R3 Acetyl chlonde ~ ll3 N;methylpynolidene, XXD l~.YX~
M~= O H - -NC~N~ SNHCI NC~ ~ R
~ It3 Ace~oni~e ~ 3 :
s xxxm ~v ~, . .
Bromination of indole XXV with N-bromosuccinimidc 8ives the dibromide of fonnula XXVI which upon acid hydrolysis (sulfuric acid, :
hydrochloric acid in an organic solvent such as dioxane) provides thc : .
amide of fonnula XXVD~ e ni~ogen in XXV~ is protect~d (acetic ~ -10 anhydride a td sn orgaoic base such as pyridinc or triethyl arnine) and the resul~ng acetamide XXVIII is alkylated wt~ an allyl halide and a basc such a~ sodium hydride to give X~X. l~e acetate in X~X is removed by trea~ncnt with an aqueous basc such as sodium hydroxide and thc amide X~ is reduccd with a reducing agent such as sodiwn bis(2-15 methoxyethoxy)alLuninum hydride (Red-AI). The resul~ng product X~I
is protec~d (acedc anhydride and an organic base such as pyridine or triethyl amine) as an acetamidc XX~I and the broa~inc is changed to an appropriate group (e.g., CN, CF3, ~all~yl, S-allcyl etc.) wlder standard -conditions. The acetarnide protecting group is then removcd by treatment 20 with aqucous acid ~ydrochloric acid, sulfuric acid in an organic solvent such as dioxane) to provide a compound of forrnula X~IV.
Compounds of forrnula IV are commercially available.

21~9~
HA614a Compounds of the formula V can be prepared by trcatmcnt of compounds of the forrnula VI with diphenylcyanocarbonimidate.
Compounds of formula VI are comrnercially av~ulable.
The compounds of the present invention can havc asymrnctric 5 centers at carbons 2~ of te~ahydroquinoline or carbons 2, 3 of indolinc rings. Also, any one of the R's can havc an asyrnmetlic carbon.
Consequently, compounds of formula I can exist in diastereomeric forrns or in mixtures thereof. The above descri~ed prosess can utilizc racemates, enantiomers or diastereomers as star~ng materials. Wllen diastereomenc products are prepared, they can be separated by conventional ~ --chromatographic or fracdonal crystallization methods.
The compounds of thc present invention wherein R2 is hydrogen can exist as a mLsture of tautomers represented by thc following structures. The tau~omeric products arc obtained in reladve amoun~s that 15 differ from compound to compound. All forms arc includcd in d~c scopc of fonnula I
l 2 Rl-N
~CX

=~A l--R3 such as cornpounds of formula 20 1' Rl-N~
. .
R~

2~09186 HA614a Preferred compounds are those wherein A is ~ or a single bond;
R7 Rg Rl is aryl, arylalkyl, heterocyclo or (heterocyclo)alkyl;
S R2 is hydrogen or alkyl;
R3 and R4 are independcntly hydrogen or alkyl;
RS is an electron withdrawing group; -~
R6 is hydrogen, alkyl or O-al~yl;
R7 and R8 are independently aLIcyl; and X is O or NCN. -Most preferred are those compounds wherein A is ~ or a singlc bond;

Rl is phenyl, phenylrnethyl, substitutcd phcnyL ~:
substitutedphenyllnethylorpyridyl;
R2 is hydrogen; ~ -R3 and R4 are independently hydrogcn or methyl;
Rsis-CNor-NO2;
R6 is hydrogen;
R7 and R8 are independent1y hydrogen or me~yl; and ~ -X is O or NCN.
The compounds of fo~nula I and thc pharmaceutically acceptable salts act as potassium channel activators. Thus, compounds of the prcscnt invention are uscful cardio ~ascular agents, e.g. as anti-a~hy~nic agents and antiischcmic agents.
Compounds of fonnula I are parlicularly useful as andischernic agenS since they havc bcen found to possess little or no vasodilatory activiny. Tbus, compounds of formula I are uscful for ~e treabnent of ischemic conditions, e.g. myocardial ischernia, cereb~al ischemia, low~r limb ischernia and the lilce. The selecdvity, i.e., antiischen~ic activity with little or no vasodilatory activity, means that Dl the treatment of, for example, ischemic heart, these compounds are less lil~ely to causc coronary steal, profound hypotension and coronary undeIpafusion. By .. :: , , 210918fi HA614a little or no vasodiladon acdvity is meant that these compounds havc ICS0 (rat aorta) values greater than that of the potassium channel activator, cromakalim. The "selective" andischemic agents typically are those having ICso (rat aorta) values >lO dmes that of cromakalim (i.e., have 1/10 the vasodilatory action) and preferably those having ICS0 values >50 times that of cromakalim.
Thus, for example, by the adn~inistration of a composidon containing one (or a combinadon) of the compounds of this invendon, -ischemic conditions of a mammalian ~e.g., human) host are reduced. A
single dose, or preferably two to four divided daily doses, provided on a basis of about 0.001 to 100 mg pcr Idlogram of bodiy weight per day, preferably from about 0.1 to about 25 mg per Itilograrn per day, is -appropriate to reduce ischemic conditions. The substance is preferably administered orally, but parenteral routes, such as the subcutaneous, int~nuscular, or in~avenous routes or any other convenien~ delivery system, such as inhalation or in~anasal solu~ons or transdermal patches, can also be employed. The abovc doses are also suitable for the other cardiovascular and non-cardiovascular uses.
As a result of the potassium channel acdvating activity of compounds of this invendon, these compounds are also uscful in the treatment of cardiovascular disorders. For example, compounds of the present invention are useful as therapy for congestive hea~t failure, as anti-anginal agents, as anti-fibrillatory agents, and in limidng myocardial infarction.
Compounds of thc present invendon are additionally expected to be usefill in the treatment of cen~al nervous system disordcrs (e.g., Parkinsonism, as and-tremor agents, epilepsy).
The compounds of this invention can also be formulated in combination with a diuretic such as, chlorothiazide, hydrochlorothiazide, flumethiazidc, hydroflumethiazidc, bendroflumcthiazidc, methylchlothiazidc, trichloromcthiazidc, polythiazide or bcnzthiazidc as wcll as cthacrynic acid, tricrynafen, chlorthalidonc, furosemidc, musoliminc, bwnetanide, ~iamterene, amiloride and spironola~one and salts of sueh compoundis, angiotcnsin convefing enz~lme inhibitors s~lch " 210918B
HA614a as captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopnl, quinapril, ramipril, lisinopril, and salts of such compounds, thrombolytic agents such as tissue plasminogen activator (tPA), recombinant tPA, st eptokinase, urokinaso, prourokinase, and 5 anisoylated plasminogen streptokinase acdvator complex (APSAC, Eminase, Beecham Laboratories), or calcium channel blocking agents such as nifedipine or diltiazem. Such combination products if formulated as~fixed dose employ the compounds of this invendon within the dose range deseribcd above and the other pharmaceutically active agent within 10 its approved dose range.
Thc compounds of formula 1, and combinations thereof, can be formulated, as described above, in compositions such as tablets, capsules or eli~drs for oral administration, in sterile solutions or suspensions for parenteral administration, and may also be administered via transderrnal 15 patch or nasal inhalation solutions. About 10 to 5Q0 milligrams of a compound of formula I is compounded with physiologically acceptable vehicle, carner, excipient, binder, preservadve, stabilizer, flavor, etc., in a udt dosage form as called for by accepted pharmaceutical practice. The amount of active substance i~ these composidons or prepa~ations is such 20 that~suitabh dosage in the range indicated is obtained.
Specific embodimen~s of the present invention are described hereinafter in the following examples.

2109~86 - 14 - HA614a ExalnRI~ 1 7-Cyano-3,~dihydro~,4-dimethyl-N-phenyl- 1 (2H)~uinolinc-A. 4-1~
To a slu~y of AIC13 (40.0 g, 0.3 mole) in benzene (90 mL) ~~ maintained at 10C under argon was added dropwise mesityl oxide :
(0.2 mole, 19.63 g). Upon,compledon of the addidon the reactiorl was stirred at room temperature for 1.5 hours. The reaction mixture wæ
poured onto ice/10% HCI (350 g). The organic layer was separated and -, - , the aqueous layer was extracted with ethyl acetatc (100 mL). The ' ' combined organics were washcd with disdlled H20, saturated NaHCO
solution, saturated NaCI soludon and dried over Na2SO4. The solvcnt wæ
recovered under vacuum and the crudc product (31.6 g) was vacuum disdlled (b.p. = 107C @ 3.0 mmHg) to obtain 24.5 g (69%) of the title A
compound as a colorless oil. MS: (M+H)+ @ 177.

B. 3-~hy~ pheny~ acid To a solution of NaOH (47.2 g, 1.18 mole) in icclH20 (270 g) rnaintained at 45C was addcd Br2 (68.7 g, û.43 mole) followed by 4 me~yl-4phenyl-2-pcntanone (23.7 g, 0.135 mole). The rcacdon was sti~Tcd for 18 hours at room tcmpcrature. Thc crudc rcaction mL~ture was cxtracted with CCl~ (discarded), acidified to pH 1-2 with conccntrated HCI solution and extractcd with ethyl acctatc. The combined organics were washed with saturatcd NaCI solution, dried over Na2SO~, and cvaporated in vacuo to ob~ain 22.5 g of thc ~tlc B compound as an off-white solid. This was used in thc ncxt step without fu~hcr pudfication.
MS: (M+NH4h @ 196.
3û
C. ,3~,3,-~ hyl-1-indanQn~ ~ :
To a solution of 3-methyl-3-phcnyl butanoic acid (17.1 g, 95.5 mmoles) in benzene (70 mL) was adlded K~ls (23.û g, 0.11 molc, . ~' l.lS eq.) por~onwi~c widl cooling. Upon completion of thc addition, the 2109~8~
.
HA614a reaction mixture was refluxed for 30 minutes and cooled to room temperature. Aluminum chloride (13.1 g, 98.3 mmoles) was added in increments and the reaction was heated at reflux for 30 minutes. The reaction mixture was poured onto ice; the oily layer was separated and the 5 aqueous layer was extracted with ethyl acetate. The combined organics wer~ washed with 5% HCI soludon, saturatçd NaHC03 solution, saturated NaCI solution and dried over MgS04. The solvent was evaporated ln --vacuo and the crude product (14.3 g) was vacuum distilled (b.p. = 103C
@ 2.3 mmHg) to obtain 9.98 g of the title C compound as a colorless oil.
10 MS: (M+H)~@ 161.

D. 1 1-l:)imç~l-5-nitro-3-inda~
A mixture of nitric acid (90% fuming, 35 mL) and urea (0.17 g) was eooled to -10C and purged with air for 20 minutes; 3,3-dimethyl-1-lS indanone (8.68 g, S4.2 mmoles) was added and the reaetion was stirred for two hours at -10C to SC. llle reacdon mL~cture was pou ed into iee/H20 and extraeted with ethyl aeetate. The eombined ex~aets were washcd with distilled H20, saturated NaHC03 soludon, saturated NaCI solution, and dried over MgS04. The solvent was reeovered under vaeuum to obtain 20 10.0 g of a yellow so1id. llle aude produet was reerystallized from - - methanol in two erops to obtain 8.08g (71%) of the title D eompound as yellow needles. MS: M- @ 205.

E. ~ dimethy~ -Gne A solution of the title D compound (6.5 g, 31,7 mmoles) in methanol (lS0 mL) containing 5% Pd/C (0.7S g) was sti~red under H2 at 15 psi for four hours. The catalyst was fltered and the me~and was reeovered under vacuum to obtain 5.72 g of the dtle E eompound as a green solid. The reaetion produet was uscd in the next step without further 30 purifieadon.

F. 5-~lQml~ i~lindan-3-one To a soludon of the title E eompound (6.02 g, 34.4 mmole) in a ture of 48% aqueous HBr solution (9.7 mL) and ethanol (30 mL) ;

; ~, .

2109~8$
HA614a cooled to 0C was added NaNO2 until a positive starch-iodidc test was obtained. The cold diazonium salt solution was added via pipette to a mixture of CuBr (5.42 g, 18.9 mmole) and 48% aqucous HBr solution at 95C. The reaction mixture wæ heated at reflux for 15 nunutcs, coolcd to S room temperature and partitioned betwccn cthyl acctatc and distilled H20.
The organic phase was washcd with saturated NsHCO3 solution, saturated NaCI solution, dried over MgSO4 and evaporated in vacuo to obtain 7.33 g of an orange solid. The crude product was chrornatographed on silica cluting with hexane/ethyl acetate (4:1) to obtain 6.52 g of the title F
compoundasaycllowsolid;m.p. 117-118C.

G. 5 ~L~
A solution of the dtle F compound (6.52 g, 27.3 mrnole) in cthanol (130 mL) containing NH20H-HCI (3.79 g, 54.5 mrnolc) and sodium acetate (4.03 g, 49.1 mmolc) was hcated at reflux far 2.5 hours.
The solvent W8S recovered under vacuum and thc residuc was partitioned between ethyl acetate and dis~lled H20. The organic phase was washed with saturate~l NaCI, dried over MgSO4, and evaporatcd in vacuo to obtain 6.94 g of the ~tle G compound as a ycllow solid. Thc product was uscd in thenextstepwithoutf~herpurification;m.p. 115-117C

H. $-Bromo-1.1-dim~thylindan-3-one oxime tQ~
To a soludon of the title G compound (S.30 g, 20.9 m~slole) in py~idine (50 mL) cooled to 0C was added ~toluenesulfonyl chloride ~ -(4.77 g, 2S.0 mm~le). The soludon was warmed to room tcmpera~e and stilrcd for 18 hours. The reacdon mixnlre was dilutcd with ethyl acetatc and washed with cold 109~ aqueous HCI solution, distilled H20, saturated NaHCO3 solution, saturated NaCl solution and dried over MgSO4 Thc solvent was recoYer~d under vacuum to obtain 8.74 g of the title H
compound as an orangc gum which slowly crystallized on standing. The compound was used in the ncxt step without fur~er purification.

--` 2109186 HA614a I. 7-Bromo-3.4-diby~ Q-4.4-di ~ ~
To a solution of the dtle H compound (7.74 g, 19.0 mrnole) in methylene chloride (95.0 mL) cooled to -78C was added diisobutylaluminum hydridc (lM solution in hcxane, 95.0 mL). The S reacdon mLl~turc was stirred 0.5 hours at -78C followed by five hour~ at 0C. The crude product solution was diluted wi~h methylenc chloride (200 mL) and quenched while stining vigorously by the addition of sodium fluonde (16.0 g) and distilled H20 (5.20 g). Thc solids were filtered and the filtrate was dried over MgS04 and evaporated in vacuo to obtain 4.X0 g of an orange gum. The crude product was chromato~aphed on silica eluting with 15% ethyl acetate in hexanc to obtain 2.23 g of the title I compound as a light yellow oil.

J. ~
A mL~tu~e of the title I compound (2.24 g, 9.33 mmole), CuC N
(1.67 g, 18.7 mrnob) and 1-methyl-2-py~olidinonc (22.5 mL) W8S heated at 185-190C for 3.25 hours. The reaction n~ucture was diluted with ethyl acetate and filtered. The volatiles were recovercd under vacuum and the re~idue was chromatographed on silica duting with 15% ethyl acetate in hexane to obtain 0.92 g (53%) of thc desired title J p~oduct as a light yellowoil.

K 7-Cyano-3,4 dihydro 4,~dimethyl-N-phenyl-1(2H)-inoline~mig~ -A soludon of the dtle J compound (0.20 g, 1.07 ~unole), phenyl ~ -isocyanate (0.13 g, 1.07 mrnole) and ~dirnethylaminopy idine (50 mg) in acetonit~ile (AS mL) was heatcd under argon at reflux for one hour. Ibe solvent was recovered under vacuum and the residue was triturated with ~ -isopropyl ether to afford 0.27 g of ~e dtle compound as an off-whitc solid~ m.p. 17~17SC. -Analysis calculated for ClgH19N30 C, 74.73; H, 6.27; N, 13.76;
Found: C, 74.46; H, 6.26; N, 13.77.

'' ' ~

.

- - - ;,: :, .
, ~ . , -. . ~ - , .,. . , .. . :
~: .... .. . .

- 2109~8~
HA614a Exam~lc 2 7-Cyano-3,4-dihydro~,4 dimethyl-N-(phenylme~hyl)- 1 (2H)-A solution of the ~tle J compound from Examplc 1 (0.20 g, 1.07 mmole), benzyl isocyanatc (0.14 g, 1.07 mrnolc) and ~dimethyl-aminopyridiine (50 mg) in acetonitrile (4.5 mL) was heated under argon at rcflux for one hour. The solvent was reco~ered under vacuum and th crude product was chromatographed on silica eludng with hexane/cthyl acetate (7:3) to afford 0.30 g of the title compound as a white solid; m.p.

Analysis calculated for C2oH21N3O:
C, 75.21; H, 6.63; N, 13.16;
Found: C, 75.05; H, 6.63; N, 12.98. ~ `
lS
Example 3 N-(3-chlorophenyl)-7-cyano-3,4dihydro4,4 dimethyl-1-(2H)-~uinolinecar~xamide A soludon of 7-cyan~3,~dihydro-4,4 dirncthyl-1(2H)-quino1ine (0.16 g, 0.86 mmolcs, compound of exan~le 1, part n and 3-chlorophenyl-isocyanate (0.14 g, 0.90 nunoles) in acetooi~ile (3.75 mL) containing N,N-dimethylaminopyIidine (30 mg) was hca~d at r~flux under algon for threc hours. lbc solvcn~ was recovered under vacuum to obtain 0.38 g of crude product as a ycllow gum. The crude nut~ial was purificd by chromatography on silica eluting with hexane/e~yl acetate (3:1) to obtain 270 mg of a white solid. llle chromatography isolate was funhes purified by crys~allization ~om isopropanol to obtain ~e title compound (190 mg, 65%) as a white solid; nLp. IS~152C MS:(~+H~+
@ 340.
Analysis calculatcd for ClgH18ClN3O~0.22 H20:
C, 66.38; H, S.41; N, 12.22; Cl, 10.31;
Found: C, 66.SS; H, 5.37; N, 12.0S; Cl, lO.S0.

,. . ", ,, ,.. ; .
.. ,,, ... ,.,., , ~ .. ..

210918g HA614a Exam~le 4 ?~ 3~4-tetrahydro-3~3-dimethyl-N-~henyl-l-qu~ camidr 5 A. ~ 2imetl~x~-1-one To a soludon of l-indanone (30 g, 0.23 mole) in dry benzene (350 mL~ at room temperaturc under argon was added solid potassium-(~butoxide (95%, 68 g, 0.58 mole). Mcthyl iodide (6S.3 g, 0.46 molc) was added to the decp purple slu~y with cooling over onc hour. Thc 10 reaction mLl~turc was heated at rcflux for two hours and pourcd oYer 400 g of ice containing conccntrated HCI solutiorl (90 mL). Diethyl ether was added and the organic phase was separated. The aqucous phase was extracted with diethyl ether. Thc combirled organic laycrs were washed -~
with 5% sodium carbonate solution followed by sahlrated sodium chloride 15 solution. The extrac~s were dried over magnesium sulfate and e~aporated in vacuo to obtain 40 g of a dark brown oil. The oil was dissolved in ethyl - ~ -acctate, treated with activated charcoal, and filte~ed through a pad of celite and silica gel. The filtrate was concentrated to obtaun 34.6 g of an orange ~ -solid Thc p~ally purified material was triturated with cold pentanc to 20 affo~24.3 g (66%) of thc ~tle compound as a yellow solid. I~SS: (M+H)+
@ 161. ~-B. ~
A soludon of u~ea (0.40 g) in nitric acid (90% fwning, 80 mL) 25 was purged with air for twenty minutes, then coolcd to -5C. To this soludon was added the title A compound (20.0 g, 0.12 molc3 in por~ons -whilc nuintaining the reaction tcmperature ~5C Ttlc reacdon mL~
was sdlTed at-S to +5C for two hours and poured over ice. The aqueous ~ -muc~ was extracted with ethyl acctate. Thc ext~cts wae washed wid 30 satumtcd sodium bicarbonate solution, sat~ratcd sodium chloride solution, and dried over magncsium sulfate. The solvent was lecove~
vacuum to obtain 27.3 g of an orange solid. The crude material was crystallized from methanol to obtain 18.0 g (73%) of the dtle compound as ayellowcrystallinesolid. MS:(M+NH4)+@223.

--` 2109~6 HA614a C. 6-~mino ~.3-dimethvlindall-1-one To a soludon of the title B eompound (10.0 g, 48.7 mrnole) in ethanol (100 mL) was added stannous chloridc dihydrate (54.9 g, 5 0.24 mole). The mixture was heated at 75C for one hour. The reac~on mixtule was poured over ice and neutralized by the addidon of solid sodium bicarbonate. Thc pH was adjusted to 11-12 with ION sodium hydroxide soludon and the reaction mass was extracted with ethyl acetate.
l~e cxtracts were washed with saturated sodium chloride solution, dried 10 over magnesium sulfate and evaporated in vacuo to obtain 8.19 g (96%) of the title compound as a tan solid. The compound was used in the next step without further purificadon.

D. ~Bram~3r~
lS To a soludon of title C compound (21.48 g, 71.2 mrnole~ in ethanol (65 mL) cooled to 0C was added 48% aqueous HBr (20 mL) followed by sodium nitrite soludon (4.91 g dissolvcd in 8.8 mL of H20) -until a positive starchhodide test result was obtained. The cold diazonium salt solutdon was added directly via pipette to a refluxing mLlcture of CuBr 20 (11.23 g, 78.3 mmole) and 48% aqueous HBr (20 mL). The xacdon mix~re was refluxed an additional lS minutes upon compledon of the addition, cooled to room temperature, and pardtioncd between ethyl acetate and 2N HCI. The organic phase was w~shed with 2N HCL
saturated sodium bicarbonatc soludon, saturated sodium chlo~ide soludon, 25 and dricd over magnesium sulfate. Thc solvent was recoYered under vacuum to obtain 15.SS g of an orange solid. Thc product was purified by tritwadon with cold pentane to obtain 13.17 g (77%) of the dtle compound as a pale yellow soL;~ MS: (M+H)~ @ 239.

30 E. 5-Bromo-3.3-dimethy~da~-1-one oxime A mixn~re of dtle D compound (11.64 g, 48.67 mmole), hydroxylamine hydrochloride (6.76 g, 97.3 mmole) and sodium acetate (7.19 g, 87.6 mmole) in ethanol (2301) was heated at rcflux for 36 hours.
The ethanol was recovered under vacuum and the residuc was partidoncd ~ 2lasl~u HA614a betwecn distilled H20 and ethyl acetate. The organic fraction was washcd with lN NaOH solution, saturated sodium chloride soludon, dricd ovcr magnesium sulfate and evaporated in vacuo to obtain 12.27 g (99%) of an off-white solid as a 2.9:1 rnixture of syn and anti oximes. Thc isomcr 5 mixture was chromatographed on silica eluting with 7.5% ethyl acetate in hexane to afford 8.94 g of the title product (syn isomer) as a whitc solid.
MS: (M I H)+ @ 254.

F. 7-Bromo-3.3-dimethyl-l.23~4-tetrah~~ qinQ~
To a solution of title E compound (5.0 g, 19.7 mmole) in ~ - -methylenc chloride (200 mL) at 0C was added diisobutylaluminum hydride solution (lM in hexane, S eq., 147 mL) dropwisc with stirring.; -~ ~
The reacdon mixture was stirred at 0C for 18 hours after which timc it ~ - -was dilutcd with mcthylene chloride (400 mL) and quenched by the lS addidon of sodium fluoride (24.8 g) followcd by distilled H20 (8 mL).
The solids were filtered and the fil~ate was evaporated under vacuum to obtain an off-white solid ~S.0 g). The crude material was chromatographed on silica eluting with hcxane/ethyl acetatc (9:1) to obtain -the title compol~nd (2.26 g, 48%) as a white solid. ~ -~' G. 7-Cyano-3.3-dimethyl-1.2.3.~tetrallydro ~Uir~Q
A solution of title F compound (3.75 g, IS.6 mmole) in 1-methyl-2-pyrrolidinone (40 mL) containing copper(I)cyanidc (2.80 g, 31.2 mmole) was heatcd at 180-C for two hours. Thc reaction n~Lxture -was cooled to room temperature, diluted with a large volume of diethyl ether, and filtered. The filtrate was washed with lN sodium hydroxide solution followcd by sahlrated sodium chloride solution and dried over sodium sulfatc. Thc solvent was evaporated in vacuo to obtain 2.89 g of a brown solid. The crude product was chromatographed on silica eluting with 15% ethyl acetatc in hexane to obtain the title G product (1.80 g, ~ -62%) as a yellow solid. MS: (M+H)+ @ 187. ~

~: ' --` 210918~
HA614a - 22 ~

H. 7-cyano- 1 ,2,3,4-tetrahydro-3,3-dimethyl-N-phcnyl- I -quinQlinami~
A solu~on of title G compound (0.275 g, 1.48 mmoles) and phcnylisocyanatc (0.18 g, 1.49 mmoles) in acetoni~ile (6 mL) containing a 5 catalytic arnount of N,N-dirnethylaminopyridine was hcated at reflux undcr argon for one hour. The solvcnt was evaporated in vacuo and the residue thus obtained was tnturatcd with isopropyl ether to afford the title compound 0.44 g (97%) as a colorless solid; m.p. 17~171C. MS:
(M+H)+ @ 306.
10 Analysis calculated for ClgHIgN3O:
C, 74.73; H, 6.27; N, 13.76;
Found: C, 74.62; H, 6.22; N, 13.74.

Exa~
lS
7-Cyano-1,2,3,~tetrahydro 3,3-dimcthyl-N-(phenylmethyl)-l-quinolin~ami~ . . .
A solution of 7-cyano-1,2,3,~tctrahydr~3,3-dimethyl~uinoline (0.30 g, 1.61 mmoles, ccmpound of cxample 19 part G) and 20 benzylisocyanate (0.18 g, 1.49 mmoles) in acetoni~rile (6.75 mL) containing a cataly~c amount of N,N~imethylaminopyridine was heated at rcflux under argon for twelYc hours. The solvent was e~aporated in vacuo and ~e rcsidu¢ was triturated with isopropyl edler to afford ~e ~tle compound (0.37 g, 72%) as a colorlcss solid; m.p. 162-163C MS:
25 (M+H)~ @ 320.
Analysis calculated for C20H21N3O~0.12H2O:
C9 74.71; H, 6.66; N, 13.07;
Found: C, 74.80; H, 6.58; N, 12.98.

-` 210918~
- 23 - HA614a Exarn~

7-Cyano- 1 ,2,3,4-tetrahydro-4,4-dimethyl-N-(3-pyridinyl)- 1 -quinoline-carboxamide, The ti~le compound was prepared from 7-cyano-3,4 dihydro-4,4-dirnethyl-1(2H)-quinoline (compound of example 1, part n and 3-pyridylisocyanatc by the same method as described in example 1, part K. The product was obtained u a colorless powder, m.p. 183-185C.
Analysis calculated for ClgHIgN4O.O. lethyl acetate.O. l9H2O:
10C, 69.37; H, 6.07; N, 17.59; - ~ -Found: C, 69.35; H, 5.94; N, 17.32. ~ -Exam~

7-Cvaoo-1~ .4-tetral~o-3.3~imethy~
A soludon of dtle 4G compound (0.2Sg, 1.34 mmoles) and nicotinyl azidc (0.2Sg, 1.69 mmoles, precursor for 3-pyridylisocyanate) in toluenc (5.0 rnL) was heated at 85C under argon for three hours. The reacdon mLxture was panidoned between ethyl aeetate and saturat~d sodium bicsrbonate solution. Thc organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo to obtain a colorless foam (0.52 g). ~ -The crude product was chromatographed on silica cluting with e~yl acetate to obtain the title compound as a whitc solid (0.40 g, 97%); nLp. 164166C.
Analysis calculated for Cl8HI8N4O-0.23H2o:
C, 69.63; H, 5.99; N, 18.05;
Found: C, 69.99; H, S.86; N, 17.69. ~

~ .

30 6-Cvano-2.3-dilutdro 33-dimethyl-N-(3-v-~ridin-vlt-lH-indQ~ -carl~ox~ide A. 2.6-Dibromo-3-methylindole A solution of 3-methylindole ~13.3 g, 0.1 mole) and N-bromophthalimidc (48.2 g, 0.2 mole) in bcnzene (265 mL) was heated at reflux for onc-half hour.

2109~6 HA614a The reacdon mixh~re was diluted with ethyl acetate and extraeted with lN sodium hydroxide solution. The organic phase was washed with saturated sodium chloride soludon, dried over magnesium sulfate and evaporated in vacuo to obtaina blaek solid (22 g). The crude material was chromatographed on silica eludng with 5% ethyl acetate in hexane to obtain a tan solid (18.S g) which was erystallized from hexanes to obtain the ~tle compound as an off-white crystalline solid (14.84 g, 51%).

B. L~=~L~Ic A solution of dtle A compound (12.65 g, 44 mmoles) in dioxane (peroxide f~ee, 250 mL) and 2.5N sulfuric acid (250 mL) was heated at reflux under argon ~or 24 hours. The reacdon mixture was eooled to room temperature, diluted with 1liter of distilled water and extraeted with ethyl aeetate. The organie fraetion was washed with saturated sodium earbonate solution, saturated sodium ehloride lS soludon and dried over magnesium sulfate. lbe solvent was evaporated in vacuo to give the title eompound (9.74 g, 98%) as a yellow solid whieh was used in thenext step withou~ further purifieation.

C. 6-Brom~3-methyl-2-ox~lH-indole-l-aeetarnidç
A solution of dtle B compound (9.31g, 41.2 mmoles) in xylene (100 mL) eontaining aeetie anhydride (6.31g, 1.5 eq.) was heated at reflux forfive hours after whieh ~ne the reaetion was ineomplete. An additional 0.75 equivalents of acede anhydride was added and the reaction mL~cture was heated an additional twohours at reflux. The reac~on snixturc was coded to room temperature and dilutcd with ethyl acetate. The crude product solution was washcd wi~ distilled water followed by saturated sodium bicarbonate soludon and sahlratod sodium ehloride solution. The solvent extraet was dr~ed over magne~ium sulfate and the solvent was recovered under vacuum to obtain an orange solid (11.4 g). l~le crude material was chromatographed on silica eluting with hexane/ethyl acctaoe (3:1) to obtain the dtle compound (9.18 g, 78% ) as an off-white solid; m.p.102-104C
Analysis calculated for CIlHloNBrc)2:
C, 49.28; H, 3.76; N, S.22;
Found: C, 49.23; H, 3.74; N, 5.21.

:

.

109~
HA614a D. ~-BrQm~ .3-dimethyl-2-Qxg-!H-indQ~ l-acetamide To a soludon of dtle C compound (8.98 g, 33.5 mmolcs) in dry tetrahydrofuran (90 mL) unda argon and cooled to 0C was addcd sodium hydride dispersion (60% in mineral oil, l.OS cq., 1.41g). Thc rcædon mixture 5 became viscous and was diluted with dry tetrahydrofuran (25 mL). Aftçr stimng for 10 minutes, methyl iodidc (1.05 eq, 4.75g) was added dropwisc. Thc rcaction mixture was stirred two hours at room temperature, quenched by the addition of s~ated ammonium chlonde solution and extractcd with ethyl acetate. The organic phase was washed with distilled watcr, saturated sodium chloride solution and dried over magnesium sulfate. The solvent was rccovered under ~acuum to ~ -obtain the tide compound (9.67 g, 1009~o) as an off-white solid. (M+H)~ @ 282.

E. ~-Bromo-3.3-dimethyl-2-oxo-indol~
A soludon of titlc D compound (9.61 g, 34.1 m~nole) in ethanol (80 mL) 15 and lN sodium hydroxide (20 mL) was stirrcd at room tcmpcrature for one hour.Thc reacdon mixture was partitioned between distilled water and diethyl ether. ~
The organic phasc was washed with distillcd water, saturatcd sodium chlonde ~ ~ -soludon and dricd over magnesium sulfatc. Thc solvent wa~ reco~rered undcr vacuum to obtain the dtle compound (8.03 g, 98%) as an off-white solid.
F. ~B~o~,~jmç~-dihy~in~
To a solution of title E compound (8.0 g, 33.3 mrnde) in dly toluene (18S mL) heated to 85C was added sodium bis(2-methoxyethoxy)aluminum hydride, ~3.4 M in toluene, 14.7 mL, S0 mmolc) o~er the course of 15 minutes.
25 The reaction mLlcture was heated an additional lS n~inutes at 85C, cooled to 0C
and quenchcd by the addition of lN sodium hydroxide solution. lbe phases were separatcd and the organic phase was washed with lN sodium hydroxide ~olution followed by sanJrated sodium chlodde soludon. The p~duc- soludon was dried ova magnesium sulfatc and evaporatcd in vacuo to obtain a tan soL~d (7.34 g).
30 The crudc mat~rial was cluomatographed on silica eludng with hexane/ethyl acetate (9:1) to obtain the title compound (S.48 g, 73%) as a pale g een solid; m.p.
10~102C.

~10~18~
HA614a Analysis calculated for CloHI2NBr:
C, 53.12; H, 5.35; N, 6.19;
Found: C, 53.15; H, 5.32; N, 6.20. MS: (M+H)+@ 226.

S ~ .3-dimcthyl-lH-indol~-1-açetam~
To a solution of title F compound (5.45 g, 24.1 mrnole) in methylene chloride (55 mL) containing triethylamine (2.68 g, 26.5 mmol) coolcd to 0C was `~~ ~ added acetyl chloride dropwise over five minutcs. The reaction mLxnlrc was s~rred 45 minutes at room temperature and partidoned between lN aqueous 10 hydrochloric acid solution and ethyl aceta~e. The organic phase was washcd with sa~urated sodium bicarbonate solution, saturated sodium chloride solution; driedover magnesium sulfa~ and evaporated in vacuo to obtain thc title compound (6.42 g, 99%) as a pale ycllow solid. MS: (M+H) ' ~ 268.

lS H. 6-cvano~ H-in~ -acetarnid~ -A solu~on of ~le G compound (6.56 g, 24.5 mmole) in N-methyl-pyrrolidonc (70 mL) containing copper(l)cy~de (4.38 g, 48.9 mmole) was hca~ed under argon a~ 175C for three hours. The reac~on mu~3re was cooled to room tcmperatlue, dilutcd with diethyl ether and fîlsercd. The filtra~c was washed 20 with distilled water, lN aqueous hydrochlodc acid soludon, sablrated sodium bicarbonate soludon and saturated sodium chloride solution. The crude p~duct solution was dried over magnesium sulfate and cvaporated ~n vacuo to ob~in the d~e compound (4.37 g, 83%) as an off-white soli~ MS: (lM+H)~ @) 215.
.:
25 I. ~5 A solu~on of dtle H compound (4.33 g, 20.2 IT~nole) in a mL~t~e of acctonitrile (120 n~) and 5N aqueous hydrochloric acid (40 mL) was heated at -rcflux for 1.5 hours. The reacdon mixh~rc was coolcd to room temperaturc and ca¢efully neutJalized with sahJratcd sodium chloridc solution. The oily layer was 30 scparatcd and ~he aqucous layer was extracted with ethyl acetate. The combincd organic laycrs were washed with saturatcd sodium chloridc soludon, dried over sodium sulfate and evaporatcd in vacuo to obtain a brown oil. The crude materialwas purified by chroma~ography on silica gcl eludng with hexane/ethyl acctatc ~ . - ::' : ~ ~ : ' ~--"` 2~09186 - 27 - HA614a (3:2) to give the title compound (3.16 g, 91 %) as a yellow solid. MS: ~M+H)~ @
173.

J. 6-Cyano-2,3-dihydro-3,3-dimethyl-N-(3-pyridinyl)-lH-indolç-1-S carboxamide A solution of dtle I compound (0.30 g, 1.74 mrnolcs) and nicotinyl azide (0.32 g, 2.18 Isunoles) in toluene (6 mL) was hcated at 85C for one hour. The reaction mixture was cooled to room temperature and parti~ioned bctween ethyl acetate and distilled water. The organic phase was washed with saturated sodium 10 bicarbonate solution followed by saturated sodium chloride solu~on. l~e crudeproduct solution was dried over magnesium sulfate and evaporated under vacuum to obtain a yellow solid. The crude mate~al was pu~ificd by chromatography on silica gel eludng with 100% ethyl acetate to afford the title compound (0.41g) as a white solid; m.p. 220-222C.
lS Analysis calculated for C17H16N4:
C, 69.8S; E~, 5.52; N, 19.16;
Found: C, 69.88; H, 5.55; N, 19.00.

Exarnple 9 ~) 20 (Cy noitnino)(phenylamino)methyl1-2,3-dihydro-3,3-di-meth~yr-1H- I ~ 6 ,,.,,. carboqltrile , ,?
~_,,-- l . ~ ", , .-A. l-[(Cyanoimino)(phenoxymethyl)]-2,3-dihydro 3,3-dimethyl-lH-indole-6carbonilri~
A soludon of dtlc ~Ic 8I compound (0.65 g, 3.77 mmole), diphenylcyanocarbonimidate (1.08 g, 4.53 mmole) and 1,8-diazabicyclo-[5.4.0]undoc-7-ene (0.63 g, 4.15 mmole) in 1,2-dichlorocthane (26 mL) was ~ -heatcd at ~flux undcr argon for eight hours. The rea~ don mLxturc was diluted 30 with cthyl ace~ate and washcd with 2N hydrochloric acid soludon, lN sodium hydroxide solution and saturatcd sodium chloridc soludon. Thc ex~act wa~ dricd ~ -ovcr magnesium sulfatc and cvaporatcd In vacuo to obtain a yellow solid (1~5 g).The crudc matcrial was ~edissolvcd in ethyl acctate and filterod tluough a pad of ~i~918~
HA614a silica gel to obtain the title compound as a yellow solid tO.99 g, 83%); m p.
168-170C. MS: (M+H)~@317.

B . 1 -[(Cyanoimino)(phenylan~ino)methyl~-2,3-dihydro-3 ,3-di-mcthyl- 1 H-irl~Q~-6~c~QDi~
T~imethylaluminum (2M soludon in hexane, 1.74 mmole, 0.87 mL) was added to a soludon of aniline (0.16 g, 1.74 mmole) in 1,2-dichlorocthanc (3.25 rnL~under argon. The mixture was s~rred at room temperature for ln hour.
To the reaction mixtur~ was added a solu~on of dtlc A compound (O.S g, l.S8 mmole) in 1,2-dichloroethane (3.25 mL). The reac~on mL~turc was stined at room tcmperature for 18 hours, quenched with water, and partitioned bctween ethyl acetate and lN sodium hydroxide solu~on. The organic phase was washcd with brine, dried over magnesium sulfate and evaporatcd in vacuo to obtain a palc yellow solid. This was purified by chromatography on silica gel elu~ng with ethyl acetate/hexane (1:1) and crystallized ~om isopropanol to obtain the title product (0.22 g, 44%) as an off-white solid; m.p. 224225C
Analysis calculated for ClgH17NS-0.30C3H80:
C, 71.69; H, S.87; N, 21.01;
Found: C, 71.35; H, S.40; N, 20.80. - -

Claims (16)

What we claim is:

1. A compound of the formula I

, or pharmaceutically acceptable salts thereof wherein A is or a single bond to complete an indoline nucleus;
X is -O-, -S- or -NCN;
R1 is aryl, arylalkyl, heterocyclo or (heterocyclo)alkyl;
R2 is hydrogen, alkyl or arylalkyl;
or R1 and R2 taken together form a 5- to 7-membered saturated or unsaturated ring, which may further include an aryl group fused to 2 carbon atoms of such 5- to 7-membered ring;
R3, R4, R7 and R8 are each independently hydrogen, alkyl or arylalkyl; or R3 and R4, or independently R7 and R8, taken together with the carbon atoms to which they are attached form a 5- to 7-membered carbocyclic ring, with the proviso that when A is , and R7 and R8 are other than hydrogen, then R3 and R4 are hydrogen, or when R7 and R8 are hydrogen then, R3 and R4 are other than hydrogen;
R5 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, (cycloalkyl)alkyl, -CN, -NO2, -COR, -COOR, -CONHR, -CON(R)2, -CF3, S-alkyl, -SOalkyl, -SO2alkyl, , , halogen, amino, substituted amino, -O-alkyl, -OCF3, -OCH2CF3, -OCOalkyl, -OCONRalkyl, -NRCOalkyl, NRCOOalkyl or -NRCON(R)2 wherein R is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl or haloalkyl;
R6 is hydrogen, alkyl, halo, -OH, -O-alkyl, amino, substituted amino, -O-alkyl, -OCOalkyl, -OCONRalkyl, -NRCOalkyl, -NRCOOalkyl or-NRCON(R)2; and n is an integer of 1, 2 or 3.

2. A compound of claim 1 wherein A is or a single bond, R1 is aryl, arylalkyl, heterocyclo or (heterocyclo)alkyl;
R2 is hydrogen or alkyl;
R3 and R4 are independently hydrogen or alkyl;
R5 is an electron withdrawing group;
R6 is hydrogen, alkyl or O-alkyl;
R7 and R8 are independently alkyl; and X is O or NCN.

3. A compound of claim wherein A is or a single bond, R1 is phenyl, phenylmethyl, substituted phenyl, substituted phenylmethyl or pyridyl;
R2 is hydrogen;
R3 and R4 are independently hydrogen or methyl;
R5 is -CN or -NO2;
R6 is hydrogen;

R7 and R8 are independently hydrogen or methyl; and X is O or NCN.

4. A compound of claim 1 which is 7-cyano-3,4-dihydro-4,4-dimethyl-N-phenyl-1(2H)-quinoline-carboxamide.

5. A compound of claim 1 which is 7-cyano-3,4-dihydro-4,4-dimethyl-N-(phenylmethyl)-1(2H)-quinoline-carboxamide.

6. A compound of claim 1 which is N-(3-chlorophenyl)-7-cyano-3,4-dihydro-4,4-dimethyl-1-(2H)-quinoline-carboxamide.

7. A compound of claim 1 which is 7-cyano-1,2,3,4-tetrahydro-3,3-dimethyl-N-phenyl-1-quinoline-amide.

8. A compound of claim 1 which is 7-cyano-1,2,3,4-tetrahydro-3,3-dimethyl-N-(phenylmethyl)-1-quinoline-amide.

9. A compound of claim 1 which is 7-cyano-1,2,3,4-tetrahydro-4,4-dimethyl-N-(3-pyridinyl)-1-quinoline-carboxamide.

10. A compound of claim 1 which is 7-cyano-1,2,3,4-tetrahydro-3,3-dimethyl-N-(3-pyridinyl)-1-quinolinamide.

11. A compound of claim 1 which is 6-cyano-2,3-dihydro-3,3-dimethyl-N-(3-pyridinyl)-1H-indole-1-carboxamide.

12. A compound of claim 1 which is 1-[(cyanoimino)(phenylamino)-methyl]-2,3-dihydro-3,3-di-methyl-1H-carbonitrile.

13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier therefor.

14. A method of treating an ischemic condition in a mammalian specie comprising administering to a mammal in need thereof a com-pound of claim 1.

15. A pharmaceutical composition comprising an effective amount of a compound, as claimed in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, or a pharmaceutically acceptable salt thereof, together with a pharmaceu-tically acceptable carrier therefor.

16. A pharmaceutical composition for use in the treatment of an ischemic condition in a patient comprising an effective anti-ischemic amount of a compound, as claimed in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor.