CA2225282A1 - 1,6-disubstituted isochromans for treatment of migraine headaches - Google Patents

Abstract

The present invention is 1,6-disubstituted isochromans of formula (I) and aromatic bicyclic amines (ABA) which are useful for the treatment of headaches, especially migraine and cluster headaches and also useful as antipsychotics and for the treatment of other CNS and/or cardiovascular disorders and as analgesics.

Description

W O 97/022S9 PCTrUS96/08681 1 6-T)I~'UR~;ll'l U l l~ I ) ISOC~RO~A'~S FOR TRF.Q.TMF.~T OF
MT~.RAT~n~ ~n~AnAC~n~.~

R~-cRcTRo7uN~ OF T'~F I'iWF.~TION
51. Field of the Tnv~ntinn The invention relates to isochroman-alkyl-piperazinyVpiperidinyl-aryl compounds useful for the treatment of hR~ h~R, especially migraine and cluster h~P~ rhps, as analgesics, and also useful as antipsychotics and for the tre~tmPnt. of other CNS and/or cardiovascular disorders.
10 2. ne~V~ n of thR Related ~rt Chromans (also known as l-benzo~yL~s, where the oxygen atom is ~tt~rhe~l to the aromatic ring) and isochromans (also known as 2-benzopyrans, where the oxygen atom is not ~tt~rhe~l to the aromatic ring) are known in the art, as are aryl-piperazines (or 4-alylpi,uel;dines). Chromans and aryl piperazines linked together 1~ with an alkyl chain are also known. European Patent 300,908 ~ closes (1-benzopyran)]-alkyl-(~i~eldzhlyl or aminopiperidine)-aryls useful as antivsrrythmics and anti-fibrillatory agents. The co~..puu. ds of this invention require -a'lkyl-piperazinyl (or piperidinyl)-aryl at carbon 1 of a 2-benzu~y~d~l ring and also require substitution at the 6-position of the isochroman which are useful for the tre~tnnPnt 20 of vascular (migraine and cluster) hP~ 'hPg and CNS and cardiovascular disorders.
Various isochromans, thini~orhromans~ ben7n~RpinRc, and benzothiRpinRs with hyvllu~y, alkoxy, or o-methylenR-lim~y snhstitnt;on on their aromatic rings, and linked to aryl pi~elaz..~es(pipPri-linPs) by alkyl chains are known. These cu~ oullds are ~i.qrloserl as being useful as anii~yvhotics and hypotensives. The compounds of 25 this invention do not permit oxygen sllhs~'itlltinn on the aromatic ring of the isochroman, thioisochroman, bPn7~rRpin, or benzothiepin ring system for their usefulness in CNS and cardiovascular disorders.
Another group of isochromans, thlnj~o~h~ v~ans, bens~ rRpinR~s and benzothiepines with hydroxy, aLkûxy, or o-methylPnR~ n~y fimrtil)nAlity ~tt~rh~ to 30 their aromatic rings, and linked to aryl piperazines(pipRri~linPs) by alkyl chains are known, useful as antipsychotics and hy~ùte~sives. The COlllpC ullds of this invention " do not permit oxygen sllhs~'it~lti-.n on the aromatic ring of the isochroman, thi~ orhroman~ bPn7mrPpin, or benzothiepin ring system for their usefulness in CNS
t and cardiovascular disorders.
US Patent 4,179,510 and the many diVi~ion~lR thereof rli~rlosRs isochroman-alkyl-~i~eL~ yl (or aminopiperidinyl)-aryls l~u,ui~hlg oxygen as a sllhstihlRnt on CA 02225282 l997-l2-l9 W O 97/02259 PCT~US96/08681 the isoclllo,l,an aromatic ring. These compounds are ~liRrlnsed as being useful as hypotensive and ~ iy~otic agents.
Al8o~ rl~)secl are isochroman~ othiorhroman-, 2-b~n7n~r~pin-, and -2-benzothiepin-alkyloxyet~n-lR as being useful for prep~rinF the above compounds.
5 More sperific~lly 7~8--limPthn~ybPr7~xPpiop~ are rliRclose(l as are 1-[(6,7-~imPthnYyisochroman)alkyl]-4-(aryl)piperazines. Further ~iRrloserl are 2-b~n7n~rPpinq-alkyl-piperazine(aminopiperidine)-aryls, 2-benzothiPpinR and 2-ben7m~pin~s all ~ uilillg an oxygen atom as a substituent on the aromatic ring and useful for the same pu~oses.
Dutch Patent 8,001,981 ~ closqs 1-(2-chlorophenyl)-4-[2-(1,3,4,5-tetrahydro-7,8 rlimethr~xy-2-bPn7n~ppin-l-yl)ethyl]piperazine useful as an antipsychotic agent.
Intern~;nn~l Patent pllhlir~tinn WO 92/18089 ~ rlospR isoch~ an-alkyl-piperazinyl (aminopiperidinyl)-aryls, with the requirement that oxygen be present on the aromatic ring of the isochroman which are useful in spn~it;7inF cells against lb multi-drug rq~ n~ç.
Intern~tinn~l Patent pllhlir~tion WO 88/08424 ~liRrl~se~s isochromans-alkyl-piperazinyl (or aminopiperidinyl)-aryls, with the e:~luil~ ent that oxygen be present on the aromatic ring of the isochroman, useful in the tre~t nPnt of head injury,spinal trauma, and stroke.
Intern~ffon~l Patent pllhlir~tion WO 90/15056 and US Patent 5,140,040 ~liRclnse isochromans, tetralins, and dihydro~n~phth~lpnes sllh~ l with various alkyl amines for the tre~t nPnt of gl~llrcm~, depression, hy~e~ LQnRion, congestive heart failure and vascular spastic ronrlitionR
US Patent 4,994,486 ~liRrlose~ isochroman-alkyl-~nnines for treating psychoses, p~rkin~on's ~ e~e, and addictive behavior.
J~psinPse Patent 61083180 ~3iRrloses isochroman-alkyl-(alkyl)~minps as antiulcer agents.
European Patent 404,197 fliRrloses isochl~..an-alkyl-piperazine-alkyl-keto (alcohol)-aryls with bronrho~ trr and ~nti~llPrgy activity.
J~r~nP~e Patent 51125287 (J 52083846) ~ rloses isochroman-alkyl-~minPs(piperazine) with antideples~iv~, analgesic, diuretic, ~ntiinfl~mmP~t,Qry, and anti-~ m~ activity.
German Patent DE 2,624,693 and Great Britain Patent GB 1552004 (liRrloses isochroman-alkyl-amines including aryl piperazines as AnAlgP~ir~, hypotensives, ,~
Anti~leprçs~Ant~, diuretics, AntiinflAmmA~orips) muscle rPlAYAnt~, and vARorlilAt~rs.
The compounds differ from the cvl~puu~ds of this invention in that oxygen

-2-WO 97/022S9 PCT/1,7S96/08681 sl7hEtit~l~ion is required on the isochroman aromatic ring.
J~p~n~ce Patent 571~9713 tliR~ isochroman- and tetralin-(no alkyl spacer)-piperazine-sryls as ~nti~ srgics. The ~v ~ouuds of this invention require at least one carbon as a linker.
US Patents 3,549,656 and 3,467,675 and Belgium Patent 678,035 ~ ç
phthsll~n-, igochroman-, and isochromen-alkylene-amines for the tre~tm~nt of depresslon.
Eu~/pesll Patent 458,387 and US Patent 5,137,911 ~ flose isochroman-alkylene-piperazine-aLkylene-aryls useful as blood pl~telet a~ Lion inhihitors, as intr~ r calcium antagonists, and for treating cardiac dy~hyLllmiss, angina pectoris, stroke, and lllyucallial infarction.
(~Tarms~n Patent DE 3,409,612 ~1;R~ S~ rliml~th~Yyisochroman- and bQn~ pin~-alkyl-amino-alkyls for prophylaxis of coronary heart disease or hypertencion Jslrs~nP~e Patent 6 1083180 .~ losç~3 isochroman-alkyl-amines useful for treating ulcers. ~ ea~ Patent 457,686 ~iR~lnse~ phth~l~n and indane alkyl aminopir~7- i-linyl ureas or carb~m~t~ for the tre~tm~nt of stress, pain, and schizophrenia.
J. Med. Chem., 25(1), 75-81 (1982) t~ losçR 6~7-(limpthr~yyisochroman-alk piperazinyl-aryl type compounds which have hy~o~ sive activity.
US P~l~llt~ 5,032,598 and 5,215,989 generically enromr~ the isochromans and tetralins of the present invention if the variable snhstitll~nt~ are ~ppl~,~l;ately chosen.
Tnt*rn~ti~ n~l pllhli(~ti~n No. W0 88/08424 a7ld US Patent 5,120,843 ~ lose 25 a diaLkoxyisocl-l~ ~an C0t~ iF a sllh~l;l .led pyridiyl~iperazil-ylethyl side chain.
However, the compounds of the present invention do not permit alkoxy snh~tit~ n Intern~t;~n~l pllhli~t;~n No. W0 95/18118 (PCT/US94/13284) ~ s~
various isochromans intlutlinF 6-(snh~L~ le~ mino (6-NRR) and 6-(snh~l;l ~l~~1)amide (6-CO-NRR) isochromans which are useful in treating hllm~n~who have a central nervous system disorders including psychosis, paraphrenia, psychotic depression, mania, schizophrenia, schizophreniform disorders. These c~ poullds are also useful in the tre~tm~nt of vascular he~ he~s~ particularly migraine h~ he,s Other central nervous system disorders which can be treated with these c~, LpouLIds include anxiety, drug ~ ff~n, convulsive disorders, ~ecLl~ disorders, personality disorders, ~t~ntion deficit disorders in children and adults, post tr~llm~ti~ stress syndrome and dysthynua. WO 95/18118 ~ 1OBQ~

-3 -CA 02225282 l997-l2-l9 W O 97/02259 PCT~US96/08681 racemic 1-(4-mP~ yphenyl)-4-[2-(6-~minfJf A . l.o~ylisochroman-l-yl)-eLllyl~i~erazine (F~AMPLE 138) and 1-(4-methoxyphenyl)-4-[2-(6-methyl~minoc ~ . I.c,llylisochroman-1-yl)-eLhyl~i~erazine (EXAMPLE 139).
SU~lvlAR.Y OF I~Vh:l~TION
Di~lo~e~l are 1,6-~ hs~itnte~l isochromans offormula (I) Q~--X~ ~
/~ Rl (I) N Wl ~ R2 where:
(I) W1 iB a nitrogen (-N-) or carbon (-CH-) atom;
(II) Xl is:
(A) -(CH2)n1- where n1 is 0 thru 3, (B) -CH=CH-;
(III) Rl is:
(A) -H, (B) -F, -Cl, -Br, -I, (C) Cl-C8 alkyl, (D) C2-C8 alkenyl co~ i..i..g 1 thru 3 double bonds (=), (E) C2-C8 alkynyl c~nt~ininF 1 or 2 triple bonds (=), (F) C3-C8 cycloaL~yl, (G) -Cl-C3 alkyl-C3-C8 cycloalkyl, (H) -N02, (I) -C~N, (J)-CF3, (K~ -O-Rl l where Rl l is:
(1) -H, (2) Cl-C8 alkyl, (3) C2-C8 aLkenyl f;o~t~i..i..F 1 thru 3 double bonds (=),

(4) C2-C8 aLkynyl c-~nt~ininF 1 or 2 triple bonds (=),

(5) C3-C8 cycloalkyl, CA 02225282 l997-l2-l9 W O 971022~9 PCTnUS96/08681

(6) -Cl-C3 alkyl-C3-C8 cycloalkyl,

(7) -CF3,

(8) -S02-CF3,

(9) -(CH2)n2-~ where n2 i8 0 thru 4 and where -~ is optionally 5 substituted with one or two:
(a) -F, -Cl, -Br, -I, (b) -C_N, (c) -CF3, (d) Cl-C3 alkyl, (e) -O-R1 ~A where R1 LA is -H, Cl-C6 alkyl, -CF3 or -CH2-~, (f~ NRl lARl lB where the R1 lA and R1 1B are the same or di~ere~lt and where R1-1B is -H, C1-C6 alkyl, -CF3 or -CH2-~, and where R1-LA is as defined above, (g) -co-NRl-lARl-~-B where Rl ~A and Rl ~B are as defined above, (h) -S02-NRl lARl B where R1 lA and R1-1B are as defined above, (i) -NRl lA-SO2-Rl lB where R1-1A and R1-1B are as 20 defined above, (j) -N02, (k) -O-SO2-CF3, (L) -N(R1 1)2 where the R1 1 can be the same or different and are as defined above, (M) -CO-N(Rl l)2 where the Rl 1 are the same or dif~erent and are as defined above, (N) -SO2-R1 3 where R1 3 is:
(1) -H, (2) -CF3, (3) C1-C8 alkyl, (4) C2-C8 aLkenyl cont~inin~ 1 thru 3 double bonds (=), (5) C2-C8 alkynyl c.~..t~i..;..F 1 or 2 triple bonds (-), (6) C3-C8 cycloalkyl, p (7) -Cl-C3 alkyl-C3-C8 cycloalkyl, (8) -(CH2)n2-~ where n2 is as defined above and ~ is optionally gllh~l: l ., l~l with one or two:

CA 0222~282 l997-l2-l9 W O 97/022S9 PCT~US96/08681 (a) -F, -Cl, -Br, -I, (b) -C-N, (C)-CF3, (d) C1-C3 alkyl, (e) -O-Rl-3A where Rl3Ai8 -H, C1-C6 alkyl, -CF3 or -CH2-~
(f-) -NRl 3ARl-3B where the R1-3A and R1-3B are the same or different and where R1 3B is -H, C1 C6 alkyl, -CF3 or -CH2-~, and where R1-3A is as defined above, (g) -CO-NRl 3ARl 3B where R1 3A and R13B are as defined above, (h) -SO2-NR1 3ARl 3B where R1-3A and Rl 3B are as defined above, (i) -NRl 3A-SO2-R1 3B where R1-3A and R1-3B are as defined above, (j) -N02, (k) -O-SO2-CF3, (9) -O-Rl 3A where R1 3A is as defined above,

(10) -NR1-3AR1-3B where R1-3A and R1-3B are as defined above, (O) -NRl l-S02-Rl 3 where Rl l and Rl 3 may be the same or dirre~ t and are as defined above, (P) -(CH2)n2~p where n2 is as defined above and where -~ is optionally s~lh;~ l e-l with one or two:
( 1) -F, -Cl, -Br, -I, (2)-C--N, (3) -CF3, (4) Cl-C6 alkyl, (5) -O-R1 1 where Rl l is as defined above, (6) -N(Rl l)2 where the Rl ls are the same or dif~erent and are as defined above, (7) -CO-N(Rl l)2 where the Rl ls are the saIne or different and are as defined above, (8) -S02-N(Rl l)2 where the Rl ls are the same or dirrel~lt and are as defined above, (9) -NR1 1-SO2-Rl l where the Rl ls are the same or di~ere~t and are as defined above, (10) -N02,

(11) -O-SO2-CF3;
(Q) -CO-R1 1 where R1 1 i8 as defined above, (R) -C~-~-Q1 2 where Q12 is defined below;
. (IV) R2 is defined the saIne as Rl, R2 can be the saIne or different than Rl;
(V) Ql is:
(A) -CO-NQ1 1Q12 where Q11 is (1) -H, (2) Cl-C8 aLkyl, (3) C2-C8 aL~enyl cont~ining 1 thru 3 double bonds (=), (4) C2-C8 alkynyl cont~ininF 1 or 2 triple bonds (a), (5) C3-C8 cycloalkyl, (6) -C1-C3 alkyl-C3-C8 cycloalkyl, (7) -CF3, (8)-SO2-CF3, (9) -(CH2)n7-~ where n7 is 0 thru 4 and where -~ is optionally 8llh~L;~ l with one or two:
(a) -F, -Cl, -Br, -I, (b) -C=N, (c)-CF3, (d) C1-C3 alkyl, (e) -~-Q1-~A where Q1 1A is -H, C1-C6 alkyl, -CF3 or -CH2-~
(f~ NQl-lAQl-lB where the Q1-1A and Q1-1B are the 25 same or cli~e~ t and where Q1-1B is -H, C1-C6 alkyl, -CF3 or -CH2-~, and where Q1-1A i8 as defined above, (g) CO-NQ1LAQ1 LB where Q1-~A and Q1-1B are as defined above, (h) -S02-NQl lAQl B where Q1-~A and Q1- LB are a8 30 defined above, (i) -NQl-lA-so2-Ql-lB where Q1-1A and Q1-1B are a8 defined above, (j) -NO2, (k) -O-SO2-CF3, and where Q1-2 i8:
(1)-H, (2) Cl-C8 alkyl, W O 97/022S9 PCTrUS96/08481 (3) C2-C8 alkenyl CJ--f~ g 1 thru 3 double bonds (=), (4) C2-C8 aL~ynyl co..1~ F 1 or 2 triple bonds (=), (5) C3-C8 cycloalkyl, (6) -Cl-C3 aLkyl-C3-C8 cycloalkyl, (7)-CF3, (8) -(CH2)n2-~ where n2 is as defined above and -~ i6 optionally substituted with one or two:
(a) -F, -Cl, -Br, -I, (b) -C~N, (c)-CF3, (d) Cl-C6 alkyl, (e) -O-Ql 2A where Q1-2A is:
(i) -H, (ii) Cl-C6 alkyl, (iii)-CF3, (iV) -(CH2)~, (9) ~(cH2)n9-Ql-2B(cH2)nlo-Ql-2c where ng and n10 are the same or di~elent and are 0 thru 4, where Q1-2B is -O- or -NQl-2D-~ where Q1-2D is (a) -H, (b) Cl-C8 alkyl, (c) C2-C8 alkenyl c~ t~ F 1 thru 3 double bonds, (d) C2-C8 alkynyl cont~ininF 1 or 2 triple bonds, (e) C3-C8 cycloalkyl, (f~ -Cl-C3 alkyl-C3-C8 cycloalkyl, (g)-CF3, (h) -(CH2)nll <p where nll is 0 thru 4 and -~ is optionally gllh~ ..4~d with one or two:
(i) -F, -Cl, -Br, -I, (ii) -CaN, (iii)-CF3, (iv) Cl-C3 alkyl, (V) -O-Q1-2E where Q1-2E i8 -H, C1-C6 alkyl, -CF3 or -CH2-~, (vi) -NQl-2EQl-2F where the Q1-2E and Q1 2F are 35 the same or d~el~nt and where Q1-2F i8 -H, C1 C6 alkyl, -CF3 or C 2 where Q1-2E is as defined above, (vii) -CO-NQ1 2EQ12F where Q1-2E and Q12F
are as defined above, (viii) -S02-NQl 2EQl ZF where Q1-2E and Q1-2F
are as defined above, (ix) -NQl 2E-SO2-Ql 2F where Q1-2E and Q12F
are as defined above, (X) -N02, (xi) -O-SO2-CF3, and where Q1-2C is defined the Bame as Q1-2D and the Q12C and Q1-2D can be the same or di~elellt, and where Ql l and Ql 2 are taken together with the ~tt~rhetl nitrogen atom to form a 5 or 6 member ring which can include one ~ ition~l nitrogen or oxygen atom;
(B) -S~2-NQl lQl 2 where Q1-1 and Q1-2 are as defined above, (C) -CO-O-Q1 3 where Q13 is:
(1)-H, (2) -CF3, (3) Cl-C8 aLkyl, (4) C2-C8 alkenyl c.~...ts.i-);..g 1 thru 3 double bonds (=), (5) C2-C8 alkynyl cont~inin~ 1 or 2 triple bonds (_), (6) C3-C8 cycloaL~yl, (7) -Cl-C3 alkyl-C3-C8 cycloalkyl, (8) -(CH2)n7-~ where n7 is as defined above and -~ is optionally snhs~ le~ with one or two:
(a) -F, -Cl, -Br, -I, (b)-C=N, (C) -CF3, (d) Cl-C3 alkyl, (e) -O-Ql 3A where Q1-3A is -H, C1-C6 alkyl, -CF3 or -CH2-~
(f~ -NQl-3AQl 3B where the Q1-3A and Q1-3B are the same or di~TeLc:llt and where Q1-3B is -H, C1-C6 alkyl, -CF3 or -CH2~, and where Q1-3A is as defined above, (g) CO NQl-3AQl 3s where Q1-3A and Q1-3B are as defined above, (h) -so2-NQl-3AQl-3B where Q1-3A and Q1-3B are as defined above, CA 0222~282 1997-12-19 W O 97/02259 . PCTrUS96/08681 (i) -NQ1 3A-SO2-Ql 3B where Q1-3A and Q1-3B are ag defined above, (j) -NO2, (k) -0-$02-CF3, (D) -CO-Ql 3 where Q1-3 is as defined above, (E)-CO-i~nifl~o~
(F) -NQl lQl 2 where Q1-1 and Q1-2 are as defined above, (F ) -NQl l-C~-Ql 2 where Q1-1 and Q1-2 are as defined above, (G) -C(Ql 3)=N-O-Ql 4 where Q14 is defined the same as Q13 and Q1 3 is as defined above, the Q1-3 and Q1-4 can be the same or different, (H) -SO2-Ql 3 where Q13 is as defined above, (I) -N(Ql l)-S~2-Ql 3 where Q1-1 and Q1-3 is as defined above, (J) 6-f~ ole optionally sllh~;t~-tP-1 with one Q15 where Ql 5 is:
(1) -H, (2)-F,-Cl,-Br,-I, (3) Cl-C8 aL~cyl, (4) C2-C8 alkenyl c.~ F 1 thru 3 double bonds (=), (5) C2-C8 alkynyl ~ol~t~i..;..~ 1 or 2 triple bonds (_), (6) C3-C8 cycloalkyl, (7) -Cl-C3 aL~cyl-C3-C8 cycloalkyl, (8) -NO2, (9) -C-N, (10)-CF3, (11) -O-Ql 6A where Q1-5A is (a)-H, (b) Cl-C8 alkyl, (c) C2-C8 alkenyl c~r.t~i..i..e 1 thru 3 double bonds, (d) C2-C8 aLkynyl c~ 1 or 2 triple bonds, (e) C3-C8 cycloalkyl, (f~ -Cl-C3 alkyl-C3-C8 cycloaLkyl, (g) -CF3, (h) -SO2-CF3, (i) -(CH2)n7~ where n7 is 0 thru 4,

(12) -NQl-5AQ1 5D where Q1-5A is as defined above, Q1 5D is:
36 (a)-H, (b) Cl-C8 alkyl, (c) C2-C8 alkenyl cont~ining 1 thru 3 double bonds, (d) C2-C8 aLkynyl cont~inin~ 1 or 2 triple bonds (_), (e) C3-C8 cycloalkyl, Cl-C3 alkyl-C3-C8 cycloalkyl, . (g)-CF3, s (h) ~(CH2)n7~~ where n7 is as defined above,

(13) -CO-NQ1 5AQl 5D where Q1-5A and Q1-5D are as defined above,

(14) -SO2-Q1 6K where Q1-5K is:
(a)-H, (b) -CF3, (c) Cl-C8 alkyl, (d) C2-C8 alkenyl cont~ininF 1 thru 3 double bonds (=), (e) C2-C8 alkynyl cont~inin~ 1 or 2 triple bonds (_), (f~ C3-C8 cycloaLkyl, (g) -Cl-C3 alkyl-C3-C8 cycloaLkyl, (h) ~(CH2)n7~P where n7 is as defined above,

(15) -NQl-5A-so2-Ql-sK where Q1-6A and Q1-6K may be the same or di~Tele;llt and are as defined above,

(16) -(CH2)n7~p where n7 is as defined above and where -~ is optionally sl-h~itllt~cl with one or two:
(a) -F, -Cl, -Br, -I, (b) -C_N, (c) -CF3, (d) Cl-C6 alkyl, (e) -~-Q1 5A where Q1-6A is as defined above, (f~ -NQl-5AQl-5D where Q1-5A and Q1-5D are as defined above, g) Q1-6AQ1-6D where Q1-6A and Q1 5D are as defined above, (h) -so2-NQl-6AQl-6D where Q16A and Q1-6D are as defined above, (i) -NQ1 5A-SO2-Q1 5D where Q1-5A and Q1-5D are a8 defined above, (J)-N02, (k) -O-SO2-CF3;

CA 02225282 l997-l2-l9 W O 97/022S9 PCTrUS96/08681 (K) 3 nY~ 701e optionally 81lhE~ with one Ql5 where Ql-5 iB as defined above, (L) triazole optionally sllh~ with one or two Ql-5 which may be the same or di~ele~t, where Ql5 is as defined above, (M) 5 thi~ ol~ optionally sllhEL:I .Le~ with one Ql 5, where Ql6 i6 as defined above, (N) 3 thi~ 7O1e optionally sllhstitll~rl with one Ql-5~ where Ql5is as defined above, (O) 2-oxazole optionally sllhEL:I ..4.1 with one or two Ql5 which may 10 be the same or difrelent, where Ql5is as defined above, (P) 2-t~ ole optionally substituted with one or two Ql5 which may be the same or di~erellt, where Ql5is as defined above, (Q) 2-imi~ ol~ optionally sllh~ c1 with one, two or three Ql-5 which may be the same or diCr~.e.lt, where Ql5is as defined above, 16 (R) 1-imi~ole optionally sllh~ .l~d with one, two or three Ql-5 which may be the same or dil~ , where Ql5is as defined sbove, (S) tetrazole optionally sllh ~ 1 e.l with one Ql5~ where Ql5is as defined above, (T) cyclobllt~n~1irne optionally sllhsL;~ 1 with one Q11 and one Ql5 where Ql-l and Ql-5 are as defined above, (U) l-pyrimi~linyl optionally sllh~ ~ :1 .1 e-l with one Ql5~ where Ql5 is as defined above, (V) 2-pyridinyl optionally Sllhhil 1 .IDd with one Ql-5~ where Ql5 is as defined above, (~1V) 3-pyridinyl optionally Sllhhl ;1 ~ with one Ql5~ where Ql5is as defined above, (X) 4-pyridinyl optionally sllhsl:l .led with one Ql5~ where Ql5is as defined above, (Y) -Zl-CO-Z2-Ql 2 where Q12 is as defined above and Zl is -O- or -NQ1 1- where Ql l is as defined above, where Z2 is -O- or -NQ11- where Ql l is as defined above, with the proviso that when Xl is -(CH2)nl-, where nl is 0 and Q1 is:
-CO-NQl lQl-2~

CA 02225282 l997-l2-l9 W O 97/02259 PCTrUS96/08681 -S02-NQl lQl-2 or -NQl-lQl 2 -NQl l-CO-Ql 2 then Ql-l and Ql-2 cannot both be spl~octe from:
-H, -Cl-C6 alkyl, -C3-C7 cycloaLkyl, -Cl-C3 alkyl-(C3-C7) cycloalkyl and pharmaceutically acceptable salts thereof.
Also ~ lo,se-l are aromatic bicyclic amines of the formula (ABA) Ql--X, ~
~ R1 (ABA) N~ ~W1~ R2 20 where:
(I) Wl is a nitrogen (-N-) or carbon (-CH-) atom;
(II) Xl is -(CH2)nl-, and nl is 0, (III) Ql is ~ (A) -CO-NQl lQl 2 where Ql-l i8 ( 1) -H, (2) Cl-C8 alkyl, (3) C2-C8 aLkenyl cont~ininF 1 thru 3 double bonds (=), (4) C2-C8 aLkynyl c~nt~inin~ 1 or 2 triple bonds (_), (5) -(CH2)n7~ where n7 is 0 thru 4 and where -~ is optionally 30 sl~hstit~ l with one or two:
(a) -F, -Cl, -Br, -I, (b) -C-N, (c) -CF3, (d) Cl-C3 aL~yl, (e) -~-Q1-1A where Q1-1A is -H, C1-C6 a~yl, -CF3 or -CH2-~

CA 0222~282 l997-l2-l9 W O 97/02259 PCTrUS96/08681 (f~ NQ1-~AQ1 lB where the Q1-1A and Q1-1B are the.
same or different and where Q1-1B is -H, C1-C6 alkyl, -CF3 or -CH2-~, and where Q1-1A i8 as defined above, (g) Co-NQl-lAQl-lB where Q1 1A and Q1-~B are as 6 defined above, (h) -S~2-NQ1 ~AQl B where Q1-~A and Q1 1B are as defined above, (i) -NQl-lA-so2-Ql-lB where Q1-~ and Q1-1B are as defined above, (j) -N02, (k) -O-SO2-CF3, and where Q12 is:
(6) C1-Cg aLkyl, (7) C2-C8 alkenyl co~ i..F 1 thru 3 double bonds (=), (8) C2-C8 alkynyl contsininF 1 or 2 triple bonds (-), (9) -(CH2)n2-~ where n2 is as defined above and -~ is optionally 8llhs~ eA with one or two:
(a) -F, -Cl, -Br, -I, (b) -C_N, (c) -CF3, (d) Cl-C6 alkyl, (e) -O-Q1 2A where Q1-2A is:
(i) -H, (ii) Cl-C6 aL~yl, (iii) -CF3, (iv)-(CH2)-~, (B) -S~2-NQ1 lQ12 where Q11 and Q12 are as defined above, (C) -NQ1 lQ12 where Q11 and Q12 are as defined above, (D) -NQ1 1-CO-Ql 2 where Q1-1 and Q1-2 are as defined above, (III) R1 is:
(A)-H, (B) -F, -Cl, -Br, -I, (C) C1-C8 alkyl, (D) -C-N, (E) -CF3, (F) -O-R1 1 where R1 1 i8:
( 1) -H, -1~

(O C1-C8 alkyl, (3) -CF3, (4) -S02-CF3, (5) -(CH2)n2-~ where n2 is O thru 4 (G) -N(R1 1)2 where the R1 1 can be the saIne or different and are as defined above, (H) -CO-N(R1 1)2 where the R1 1 are the same or different and are as defined above, (I) -S02-R1 3 where R1 3 is:
(1)-CF3, (2) C1-C8 alkyl, (3) -O-Rl-3A where R1-3A is as defined above, (4) -NRl-3ARl-3B where R1 3A and R1 3g are as defined above, (J) -CO-R1 1 where R1 1 is as defined above;
(IV) R2 is defined the same as Rl, R2 can be the same or different than Rl;
and pharmaceutically acceptable salts thereof.
Further (~icrlosetl are the aromatic bicyclic amines of EXAMPES 1, 2, 11, 12, 14, 24, 40, 72, 84, 86 and 88.
T)T~,T,~TT ~1) n~CRTRTION OF T~P~ TION
The invention conAictC of novel colllpou~ds, 1,6-~ lh~ l isochroman (I) and a small group of aromatic bicyclic amines (ABA) which are previously generically rliRrlose-l in Intern~tion~l pllhlir~tion WO 95/18118 (PCT/US94/13284) with a unique spectrum of activity, highly active against vascular hP~ rhPs P~peri~lly migraine and cluster hp~ rhp~s~ The processes used to produce the novel 25 compounds of the rl~im~ invention are known to those skilled in the art. By starting with the ap~rop~;ate starting m~teri~l~ and org~ni7in~ the process steps in a particular order (using protective groups where nece~ ) the novel compounds ofthe invention are produced. The process of each step of the invention is known to those skilled in the art. One skilled in the art given the rhPmir~l structure of any of 30 the 1,6-disllh~ f~ l isochroman (I) or aromatic bicyclic amines (ABA), could readily prepare the compounds from known cc~ll,uou~ds by mPtho~ known to those skilled in the art even without the ~;RC11~;On and EXAMPLEs below.
CHART A describes the construction of the 6-bromoi~orhroman (VI), which is a useful intermP~i~tfe for many of the 1,6-disub~iluLed isochroman (I) and aromatic 35 bicyclic amines (ABA). RP~rti~m of 3-bromophan~th~nnl (II) with ethyl 3,3-diethu~yulu~ionate in the presence of l~ ... tetr~rhl- ridP in nitromPth~nP or CA 02225282 l997-l2-l9 W O 97/022S9 PCTrUS96/08681 dichloromPt~ne gives the isochroman ester (III). Standard hydrolysis using lithium hydroxide in THF-water provides the acid (IV), which can be coupled to a variety of sllhstit~lt~cl arylpiperazines or 4-aLyl,ui~t ~;dines to give the amides (V). The ~Lyl~i,uelazine moiety carries the Rl and R2 sllhstitmpnt~ It is pl~relL~d that the 5 desired R1 and R2 sllhstit~lent~ be on the aryl group prior to the production of the amide (V). The starting Rl and R2 aryl gTOUpS are known to those skilled in the art or can be readily prepared by known mPth~ from known cu,lluoullds. Many of the arylpiperazine moiPt;A are commPrcially available or known in the (-hPmic, l lilelatu~.:. Those that are not commPrcially available or known can readily be 10 prepared as illustrated in CHARTS Q and R. These amides are reduced using borane to provide the brAmniRo~hromans (VI).
CHART B describes the cullvt~ ion of the 6-bromriRochroman (VI) into the cu~ onding 6-amide and 6-ester Qn~logR Conversion of the aryl bromide to the primary amide is Qccomrli~hp~rl via metal-halogen PY~hQnEe uging t-butyl lithillm 15 and qllPn~.hing the reslllting aryl anion with trimPthylsilylisocyanate, see J. Med.
Chem., 36, 2208 (1993). The aryl anion can also be treated with gaseous carbon Yi~le, followed by treQtmpnt with oxalyl chloride in DMF and subsequent reactionwith amines to provide the amides (IX) dile~ ~ly. Alternatively, the 6-brom~iRochroman (VI), can be reacted with carbon mt~n~y~ p in the presence of 20 pQllQrlillm (II) Q~etQt~, 1,3-l~iR-3irhPnylph--?3Fhinoplùpalle, diisu,ulu,uylamine, and h~ -yl~liRilQ~Qnp in solvents such as DMF to give the amide (VII). Other pQllQ~illm catlysts, such as in situ pl~aled pQllQrlillm(O) with organorhosphinPR, or pre-prepared palladium(O) pho~hine catalysts can be llt;li~.e~i The amide (VII) can be cu~lvt:~led into either snhsl;~ lRcl amides (IX) or esters (X) via the bis-BOC
25 del;v~live (VIII) using the pl~ edul~ described in J. Org Chem., 56, 5482 (1991).
The 6-broml~iRo~hroman (VI) can be cûn~ ,ed to N-methyl sllh ~ -I~cl amides (IX)dil~ lly by using either methylamine or N-methylrnl...Qmi-le in place of hPYslm~hyl-liQilQ7.QQnP in the pQllQ~lillm mP~liQt~tl reaction ~l~scrihe~1 above (see ~AMPLES 5 and 6). ~lt~rnQtively~ other pQtt~rn~ of N-EnhE~;tllt;on can be 30 obtained by using other primary or secc n~Qry amines in place of hPYQmethyl(li~ilQ~QnP~ in the pQllQrlillm-mPrliQt~l reaction rl~rihecl above.
CHART C describes the enzymatic resollltinn of racemic (II). MiYing (II) with an enzyme such as the lipase derived from Psezldomonas cepacia in aqueous buffer(plerel~2d pH 5-8) results in selective hydrolysis of the (-)-ester to give t-h-e (-)-acid 35 (XI). It is pl. r. .L~d to carry out this reaction at room temp- .dlu~e (20-35~) using 5-20% by weight of the enzyme. The reaction is mnni~red by known means of removing an aliquot, acidifying, and ~Y~ by HPLC. When the reaction is complete, the products (XI), the (-)-acid, and (XII), the (+)-ester are ~ ~Ovèl'ed and separated by acid/base ~I-L~cLv~ techniques well-Lnown by those sLilled in the art.
These optically-active cu..ll~.,ullds can be used when appropriate in any of the5 illustrated Charts to prepare optically pure versions of the described compounds.
The undesired ~nAnt;om~r, (+)-ethyl (isochroman-1-yl)Acet~te (XII), .~cvverad from the Pseudomonas cepacia m~rliAt~1 kinetic resolllt;~n of enAntiomars~ can be e~ Livèly recycled back to the racemic ~ Lula for subsequent further trAAtnnant with the Pseudomonas lipase. This ile~r~l,ive process optimizes the overall yield of 10 the desired (-)-isochroman-l-yl-acetic acid (XI). Suitable bases for this rArAmi7Atinn are those with pKa's greater than 11, preferably greater than 12. Operable basesinclude alkali metal amide bases, aLali metal Alk-Yitl~,s, and alkali metal carbonat,es which can all induce this rA~emi7~t;on It is pl~arel~d that the base be alkali metal amide bases or alkali metal ~lkn~i~lç5; it is more preferred that the base 15 be the alkali metal ~lk~ , such as sodillm or pot~ lm t-butoxide or eth~
At the completion of the rAcemi~Ati~ r, the reaction is ql]~nrhe-l with a proton donor.
Virtually any proton donor is operable, for PY~mpl~ even water will quench the re~rt;~n However, oper~t;~.n~lly water is not p~f~ d. Usually the proton donor is an acid. Most comm~n proton donors a~ydl.,cllloric acid, Amm~nillm chloride) 20 used to quench enolate anions can be used for this qll~nrhing, however, for ease of wu~Lup and pllrifirAt;on, acetic acid or trifluoroacetic acid is pr~ ad.
CHART D ~1e~rrihe~ the preparation of amides and esters which are linLed to the isochroman nllrl~n~ by a one-carbon methylene spacer (I, Xl = -CH2-).
Tr~At~n~nt of the aryl bromide (VI) with ~rim~t~ylsilylacetylene in the presence of 25 p~ lm (II) Aret~t~, copper(I) iodide, and triethylamine provides the acetylenic isochroman (XIII). R~ction of the acetylenic isochroman (XIII) with a dialkylborane such as dicyclohexylborane followed by an oxidative work-up using basic h~dL~I~ell peroxide gives the carboxylic acid (XIV, Ql-3 = H), from which the generalized esters (XIV) or amides (XV) can be derived by st~n~Ard techniques known to those skilled 30 in the art.
CHART E rl~srrihe~ the preparation of amides and esters which are linked to ~, the isochroman nucleus by a two-carbon spacer which can be either 8d~u~dted (I, Xl = -CH2CH2-) or lmAAI,~..ated (I, Xl = -CH=CH-). Tr~Atm~nt of the bromide (VI) with an acrylate ester in the presence of a palladium catalyst, preferably pAllA~ m (II) 35 Aret~, along with 1,3 hiR-liph~nylrho~rhinopropane and diisopr~ylamine in an organic solvent such as dimetllylru~...Ami~e gives (XVI). Hydrogenation of (XVI) by

-17-W O 97102259 PCTrUS96/08681 s~n-lArd techniques known to those skilled in the art provides the saturated species (XVII). Similarly, treAtTn~ont of the bromide (VI) with an acrylamide in the presence of a palladium catalyst, preferably palladium(II) ~ret~te, along with 1,3-hi~tiirhçnylrhl sphinopropane and dii~;u~urùpylamine in an organic solvent such as dime~lylro~ mi~ gives ~VIII). IIyd~v~ Ati~n of ~rVIII by standard techniques known to those skilled in the art provides the saturated species (XIX).
CHART F describes the preparation of amides and esters which are linked to the isochroman nucleus by a three-carbon methylene spacer (I, Xl = -CH2CH2CH2-).Caubu~ylic acid (X, Ql 3 = H) is treated with two equivalents of propyl lithil~m to 10 provide the buLylvl~henone (X~). ~çAffng to reflux a sol~lt;on of the bu~yLvl)henon~
(X~) in morpholine with an equivalent of ~lem~nt~l sulfur and morpholine for 10 -20 hours gives the thiolArt~m (XXI, see Org. ReArti~n.~, Vol III, Chapter 2, pp 83, 1946, John Wiley & Sons, New York.) Hydrolysis of the thi- lArt~m (XXI) with aqueous hy-l~vchloric acid using techniques known to those skilled in the art gives the c~l,u,.ylic acid (XXII, Q13 = H), from which the esters (XXII) and the amides (X~II) can be readily obtained using ~.cevu~:s well-known to those skilled in the art.
CHART G describes the preparation of isochromans bearing a 6-acyl 8llh~itllent such as an acid, an ester, a ketone, or an oxime. Metal-halogen 20 ~Yrh~nFe of the arylbromide (VI) generates an aryl-lithillm reagent which can be qll~nrh~ with carbon dioxide to give call,u~ylic acids (X, Q13 = H). PAllA~illm-mP~iiAte~ carbonylation of the aryl brom-ide (IV) in the presence of an alcohol generates the correspon-ling esters (X) via con-1iti-~n~ well-~ocllm~nt~(l in the literature. Similarly, pAllA~lillm-m~liAt~l cross-coupling of (VI) with enol-ethers gives rise to k~t~nes (~IV) following st~n-l~rd acidic hydrolysis of the enol-ether interm~ At~. Alternatively, treAtTn~nt of the carboxylic acid (X, Ql 3 = H) with two equivalents of an alkyl lithium l~a~ generates the corre.sponrling ketone (XXIV).
ContlQn~Ati-T- of the ketone (XXIV) with either hydlv~ylamine or any readily-available O-sllh~ l 9~1 hydroxylamine using toluene as the solvent and a Dean-30 Stark apparatus for water removal provides the desired oximes (~V).
C~IART H describes the preparation of the slllfon~mitles (XXVII) and theglllfnnes (~X). TreAtm~nt of the aryl bromide (VI) with t-butyl lithillm results in metal-halogen PYrhAnge~ and the r~.slllting aryl lithillm can be qll~nrh~cl with sulfur dioxide to afford the litl~imn salt (XXVI). This salt is then treated with phosphorûus 35 p~nts~r.hlnri-l-q and the resllltin~ sulfonyl chloride is mixed with the appru~;ate amine to generate the cc.lle ~,uonding slllf -nAmi-3e (XXVII). ~ltsrnAtively~ aryl

-18-W O 97/OZ2S9 PCT~US96/08681 bromide (VI) is cu~lvtLLed to the aryl lit~ m species as ri~R~rihe~ above a~d qn~n~heri with the ~p~lùp~;ate ~liRlllfir-ie to give the sulfide (X2~Vlll). This 8ulfide is then rYirii~etl using st~n-~rd procedures and rYiri~ntR such as m-chloroperbenzoic acid to give the sulfone (X~X).
CHART I ~ Rrrihe~ the preparation of the sulfones (~IV) in which the sulfone moiety is linked to the isochroman nllrlr~llR with a methylene tether of 1, 2, or 3 carbon atoms. In CHARTs I thru N, the extra carbon atom present (which becomes part of the Xl linker) in the fimr~t;nn~lit;er illustrated nr~cr~ t,e~3 the "n"
to be = 0-2, which cU~-s~on~iR to an nl in the 1,6-disnhsl;l ~.I,Pr isochromans (I). The calbo~ylic acids (~) can be reduced to the primary- ~lr.nhnl~ (X~) using well-known techniques and reagents such as lithitlm ~hlminllm hydride or borane. The nh~ (XXXI) can be cv~ led to the cvl~e~l on~-inE bromides (X~II) using well-known techniques and reagents such as phr s~horous tribromide or carbon tetrabromide and triphenylrhosFhine. The bromides (~II) can be used to alkylate 16 thiols using techniques known to those 8killed in the art to provide the ~ulfides x x x l l l ). The sulfides ~x xx 111 ) can be ~Y~ e(l to the sulfones (X2~V) by using st~n-i~rd oxidative techniques and reagents such as oY.. ;.. tetroxide and N-methylmorpholine N-oxide.
CHART J describes the preparation of the 8ll1frnzlmirlr~13(2 ~ Vll) in which 20 the slllfon~mi(le moiety is linked to the isochroman m~ with a methylene tether of 1, 2, or 3 carbon atoms. The bromides (X~II can be treated with sodium sulfite in ~ -X;--F 10% aqueous sodium hydroxide solnti~n to provided the snlfon~t~ salts (XXXV). The slllfon~t~ salts are CVI1~L led to the suLfonyl chlorides (2~X2S.Vl) using phosphnrous prntS~rh1orirlr~ and phosphorous oYych1nric7e. Tr~ tm~nt of (X2~Vl) 25 with amines (NQl lQl 2) gives the slllfnn~mirl~s (2~Vll).
CHART K ~l~s~rihe~ the preparation of sllh~ ;mitl~o1~ and triazoles which are linked to the isochroman nucleus with a methylene tether of l, 2 or 3 carbon atoms. In CHART K, when the "X" in the ~nhstitll~nt is nitrogen the 811h~tih1~nt is a tri~o1e and when the "X" is a carbon atom the s11hst;h1F-nt is an 30 imi~l~701e. These cv-llpou~lds are obtained by alkylating the appIv~;ate imirl~o]e or triazole with the bromides (X~II). The imirl~7ole~ and trisl~ol~!; are either~, commercially available or can be prepared as described in the ~hemic~l lil,eLa~u~e using techniques known to those skilled in the art. In this fashion are obtained the compounds (2~X2~Vlll).
3~ CHART L c~e~t~rih~s the preparation of the oY~ 7o1~s (XL) which are linked to the isochroman nucleus with a methylene tether of l, 2 or 3 carbon atoms. The

-19-W O 97/02259 PCTrUS96/08681 requisite oxime amides are prepared from the cc,l~ ling nitriles using hydlu~ylamine hydr)~loride and sodium meW in mPth~nol according to the plocedu~a ~icrlose~l in J. Med. Chem., 36, 1529 (1993). The nitriles are either cnmm~rcially available or can be readily pla~,al~ d as degcribed in the ~h~mics~l 5 li~l~Lule: using techniques known to those skilled in the art. The oxime amides are treated with either sodium hydride or sodium metal and then further treated withthe ester (xxxlx) according to the p~ocellula ~liR~lnse(l in J. Med. Chem., 36, 1529 (1993) to give the heteru~clic products (XL).
CHART M describes the preparation of mono-(XLII) or di-snh,-L:l ~.~d 10 tetrazoles (XLIII) which are linked to the isochroman nucleus with a methylene tether of 1, 2 or 3 carbon atoms. The bromides (X~II) are col-vt,l L~d to the col.~s~u~ding nitriles (XLI) via a cyanide ~liRpl~cPmpnt reaction known to thoseskilled in the art. These nitriles are then coll-vt:l L~d to the mono-snh~
tetrazoles (XLII) by the action of sodium azide in a solvent such as N-methyl-2-15 pyrr~ linonP, accùl.li--g to the ~l~JCedu~ iR~lo~e-l in J. Med. Chem., 38, 1799 (1995).
The mono-snh L:l .l~d tetrazoles are co~lvt:lL~d to the di-sl-hs~itlltRcl tetrazoles (XLIII) by ~tsntl~rd aIkylation re~ff~nR (R-X"~r~~o~.il ;1P" triethylamine).
CHART N de~rrihP~ the plaparaLion of the isomeric triazoles (XLIII) and (XLIV) which are linked to the isochroman nllrlPll~ with a methylene tether of 1, 2

20 or 3 carbon atoms. The nitriles (XLI) can be COnvt~ Led to the imi~ln~~~ars (XLII) by the action of e~h~nr~ hylllvchloric acid according to the ploced,,le ~lic~loRe~1 in J.
Med. Chem., 38, 1799 (1995). Following this same pl~cedula, l1~AI I~P~t of (XLII) with alkyl hydrazines (either commPrcially available or prepared by means known in the lilel.llula) in a solvent such as ethAnnl and subsequent treAtTn~nt with formic 25 acid gives a ~il-Lura of (XLIII) and (XLIV). This nli~L,ul2 can be separated into its components by st~n~rd labolal,uly techniques such as chrom~tl~graphy or cry8t~11i7A~;~>n .
CHART O describes the preparation of sllhsL;~ l triA7olp-R and nYA~i~7~ R
from primary call,ux~ Ps (VII) using mPt~o~R known to those skilled in the art, 30 see for PYAmplP~ J. Org Chem., 44, 4160-4164 (1979). When "X" in (0-2) is nitrogen, the product is a triazole. When "X" in (0-2) is oYygen, the product is a nY~ 7ole Tre~t~nPnt of Amides (VII) with dimethylamide acetals in non-polar, high boilingsolvents such as toluene at 50-100~ generates the int,çrmP~iAte (0-1). This int-qrmf~iAte iS then reacted with either hydrazine, 1-snh~ e~ hydrazines, 35 hy~lluAylAminP, or N-sllh~ y~lru~ylAminPR under acidic con~litirlnR (usually acetic acid) at room temperature (20-25~) to give the in~lisAte~ products (0-2).

W O 97/022S9 PCTnUS96/08681 CHART P describes the preparation of mono-sllhs' 1..~ oAazole d~l;v~Livt:s (P-2) from the co~l~s~onding propargylic amides (~-1) using m~thntlR known to those skilled in the art, see for ~Y~mrle, J. Med. Chem., 36, 1529 (1993). Tre~t~n~nt of (P-1) with mercuric acetate in ~ xirl~ acetic acid generates the illu8trated C~ 7~le~S
(P-2).
CHART Q tli~rlnses the synthesis of piperszine (Q-3) in which Rl is an electron withdrawing substituent ortho or para to the aniline nitrogen of t,he piperazine.
Amine (Q-1) and aryl halide (Q-2) where a fluorine or bromine atom is ortho or para to the electron wit,hdrawing sl]hstitll~nt are heated without solvent or in a polar solvent such as water, DMF, dimethyl~ret~mi~e, or other such solvents with a base (eit,her excess (Q-l) or diisopropylethylamine, pot~Qqinm carbonate or the like) at elevated temperature (60-200~) to give piperazine (Q-3).
CHART R ~liqrl~ses the synthesis of piperazines (R-3). Nitro aryl (R-l) is reduced to aniline (R-2) using hydlu~n and a catalyst such as palladium on carbon, Raney nickel, stannous rhlorirl~o or the like. Alternatively, (R-2) can be purchased cQmm~rcially. Aniline (R-2) is then heated (about 80 to aboutl65~) with bis(2-h~lnethyl)amine hy.llochloride with or without added base in solvents such as THF, tolll~n~, ethylene glycol, or chlorobenzene to give piperazine (R-3).
CHART S illustrates an the preparation of an important int,Prm~ te useful for the preparation of compounds cl~im~l in this patent. The hydloAy amide (S-3) is conveniently prepared from the hydluAy bromide (S-l; see CHART T) either directly via a p~ lillm m~ te~l ~mitl~t;nn reaction (i~l~nti~l to that illustrated in CHART
B) or via the intermediacy of an ester (S-2). This ester is readily syntl ~qi7~d from (S-1) via a p~ illm-based call,ullylation reaction known to those skilled in the art as similar to those already clesrrihe~l The conversion of (S-2) to the amide (S-3) is ~rcompli.qhed by treating (S-2) with an ~l~nhnlir sollltif)n (typically m~th~nol) co~ g the appropriate amine reagent in a mslnn~r similar to that ~ q-rrihe~l in J. Org. Chem., 52, 2033-2036 (1987). This reaction can be carried at at room temperature (20-25~) or preferably at 50-100~.
CHART T illustrates two i. . .~o. L~t alternative approaches to the compounds r,k~im~rl in this patent. Reduction of the previously described acid (IV) using st~nrl~rd re~lllring contlit;onq and reagents (p}ef~l,ed is borane) gives the primary alcohol (S-1). This cum~oulld is then cunvt:l~,ed into the 11YI11UAY a-mide (S-3) as ~3~qrrihed in CHART S. This hydluAy amide is cc,~Led into an alkylating agent (T-2, typical X is 8 mesylate or a bromide) by s~sn~ rd rh~mir~l transform~ti~nq

-21-W O 97/02259 PCT~US96108681 and is used to alkylate an appropriate 4-arylpiperazine or 4-~ "lpiperidine to provide the final compounds (IX). AltArn~tively, the hydlu~y bromide (S-1) is collve~ led into an alkylating agent (T-l, typical X is a mesylate or a bromide) by stS~ntl~rd ~hPmi~
transform~tionc and is used to alkylate an 2l~p.up~.ate 4-arylpiperazine or 4-5 alyl~ui~ue-;dine to provide the bromides (VI). These bromides are then converted into final compounds (IX) as previously illustrated.
CHART U tliR~loBes the Cullvè~diOn of chiral bromo acid (U-1) which is (XI) in CHART C to the amide alcohol (U-5) which is (S-3) in CHART T. The bromo acid (U-1) i8 alkylated to the bromo ester (U-2) using mPthorlc known to those skilled in 10 the art. An example is tre~tm~nt of the bromo acid (U-l) with 1,1'-carbonykliimitl~7Qle in a solvent such as THF to form an activated ester, followed by an alcohol to form the bromo ester (U-2). The bromo ester (U-2) is then treated under the con~iti-n~ tliRCllcced for CHART V for the con~vel~ion of (V-1) to (V-2), to give the amide ester (U-3). Hydrolysis of the amide ester (U-3) with aqueous base, 15 taking care not to also hydrolyze the amide group of (U-3), followed by aqueous acid tre~t~n~nt gives acid amide (U~). The acid amide (U4) is then treated with re~ inE agents such as borane or borane-methyl sulfide in THF as solvent to givethe amide alcohol (U-5).
CHART V ~1;RC1C~8ÇC a method for the co~lvè~;jiOn of ester (V-1) to ~ mi~le (V-20 4). Ester (V-1) is prepared from bromo isochroman (T-1) and piperazine (Q-3),CHART Q, by m~thr~lc rliccl-cce.1 for CHART T. Ester (V-1) is Cu~ Led to the amide ester (V-2) using p~ illm (II) ~etst,e, a co-catalyst such as bis(diphenylphnsphino)propane, diisopluAuylethylamine, carbon mnnn~i~e and methyl amine as ~li-cc~cce~l with regard to CHART B. Solvents for the cûllve~i~ion may be 25 chosen from DMF, dimethyl~cet~mi~P, N-methyl~u,...~mi-le and ~cetonitrile with dimethyl~et~mi~le and N-melhylrul...~mirle p~c:fe-.~d when methyl ~mine gas is used. Flefe~led tempe.c.~u~es are 50 to 120~. The amide ester (V-2) is further co~ve~ed to the cu.Lr~l,ontling amide acid (V-3) using aqueous base followed by acid neutr~li7~t;~n to give (V-3) or a salt thereo~ When the ester is the tert-butyl ester, trifluoroacetic acid or hyLuchlnric acid in solvents such as ether or ethyl acetate are used to convert the a_ide ester (V-2) to the corresponding amide acid (V-3). Theamide acid (V-3) t_en is treated with a c- nC~Pn~inF agent and an amine to provide the Cu~e~On~inF ~ mi-le (V-4) using mPt~o-lc known to those skilled in the art such as (~iRcll~c~cef~ with regrd to CHART W.
CHART W ~liR~loReR a synthesis of h yd~u~ic acid de-iv~tives (W-7) and (W-8). These compounds are also prepared by the prùcesses of CHARTS A and B. The

-22-W O 97/022S9 PCTÇUS96/08681 alcohol group of the ester alcohol (S-2), Chart S, i8pL~te~ d with a suitable ~/le.,Lillg group such as a dih~lLo~yL~ulyl group, which is stable to basic conllition to give tetrahyd~ yLdLlyl ether (~7V-2). The ester group of the ether (W-2) is then hydrolyzed with aqueous base and then ~ ifif~cl carefully (BO as not to remove the 5 protecting group) to give carboxylic acid (W-3). The carboxylic acid (W-3) is then treated with a con-lAn~ing agent such as carbonyl~iiTnitl~ole, diethylcyanorhosphnn~te, dicyclohexylcarbo~iimi-1e, or other suitable con~l~Ancing agents (see, for AY~mrlA, Major Methods of Peptide Bond ForTn~t;~ n, Volume One of The Peptides: Analysis, Srth~iR, Biology, E. Gross and d. MpiAnhofA~rl eds., 10 ~r~lPmi~ Press) in solvents such as dichlornmPth~nP or DMF and a base such astriethylamine in the presence of an amine such as an O-alkyl, N-alkylhydL~.~.ylamine (itself prepared by the method of Sulsky et al., Tet. Lett. 30, 31-34 (1989) to give hydl.~ te ether (W 1). The hydl..Y,~ Ate ether (W~) is then deprotected using m~t~ such as those found in Protective Groups in Organic Synthesis by l'heodora 15 W. Greene and pllhliRhPtl by John Wiley and Sons to give the hy~ t~ alcohol (W-5). The hydroxyl group of hydL.~x~ te alcohol (W-5) is then COL1V~ d to a leaving group by one of the many mPthorlR known to those skilled in the art, such as forming a mesylate, tosylate, or chloride, bromide, or iodide, to give the hy~ x~ t,P
(W-6); the hydl.~ t~ (W-6) i6 then coupled to an amine such a6 piperazine (Q-3) 20 of CEIART Q or piperazine (R-3) of CHART R or comm~rcially available amines to give hy~ t~ anune (W-7). The hylll..-S~...~te amine (W-7) can be further cvLlv~lLed to hy~ ~ic acid amine (W-8) when alkyl-1 is a protecting group such as benzyl by palladium on carbon or other such mPthorlR known to those skilled in the art.
CHART X .li~ sçs the synthesis of the carbamate (X-6). The phenoVaniline (X-l) is reacted with alkyl diethc.~y~L~,~L;onate in a similar m~nn~r as the transformation of the 3-bromophenPtl ~nol (II) to the corresponding isochroman ester (III) of CHART A, to give the phenol/aniline ester (X-2). The phenol/aniline ester (X-2) is hydrolyzed to the phenol/aniline acid (X-3) by aqueous base followed by aqueous acid. The phenol/aniline acid (X-3) is then con-~nRe~ with piperazines (Q-3) of CHART Q or (R-3) of CHART R or comm~rcially available amines to give the phenol/aniline amide (X-4) using m~thf~ such as those ~liRcl~RRed in CHART W.
The phenol/aniline amide (X-4) is then reduced to the phenol/aniline amine (X-5)with redll~in~ agents such as borane or borane-methyl sulfide in solvents such as T~. The phenol/aniline amine (X-5) is then reacted with 1,8-hjcyclo[5.4.0]undec-7-ene (DBU) or godium hydride or other such bases and an

-23-CA 02225282 l997-l2-l9 W O 97/022S9 PCT~US96/08681 isocyanate in dichloromptll~ne or T~ as the solvent to give the carb~m~tp/urea (X-6).
CHART Y ~ ç~ the synthesis of racemic (Y-5) starting with the phenol (Y-1). The phenol (Y-l) is reacted with chlùlv~uropion~ hyde diethyl acetal in the presence of a Lewis acid such as boron trifll-ori-lP etherate or I :l .. i.. tetr~ohl-)ri~
in solvents such as dichlorom~th~nP or nitrnmPth~nP, to give the chloro phenol (Y-2).
The phenol of chloro phenol (Y-2) is then CUllVel Led to a leaving group using trifuorom~thAnesl-lfoni-~ anhydride or N-phe~ylL.;~luornmeth~nPclllfonimi~ in the presence of a base such as triethylamine and optionally adding a catalyst such as 4-10 dimethylaminopyridine and in a solvent such as dichloromPth~nP~ to give the triflate (Y-3). The triflate (Y-3) is then be co~ve, Led to the amide chloride (Y4) usingps3ll~ m (II) ~et~e~ a co-catalyst, diiso~u~ylethylamine, carbon mnn~Yi-le and methyl amine as ~liccllcce-l with regard to CHART W. Solvents for the cullveLdion include D~, dimethyl~ et~mi~ N-meLhylrul ...Ami-le, and ~-etonitril~ with 15 ~imethylPcet~mi-lP and N-meLllyl~....~micle uiefellèd when methyl Pmine gas is used. P~èré~èd tempo,dLules are about 50 to about 120~. The amide chloride (Y-4)is then stirred at 60 to 110~ in the presence of the piperazine (Q-3) or (R-3) or comm~rcial ~minP~, a base such as triethylamine or dii&uu. uuylethylamine, and asolvent such as ethylene glycol, T~, DMF or ~ ~t~ to give the amide amine 20 (Y-6).
CHART Z ~P~rihes the ~l~al~tion of a nnmh~r of aniline-based de-;v~tivès (Z-2), (Z-3), (Z4), (Z-5), (Z-6) and (Z-7). These cc,luuuuuds arise from si~nrl~rd derivations of the aniline (Z-1), itself prè~a~ed from the bromide (VI) via metal-halogen PY~h~nFe (typically using either n-butyllithillm or t-butyllithillm) followed 25 ~c~ n of diphenylrho~Fhoryl azide (usually in THF at -78~) and subsequent red~lct;~.n with bis(2-mpt~yyetho~y-y)plllminllm hydride. This cu~ .dion of (VI) to (Z-1) clûsely follows known chPmi~try, see Tetrahedron Letters, 25, 429432 (1984) and J. Am. Chem. S~oc., 94, 6203-6205 (1972). The reA- ti~nR conve.Li~lg (Z-1) into the dé~;vdLivës (Z-2)-(Z-7) are standard trAnRformAt~ , known to those skilled in 30 the art, and involve acylations (typically with acid ~-hlori~l~R or anhydrides), mesylations, and stsn~Ard lactam re-lll. tionR as presviously d~R~rihe~
CHART AA illustrates the preparation of one-carbon hom--logAted isochroman-6~arl,u~---ifl-ss (AA-5). The sequence involves metal-halogen PY~hAnge of the bromide (VI) using alkyllit~illm reagênts (typically t-butyl lithillm) followed 35 by qn~n~hin~ of the r~slllffng anion with D~ to give the aldehyde (AA-1). This aldehyde i8 reduced using st~n~rd reA~ntR (such as sodium borohydride in THF),

-24-W O 97102259 PCTnUS96/08681 and the resulting alcohol (AA-2) iBConv~l led to the nitrile (A~-3) by activation with m~th~ne~ f ~nyl chloride and fii~pl~ m~nt of the r. sllltinF mesylate with cyanide anion. Hydrolysis of the nitrile i6 carried out by treating a solution of (AA-3) in D~ with 30% h~d. v~.. peroxide in the presence of potassium carbonate and 5 stirring the reaction llli~llUle at room t~lllpeld~ul~ (20-25~) for 20 hrs. The resulting amide (AA-4) i6 convt,~Led into snh~i;l .(etl a_ides (AA-5) as previously described.
CHART BB illustrates a generalized procedule: for the preparation of tethered amines such as (BB-2) by reclllrti~n of the corresponding a-m-ides (BB-1) ntili7in~
~t~n~1~rd amide reduction con lition~ as previously des-~riheri (typically either 10 employing borane or lithium alulllillu~l hydride in THF).
CHART CC illustrates that fi~nrt;~n~l groups on the arylpiperazine portion of these molec~llPs (ie, Rl and R2) can be transformed into other fi~n~t;~n~l groups.
Depicted is a standard hy~llù~t~nolytic debenzylation of the an aryl-ether (CC-1) to provide the cul~e~ollding phenol (CC-2). Conversion of the phenol (CC-2) into the 15 corl~s~onding trifluor m~th~n~st~lfon~t,e (CC-3) by standard m~thofl~ is illU~Lldtive of typical derivations of phen~ such as (CC-2). Conversion of the triflate (CC-8) into numerous dt:Livt ~,ivt:s can be ~ccomrli~hf~l by p~ ]m-mf~ t~r~ collplin~
For ~Y~m~]~, coupling (CC-3) with enol-ethers provides ketone-sllh~ Pr1 aryl d~.;v~Liv~s. These r~rt;-n~ are typically carried out in DMF or ~etonitrile using 20 p~ lillm(II) ~et~te~ 1,3-bis(diphenylphosphino)propane, and triethylamine at elevated tempe.d~ult,s (50-120~).
CHART DD illustrates an ~ltern~t;ve preparation of isochroman-6 tri~oles (DD-4) and isochroman-6-o~ 70les (DD-6). The primary alcohol of the previously-described amide (DD-1) is be l lute~ Led by Et~n~rd techniques, preferably as the

25 benzyl ether (P = -CH2-phenyl). This material is be reacted with amide acetals as described in CHART O and the resulting interm~ t;e (DD-2) is treated with hydlr zi~e, sllh~L~ l hy.lldzi~le, hydlu~yl amine, or N-snh~;t~ltR~l hy ;ll~u~yl ~mines as tl~srrihe~l in CHART O to generate the tri~ol~s (DD-3) or n~ 701ec (DD-5).
The plole- ti~lg group "P" is rellluve d using eton-l~rd contlition~ (typically 30 hydlù~ olysis using a tr~n~i~;on metal catalyst such as p~ linm or platinum) and the re~lllting alcohol can be activated (usually as a snlfor ~te ester or halide) and reacted with the d~,ulu~llate aryl piperazine as described previously in CHART T.
For the 1,6-~ llh~L;l ~L~c~ isochlulllans (I) it is pr~Çellad that nl is 0 or 1; it is more plarell~ d that nl is 0. It is ,ul~fell~d that Rl is -O-Rl l, -CF3, -CO-N(Rl l)2, 35 -CO-Rl l and it is ~l~Ç~l.ad that Rll is Cl-C3 alkyl. It is pl~:r~ d that R2 is H.
It is plerell~d that Q1 is selected from the group con~ ;ng of -CO-NQ1 1Q12~ -S~2-W 097/022S9 PCT~US96/08681 NQ1 1Q1 2 and -NQ1 1Ql 2; it i8 more prefellad that Q1 iB -CO-NQl lQl 2.
For the aromatic bicyclic amines (ABA) it i8 ~ul~r~ d that Wl iB nitrogen (-N-) and it is plefellad that one of Rl or R2 i8 -H. It iB pr~r~llad that Q1 i8 (A) -CO-NQl lQl 2 and that Q11 is -H and that Q12 i8 -CH3 (C1 alkyl).
The 1,6--liRl1hb~ I,ecl isochroman (I) and aromatic bicyclic amines (ABA) contain an asymmetric center and therefore produce two Pn~ntir~mPrs one "S" which is (-) and the other "R" which is (+). In some cases both en~ntiomp-rs (+) and (-) are useful in the same way as the optically impure (racemic, i) .~ I,ula. Hence, they may be utilized in the racemic form without se~u~clLi-~g them. However, if it isdesired to utilize one of the çn~ntiomP,rs, the optically impure ~ ,Ul~: or intermP~ tç can be resolved by means known to those skilled in the art. It is preferable to resolve the racemic intermP~ t~ (II) using the lipase mPthod described in C~IART C, alternatively rhPmir~l mPtho~ known to those skilled in the art canbe used, see for PY~mplP, Optical RPsollltion Procedures for ChPmir~l Compounds,Vol 1, ~minPs and Rel~t~d Co l,uuuuds, Paul Newman, Optical Resolllti~n Informa-tion Center, M~nh~ttDn College, Riverdale, NY, 10471, 1978. The optically impurei~Lula can also be separated using chrrm~ . ~hic techniques on chiral b~Dtir~n~ry phages, see Chrom~t~graphic ~ln~nt;r~sep~ration~ 2nd edition, John Wiley & Sons, NY, 1992. These optically pure cu~,uuullds are then used in the same wayas the racemic llli~Lu~t:. When used in this patent applir~t;on the term 1,6-~;R11h~ 1 isochroman (I) aromatic bicyclic amines (ABA) refers to and inrhl~lPR
both çn~nt;omPrs as well as optically impure forms thereof, the most c~lmmon of which is a racemic lllL~Lule7 (~, dl).
Some 1,6-disnh~L;l~le(l isochroman (I) and aromatic bicyclic amines (ABA) contain two asymmetric centers and therefore four stereoiRomPrs (SS, RR, SR, RS)exist producing two diastereomeric pairs of ~n~ntiomprs~ one SS,RR and the otherSR,RS. The diastereomeric pairs of çn~nti~mprs can be readily separated by meansknown to those skilled in the art. When used in this patent applir,~tion the term 1,6-~1;R11h~ isochroman(I) and aromatic bicyclic amines (ABA) inrln(la~ all four~nslnt;~mf~rs as well as optically impure forms thereof, the most commr~n of which is a racemic ~xLul~
The 1,6--liR~hbL:I ~L~l isochroman (I) and aromatic bicyclic amines (ABA) are slminPS, and as such form acid ~lrlit;- n salts when reacted with acids of s--ffiriPnt strength. Pharm~rellt;r,~lly acceptable salts include salts of both inorganic and organic acids. The ph~rm~r,eutically acceptable salt8 are s~mPt;m~qs but not always pLef~ . . ad over the corresponding free amines since they produce compounds which

-26-W O 97/02259 PCT~US96/08681 are more water soluble and more crysts11ine The ~.~f~ d pharm~relltir~lly accep-table salts include salts of the following acids mPt~ neclllfonic, h~.hucllloric, hydrobromic, sulfuric, phosphoric~ nitric, benzoic, citric, tartaric, fumaric, maleic, CH3-(CH2)~,-COOH where n is O thru 4, HOOC-(CH2)n-COOH where n is as defined 5 above.
The 1,6~ 11hstituted isochroman (I) and aromatic bicyclic amines (ABA) of this invention posses selective pharm,.~A,o1ngirA1 plop~lies and are useful in treating hllm, n~ with vascular heArl~Arh~s, particularly migraine and duster he~ rhp~ The 1,6-~i~11h~ .1 isochroman (I) and aromatic bicyclic ,.~nines (ABA) are also useful 10 as analgesic agents.
In clinical practice the 1,6-~ 11h~L;~ .l isochroman (I) and aromatic bicyclic amines (ABA) of the present invention will normally be ~-lmini~tP~red orally, nasally, rectally, vaginally or by injection in the form of pharm, re11t;As~1 compo~it;~An~
c.~l1f ~i.,i..g the active ingredient either as a free base or as a pharmaceutically acceptable acid ,.~1~fition salt in, RRo~iAtion with one or more phar~n, relltict~lly acceptable carriers. It is p~er~ d that the 1,6-~ qllh~L;~uled isochroman (I) and aromatic bicyclic amines (ABA) be ~ lmini~t~ ed either orally or nasally.
For the~ap~uLical treatment of migraine or cluster hePtlArhPs and for trÇ~tnA~nt of pain as analgesic agents the suitable daily do~es of the 1,6-rfiRllh~lil uf~,e~f isochroman (I) are aromatic bicyclic a_ines (ABA) are from about 0.005 to about 60 mg/kg for oral or nasal app.1i~tiAn, preferably from about 0.1 to about 30 mgtkg, and from about 0.05 to about 10 mg/kg for parenteral applirAtiAn, preferably from about 0.03 to about 3 mg/kg. The use and 7~rlmini~tration to a patient to be treated in the clinic would be readily apparent to a person of ordinary skill in the art.
The exact dosage and frequency of ,~lminir~ration ~epen-lR on the particular 1,6-~iC11h~ a~ isochroman (I) or aromatic bicyclic amine (ABA) used, the particular con~liti~A,n being treated, the severity of the c ~n~liti~An being treated, the age, weight, general physical cor.-lit;cn of the particular p~t;AA~t~ other mrtliC~ti9Tl the individual may be taking as is well known to those skilled in the art and can be more ac.;u~a~ely dete~ ed by measuring the blood level or Aon~r~ Lion of the 1,6-hs~ isochroman (I) and/or aromatic bicyclic amine (ABA) in the patient's blood and/or the patient's response to the particular cAnrlitiAn being treated.
nP~TNITION~: ~) CONVh~l~TION~
The ~finiffonR and _~p1An, tionR below are for the ter-m-s as used throughout this entire clocllm~nt inr111rlinF both the ~perifirc~;An and the claims.

-27-W O 97/02259 PCT~US96/08681 I. CONV~ TION,q FOR FOR~UT ~ A~T) T)F.~I~ITIONS OF V~RTART.
The rhPmir~l form~ R repl-~A~ g various compounds or mohpc~ r fr~gmPntA in the sperifir~ti~ n and clPims may contain variable snhstit~llpntA in f3tl~1it;~n to expressly defined structural feaLur~s. These variable sllhs~itslpntA are i~1PntifiPrl by a letter or a letter followed by a nllmpric~l subscript, for PY~mIlle~ "Zl"
or "Ri" where "i" is an integer. These variable sllhstit~lp-ntA are either monovalent or bivalent, that is, they r~pl. ~e,1t a group ~t~rhP-l to the formula by one or two rhPmir~l bonds. For example, a group Zl would represent a bivalent variable if ~t~rhPcl to the formula CH3-C(=Zl)H. Groups Ri and Rj would leplesent monoval-ent variable sllhstitllpntA if ~tt~ ?tl to the form~ CH3-CH2-C(R~ )-H. When rhPmir~l formnl~A are drawn in a linear f~hil n, such as those above, variable sub-stitslent~ contoinpcl in parPnt~e~es are bonded to the atom immP~liAt~ly to the left of the variable ~llhstit~lPnt enrlosed in parPnthPAiR. When two or more c~nAe. .~i ;v~
variable sllhs~;hlentR are enrlose-l in parenth~oses~ each of the con~e~ ;ve variable sllhstitllp-ntA is bonded to the immP~ t~ply ~ edi~g atom to the left which is not Pnrl~se-l in parPnthPseR Thus, in the forsnula above, both Ri and Rj are bonded to the prece~ing carbon atom.
Ch~mic~l formnl~A or portions thereof drawn in a linear fashion l~pl~e t atoms in a linear chain. The symbol "-" in general ~ e~l~ a bond between two atoms in the chain. Thus CH3-O-CH2-CH(Ri)-CH3 ~ s~ a 2-sllh~ ule~l-1-metho,.y~Lvpane co ,puu~d. In a siilar f~Rhion~ the symbol "=" ~ep~esellts a double bond, e.g., CH2=C(Ri)-O-CH3, and the symbol "_" 1ePL~:Se~t~ a triple bond, e.g.,HC=C-CH(Ri)-CH2-CH3. Carbonyl groups are ~. ples~tP~ in either one of two ways: -CO- or -C(=O)-, with the former being piefe,~ed for Aimplirity.
~hPmirs~l formlllsi~ of cyclic (ring) cu~,~uul ds or m~lPcnl~r fr~gmPntR can be Lepr~se..tPd in a linear f~hiorl Thus, the c v~llpoulld 4-chloro-2-mel~1yl~yl;dine can be ~ sf~..t4~l in linear fashion by N =C(CH3)-CH=CCl-CH=C H with the cv11ve llLion that the atoms m~rk.orl with an ~riRk (*) are bonded to each otherrP~nlt;nE~ in the form~t;on of a ring. Li_ewise, the cyclic ml~lpclll~r frSIgmPnt 4 30 (ethyl)-l-~ipt.~i11yl can be le~ te~l by -N -(CH2)2-N(C2H5)-CH2-C H2.
A rigid cyclic (ring) structure for any co...~uu lds herein define8 an orient~t;~n with respect to the plane of the ring for ~nhS~;t~lpnt~ ~tt~rh~l to each carbon atom of the rigid cyclic co ,~uuulld. For saLulalad cvlll,uuullds which have two snh~;t,llPntR
~h~d to a carbon atom which is part of a cyclic system, -C(Xl)(X2)- the two sub-35 st;tnPnt,R may be in either an axial or equatorial position relative to the ring and may change between axial/eqll~ri~l However, the po~it;on of the two snhs~;t~lentR

-28-W O 97/02259 PCT~US96/08681 relative to the ring and each other remains fixed. While either sllhE~ihl~nt at times may lie in the plane of the ring (eqllAtwriAl) rather than above or below the plane (axial), one substituent is always above the other. In rhemirs~l structural formulas depicting such compounds, a sl~hs+it,~lçnt (X1) which is "below" another snhs+it~pnt 5 (X2) will be i-lentifiç~l as being in the alpha (a) configuration and is i(lentifipd by a broken, dashed or dotted line ~tt~rhmpnt to the carbon atom, i.e., by the symbol"- - -" or "...". The corresponding sllhstitllPnt Att~~hP~l "above" (X2) the other (X1) is i~ent;fiP~ as being in the beta (13) configuration and is in~lirslte~l by an unbroken line ~t+~ l m~nt to the carbon atom.
When a variable sllhst;t~lPnt is bivalent, the valences may be taken together or separately or both in the rlPfinitio~ of the v~ri~hle For PY~m~ a variable RiAtt~'h~Pd to a carbon atom as -C(=Ri)- might be bivalent and be defined as oxo or keto (thus forming a carbonyl group (-CO-) or as two separately ~tt~rhPCl monovalent variable sllhstihlPnt~ a-Rij and J3-Ri k. When a bivalent v~ri~hlç, Ri, is defined to 15 consist of two monovalent variable sllhE~;hlPnt~, the convention used to define the bivalent variable i8 of the form "a-Rij:~-Ri k" or some variant thereof. In such a case both a-Ri j and B-Ri k are ~tt ~hP~l to the carbon atom to give -C(a-Rij)(13-R~ k)-. For PYAmrle, when the bivalent variable R6, -C(=R6)- is defined to consist of two monovalent variable sllhA~;tllPntc~ the two monovalent variable sllhE~itllpnt~ are a-20 R6 1:B-R6 2~ .... a-R6 g:~3-R6 1o, etc, giving -C(a-R6 1)(~3-R6 2)-, ~--- -C(a R6 9)( 6-10 etc. Likewise, for the bivalent variable R11, -C(=R11)-, two monovalent variableEllhEt;t~lPnt~ are a-Rll l:J3-Rll 2. For a ring sllhstit~lPnt for which separate a and B
~riPnt~tion.A~ do not exist (e.g. due to the presence of a carbon carbon double bond in the ring), and for a sllhst;tmPnt bonded to a carbon atom which is not part of a ring 25 the above co~v-:n~ion is still used, but the a and ~3 dPA~ignAtir~nr. are omittP-l Just as a bivalent variable may be defined as two separate monovalent variable ~llhA~it,~lPntA~, two separate monovalent variable sllhst;t~pntr~ may be defined to be taken together to form a bivalent vAriAhlP For PY~mrl-p~ in the formula -C1(Ri)H-C2(Rj)H- (Cl and C2 define arbitrarily a first and second carbon atom, 30 respectively) Ri and RJ may be defined to be taken together to form (1) a second bond between Cl and C2 or (2) a bivalent group such as oxa (-O-) and the fnr nnl~
thereby describes an epoxide. When Ri and Rj are taken together to form a more comrhPY entity, such as the group -X-Y-, then the oriPnt~tion of the entity is such that Cl in the above fi~rmlll~ is bonded to X and C2 is bonded to Y. Thus, by 35 convention the dçRigl~Ation "... Ri and R,j are taken together to form -CH2-CH2-O-CO- ..." means a lactone in which the carbonyl is bonded to C2. However, when

-29-CA 02225282 l997-l2-l9 W O 97/02259 PCTnUS96/08681 cleRign~3t,P~cl 1'... R~ and R~ are taken together to form -CO-O-CH2-CH2-the ~unv~Lion means a lactone in which the ca,l"~llyl is bonded to Cl.
The carbon atom content of variable 8llhstihl~nt.~ i8in~ tR~ in one of two ways. The first mPthod uses a prefix to the entire name of the variable such as "C1-5 C4", where both "1" and "4" are integers le~l~PAellt:rlg the minimnm and m~x;.......number of carbon atoms in the variable. The prefix is separated from the variable by a space. For PY~mrle, "C1-C4 aLkyl" l~resellts alkyl of 1 through 4 carbon atoms, (inrlllrling isomeric forms thereof unless an express intlit~t;on to the contrary is given). Whenever this single prefix is given, the prefix in~ tes the entire carbon 10 atom content of the variable being flPfinP~ Thus C2-C4 alkoxycarbonyl flPR~rihes a group CH3-(CH2)n-O-CO- where n is zero, one or two. By the second method the carbon atom content of only each portion of the tlefinitinn is in~ te~l separately by Pn~-loAing the "Ci-Cj" deAign~ti-n in parRntl~eseA and placing it imme~izi~ely (no ing space) before the portion of the rl~finition being d~finA-l By this 15 optional collvenLion (C1-C3)aL~u~,carl,u~yl has the same mR~ning as C2-C4 alkoxy-carbonyl because the "C1-C3" refers only to the carbon atom content of the alkoxy group. Similarly while both C2-C6 alkoxyalkyl and (C1-C3)aLkoYy(C1-C3)alkyl define aL~coxyalkyl groups cont~ininF from 2 to 6 carbon atoms, the two ~lRfiniti.~n~ differ since the former flRfinition allows either the alkoxy or alkyl portion alone to contain 20 4 or 5 carbon atoms while the latter ~lPfiniti~n limits either of these groups to 3 carbon atoms.
When the claims contain a fairly complPY (cyclic) substituent, at the end of the phrase n~min~PAign~tin~ that particular sllhstit~lRnt will be a notation in (parRnthRses) which will cu..e ~,uulld to the same name~le~ign~ti~n in one of the 25 CHARTS which will also set forth the ~ hRmi~l structural formula of that particular Sllhstit-uPnt !qt~tpmpnt Ahr~ut N~mRn~ tllre Several methods exist for the r~slmin~ of the compounds of this invention, ~iffPrin~ prinl ir~lly in the use of the term "isochroman" or "3,4-dihydro-lH-2-

30 benzopy~dnll for the bicyclic group within the compound. For PY~mple, one name forthe compound of ~Y~mrle 6 is (S)-(-)-1-[2-[4-[4-(~minoc~.lJollyl)phenyl]-1-piperazinyl]ethyl]-N-methylisochru"lan-6-c~1,..~ P or (s)-(-)-l-(bRn~mi(l~p4-yl)4 [2-(6-methylAminoc~rbonylisochroman-l-yl)eLhyl~ui~uelazil~e. Another name is (S)-l-[2-[4-[4-(~mino~A~bù~yl)phenyl]-l-pi,u~ zillyl]ethyl]-3,4-dihydro-N-methyl-lH-2-35 benZu~yl~11-6-Ch~l~u,c~ R.

W O 97/022S9 PCT/U',S.r~6~1 TT n~,~q~lTIONS
Als t~e~e~d~use8 are in degrees Centigrade.
TLC refers to thin-layer chrom~t~graphy.
HPLC refers to high plef~2~uS~ liquid chrom~tc,~.dphy.
THF refers to tetral-ydl~rulz~.
DMF refers to dimethylrul...~mi~l~
DMSO refers to dimethylgnlf Yi-l~
LDA refers to lithium diisopropylamide.
p-TSA refers to p-toln~nesulfonic acid monohydLd~e.
TEA refers to triethylamine.
BOC refers to 1,1-dimethylethoxy carbonyl or tert-blslu,.y~iarbonyl -CO-O-C(CHS)3.
DMAP refers to dimethylaminopyridine, (CH3)2N-pyridin-l-yl.
TFA refers to trifluorscetic acid, CF3-COOH.
Saline refers to an aqueous ~alusa~d sûdium chloride sohlt;~n Chr~m~. dphy (column and flash chro~ . d~hy) refers to pnrifi~ti~m/geparation of cul-lpouslds é~ è6~ed as (~u~os 1" eluent). It is understood that the appropriate fractions are pooled and c~n~~..t-dted to give the desired co uuu~ d(s).
IR refers to inrlased spe~lsusc~llJy.
CMR refers to C-13 ms~gn~t;~ re~on~n-e ~,ue~,Lsv~cv~uy~ fh~mirsll shifts are se:~olled in ppm (8) downfield from TMS.
NMR refers to nuclear (proton) m~gn~ti~ resrn~n-e spe~L-)scopy, t~.h~mi~l shifts are reported in ppm (o) downfield from tetramethylsilane.
~p refers to phenyl (C6H5).
[a]D refers to the angle of rotation of plane polarized light (specific optical rotation) at 25~ with the sodium D line (589A).
MS refers to mass ~ue.;~l~"5.etry ~lessed as m/e or mass/charge unit.
[M + sHl+ refers to the ,uo~i~ive ion of a parent plus a hydrogen atom. EI refers to electron impact. CI refers to th~mir~l ioni7slti~n FAB refers to fast atom bombardment.
HRMS refers to high re~ohltion mass spectrometry.
Ether refers to diethyl ether.
Pharmaceutically acceptable refers to those ,uS~per(~ies and/or sllhstsncP~
which are acceptable to the patient from a pharm~coltgi~l/t~ ol~ gi~l point of' view and to the m~nllf~tnrinF ph~rm~euticalrh~mi~+ from a phygica~h~mi~

-31-W O 97/02259 PCTrUS96/08681 point of view re~ Lg c~ l,o~il,ion, form~ t;on, stability, patient accep~a lce and bioav~ hility.
When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).
phslrm~eutically acceptable anion salts include mesylate, ~hlnride~ sulfate, phosphflte nitrate, citrate, CH3-tCH2)nl-COO-1 where nl is 0 thru 4, -looc-(CH2)n1-COO~1 where n is as defined above, -lOOC-CH=CH-COO-1, ~-coo-1, F~ANrPT,P'..C~
Without further elaboration, it i8 believed that one skilled in the art can, 10 using the prece~ g description, practice the present invention to its fullest extent.
The following ~t~ mpl~s (l~R~rihe how to prepare the various compounds and/or perform the various p,oce~es of the invention and are to be construed as merely illus~ldl~ive, and not limit~ffonR of the prece.li--g disclosure in any way whal,soevt:r. Those skilled in the art will p~ tly recogni~e applopl;ate variations 15 from the p~OCédllleS both as to rçn~ and as to reaction cnn~itionR and techniques.
PREPARATION 1 4~Piperazin-1-yl)bPn7s-mi~
A ll~i~l~ue of 4-fluorobçn7~mi-1~ (2.45 g, 17.6 mmol), piperazine (7.56 g, 87.9 mmol) and water (10 mT ) i8 stirred at 100~ for 24 hr. APcer cooling, the solid is 20 coll~ctç~l and washed with water and toluene and then dried under reduced ~ L_Juè
to give the title c~lllpc.ulld, mp = 240-248~; MS (M/Z) at 205; NMR (DMSO-d6) 2.59, 2.80, 3.14, 6.90, 7.02, 7.72 and 7.73 o.
PREPARATION 2 N-[4-(Trifluoromethyl)phenyl]piperazine A 100 mT- flask e.lui~ped with spinbar was charged with 4-25 bromobenzotrifluoride (19.70 g, 0.088 mol) and ~i~elf~zille (37.71 g, 0.438 mol). There~r~nt~ were heated to 130~. After 48 hours, the ~ulè cnntoin~ nifi~nt amounts of p~ ~ and is cooled to 20-25~. During the cooling, the reaction ,Ule iS diluted with sodium hydroxide (3N, 200 mL) r~s--lting in s--ltlit;ons~l allwull~ of ~re :l,;'Dl~ and i8 extracted twice with ethyl acetate (200 mT-). If the 30 reaction ~Lulè is allowed to cool to 20-25~ before adding aqueous base, the reaction becom~s a solid mass m~king further maniplll~t;onR ~lifficlllt~ The comhine organics are washed once with saline (300 mT-), dried over m~f~nPcium sulfate, filtered, and cor.c~ a~ed to give the procuct. Recryst~lli7~t;rln~ from h~Ynn~ gives the title ~,v~uu~ld, mp 87-89~ (lit. 86-88~), Rf = 0.20 (mPth~n-~/dichior mf~t~n~, 35 7193).
EXA~LE 1 (S)-(-)- 1-[2-[4-(4-M~h ~~Yyphenyl)- 1-pipc. ~illyUethyl]-

-32-CA 02225282 l997-l2-l9 W O 97/02259 P~1/~ J~08681 isochroman-6-c~l,...~1...i-le (S)-(VII) also known as (S)-(~ (4-M~thnY~yphenyl),4 [2-(6-~minoc~rbonylisochroman-1-yl)-~Lhylui~uerazine Step 1: Ethyl (6-bromoiRochroman-1-yl)~cet~te (III) A lllixLu~e of 3-bromoph.?n~qthyl alcohol (II, 14.8 g) in dichlorompths~ne (37 mL) under argon is cooled to 0~ with an ice bath. Ethyl 3,3-diethu~y,ulupionate (90%, 19.1 mL) is added via syringe. A titanium tetrachloride soll~tion (1 M in methylene rhl~ritle, 236 mL) is added via a canula to an sl~3i*on funnel and added semi-dropwise to the reaction ~ lu~ over one hr. The reaction is then l~lu~ d for 10 18 hr, after which time it is poured into a ~ Luie of aqueous hydrochloric acid (lN) and saline (1/2) and extracted with methylene chloride. The organic phases are ~omhin~-l, dried over sodium sulfate, filtered, and con-~r.l-~ted. The con~ntrate is purified by chrom~t~graphy (silica gel; ethyl acetateth~Y~ne 10/90) to give ethyl (6-bromoiRorhroman-1-yl)~cetP~ts (III); Rf = 0.40 (ethyl acetate/h~Y~n~, 25/76); IR (neat) 15 1736, 1483, 1374, 1288, 1280, 1183, 1163, 1110, 1050, 1037 cm~1; NMR (300 MHz, CDCl3) 7.30, 7.28, 6.92, 5.17, 4.20, 4.10, 3.79, 3.01-2.91, 2.87-2.65 and 1.28 ~; C~
(75 MH[z, CDCl3) 170.7, 136.0, 135.5, 131.6, 129.1, 126.0, 120.2, 62.6, 60.5, 41.3, 28.3 and 13.9 o; HRMS Calcd for Cl3H15O3Br = 298.0205, found = 298.0204.
Step 2: (R)-(+)-Ethyl (6-bromoiRochroman-1-yl)~retst~ (XII) and (S)-(-)-(6-20 bromoiRûrhrûman-1-yl)acetic acid (XI).
Ethyl (6-brom- iRorhroman-l-yl)~ret~ (III, Step 1, 29.49 g), Amano P-30 lipase (15 g, lot #LPSAR01520, act = 32,600 u/g), and pH 7 buffer (590 mL) are combined. The reaction is stirred vigorously and the hydrolysis is followed by HPLC
as follows. A 100 uL aliquot iB added to an opticlear vial c..~.t .i..i..g hydlvd~loric 25 acid (one drop). Ethyl acetate (1.5 mT.) is then added to the vial and the collt,~..t~
are mixed well. The reRlllt;nF mil~L~t: iB filtered through celite and assayed by HPLC (llBon-l~r~k C18 3.9 mm x 30 cm reverse-phase colllmn, 10% ~cetonitrile/90%rhr 3rh~t~ buffer (4 L water, 5.22 g sodium dillyd~u~n pho,~E~h~t~ (hyLdte), 0.76 mT
phosrhoric acid) gradient to 85/15 over 15 min, then isocratic at that ratio, 2 30 mL/min, ~i~tectQr at 215 nm), (XI) Rt = 10.5 min., (XII) Rt = 13.5 min. When the reaction reached the 50% collv~iion point, it iB filtered and the filtrate iB rinsed succes~ively with water aqueous hyd.ucllloric acid (lN) and ethyl ~cet~te, several times. The filtrates are comhinecl and extracted (two times) with ethyl ~-et~te. The cc~mhin~(l organic extracts are washed with an equal volume of sa~u~a(ed aqueous35 sodium carbonate (3 x), dried over sodium sulfate, filtered and conc~ ated to give Pn~nti~ln~rically enriched (XII). The saLul~Led aqueous sodium carbonate washes

-33-W O 97/022S9 PCT~US96/08681 are ~ ified with con~ e..l ~ated hydlochloric acid and extracted three times with methylene chloride, dried over sodium sulfate, filtered and con~entrated to give (XI).
The acid (XI) was assayed for en~nt;nmPric purity as follows. A ~xLu e of the acid (XI, 15 mg) in THF (0.5 mL) is reduced with borane-T~ cnmrl~Y (lM in THF, 0.12 5 mL) at -5~ to 20-25~ over 18 hrs. The reaction is cooled to 0~, qllpn~hpcl with mPth~nol (0.1 mL), then warmed to 20-25~ and hyd.ocllloric acid (lN, 0.4 mL) areadded via pipette. The reaction is then heated to reflux for 10 min., at which point the volatiles are removed under reduced pressure and the residue is partitinned between ethyl acetate and sa~uldted aqueous sodium carbonate. The organic phases10 are separated, dried over ma~nA~illm, filtered, and con~r-..t- dted. The residue is weighed and diluted to a conr~t-,1Lion of 10 mg/mT with a sol~t;nn of isopropanol in hexane (7~o). The llli~l.Ule iS assayed on a Chiracel OJ column using hexane/isopropanol 90/10, 15 min, 1 L/min), then 80/20 for an s~ lit;onç~l 10 m-in (2 mL/min), wavelength 254 nm; (S)-alcohol Rt = 12.46 min, (R)-alcohol Rt = 10.46 min.
16 The ester (XII) could be analyzed in a similar way following hydrolysis (vide infra).
If nPe~P~, the en~nt;omPrically enriched ester could be re-subjected to another cycle of the enzymatic hydrolysis if intlir~te~1 by the HPLC analysis. In this mnnnPr (R)-(+)-ethyl (6-bromnicocl~v~an-l-yl)~et~t~ (XII) is obtained, (96% ee); Rf = 0.40 (ethyl acetate~PY~nP, 25/75); [a]D +72~ (c = 0.383, ethsmnl); IR (neat) 1736, 1483, 1374, 20 1288, 1280, 1183, 1163, 1110, 1050, 1037 cm~l; NMR (300 MEIz, CDC13) 7.30, 7.28, 6.92, 5.17, 4.20, 4.10, 3.79, 3.01-2.91, 2.87-2.66 and 1.28; CMR (75 MHz, CDCl3)170.7, 136.0, 135.5, 131.6, 129.1, 126.0, 120.2, 62.6, 60.5, 41.3, 28.3, 13.9; HR~IS
Calcd for C13H1503Br = 298.0205, found = 298.0206. Also, (S)-(-)-(6-bromoi~o~hroman-1-yl)acetic acid (XI) is i~ol~t,e-l, (99% ee); mp = 160-161~; Rf =
25 origin (ethyl ~et~t~/hPY~ne, 25M5); ta]D = - 90~ (c = 1, eth~nol); IR (neat) 1711, 1482, 1428, 14406, 1330, 1297, 1111, 1101, 1003, 971 cm~l; NMR (300 ~Iz, CDC13) 7.30, 6.92, 5.17, 4.184.11, 3.86-3.78 and 3.04-2.69; CMR (75 MHz, CDC13) 175.7, 136.2, 135.1, 132.0, 129.6, 126.2, 120.8, 72.4, 63.1, 45.5, 41.1 and 28.5 ~.
Step 3: (S)-(-)-1-[2-(6-Brnmoi~o~hroman-1-yl)acetyl]4-(4-mPthnYyphenyl)-30 piperazine (S) (V) (S)-(-)-(6-bromni~o~ ~an-1-yl)acetic acid (XI, Step 2, 3 g), N-(4-methoxyphenyl)piperazine (2.34 g) and dichloromPth~nP (20 mL) are comhinP~ and cooled to 0~. Diethylcyanophnsph~tD (2.0 mT-) and triethyla_ine (1.7 mL) are added . eL~e~ Lively via syringe. The ice bath is allowed to expire and the ll~ is stirred 35 at 20-25~ for 18 hours. The reaction ....xLu~a is conc.q~ ated under reduced ple~ e to give crude material which is chrom~t,o~;. aphed (silica gel; ethyl acetate/h~YSInl~,

-34-W O 97/022S9 PCT/U~ 6~1 60-80/40-20) to give (S)-(-)-1-[2-(6-bromoisochroman-1-yl)acetyl]-4~4-methoxyphenyl)-~i~t,la~i"e (S)-(V) (which after r~ y~ liPsticn from ethyl acetate~hexane), mp =122-123~; Rf = 0.26 (ethyl acetate/h~Y~ne, 70/30); [a]D = - 86~(c = 0.99, ethanol); IR
(mull) 1639, 1512, 1446, 1439, 1249, 1214, 1112, 1030, 1028, 820 c_-1; NMR (300 5 MHz, CDCl3) 7.32-7.26, 7.00, 6.88, 5.27, 4.16-4.07, 3.89, 3.80-3.60, 3.77, 3.05, 2.97-2.90, 2.76 and 2.65 o; CMR (75 MHz, CDCl3) 168.9, 154.3, 145.2, 136.5, 136.2, 131.7, 129.3, 126.4, 120.3, 118.8, 114.4, 73.4, 63.4, 65.5, 51.3, 60.7, 46.1, 41.9, 39.9 and 28.7 o.
Step 4: (S)-(-)-1-[2-(6-BromoiAo~ ul~an-l-yl)ethyl]-4-(4-mpthr~yyphenyl) 10 piperazine (S)-(VI) (S)-(-)-1-[2-(6-Bromoisochroman-l-yl)acetyl]-4-(4-mPthnYyphenyl)-piperazine ((S)-(V), Step 3, 3.7 g) in THF (84 mL) iB cooled to 0~ and a u~il~ of borane-THF com~ Y (lM in THF, 25 mL) is added via syringe. The ice bath is removed and the llli~LUle iS heated to reflux for 18 hrs. The reaction is cooled to 0~
15 and 810wly qllPnrhP~ with aqueous hyll~ocl~loric acid (lN, 100 mL), and renu-~ed for an S3cl~it;~n-91 1.5 hrs. The llliXl,U~ iB cooled to 20-25~ and the solvents are removed under reduced p~ u~, and the aqueous residue is diluted with saline and b~RifiPdto pH 14 with aqueous sodium hydroYide. The ~ is eYtracted with dichloromP~qne and the comhinP~l organic phases are dried over sodium sulfate, 20 filtered, and cnnCe~ a~ed. The conr,~.t al~ is purified by le~yYl~ pstinn from ethyl ~cetatR~hexane to give (S)-(-)-1-[2-(6-bromoiRof~ u,l,an-1-yl)ethyl]-4-(4-mP~hm~yphenyl)-piperazine (S)-(VI), mp = 85-86~; Rf = 0.23 (ethyl acetate); ta]D -48~ (c = 0.73, eth:~nol); IR (neat) 1518, 1479, 1266, 1250, 1155, 1140, 1112, 1103, 1041, 818 cm~1; 1H NMR (300 MHz, CDCl3) 7.29, 7.27, 6.97, 6.85, 4.78, 4.14-4.07,25 3.76-3.69, 3.76, 3.10, 2.95, 2.70-2.50, 2.13 and 2.02 ~; CMR (75 MHz, CDCl3) 153.6, 145.5, 136.8, 136.0, 131.4, 129.0, 126.3, 119.7, 117.9, 114.2, 74.1, 62.5, 55.3, 54.4, 53.3, 50.4, 32.9 and 28.6 o; HR~IS Calcd for C22H27N2o2Brl = 430-1256~ found =
430.1270.
Step 5: (S)-(-)-1-[2-[4-(4-MPt~o~ryphenyl)-1-~il,elazi~,yl]ethyl]-isochroman-6-30 ~ le (S)-(VII) (S)-(-)-1-[2-(6-Brnmnico-~.hroman-l-yl)ethyU-4-(4-methoxyphenyl)-piperazine ((S)-(VI), Step 4, 364 mg), p~ m(II) acetate (98%, 9.7 mg) and 1,3-bis-diphenylph~srhinopropane (97%, 22 mg). A carbon monn~ e ~tmosph~re is e~tohli~he~ in the vial, then into the reaction vessel are introduced via syringe DMF

35 (2 mL), 1,1,1,3,3,3-hPY~mP~hyl~ nP (98%, 1.25 mL) and diiso~u~ylethylamine (0.29 mL). The ~u~e is heated to 100~ for 18 hr. After cooling to 20-25~, the W O 97/02259 PCT~US96/08681 reaction 8epard~Gd into two phases. The reaction ~u~Ga is poured into aqueous llyd~v~ loric acid (lN) and washed two times with ether. The acidic solllt;-~n is k~ifi ,~1 with aqueous sodium hydroxide and extracted three times wit~ ethyl ~r,et~t~ The ethyl acetate phases are comhinPd and con-c~ d~ed. The is purified 5 by chromS-1"J~-dphy (silica gel; mPt~nnl/dichloromPth~np~ 5/95) to give (S)-(-)-1-[2-[4-4 mPtho,Yyphenyl)-l-piperazinyl]ethyl]-isochroman-6-ca~ x~ ;de (S)-(VII), mp =
186-187~; Rf = 0.27 (m~th~n- l/ethyl ~retstç, 10/90); [a]D - 53~ (c = 0.92, methylene chloride/mPth~n.~l (1/1)); IR (mull) 3366, 3198, 1628, 1642, 1602, 1514, 1437, 1245, 1109 and 815 cm~l; NM, R (300 MHz,CDCl3) 7.61-7.58, 7.18, 6.85, 5.90, 4.86, 4.18-10 4.11, 3.80-3.72, 3.76, 3.10, 2.99, 2.73, 2.66-2.49, 2.15 and 2.04 o; CMR (75 MHz, CDCl3) 168.7, 153.5, 145.4, 142.0, 134.3, 131.0, 127.9, 124.8, 124.6, 117.8, 114.1, 74.2, 62.6, 55.2, 54.3, 53.2, 50.3, 32.8, 28.7 and 27.2 o; HRMS Calcd for C23H29N3O3 = 395.2209, found = 395.2227.
T~'XAMPLE 2 (R)-(+)-1-t2-[4-(4-MPthnYyphenyl)-1-piperazinyl]ethyl]-isochro lan-6-ca~ J.. irlP (R)-(VII) also known as (R)-(+)-1~4-MPth-n~yphenyl)-4-[2-(6-, min.~,cArbonylisochroman-l-yl)-G-Ll.yl~i~erazine Step 1: (R)-(+)-6-(Bromni~orhroman-l-yl)acetic acid (R)-IV.
A mixlu~Ga of lit~illm hydroxide (3M, 150 mT-) is added to (R)-(+)-ethyl (6-20 brom~i~o~l..v lan-1-yl)nr~ ~ (XII, TiXAMPLE 1 Step 2, 13.3 g) in THF (150 mL)and the ~ L~a is stirred at 20-25~ for 18 hours. The volatile 60lvents are removed under reduced pr~ a~ and the residue is ~rirlifiP~ with aqueous llydlo~loric acid to pH = 1. The resulting ~ix~ is extracted wit~ methylene r~hl~~ri~la and the comhinP~ organics are dried over sodium sulfate, filtered and cnnc~ dted. The 25 cQn~ dte is purified by ~-G",.~ lli7~t;~n from dichloromP~l ~nP/hexane to give (R)-(+)-6-(brom~i~orhroman-1-yl)acetic acid (R)-IV, mp = 160-161~; Rf = origin (ethyl .~etst~/hPY~nP~ 25/75); [a]D = +83~(c = 0. 99, etl~nnl); IR (neat) 1711, 1482, 1428, 14406, 1330, 1297, 1111, 1101, 1003 and 971 cm~l; NMR (300 MHz, CDCl3) 7.30, 6.92, 5.17, 4.18-4.11, 3.86-3.78 and 3.04-2.69 o; CMR (75 I~Iz, CDCl3) 175.7, 136.2, 30 135.1, 132.0, 129.6, 126.2, 120.8, 72.4, 63.1, 45.5, 41.1 and 28.5 o.
Step 2: (R)-(+)-1-[2-(6-Bromni~orhroman-1-yl)acetyl]-4-(4-mPth.~Yyphenyl)-~i~e.~zille (R)-(V).
Following the general plwedu~a of li'XAlVIPLE 1, Step 3 and m~king non-critical v~ri~ t;~n~ but starting with (R)-(+)-6-(brom.~i~Gf,1.1 v~an-1-yl)acetic acid 35 ((~XA1VIPLE 2, Step 1, (R)-(IV)), a crude product is obtained which is first purified by silica gel chrom~t~.d~hy using a gradient of 60-80% ethyl acetate/hPY~nQ, and

-36-W O 97/022S9 PCTrUS96108681 the resulting solid is then re~ L.~dl4lli7ed (ethyl f~cetDt~hexane) to give (R)-(+)-1-[2-(6-brom~i~orhroman-l-yl)acetyl]-4-(4-methoxyphenyl)-piperazine (R)-(V), mp = 122-123~; Rf = 0.26 (ethyl acetate/hPY~nP~ 70/30); [a]D = +89~(c = 1.00, e~llS~nol); IR
(mull) 1639, 1512, 1446, 1439, 1249, lZ14, 1112, 1030, 1028 and 820 cm~l; NMR
5 (300 MHz, CDC18) 7.32-7.26, 7.0, 6.88, 5.27, 4.16-4.07, 3.89, 3.80-3.60, 3.77, 3.05, 2.97-2.90, 2.76 and 2.65 o; CMR (75 MHz, CDCl3) 168.9, 154.3, 145.2, 136.5, 136.2, 131.7, 129.3, 126.4, 120.3, 118.8, 114.4, 73.4, 63.4, 55.5, 51.3, 50.7, 46.1, 41.9, 39.9 and 28.7 o.
Step 3: (R)-(+)-1-[2-(6-Brqmoi~orhroman-l-yl)ethyl]-4-(4-methoxyphenyl)-10 piperazine (R)-(VI) Following the general ~l~,cedul~ of lixAMpLE 1, Step 4 and making non-critical v~ri~tion~ but starting with (R)-(+)-1-[2-(6-br~mniRorhroman-1-yl)acetyl]-4-(4-methoxyphenyl)-piperazine (R)-(V) ((EXAMPLE 2, Step 2 ), (R)-(+)-1-[2-(6-brom~ orhroman-1-yl)ethyl]-4-(4-mPthnYyphenyl)-piperazine (R)-(VI) is obtained, 15 mp = 86-86~; Rf = 0.23 (ethyl acetate); [a]D = l 47~(c = 0.94, et~nl)l); IR (neat) 1518, 1479, 1266, 1250, 1155, 1140, 1112, 1103, 1041 and 818 cm~l; NMR (300 MHz,CDCl3) 7.29, 7.27, 6.97, 6.85, 4.78, 4.14-4.07, 3.76-3.69, 3.76, 3.10, 2.95, 2.70-2.50, 2.13 and, 2.02 8; CMR (76 MHz, CDCl3) 153.5, 145.5, 136.8, 136.0, 131.4, 129.0, 126.3, 119.7, 117.9, 114.2, 74.1, 62.5, 55.3, 54.4, 53.3, 50.4, 32.9 and 28.6;
20 HRMS Calcd for C22H27N2O2Br1 = 430.1256, found = 430.1274.
Step 4: (R)-(+)-1-[2-[4-(4-M~th~.~ryphenyl)-1-piperazinyl]ethyl]-isochroman-6-ca~ (R)-(VII) Following the general p~ cedu~e of F~AMpLE 1, Step 5 and making non-critical variations but starting with (R)-(+)-1-[2-(6-brom- i~orhroman-1-yl)ethyl]-4-(4-25 methoxyphenyl)-piperazine (R)-(VI) (~XAMPLE 2, Step 3), a crude m~t~ri~l is obtained which is purified by flash chrom:~to~.a~hy (silica gel, 50 g; m~th~n~l/eth ~ret~to~ 5/95) to give (R)-(~)-1-[2-[4-(4-m~h- ~ryphenyl)-1-piperazinyl]ethyl]-isochroman-6-ca~ icle (R)-(VII), mp = 187-187.5~; Rf = 0.27 (m~~h~nol/ethyl ~-~et~t~, 10/90); [a]D = +52~ (c = 0.92, methylene rhk)ri~/m ~thnnol~ 1/1); IR (mull) 30 3366, 3198, 1628, 1642, 1602, 1514, 1437, 1245, 1109 and 815 cm~l; NMR (300 ~Iz, CDCl3) 7.61-7.58, 7.18, 6.85, 5.90, 4.86, 4.18-4.11, 3.80-3.72, 3.76, 3.10, 2.99, 2.73, 2.66-2.49, 2.15 and 2.04 ~; CMR (75 MHz, CDCl3) 168.7, 153.5, 145.4, 142.0, 134.3, 131.0, 127.9, 124.8, 124.6, 117.8, 114.1, 74.2, 62.6, 55.2, 54.3, 53.2, 50.3, 32.8, 28.7 and 27.2 ~; HRMS Calcd for C23H29N3O3 = 395.2209, found = 395.2208.~5 hxAlvlpLE 3 (S)-(-)-1-[2-[4-(4-M~thrlYyphenyl)-l-piperazinyl]ethyl]-N-methyl-isochroman-6-carbr.~r~nni-1e (S)-(LX) also known as (S)-(-)-1-(4-

-37-W O 97/022S9 PCTrUS96/08681 Mpthnyyphenyl)-4-[2-(6-methyls~minor~rbonylisochroman-l-yl) ~Lhylpi,ut:L ~zi~e Step 1: (s)-(-)-N~N-Di-t-butylo~c~l,ul~yl-l-t2-[4-(4-mpthnyyphenyl) piperazinyl]ethyl]-isochroman-6-carbnY~mi~P (S)-(VIII) 6 A ll~ib~Lu~ of (S)-(-)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-isochroman-6-c~b~Y~1r~ p (S)-(VII), EXAMPLE 1, Step 5, 0.71 g), di-tert-butyl dicarbonate (0.86 g) and 4-dimethylaminopyridine (0.02 g) in dichloromPth~ne (20mL) is stirred at 20-25~ under argon. After 72 hours, the reaction is concentrated under reduced lJLe~Ule and the product i8 purified by column chrom~t~graphy 10 (silica gel, using a gradient eluant starting vwith 25% ethyl acetate in hexane and prc~ g to 100% ethyl acetate) to give (S)-(-)-N,N-di-t-butylo~y~;a,Lonyl-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-isochroman-6-carbnY~mi-1P (S)-(VIII), [a]D = -32~ (c = 0.7201, et~ ~nol); HR~MS Calcd for C33H45N307 = 595.3257, found =
595.3282.
Step 2: (S)-(-)-1-[2-[4-(4-MPthnYyphenyl)-l-,ui~u~,~~iuyl]ethyl]-N-methyl-isochroman-6-cdlL.n~ P. (S)-(IX) A ~ule of (S)-(-)-N,N-di-t-butyll".y~,~l,onyl-1-[2-[4~4-mPt~lnYyphenyl)-1-piperazinyl]ethyl]-isochroman-6-c~L~ ...icle (S)-(VIII) (1.09 g) in dichlorompth~np (18 mL) in a sç~l~hlP tube is cooled under nitrogen using ~ret~ne and carbon 20 ~inYi-lP~ Into the cold tube is then cor rlPn~PCl methylamine (excess; typically 50 equivalent6), after which the tube is sealed and allowed to warm to room te ~peL~tule. After stirring for 16 hr at room te~upelcll,ule, the CC~ t~ of the tube are cnn~ a~ed under reduced pressure and the rP~ tinE crude product is purified by column chrom~;- aphy (silica gel; using mpth~nnl/dichlornmpth~na 5/95) to give 25 (S)-(-)-1-[2-[4-(4-mPthn~ryphenyl)-1-piperazinyl]ethyl]-N-methyl-isochroman-6-c~1,--~ P (S)-(IX), [a]D = -51~ (c = 0.9953, mpth~nol/dichlorompth~np~ 1/1); Anal.
Calcd for C24H31N3O3: C, 70.39; H, 7.63; N, 10.26 - found: C, 70.16; H, 7.84; N, 10.27.
~AMPLE 4 (R)-(+)-1-[2-t4-(4-MPthnYyphenyl)-1-pi~a~ lyUethyll-N-methyl-isochroman-6-c~L.. ~.. itle (R)-(IX) also known as (R)-(+)-1-(4-M~nyyphenyl) 4-[2-(6-methyls~mins~nrbonylisochroman-1-yl)-~lhyl~i~uerazine Step 1: (R)-(+)-N,N-Di-t-butylox~cdlbollyl-1-[2-[4-(4-mPthc)lryphenyl)-1-piperazinyl]ethyl]-isochroman-6-c~l,u~J....i(l~P (R)-(VIII) Following the general pl~cedu~e of F:~AMpLE 3, Step 1 and m~king non-critical variations, but starting with (R)-(+)-1-[2-[4-(4-methoxyphenyl)-1-

-38-W O 97/022S9 PCTnUS96/08681 pipt~dzi~yl]ethyU-isochroman-6-c~b~ ((R)-(VII), ~:~AlVlPLE 2, Step 4, 0.60 g) gave (R)-(+)-N,N-di-t-butylu~y~-l.o.lyl-1-t2-t4-(4-methoxyphenyl)-1-pi~e~dzi~yl]ethyl]-isochroman-6-ca~L--~r.-i-1e (R)-(VIII), which was used directly for the neYt step.
6 Step 2: (R)~+)-1-[2-[4-(4-M~hnYyphenyl)-1-piperazinyl]ethyl]-N-methyl-isochroman-6-carbnY~mi-le (R)-(~) Following the general p~ ~du~e of ~AMPLE 3, Step 2 and making non-critical v~ri~tinnR~ but starting with (R)-(+)-N,N-di-t-butylu~ l,onyl-1-[2-[4-(4-methoYyphenyl)-l-piperazinyl]ethyl]-isochroman-6 cA.b..Y~ le (R)-(VIII) gave (R)-10 (+)-1-[2-[4-(4-m~thnYyphenyl)-l-pipe,laz...~l]ethyl]-N-methyl-isochroman-6-c~l,u~ e (R)-(IX), ta]D = +48~ (c = 0.9745, m~th~nol/dichlorom~th~n~ 1/1);
HR~IS Calcd for C24H3lN303 = 409.2365, found = 409.2391.
EXAMPLE 5 (S)-(-)- 1-t2-t4-(4-Trifluoromethylphenyl)- 1-pipt:~ a~ yl]ethyl]-N-methyl-isochroman-6-ca~l,..~ ....i(le (S)-(IX) also known as (S)-(-)-1-(4-l~uoromethylphenyl)~-[2~6-methyl~minoc~ . ~u~lylisochroman-1-yl)-ethylpi~erazine Step 1: (S)-(-)-1-[2-(6-Bromnicorhroman-1-yl)acetyl]4~4-trifluoromethylphenyl)-piperazine (S) (V) (S)-(-)-(6-Bromr~i~orhroman-l-yl)acetic acid (FXAMPLE 1, XI, 642 mg, 2.0 20 mmol), 10 mL dichlorom~th~n~, 1-(4-trifluoromethyl)~i~elazi,le (607 mg, 3.3 mmol) and diethylcyanophosrhnn~ (0.33 mL, 2.2 mmol) are comhin~-l cooled to 0~ and treated with triethylamine (0.42 mL, 3.0 mmol) with no visible change followed by w~i~g to 20-25~. After 16 hours, the reaction ~i~Lule is cnn~Pnl ~d~ed. The conck..t dte ig purified by LC on 58 g (230-400) silica gel eluting with ethyl 25 acetate/hexane (40/60) to give (S)-(-)-1-[2-(6-bromoiRochroman-1-yl)acetyl]-4-(4-trifluoromethylphenyl)-piperazine (S)-(V), Rf = 0.25 (ethyl acetate/hPY~nP~ 40/60).
Step 2: (S)-(-)-1-[2-(6-BromniQorhroman-1-yl)ethyl]-4~4-trifluoromethylphenyl)-piperazine (S)-(VI).
(S)-(-)-1-[2-(6-BromoiRor.hroman-l-yl)acetyl]-4-(~ I ;n~ v~ethylphenyl)-30 piperazine (S)-(V) (Step 1, 876 mg, 1.8 mmol) and 18.0 mL freshly ~liP~;llP-1tetrahy-l~vruldll are comhinA-l and cooled to 0~. The ~ e is drop-wise treated with a lM solllt;on of borane in tetrahydluruLd~l (5.4 mT, 5.4 m mol) with fo~ming.
The reaction is warmed to 20-25~ for 16 hrs. At this time, the reaction is treated with 1M hyd~v~hlnrir acid (6.0 mL), fitted with a reflux con-lAnRAr, and heated to 35 reflux for 1 hr. The reaction is cooled to 20-25~ with the volatiles le,Luuved under reduced p~e~ ~e- The resllltinF aqueous residue is diluted with water (30 mL),

-39-W O 97/022S9 PCT~US96/08681 adjusted to pH ~ 10, and extracted twice with ethyl acetate (30 mL). The comhinP(l organic ~ ct~ are washed once with saline (30 mL), dried over m~gnPcillm sulfate, filtered, and concPntrated. The concent~ate is purified by LC on 43 g (230-400) silica gel eluting with ethyl acetate/hexane (40/60) to give (s)-(-)-l-[2-(6-brnnnni~ochroman 5 1-yl~ethyl]-4-(4-trifluoromethylphenyl)-piperazine (S)-(VI), mp = 104-105~; Rf = 0.30 (ethyl ~ret~t~/h~Y~nP, 40/60).
Step 3: (S)-(-)-1-[2-[4~4-Trifluoromethylphenyl)-l-piperazinyl]ethyl]-N-methyl-isochroman-6-cP~ le (S)-(IX) (S)-(-)-1-[2-(6-Bromoi~o~hroman-l-yl)ethyl]-4-(4-trifluoromethylphenyl)-10 piperazine (S)-(VI) (Step 2, 703 mg, 1.5 mmol), palladium (II) acetate (17 mg, .075 mmol), 1,3-bis(diphenylrho~phino)propane (37 mg, .09 mmol), 3.0 mT.
dimt~(hylr..~ mi~l~, diiso~uropylethylamine (0.52 mL, 3.0 mmol), and N-m~ ylrc~ mi~le (1.8 mL, 30 mmol) are comhinP-i and purged six times with carbon mnnnYi-lP/house vacuum followed by hP~t;ng to 120~. After 16 hours, the l~ Ule i8 15 cooled to 20-25~, treated with 25 mL lM hyl.ochloric acid, snd stirred for 10 min.
This acidic sol~lt;~ n is adjusted to pH 12 and t~ _Led three times with ethyl acetate (20 mL). The comhinPtl organic 6l~l,r..~ are washed once with saline (30 mL), dried over m~.P~ .. sulfate, filtered, and cor.ce..l-a~ed. The con-~..l a~e is purified by LC on 33 g (230-400) silica gel eluting with ~cetonp/hexane (40/60) to 20 give (S)~-)-1-[2-[4~4-trifluoromethylphenyl)-1-piperazinyl]ethyl]-N-methyl-isochlu~an-6-cs~ le (S)-(IX), mp = 169-170~; Rf z 0.30 (~-~etor P/hP~ne~ 40/60).
AMpLE 6 (S)-(-)-1-[2-[4-[4-(AminocA-I~ullyl)phenyl]-1-pi,u~ yl]ethyl]-N-methylisochroman-6 c~1,~ p (R)-(IX) also known as (S)-(-)-l-(BPn~mi-le4-yl)-4-[2-(6-methyl~minoc~ . Lullylisochroman-l-yl)-~l~y~ le Step 1. (S)4)-2~6-Brnmni~o- hroman-2-yl)ethyl alcohol (S)~-)-2-(6-Brnmnico~hroman-1-yl)acetic acid (XI) (~XAlVlPLE 1, step 2, 16.27 g, 60 mmol) and 100 mT- tetrahyd~uru~ are co~nhinptl This ~Lul~: is treated with a lOM solllt;~n of borane methyl sulfide (18.0 mL, 0.18 mol) while m~int~ining 30 20-25~ with a water bath. After 1 hr, the reaction ~u~a is cooled to 0~ and slowly ql~PnrhP~l with 160 mL mPth~nol Note: An in~lnrt;on period of ~ppl..~i...~tPly 1-2 minllte~ is noticed before a rapid and sudden generation of hyd~ . The lu~a i8 warmed to 20-25~ and the volatiles are ~ uv~d under reduced pre~/iul~.
The rç?3ll1t;ng solid is diluted with lM sodium hydroxide (150 mT ) and extracted 35 three times with ethyl acetate (100 mL). The cnmhined organic ~ are washed once with saline (100 mT ), dried over m~nPRillim sulfate, filtered, and concç~ ted

-40-CA 02225282 l997-l2-l9 W O 97/022S9 PCTnUS96/08681 to give a solid. This m~t,~ari~l is ~ y~ 7p~l from ethyl acetate/hexane to give (S)-(-)-2-(6-bromniAochroman-2-yl)ethyl alcohol (S-1), mp 95-96~; Rf= 0.28 ~n-p~ 30/70).
Step 2: (S)-(-)-6-Bromo-l-(bromoethyl)isochroman (S)-(-)-2-(6-Bronnnicorhroman-2-yl)ethyl alcohol (S-1) (Step 1, 14.0 g, 54 mmol)and 91 ~ dichlorompt~np are cnmhina-l The resnltin~ d iS treated with 25 m~ tetrahyLurur~ll. The suspension is treated with carbon tetrabromide (22.6 g, 68 mlnol)~ cooled to 0~, and portion-wise treated with triphenyl rhnsphina (21.4 g, 82 mmol). The re~llltin~ e is warmed to 20-2~~ for three hours followed by conre--t-a~ion under reduced ~laF~ to give a solid. The triphenyl phnsFhin~ oxide is removed by l~v~ ti~n from ethyl acetate/hexane with the mother liquor giving a solid. This m~t~ri~l is absorbed on 70 g silica gel and purified by LC on 700 g (230-400) silica gel eluting with ethyl acetate/hexane (5/95) to give (S)-(-)-6-bromo-l-(bromoethyl)isochroman (IV), Rf = 0.47 (10% ~e~nP/hexane).
Step 3: ($)-(-)-4-[4-[2-(6-BromniAorhroman-1-yl)ethyl]-1-pi~elazi~yl]h~qn7:~mi~
A J~ e of (S)-(-)-6-bromo-1-(bromoet~yl)isochroman (IV) (Step 2, 17.22 g, 53.8 m~nol), 14.36 g (67.0 m mol) of 4-(piperazin-l-yl?bPn7~micle (PREPARATION 1, 10.43 g (80.7 mmol) of dii~u~upylethylamine, and 125 mL of ethylene glycol is 20 heated at 85-90~ ov~rniE~ht After cooling, water (300 mT-) is added and the rPAllltinE
solid is cnll~cte~l by filtration. The cake is washed three times with water (for a total of about 200 mL) and then with toluene (for a total of about 200 mL). The filter cake is then dried under reduced ~l~s2iu~e. After drying, the crude product is slurried in mP~h~n~)l/dichlorompth~ne and silica gel is added to adsorb the ~L~d.
25 After removal of the solvents, the silica gel slurry is poured onto the top of a silica gel column equilibrated with dichloromP~nP~mPth~nol (95/5). T~ ltinn is begun using dichloromp~np/m~tl~nnl (95/5) and then changed to dichloromPth~n~/m~t~nol (92/8) to elute (S)-(-)-4-[4-[2-(6-bromniAochroman-1-yl)ethyl]-l-pipe~ yl]hPn~mitle (VI), obtained as a solid after pooling of the 30 appropriate fractions and cnnrr ~ ion..
Step 4: (S)-(-)-1-[2-[4-[4-(~minncAILollyl)phenyl]-1-piperazinyl]ethyl]-N-methylisochromanyl-6-c~boY ~ " .;-~ P
(S)~-)-4-[4-[2-(6-BromniRorhroman-l-yl)ethyl]-l-piperazinyl]h~n~mide (VI) (Step 3, 3.34g, 7.52 mmol) is slurried in 55 mL of dry D~ and ~l~Pg~R~e~l using 35 house vacuum (rPle~Aing to argon). The slurry is transferred to a 3-necked round bottom flask (using an ~ iition531 10 mL of DMF to rinse the flask) c~ illillg

-41-W O 97/02259 PCT~US96108681 p~ m acetate (0.084 g, 0.376 mmol) and 1~3-bis(diphenylrhosphino)propane (0.232 g, 0.564 mmol) and the flask is placed in an oil bath. Diisrvpl o~ylethylamine (2.6 mL, 15.3 mmol) is added and the ~ u~ is again lightly clPg~e~1 and releasedto argon. Carbon mnnnYifl~ is blown onto the surface of the ~f~Lul~ as the temperature of the bath is raised to 60~. As the tel--pe.r l u,~ increased, the llli~l,U~
became homogeneous and the tip of the needle is then placed slightly below the surface of the snlllt;on After bubbling carbon monnyi~l~ into the solution for several minlltes, methyl amine gas also is bubbled into the sol~t;on Carbon mnnoYi~l~ and methyl amine ~ ition were cont;nll~-l for 6 hr or until the starting material iscnn~llm~cl, after which the ~ u.a is cooled and DMF removed under reduced plevv.ua. The residue is applied to a silica gel column andl eluted with mf~th~nol/dichloromPth~ne (8/92) until the less polar i~u,,~ies were eluted. Theeluent is then switched to m~tl~nnl /dichlorom~h~n~ (10/90) and (S)-(-)-1-[2-[4-[4-(~minor~rbonyl)phenyl]-l-piperazinyl]ethyl]-N-methylisochromanyl-6-carbnY~mide (IX )is obtained after pooling and conr.?.,t. d~ion of the appropriate fractions and crystslli7~tinn from m~t1~nolldichlor-7m~th~n~, mp 231.5-232.5~.
ANlpLE 7 1-[2-[4-(4-Methylphenyl)-1-piperazinyl]ethyl-isochroman-6-Step 1: 6-Brom-i~orl .~ an-1-yl-acetic acid (IV) Following the general p~uce~lu a of h~ANlpLE 2, Step 1 and making non-critical variations but using racemic ethyl 6-bromni~or~ ~an-1-yl-acetate (III), 6-bromni~orhroman-1-yl-acetic acid (IV) is obtained, mp 160-161~; NMR (300 MHz, CDCl3) 7.30, 6.92, 5.17, 4.18-4.11, 3.86-3.78 and 3.04-2.69 ~.
Step 2: 1-[2-(6-Bromoi~orhroman-1-yl)acetyl]-4-(4-methylphenyl)-piperazine (V) Following the general procedure of EXAMPLE 1, Step 3 and m~king non-critical v~ri~t;r~nC but using racemic 6-bromoi~orhroman-1-yl-acetic acid (IV) and 4-methylphw~yl~i~el~zine, 1-[2-(6-bromni~orhroman-1-yl)acetyl]-4-(4-methylphenyl)-piperazine (V) is obtained which after flash chrom~to~.d~hy (silica gel 80 g; ethyl acetate/h~Y~ne, 50/50), Rf = 0.20 (ethyl ~ret~t~/h~Y~n~ 50/~0); IR (neat) 1642, 1515, 1481, 1462, 1443, 1234, 1208, 1107, 1031 and 813 cm~l; NMR (300 MHz,CDC13) 7.30, 7.09, 7.01, 6.84, 5.26, 4.13-4.07, 3.95-3.87, 3.82-3.60, 3.12, 3.05-2.89, 2.77, 2.65 and 2.28 o; C~ (75 MHz, CDCl3) 168.2, 148.3, 136.5, 136.8, 131.7, 129.6, 129.2, 126.3, 121.2, 116.8, 73.3, 63.3, 60.2, 48.7, 45.9, 41.7, 39.8, 26.6 and 20.3 o.
Step 3: 1-[2-(6-Bromnicorhroman-1-yl)-ethyl]-4~4-methylphenyl)-piperazine (VI) -4~ 2-CA 02225282 l997-l2-l9 W O 97/022S9 PCT~US96/08681 Following the general pl'~)Cedu~e of FxAlvlpLE 1, Step 4 and mPking non-critical v~ ri5~t;~nc but using 1-[2~6-br. nn niRorh roman-1-yl)acetyl]-4~4-methylphenyl)-azille (V), l-[Z-(6-brom~iRocl-rolL~an-l-yl)-ethyl]-4-(4-methylphenyl)piper~ine (VI) is obtained, Rf = 0.21 (ethyl acetate/hPY~n~, 50/50); IR (neat) 2941, 2925, 2818, 5 1515, 1481, 1379, 1239, 1143, 1111 and 813 cm~l; N~ (300 ~Iz,CDCl3) 7.32-7.26,7.07, 6.97, 6.84, 4.78, 4.14-3.07, 3.78-3.69, 3.16, 2.94, 2.7-2.48, 2.26, 2.15-1.90 o;
CMR (75 ~Iz, CDCl3) 149.0, 136.9, 136.1, 131.4, 129.4, 129.0, 128.9, 126.3, 119.8, 116.1, 74.1, 62.6, 54.4, 53.2, 49.5, 33.0, 28.6 and 20.2 ~.
Step 4: 1-[2-t4-(4-Methylphenyl)-1-~i~el~hlyl]ethyl-isGchLu ,an-6-c~l,.. ~ le (IX) Following the general pl~cedu~e of FxAMpLE 1, Step 5 and m~kin~ ncn-critical variations but using 1-[2-(6-br m~.iRorhroman-1-yl)-ethyl]-4~4-methylphenyl)-pi~e~ e (VI), l-t2-[4-(4-methylphenyl)-~ e.~ yl]ethylisûchroman-6-Ca1b~ (VII) is obtained, Rf = 0.2 (mPth~nAl/ethyl ~et~tA~ 10/90); IR (mull)15 3373, 3180, 1647, 1623, 1571, 1520, 1406, 1242, 1111 and 817 cm~l; NMR (300 MHz,CDCl3) 7.59, 7.18, 7.07, 6.84, 6.05, 4.86, 4.13, 3.77, 3.17, 3.00, 2.76-2.45, 2.26, 2.14 ard 2.02 ~; HRMS C~ t~ l for C23H29N302 = 379.2260, found = 379.2269.
FxAMPLE 8 1-[2-[4~4-Chlûrophenyl)-1-piperazinyl]ethyl-isochrûman-6-c~L.-~...;(le (VII) Step 1: 1-[2-(6-Brom~.iRorhroman-1-yl)acetyl]-4~4-chlorophenyl)piperazine (V) Following the general procedure of EXAMPLE 1, Step 3 and m~king non-critical v~ri~tinnR but using racemic 6-bromnico,~ an-1-yl-acetic acid (IV) and 4-chlorophe~lyl~i~e,~i~e, 1-[2-(6-brnmniRo~ hroman-l-yl)acetyl]-4~4-methylphenyl)-piperazine (V) is oht~inP~l Rf = 0.20 (ethyl ~ptstplhpy~ne~ 50/50); IR (mull) 1642, 26 1594, 1496, 1482, 1443, 1275, 1232, 1107, 1030 and 821 cm~l; N~ (300 MHz,CDCl3) 7.32-7.21, 7.01, 6.84, 6.26, 4.11, 3.94, 3.79-3.60, 3.14, 3.09-2.89, 2.77 and 2.65 o; CMR (75 ~Iz, CDCl3) 178.1, 148.5, 136.0, 131.8, 129.1, 128.8, 125.8,125.0, 120.0, 117.5, 73.0, 63.2, 49.7, 49.2, 55.0, 41.9, 39.6 and 28.5 ~.
Step 2: 1-[2-(6-BrnmniRo~ ol an-1-yl)-ethyU-4~4-chlorophenyl)~ zine (VI) Following the general plucedu~a of ~AMpLE 1, Step 4 and m~king non-critical v~ri~t;on~ but using 1-[2~6-brnmniRo~l-loman-1-yl)acetyl]-4{4-chlorophenyl)-piperazine (V), 1-t2-(6-brnmniRûcl .- u an-1-yl)-ethyl]-4-(4-chlorophenyl)piperazine (VI) is obtained, mp = 94-96~; Rf = 0.22 (ethyl acetate/hPY~nP, 50/50); IR (mull) 1500, 1483, 1448, 1248, 1242, 1152, 1144, 1113, 1102 and 815 cm~l; N~ (300 ~Iz,CDCl3) 7.32-7.26, 7.19, 6.97, 6.83, 4.78, 4.14-4.07, 3.78-3.69, 3.16, 3.00-2.90, W O 97/022S9 PCTrUS96/08681 2.7-2.48 and 2.15-1.90 ~; CMR (75 MHz, CDCl3) 149.6, 137.1, 136.0, 131.4, 129.1,128.7, 126.3, 124.6, 120.0, 116.9, 74.0, 62.6, 54.3, 53.3, 53.0, 48.9, 33.0 and 28.6 ~.
Step 3: 1-[2-[4~4-Chlorophenyl)-1-piperazinyl]ethylisocl~vll.an-6-C~-~YJ~ P- (IX) Followingthe general ploce~ of ~xAlvrpLE 1, Step 5 and mnkin~ non-critical v~ri~tionc but using 1-[2-(6-bromni~ochroman-1-yl)-ethyl]-4-(4-chlorophenyl)-piperazine (VI), 1-[2-[4~4-chlorophenyl)- 1-piperazinyl]ethylisocln ulllan-6-~&I,o~ P (VII) is obtained, mp = 169-171~; Rf = 0.22 (mpth~nol/ethyl ~cet~te, 10/90); IR (mull) 3365, 1649, 1661, 1623, 1500, 1403, 1241, 1112, 1096 and 821 cm~l;
N~ (300 ~Iz,CDCl3) 7.59, 7.18, 6.84, 6.05, 4.88, 4.15, 3.77, 3.17, 3.00, 2.76-2.45, 2.14 and 2.02 o.
~XAMPLE 9 1-[2-[4~4-Phenylmethyloxyphenyl)-1-piperazinyUethyl]-isoch.v~an-6-~ ~b~-Y~ 1P (VII) Step 1: 1-(4-Phenylmethyloxyphenyl)4-[2-(6-bromni~o~ .,.. an-1-yl)acetyl],ui,u~ e (V) Following the general pl~celule of F~ANlpLE 1, Step 3 and m~king non-critical v~rint;~n~ but using racemic 6-bromni~orhroman-l-yl-acetic acid (IV) and 4-phenylmethylu,-y~ui,ue.~zine, 1-(4-phenylmethyloxyphenyl)-4-[2-(6-brnmni~orhroman-1-yl)acetyll,uip~i.az e (V) is obtained, Rf = 0.47 (ethyl acetate); IR (mull) 1510, 1481, 1463, 1453, 1445, 1239, 1231, 1101 and 1027 cm~1; N~ (300 MHz, CDC13) 7.43-7.25, 7.00, 5.27, 5.02, 4.23-4.06, 3.93-3.87, 3.80-3.59, 3.06, 2.98-2.89, 2.76 and 2.65 o;
CMR (75 MHz, CDCl3) 168.9, 153.4, 145.3, 137.1, 136.4, 136.2, 131.6, 129.3, 128.4, 127.8, 127.3, 126.4, 120.2, 118.6, 115.5, 73.3, 70.3, 63.4, 51.1, 50.5, 46.0, 41.8, 39.8 and 28.7 ~. Step 2: 1~4-Phenylmethyloxyphenyl)-4-[2~6-brcmni~ofl-r~. an-1-yl)-ethyl],ui,u~.~.zine (VI) Following the general ,uloced of F~Al\/IPLE 1, Step 4 and m~king non-cAtical v~ri~t;on~ but using 1~4-phenylmethyloxyphenyl)~-[2-(6-brnmni#orhroman-l-yl)acetyl]~il,e~dzine (V), 1-(4-phenylmethyloxyphenyl)-4-t2-(6-bromni~ochroman-1-yl)-ethyl]piperazine (VI) is obtaned, mp = 87-90~; Rf = 0.43 (ethyl acetate); IR (neat) 1578, 1517, 1452, 1258, 1153, 1113, 1054, 1049, 818 and 737 cm~l; N~ (300 MHz,CDCl3) 7.43-7.26 (m, 7H, aromatic H's), 6.97 (d, lH, J=8.2 Hz, aromatic H), 6.90 (8 with broad base, 4H, aromatic H's), 5.01 (8, 2H, PhC-H2), 4.77 (m of d, lH, J=5.5 Hz, PhC-H), 4.14-4.07 (m, lH), 3.74 (d of t, lH, Ja=3.9 Hz, Jb=9.4 Hz), 3.11 (t, 4H, J=4.9 Hz, four of pip-H), 2.95 (m, lH), 2.7-2.54 (several m's, 7H), 2.11 (m, lH, pipCH-H), 2.02 (m, lH, pipCH-H) ~; C~ (75 MHz, CDCl3) 153.0, 145.1, 137.4, 137.1, 136.3, 131.6, 128.5, 127.8, 126.5, 120.0, 118.0, 115.6, 74.3, 70.5, 62.8, 54.6, CA 02225282 l997-l2-l9 W O 97/022S9 PCTnUS96/08681 53.5, 50.5, 33.1 and 28.9 o.
Step 3: 1-[2-[4-(4-Phenylmethyloxyphenyl)-1-piperazinyl]ethyl]-isochroman-6-c~1,~ "~ide (VII) Following the general ~lucedu-- of F~xAMpLE 1, Step 5 and making non-critical variations but using 1-(4-phenylmethyloYyphenyl)4-[2-(6-bromniRorhroman-1-yl)-ethyl]piperazine (VI), 1-[2-[4-(4-phenylmethyloYyphenyl)-l-piperazinyl]ethyl]-i~ocllru.llan-6 c~.l,o~ le (VII) is obtained, IR (mull) 3368, 3178, 1647, 1623, 1611, 1570, 1515, 1334, 124.6 and 1111 cm~l; NMR (300 MHz, CDCl3) 7.58 (m,2H, aromatic H'_), 7.43-7.30 (m, 5H, aromatic H's), 7.15 (d, lH, J=8.4 Hz, aromatic H), 6.90 (B, 4H, aromatic H's), 6.20-5.80 (two broad ~inE~ tq~ C(O)N-H2), 5.0 (s, 2H, PhC-H2-O), 4.87 (m of d, lH, J=5.8 Hz), 4.184.10 (m, lH), 3.81-3.73 (m, lH), 3.10 (t, 4H, J=4.8 Hz, four of pip-H), 3.0 (m, lH), 2.75 (m, lH), 2.650-2.54 (m, 6H), 2.15 (m, lH), 2.05 (m, lH) o; CMR (75 MHz, CDCl3) 169.0, 152.9, 145.8, 142.3, 137.3, 134.5, 131.3, 128.5, 128.1, 127.8, 127.4, 125.0, 124.9, 118.0, 115.5, 74.5, 70.4, 62.8, 54.6, 53.4, 50.4, 33.1 and 29.0 ~.
EXAMPLE 10 1-[2-[4-(4-Bulu~y~henyl)-l-piperazinyl]ethyl]isocl~ an-6-Step 1: 1-[2-(6-BrnrnoiRo-~hroman-1-yl)acetyl]-4-(4-buL~,~y~henyl)-piperazine (V) Following the general pl~- edul~ of F~xAMpLE 1, Step 3 and making non-critical v~ri~ti~nR but using racemic 6-bromni~o~l~t~ù ~an-1-yl-acetic acid (IV) and 4-buLu~y~he,~yl~ e~ 1-[2-(6-bromniRor,l . . ~ an-l-yl)acetyl]-4-(4-bul~,~yl3henyl)-zille (V) is obtained, Rf = 0.24 (ethyl acetate/h~Y~n~, 50/50); IR (mull) 1640, 1513, 1482, 1441, 1422, 1245, 1232, 1103, 1031, 829 cm~l; NMR (300 MHz, CDCl3) 7.29, 7.00, 6.90, 5.26, 4.13-4.07, 3.92, 3.93-3.87,3.80-3.60, 3.06, 2.98-2.89, 2.76, 2.65, 1.74, 1.48, 0.96 o; CMR (75 MHz, CDCl3) 168.8, 153.8, 145.0, 136.4, 136.2, 131.6, 129.3, 126.3, 120.2, 118.7, 115.1, 73.3, 67.9, 63.3, 51.2, 50.7, 46.1, 41.8, 39.8, 31.3, 28.7, 19.1, 17.3 and 13.7 ~.
Step 2: 1-[2-(6-Bromni~o~ ...an-l-yl)-ethyl]-4-(4-buLw~ylJhenyl)-~i~e~ e (VI) Following the general p~u~ellul~ of ~xANlpLE 1, Step 4 and making non-critical variations but using 1-[2-(6-bro7n~ o~ u..,an-1-yl)acetyl]-4-(4-bulu,.y~henyl)-piperazine (V), 1-[2-(6-bro7noiRo-~hroman-1-yl)ethyl]4~4-bul~,.y~henyl)piperazine (VI) is obtained, Rf = 0.43 (ethyl acetate); IR (neat) 2957, 2931, 28872, 1511, 1481, 1261, 35 1243, 1233, 1112, 1057 cm~l; NMR (300 MHz,CDC13) 7.32 (d, 2H, J=8.3 Hz, aromatic H's), 7.06 (d, lH, J=8.3 Hz, aromatic H), 6.85 (q, 4H, J=9.7 Hz, aromatic H's), 4.80 CA 02225282 l997-l2-l9 W O 97/022S9 PCT~US96/08681 (m of d, lH, J=6.1 Hz), 4.134.08 (m, lH), 3.98-3.89 (m, 3H), 3.71 (d of t, lH, Ja-3.7 Hz, Jb=13.7 Hz), 3.28 (broad 8, 4H), 3.10-2.72 (broad m, 7H), 2.65 (m of d, lH, J=16.5 Hz), 2.40 (m, lH), 2.22 (m, lH), 1.74 (quintet, 2H, J=6.6 Hz), 1.46 (sextet, 2H, J=7.3 Hz), 1.25 (t, 2H, J=7.0 Hz), 0.96 (t, 3H, J=7.3 Hz) o; HRMS C~ te~l for 5 C25H33N2~2Brl = 473.1804, found = 473.1796.
Step 3: 1-[2-[4-(4-Bulu~y~henyl)-l-pipe,~zi~lyl]ethyl]isochroman-6-carb-.Y~mide (VII) Following the general plocedu~e: of lixAl\lrpLE 1, Step 5 and mslking non-critic~l variations but using 1-[2-(6-br~m-i~orl-l~u~an-l-yl)-ethyl]-4~4-l~ulu..y~henyl)-10 piperazine (VI), l-t2-[4~4-bul~ y~henyl)-1-piperazinyl]ethyl]i~ocllro~an-6-C~b--Y~ e (VII) is obtained, Rf = 0.18 (mPtl~nollethyl 2qcet~te~ 10/90); IR (mull) 3364, 2820, 1647, 1624, 1570, 1517, 1413, 1260, 1245, 1111 cm~l; NMR (300 MHz, CDCl3) 7.60 (m,2H, aromatic H's), 7.18 (d, lH, J=8.5 Hz, aromatic H), 6.86 (q, 4H, J=9.2 Hz, aromatic H's), 6.20-5.80 (two broad cingl~t~, C(O)N-H2), 4.85 (m of d, lH, 15 J=18 Hz), 4.15 (m, lH), 3.90 (t, 2H, J=6.5 Hz, -O-C-H2-CH2CH2Me), 3.77 (m, lH), 3.10 (t, 4H, J=4.8 Hz, four of pip-H), 2.96 (m, lH), 2.80-2.50 (m, 6H), 2.15 (m, lH), 2.05 (m, lH), 1.74 (quintet, 2H, J=6.8 Hz, -OCH2C-H2-CH2Me), 1.48 (quintet, 2H, J=7.5 Hz, -OCH2C-H2C-H2-Me), 0.96 (t, 3H, J=7.3 Hz, -OCH2CH2CH2C-H3) o; C~
(75 MHz, CDCl3) 169.1, 160.8, 153.4, 145.6, 142.4, 134.6, 131.3, 130.3, 128.2, 127.6, 20 126.1, 125.0, 118.1, 115.1, 74.5, 68.1, 62.9, 54.7, 53.5, 50.6, 41.4, 33.2, 31.5, 29.0, 19.3 and 13.9 o; HRMS C~ tetl for C26H35N303 = 437.2678, found = 437.2678.
EXA~LE 11 1-[2-[4~4-Diethylaminophenyl)- l-pi~ yl]ethyl]isocl~l ~,~an-6-c~ 7e (VII) Step 1: 1-[2-(6-Br~moi~o~ o~an-l-yl)acetyl]-4-(4-diethylaminophenyl)-pi~elazi le (V) Following the general prucedu~cs of EXAMPLE 1, Step 3 and m~king non-critical v~ri~ n~hut using racemic 6-brl nl i~o~h~an-l-yl-acetic acid (IV) and 4-diethylaminophe--ylt)i~ -zine, 1-[2-(6-bromri~oCl .~ ~an-1-yl)acetyl]-4-(4-diethylaminophenyl)piperazine (V) is obtained, Rf = 0.21 (Sl-~eton~ Y~ne~ 30/70); IR
30 (mull) 1633, 1518, 1482, 1446, 1423, 1261, 1232, 1196, 1109, 809 cm~l; lH N~ (300 MHz, CDCl3) 7.32-7.26 (m, 2H, aromatic H's), 7.0 (d, lH, J=8.2 Hz, aromatic H), 6.88 (d, 2H, J=9.0 Hz, aromatic H's), 6.68 (d, 2H, Js9.0 Hz, aromatic H's), 5.27 (m of d, lH, J=5.9 Hz, ArC-H), 4.16-4.07 (m, lH), 3.89 (m, lH), 3.76 (m, 2H), 3.64 (m, 2H), 3.28 (q, 4H, J=7.1 Hz, two of PhNC-H2), 2.98 (m, 5H), 2.76 (d of d, lH, Ja=3.7 Hz, 35 Jb=14.9 Hz), 2.65 (m of d, lH, J=16.4 Hz) 1.12 (t, 6H, J=7.0 Hz, two of NCH2C-H3) o; C~ (7~ MHz, CDCl3) 168.8, 143.2, 141.6, 136.4, 136.2, 131.6, 129.2, 126.3, W O 97/02259 PCTrUS96/08681 120.2, 119.2, 113.7, 73.3, 63.3, 51.6, 51.0, 46.1, 44.6, 41.9, 39.8, 33.1, 28.6 and 12.4 o.

Step 2: 1-[2-(6-Brom~ o~ o~an-1-yl)-ethyl]-4-(4-diethylaminophenyl)-piperazine (VI) Following the general plwe-lt~ . e of EXAMPLE 1, Step 4 and making non-critical v~ri~ti~nc but using 1-[2-(6-bromni~orhroman-1-yl)acetyl]-4~4-diethylsminophenyl)~ t~lc z e (V), 1-[2-(6-brontniRorhroman-1-yl)-ethyl]-4~4-diethylaminophenyl)piperazine (VI) is obtained, Rf = 0.26 (ethyl acetate); IR (neat) 2931, 2965" 2814, 1516, 1374, 1262, 1232, 1144, 1109, 818 cm~l; NMR (300 MHz,CDCl3) 7.3-7.26 (m, 2H, aromatic H'~), 6.98 (d, lH, J=8.2 Hz, aromatic H), 6.88 (d, 2H, Jz9.0 Hz, aromatic H's), 6.68 (d, 2H, J=9.0 Hz, aromatic H's), 4.77 (m of d, lH, J=5.9 Hz, ArC-H), 4.14-4.07 (m, lH), 3.74 (d of t, lH, Ja=3.9 Hz, Jb=9.3 Hz), 3.26 (q, 4H, J=7.1 Hz, two of PhNC-H2), 3.08 (t, 4H, J=4.8 Hz, four of pip-H), 2.95 (m, lH), 2.70-2.53 (m, 7H), 2.11 (m, lH, pipCH-H), 2.00 (m, lH, pipCH-H), 1.11 (t, 6H, J=7.0 Hz, two of NCH2C-H3) ~; HRMS Cstlcl~k~te~l for C25H34N301BrloO.152 C4H8O2 = 472.1964, found = 472.1956.
Step 3: 1-[2-[4~4-Diethylaminophenyl)-1-pi~ 6zi. yl]ethyU-isoclllc,~an-6 ~ b~ e (VII) Following the general pl'l)Ccdule of l~xANlpLE 1, Step 5 and mAking non-critical vAriAffon~ but using 1-[2-(6-bromni~o~ c, an-1-yl)-ethyU-4~4-diethyl~minoFhpnyl)piperazine (VI), 1-[2-t4-(4-diethylaminophenyl)-1-yl]ethyl]isochrvl..an-6 c~b~ lP (VII) is obtained, Rf = 0.25 mPt~Annl/ethyl fl~etste~ 10/90); NMR (300 MHz,CDC13) 7.59, 7.18, 6.87, 6.68, 6.1, 5.7, 4.87, 4.13, 3.78, 3.26, 3.06, 2.78-2.57, 2.17, 2.05 and 1.11 o.~5 FxAMpLE 12 1-[2-t4-(3-Tl;~uo~ .,ethylphenyl)-1-piperazinyl]ethyl]isochroman-6-c~l...Y,1...i-1P (VII) Step 1: 1-t2-(6-Br mnico~l~l~an-l-yl)acetyl]-4~3 trifluoromethylphenyl)-~i~e~zi,le (V) Following the general ~ lule of ~XAMPLE 1, Step 3 and m~king non-30 critical v~ri~t;~nR but using racemic 6-br~mniRorh~oman-1-yl-acetic acid (IV) and 3-uololue(llyl~he~yl~i~e~azille~ 1-[2-(6-bromniRGcl-~o Ian-l-yl)acetyl]-4~3-uolv~elllyll~henyl)~ rnzi~e (V) is obtianed, Rf = 0.30 (ethyl acetate/hPY~nP~
40/60); IR aiq.) 1643, 1610, 1592, 1496, 1482, 1448, 1374, 1351, 1320, 1309, 1282, 1233, 1164, 1121, 1076 cm~l; NMR (300 MHz, CDCl3) 7.34 (m, 3H, aromatic), 7.08 35 (m, 4H, aromatic), 5.25 (brdd, lH, J=5.6 Hz, mP~inP), 4.11 (m, lH, OCH2a), 3.9i m, lH, O=C-N-CH2a), 3.80-3.65 (m, 4H, ~=C-N-CH2bcd~ ~CH2b)~ 3-23 (m~ 4H~ Ph-W O 97/02259 PCT~US96/08681 NCH28), 2.95 (m, 2H, Ph-CH2a & N-CO-CH2a), 2.78 (dd, lH, J=14.8 Hz & J=3.7 Hz, N-CO-CH2b), 2.66 (bd, lH, J=16.4 Hz, Ph-CH2b) ~; CMR (75 MHz, CDCl3) 169.2, 151.1, 136.4, 136.3, 131.8, 131.4, 129.7, 129.5, 126.5, 126.0, 122.4, 120.5, 119.2, 116.6, 112.7, 73.6, 63.6, 49.2, 48.8, 45.8, 41.6, 40.0 and 28.8 o; MS tEI, m/z) = 482.
Step 2: 1-[2-(6-Brnm. i~o~ u~an-l-yl)-ethyl]4~3 trifluoromethylphenyl)-piperazine (VI) Following the general plùce-lul- of ~xANlpLE 1, Step 4 and m~kin~ non-criticsl variations but using 1-t2-(6-bromoisoclnu 1an-1-yl)acetyl]-4{3-trifluoromethylphenyl)piperazine (V), the product i8 obtained. This mr t~ri, l i8 purified by LC (silica gel, 230-400, 142 g; ethyl retstQ'hQY~nQ, 30/70) to give 1-t2~6-brom.-Ji~orhroman-1-yl)-ethyl]-4-(3-Li~uolomethylphenyl)piperazine (VI), Rf = 0.40 (ethyl retstQ/h~QY- nQ~, 40/60); IR (liq.) 2824, 1610, 1496, 1481, 1449, 1357, 1319, 1293, 1239, 1164, 1123, 1076, 993, 949 and 695 cm~l; NMR (300 MHz, CDCl3) 7.32 (m, 3H, aromatic), 7.07 (m, 3H, aromatic), 6.97 (d, lH, J=8.2 Hz, aromatic), 4.79 (brdd, lH, J=5.7 Hz, m~Qtl~inQ), 4.11 (m, lH, OCH2a), 3.73 (m, lH, OCH2b), 3.23 (t, 4H, J=5.0 Hz, Ph-NCH2~), 2.93 (m, lH, Ph-CH2a), 2.58 (m, 7H, Ph-NC(H2)-CH2~-NCH2 & Ph-CH2b), 2.10 (m, lH, C(H)-CH2a), 2.00 (m, lH, C(H)-CH2b) ~; C~ (75 MHz, CDCl3) 151.4, 137.0, 136.3, 131.7, 131.4 (qrt, JCF=36 Hz), 129.5, 129.3, 126.5, 126.2, 120.0, 118.6, 115.7 (d, JCF=4 Hz), 112.1 (d, JCF=4 Hz), 74.2, 62.9, 54.5, 53.2, 48.7, 33.2, 28.9 o; MS (EI, m/z) = 468.
Step 3: 1-[2-[4~3-Tri~uo.v lelhyl~henyl)-1-~i~eL ~zillyl]ethyl]isodll u~sn-6 c~l,-. - ~ . . . ;~ (VII) Following the general pluc6dul. of F~AMPLE 1, Step 5 snd m~kinF non-criticsl vnri~ t;- n~ but using 1-[2-(6-brom.-i~orhroman-1-yl)-ethyl]-4~3-trifluoromethylphenyl)~i~eL6z~e (VI) the product is ol~tsinP~l This material is purified by LC (silics gel, 230-400, 120 g; ~cet--nP/hPY nP~ 50/50) to give 1-[2-[4~3-trifluoromethylphenyl)-l-pipe.Azillyl]ethyl]isochromsn-6-c~l,..- ~...i~e (VII). This m.~t,eri,li9le~ 11i7~ from ethyl r-~-t--tJlhexane to give 1-[2-[4~3-trifluoromethylphenyl)-1-pi~.Azillyllethyl]isochromsn-6 c~l,~ (VII), mp =
30 129-131~; Rf = 0.22 ( ~-~st-nP/hPY-n.q, 50/50); IR (mull) 3383, 1647, 1618, 1606, 1567, 1407, 1359, 1322, 1312, 1287, 1161, 1139, 1115, 1098, 952 cm~l; N~ (300 MHz, CDCl3) 7.60, 7.33, 7.18, 7.07, 6.00, 4.88, 4.14, 3.77, 3.24, 3.01, 2.78-2.48, 2.01 ~;
CMR (75 MHz, CDCl3) 169.1, 151.4, 142.4, 134.6, 131.5 (qrt, JCF=32 Hz), 131.4, 129.5, 128.2, 125.1, 125.0, 122.5, 118.6, 115.8 (d, JCF=4 Hz), 112.1 (d, JCF=4 Hz), 35 74.4, 63.0, 54.5, 53.2, 48.7, 33.2, 29.1 ~; HRMS (EI) r~lc~ t-~ for C23H26F3N3O2 =
433.1977, found = 433.1979.

CA 02225282 l997-l2-l9 W O 971022S9 P~~ 08681 ~XA~rPLE 13 1-[2-t4~4-Methyl8u~u~yl~he~yl)~ e~ yl]ethyU-isochroman e c~L~
Step 1: 1-[2-(6-Bromni~orhroman-1-yl)acetyl]-4{4-methylsulfonylphenyl)-piperazine (V) Following the general procedure of EXAMPLE 1, Step 3 and m~king non-critical v~ri~t~ but using racemic 6-brnmnicorhroman-1-yl-acetic acid (IV) and 4-methylsulfonylphe~lyl~ zine the product is obtained. This ms~t~ l is purified byLC (silica gel, 230-400, 150 g; ethyl acetate) to give 1-[2-(6-br~mnicorhroman-l-yl)acetyl]-4-(4-methylsulfonylphenyl)piperazine (V), Rf= 0.30 (ethyl acetate); IR
(mull) 1639, 1593, 1508, 1481, 1405, 1295, 1239, 1146, 1105, 1096, 1027, 1000, 958, 825, 779 cm~l; NMR (300 MHz, CDCl3) 7.77 (d, 2H, J=8.9 Hz, aromatic), 7.28 (m, 2H, aromatic), 7.00 (d, lH, J=8.2 Hz, aromatic), 6.91 (d, 2H, J=9.0 Hz, aromatic), 5.24 (brdd, lH, J=5.7 Hz, m~t~in~), 4.10 (m, lH, OCH2a ), 3.94 (m, lH, O=CN-CH2a), 3.78-3.60 (m, 4H, OCH2b, O=C-N-CH2bCd)~ 3-38 (m~ 4H~ Ph-N-CH28), 3-00-2.88 (m, 5H, Ph-CH2a, CH3, N-C=O-CH2a), 2.78 (dd, lH, J=14.7 Hz & 3.6 Hz, N-C=O-CH2b), 2.65 (brdd, lH, J=16.4 Hz, Ph-CH2b) o; CMR (75 MHz, CDCl3) 169.3, 153.9, 136.3, 131.8, 129.5, 129.2, 126.4, 120.5, 114.1, 73.7, 63.6, 47.5, 47.2, 45.5, 44.9, 41-3, 40-0 and 28-8 ~; HRMS (EI) ç~lr,~ tecl for C22H25BrN204S = 492.0719, found- 492.0714.
Step 2: 1-[2-(6-BrrmniAo~l~.v an-l-yl)-l-ethyl]~{4-methyl_ulfonylphenyl)~i~e~ e (VI) Following the general pl~cedu~ of F~AMpLE 1, Step 4 and making non-critical v~ri~t;~n~ but u_ing 1-[2-(6-brQmniAo-~] . . vlllan-l-yl)acetyl]-4{4-methylsulfonylphenyl)piperazine (V), 1-[2-(6-brnmni~o~l . . vl,.an-l-yl)-l-ethyl]-4-(4-25 methylsulru-lyl~henyl)piperazine (VI) i8 obtained, Rf = 0.26 (ethyl acetate); IR (mull) 3586, 1592, 1507, 1481, 1424, 1405, 1296, 1249, 1145, 1109, 1095, 1004, 956, 822, 779 cm~l; N~ (300 MHz, CDCl3) 7.75 (d, 2H, J=9.0 Hz, aromatic), 7.27 (m, 2H, aromatic), 6.95 (d, lH, J=8.3 Hz, aromatic), 6.90 (d, 2H, J=9.0 Hz, aromatic), 4.78 (brdd, lH, J=5.7 Hz, m~t~in~), 4.10 (m, lH, OCH2a), 3.74 (m, lH, OCH2b), 3.35 (t, 30 4H, J=6.0 Hz, Ph-NCH2s), 3.00 (8, 3H, CH3), 2.94 (m, lH, Ph-CH2a), 2.64 (m, 7H, Ph-NC(H2)-CH28-NCH2 & Ph-CH2b), 2.09 (m, lH, C(H)-CH2a), 2.01 (m, lH, C(H)-CH2b) ~; CMR (75 MHz, CDCl3) 154.3, 136.9, 136.4, 131.7, 129.3, 129.1, 128.6, 126.4, 120.1, 113.8, 74.1, 62.9, 54.4, 52.9, 47.3, 45.0, 33.1 and 28.9 8; HRMS (EI) - r~lr~ t~ for C22H27BrN2O3S = 480.0906, found = 480.0903.
Step 3: 1-[2-[4{4-Methylsulfonylphenyl)-1-pi~ yl]ethyl]isochroman-6 c~L
~9 CA 02225282 l997-l2-l9 W O 97/022S9 PCT~US96/08681 Following the general plucc~ a of ~xAlvrpLE 1, Step 5 and mAking non-critical vAriAt;~nR but using 1-[2-(6-bromrliRorhroman-1-yl)-1-ethyl]-4{4-methylsulfonylphenyl)ui,u~ L~ille (VI) the product is obtained. This mntPriAl ispurified by LC (silica gel, 230-400 mesh, 75 g; mPthAnolldichlo~ hAnp~ 6/95) to 5 give 1-t2-t4~4-methylsul~u~yl~uhenyl)-1-piperazinyl]ethyl]isocl~ ,an-6 C~bUY~ P
(VII), mp = 217-219~; Rf = 0.17 (mPt~An~l/dichlorompthAnp~ 5/95); IR (mull) 3433, 1668, 1619, 1587, 1568, 1507, 1288, 1140, 1115, 1105, 1095, 1023, 998, 812, 780 cm~l; NMR (300 MHz, DMSO-d6) 7.90 (brds, lH, NH), 7.66 (m, 4H, aromatic), 7.28 (d, 2H, J=8.0 Hz, aromatic & NH), 7.06 (d, 2H, J=9.1 Hz, aromatic), 4.79 (brdd, lH, 10 J=6.5 Hz, m~inP), 4.08 (m, lH, OCH2a), 3.67 (m, lH, OCH2b), 3.32 (t, 4H, J=4.0 Hz, Ph-N-CH2~), 3.08 (8, 3H, CH3), 2.88 (m, lH, Ph-CH2a), 2.71 (dm, lH, J=16.4 Hz, Ph-CH2b), 2.53 (m, 5H, Ph-NC(H2)-CH28-NCH2a ), 2.37 (m, lH, NCH2b), 2.13 (m, lH, C(H)-CH2a), 1.98 (m, lH, C(H)-CH2b) o; C~ (75 MHz, DMSO-d6) 168.2, 154.3, 141.8, 134.1, 132.6, 129.0, 128.9, 128.5, 125.6, 125.2, 114.0, 74.1, 62.7, 54.6, 53.0, 15 47.2, 44.7, 32.9 and 29.0 ~; HRMS (FAB) cAlrlllAt~ for C23H29N304S+Hl =
444.1957, found = 444.1959.
LE 14 (S)~-)-1-[2-t4~4-Trifluoromethylphenyl)-l-~ yUethyl]-isûcl~, I~-6-~ P (S)-(VII) Following the general P1~J~dI11C of ~XAMPLE 1, Step 5 and making 20 non-critical vAriAt;~)n~ but using (S)-(-)-l-t2-(6-brc~mnicorhroman-1-yl)-1-ethyl]-4~4-trifluoromethylphenyl),ui~ e (VI, EXA~LE 5, Step 2, 13.15 g, 28.0 mmol) the product is oht~inP~- This mAt~riAl is purified by LC (~ilica gel, 230400 me~h, 780 g;
mPthAnnl/dichloromPthAnP~ 5/95) to give a crude product which is 1~ L.~ P~ from mPthAnol/ethylAret~ to give (S)~-)-1-[2-[4~1 ~riflnoromethylphenyl)-l-25 piperazinyl]ethyl]isochroman-6-ca-l,..-~...;-le (S)-(VII), mp = 166-168~; Rf = 0.20 (mPthAnnl/dichloromPthAnP~ 5/95); [a]D = -50~(c = 0.8533, m~lhAnrl); IR (mull) 3365, 3203, 1654, 1619, 1337, 1317, 1243, 1164, 1149, 1138, 1122, 1114, 1107, 1074, 825 cm~l; NMR (300 MHz, CDCl3) 7.57 (m, 2H, _romatic), 7.42 (d, 2H, J=8.7 Hz, aromatic), 7.14 (d, lH, J=7.8 Hz, romatic), 6.87 (d, 2H, J=8.7 Hz, aromatic), 4.83 30 (brdd, lH, J=5.8 Hz, m~tllin~), 4.10 (m, lH, OCH2a), 3.73 (m, lH, OCH2b), 3.25 (t, 4H, J=4.9 Hz, Ph-N-CH28), 2.97 (m, lH, Ph-CH2a), 2.68-2.45 (m, 7H, Ph-NC(H2)-CH2 -NCH2s, Ph-CH2b), 2.13 (m, lH, C(H)~CH2a)~ 2-02 (m~ lH~ C( ) 2b (75 ~OEIz, CDCl3) 169.6, 153.2, 142.1, 134.5, 131.3, 128.2, 126.6, 126.3 (d, JCF=4 Hz), 125.0 (d, JCF=4 Hz), 122.9, 120.5 (qrt, JCF=33 Hz), 114.5, 74.4, 63.0, 54.5, 53.0, 47.8, 35 32.8 and 29.0 ~; HRMS (EI) cAlclllAt~ for C23H26F3N302 = 433.1977, 433.1978.

CA 0222~282 1997-12-19 W O 97/0225g PCT~US96tO8681 EXA~LE 15 1-[2-[4-(4-Ethoxyphenyl)-l-piperazinyl]ethyl]-N-methyl-isochroman-6-c~lJ~ r.~ide (IX) Step 1: 1-[2-(6-Bromnicorhroman-l-yl)acetyl]-4-(4-ethoxyphenyl)-piperazine (V) Following the general procedure of ~AMPLE 1, Step 3 and making non-critical vanations but using racemic 6-bromoisochroman-1-ylacetic acid (IV) and 4-ethoxyphenylpiperazine, 1-[2-(6-bromoisochroman-1-yl)acetyl]-4-(4-ethoxyphenyl)-piperazine (V) is obtained, Rf = 0.46 (ethyl acetate/heY~n~, 70/30); IR (neat) 1641, 1511, 1480, 1463, 1443, 1278, 1243, 1231, 1108, 1049 cm~l; NMR (300 MHz, CDCl3) 7.28 (m, 2H, aromatic H's), 7.0 (d, lH, J=8.2 Hz, aromatic H), 6.86 (d, 4H, J=8.2 Hz, aromatic H's), 6.25 (m of d, lH, J=6.5 Hz, PhC-H), 4.11 (m, lH), 3.99 (q, 2H, J=7.0 Hz, Proc-H2), 3.89 (m, lH), 3.80-3.59 (m, 4H), 3.05 (t, 4H, J=5.0 Hz), 3.03-2.89 (m'6, 2H), 2.77 (d of d, lH, Ja=3.6 Hz, Jb=14.9 Hz), 2.66 (m of d, lH, J=16.4 Hz), 1.39 (t, 3H, J=7.0 Hz, PhOCH2C-H3) o; CMR (75 MHz, CDCl3) 168.9, 153.6, 145.0, 136.4, 136.2, 131.6, 129.3, 126.4, 120.2, 118.7, 115.1, 73.3, 63.7, 63.55, 63.47, 63.4, 51.2, 50.7, 46.0, 41.8, 39.8, 28.7, 14.8 ~; HRMS ~~lr~ t~d for C23H27N203Br = 458.1205, found = 458.1217.
Step 2: 1-[2-(6-BromniRorhroman-1-yl)-ethyl]-4-(4-ethoxyphenyl)-piperazine (VI) Following the general proc6dw.2 of EXAMPLE 1, Step 4 and m~king non-critical variations but using l-t2-(6-bromni.corhroman-l-yl)acetyl]-4-(4-ethoxyphenyl)-piperazine (V), 1-[2-(6-bromoi.corhroman-1-yl)ethyl]-4-(4-ethoxyphenyl)piperazine (VI) is obtained, Rf = 0.56 (ethyl acetate/n-h~Y~n~, 70/30); IR (neat) 2850, 2810, 1512, 1482, 1251, 1231, 1153, 1108, 1048, 826 cm~1; NMR (300 MHz,CDC13) 7.29 (d, lH, J=8.3 Hz, aromatic H), 7.27 (8, lH, aromatic H), 6.97 (d, lH, J=8.3 Hz, aromatic H), 6.85 (q, 4H, J=9.7 Hz, aromatic H's), 4.78 (m of d, lH, J=6.1 Hz), 4.14-4.07 (m, lH), 3.97 (q, 2H, J=7.0 Hz, PhOC-H2), 3.76-3.69 (m, lH), 3.10 (t, 4H, J=4.9 Hz, four of pip-H), 2.95 (m, lH), 2.70-2.50 (m's, 7H, four pip-H, two PhCH-H, and NCH-H), 2.13 (m, lH, PhCHCH-H), 2.02 (m, lH, PhCHCH-H), 1.38 (t, 3H, J=6.9 Hz, PhOCH2C-H3) o; CMR (75 MHz, CDCl3) 153.1, 145.6, 137.1, 136.3, 131.6, 129.3, 126.5, 1120.0, 118.1, 115.2, 74.3, 62.8, 55.6, 53.5, 50.6, 33.2, 28.9, 15.0 ~.
- Step 3: 1-[2-[4-(4-Ethoxyphenyl)-l-piperazinyl]ethyl]-N-methyl-isochroman-6-ca l,.-~...i~l~ (~) Following the general plucedwe of EXAMPLE 5, Step 3 and m~king non-35 critical v~ri~ti~ nR but using 1-[2-(6-brom- i~o~hroman-l-yl)ethyl]-4-(4-ethoxyphenyl)-piperazine (VI), 1-[2-[4~4-ethoxyphenyl)-1-piperazinyl]ethyl]-N-methylisochroman-6-CA 0222~282 1997-12-19 W O 97/02259 PCTrUS96tO8681 Cd~ r..i'1e(IX)i8 obtained, mp = 148-149~; Rf = 0.22 (m~thAnol/methylene chloride, 5/95); IR (mull) 3334, 1633, 1536, 1515, 1310, 1245, 1237, 1146, 1108, 1050 cm~l; NMR (300 MHz, CDCl3) 7.54 (s, 2H, aromatic H's), 7.15 (d, lH, J=8.5 Hz, aromatic H), 6.85 (d of d, 4H, Ja=9.2 Hz, Jb=19.2 Hz, four aromatic H's), 6.15 (broad 5 d, lH, C(O)N-H), 4.85 (m of d, lH, J=6.0 Hz, PhC-H), 4.13 (m, lH, PhCH2CH-H), 3.97 (q, 2H, J=7 Hz, PhOC-H2), 3.77 (m, lH, PhCH2CH-H), 3.10 (t, 4H, J=4.8 Hz, four of pip-H), 3.00 (d, 3H, J=4.9 Hz, C(O)NHC-H3), 3.00 (m, lH, NCH-H), 2.76-2.45 (several m's, 7H, four pip-H, two PhCH-H, and NCH-H), 2.14 (m, lH, PhCHCH-H), 2.02 (m, lH, PhCHCH-H), 1.37 (t, 3H, J=7.0 Hz, PhOCH2C-H3) ~; CMR (75 MHz, 10 CDCl3) 168.0, 153.1, 145.6, 141.6, 134.5, 132.7, 127.7, 126.3, 125.0, 124.4, 118.1, 115.2, 74.5, 63.8, 62.9, 54.7, 53.5, 50.6, 33.2, 29.1, 26.8 and 15.0 ~.
EXAMPLE 16 1-[2-[4-(4-Propoxyphenyl)-l-piperazinyl]ethyl]-N-methyl-isochroman-6-carbnYAmi~le (IX) Step 1: 1-[2-(6-Bromoi~o~hroman-l-yl)acetyl]-4-(4-p,v,uu,.y,uhenyl)-piperazine (V) Following the general procedure of F~AlvrpLE 1, Step 3 and mAking non-critical vAriA~ n~ but using racemic 6-bromoiRo~hroman-l-yl-acetic acid (IV) and p-pro~uo,~y,uhe-lyl,ui,ueLazine, 1-[2-(6-bromni~o~.hroman-l-yl)acetyl]-4~4-~pc.~y~henyl) piperazine (V) is obtained, Rf = 0.50 (ethyl acetate/h~Y~n~, 70/30); IR (neat) 1641, 1511, 1481, 1464, 1443, 1278, 1242, 1230, 1108, 825 cm~l; NMR (300 MHz, CDCl3) 7.28 (m, 2H, aromatic H's), 7.0 (d, lH, J=8.2 Hz, aromatic H), 6.87 (d, 4H, J=8.2 Hz, aromatic H's), 5.25 (m of d, lH, J=6.5 Hz, PhC-H), 4.11 (m, lH), 3.87 (t, 2H, J=7.0 Hz, Proc-H2), 3.86 (m, lH), 3.80-3.59 (m, 4H), 3.06 (t, 4H, J=5.0 Hz), 3.03-2.89 (m's, 2H), 2.77 (d of d, lH, Ja=3.6 Hz, Jb=14.9 Hz), 2.66 (m of d, lH, J=16.4 Hz), 1.78 (sextet, 2H, J=7.0 Hz, PhOCH2C-H2), 1.02 (t, 3H, J=7.0 Hz, PhOCH2CH2C-H3) ~;
CMR (75 MHz, CDCl3) 168.9, 153.6, 145.0, 136.4, 136.2, 131.6, 129.3, 126.4, 118.7, 115.1, 69.8, 63.4, 41.8, 39.8, 28.7, 22.5 and 10.4 o; HRMS cA~ lAte~l for C24H29N2O3Br = 472.1362, found = 472.1356.
Step 2: 1-[2-(6-Brom ni ~orh roman- l-yl)-ethyl]-4-(4-p, vpo~y~henyl)-piperazine (VI) Following the general procedu~ of F~AlupLE 1, Step 4 and mAkinF non-critical variations but using 1-[2-(6-brom- i~ochroman-1-yl)acetyl]-4-(4-p~pu~y~henyl)-piperazine (V), 1-[2-(6-bromni~o~hroman-1-yl)-ethyl]-4~4-pro~u~y~henyl)~i~elazi~le (VI) is obtained, Rf = 0.52 (ethyl acetate/h~YAn~ 70/30); IR
(mull) 1516, 1448, 1261, 1244, 1196, 1131, 1117, 1103, 100~, 985 cm~l; NMR (300 MHz, CDCl3) 7.29 (d, lH, J=8.3 Hz, aromatic H), 7.27 (s, lH, aromatic H), 6.97 (d, W O 97/022S9 PCTrUS96/08681 lH, J=8.3 Hz, aromatic H), 6.85 (q, 4H, J=9.7 Hz, aromatic H's), 4.78 (m of d, lH, J=6.0 Hz, PhC-H), 4.13 (m, lH, PhCH2CH-H), 3.87 (t, 2H, J=6.6 Hz, PhOC-H2), 3.77(m, lH, PhCH2CH-H), 3.10 (t, 4H, J=4.8 Hz, four of pip-H), 3.00 (m, lH, NCH-H), 2.76-2.45 (several m's, 7H, four pip-H, two PhCH-H, and NCH-H), 2.14 (m, lH, 5 PhCHCH-H), 2.02 (m, lH, PhCHCH-H), 1.77 (sextet, 2H, J=6.9 Hz, PhOCH2C-H2), 1.01 (t, 8H, J=7.6 Hz, PhOCH2CH2C-H3) ~; CMR (75 MHz, CDCl3) 163.3, 14~.4, 136.8, 136.2, 131.5, 129.2, 126.4, 119.9, 118.1, 115.0, 69.8, 62.7, 54.5, 53.3, 50.4, 32.9, 28 7 22 6 10 4 o; HRMS ~lclfl~t~cl for C24H31N202Brl = 458.1561, 458.1569.
Step 3: 1-[2-[4-(4-Propoxyphenyl)-l-piperazinyl]ethyl]-N-methyl-isochlv~an-6-carbnYS-mi~le (IX) Following the general procedure of EXAMPLE 5, Step 3 and m~kinF non-critical v~ri~t;onC but using 1-[2-(6-brom-iRochromarl-l-yl)-ethyl]-4~4-propox rphenyl)-~ Ldzi~e (VI) the product i8 obtained. Rery~t~ tion from hot 15 ethyl acetate and hexane gives 1-[2-[4-(4-propol~ylJhenyl)-l-piperazinyl]ethyl]-N
methylisochroman-6-carbnY~mi~l~ (IX), Rf= 0.20 (m~th~n-~]/methylene chloride, 5/95); IR (mull) 3296, 1635, 1569, 1559, 1553, 1512, 1289, 1251, 1242, 1109 cm~l;
NMR (300 MHz, CDCl3) 7.54 (s, 2H, aromatic H's), 7.15 (d, lH, J=8.5 Hz, aromaticH), 6.85 (d of d, 4H, Ja=9.2 Hz, Jb=19.2 Hz, four aromatic H's), 6.15 (broad d, lH, 20 C(O)N-H), 4.85 (m of d, lH, J=6.0 Hz, PhC-H), 4.13 (m, lH, PhCH2CH-H), 3.86 (t, 2H, J=6.6 Hz, PhOC-H2), 3.77 (m, lH, PhCH2CH-H), 3.10 (t, 4H, J=4.8 Hz, four of pip-H), 3.00 (d, 3H, J=4.9 Hz, C(O)NHC-H3), 3.00 (m, lH, NCH-H), 2.76-2.45 (several m's, 7H, four pip-H, two PhCH-H, and NCH-H), 2.14 (m, lH, PhCHCH-H), 2.02 (m, lH, PhCHCH-H), 1.77 (sextet, 2H, J=6.9 Hz, PhOCH2C-H2),1.01 (t, 3H, 25 Js7.4 Hz, PhOCH2CH2C-H3) o; CMR (7B MHz, CDCl3) 167.9, 153.2, 145.4, 141.5, 134.3, 132.5, 127.5, 124.9, 124.3, 118.0, 115.0, 69.8, 62.8, 54.5, 53.4, 50.5, 33.0, 30.5, 28.9, 26.7, 22.5 and 10.4 o.
EXAMPLE 17 (S)-(-)-1-[2-[4-(4-Tri~uornrnPthr~Yyphenyl)-l-piperazinyl]ethyl]-N-methylisochroman-6-ca~ Y~...i~e (lX) Step 1: (S)-(-)-1-[2-(6-Bromni~o-hroman-l-yl)acetyl]-4~4-trifluorom~th-.xyphenyl)piperazine (S) (V) Following the general plvCedule of EXAMPLE 1, Step 3 and making non-critical v~ri~tionc but using 4-triflllorm~t~Yyphellyl~i~eldzine, (S)-(-)-1-[2-(6-bromri~o-~hroman-l-yl)acetyl]-4-(4-trifluor m~th~yyphenyl)piperazine (S)-(V) is obtained, [a]D = -70~ (c = 0.68, eth~nol); Rf = 0.52 (ethyl ~etot~ Y~ne 70/30); IR
(neat) 1641, 1511, 1482, 1465, 1445, 1266, 1232, 1211, 1160, 1108 cm~l; NMR (300 CA 0222~282 1997-12-19 W O 97/022S9 PCTrUS96/08681 MHz, CDCl3) 7.28 (m, 2H, aromatic H's), 7.14 (d, 2H, J=8.9 Hz, aromatic H's), 7.0 (d, lH, J=8.2 Hz, aromatic H), 6.87 (d, 2H, J=8.9 Hz, aromatic H's), 5.25 (m of d, lH, J=6.5 Hz, PhC-H), 4.11 (m, lH), 3.92 (m, lH), 3.75 (m, 4H), 3.16 (t, 4H, J=5.0 Hz), 3.03-2.89 (m's, 2H), 2.77 (d of d, lH, Ja=3.6 Hz, Jh=14.9 Hz), 2.66 (m of d, lH,5 J=16.4 Hz) 8; CMR (75 MHz, CDCl3) 168.9, 149.8, 145.0, 136.9, 136.4, 131.6, 129.3, 126.3, 122.0, 120.7, 117.1, 73.4, 63.4, 49.8, 48.2, 45.8, 42.0, 39.8, 28.7 8; HRMS
c~ t~d for C22H22N2F3~3Br = 498.0766, found = 498.0764.
Step 2: (S)-(-)-l-t2-(6-BromniRo~hroman-l-yl)-ethyl]-4-(4-trifluoromPthnYyphenyl)-piperazine (S)-(VI) Following the general pi'ocedul~ of ~AlVlPLE 1, Step 4 and making non-critic~l v~t;nn~ but using (S)-(-)-1-[2-(6-bromoi~ochroman-1-yl)acetyl]4-(4-trifluoromPthnYyphenyl)piperazine (S)-(V), (S)-(-)-1-[2-(6-bromni~o~hroman-1-yl)-ethyl]4-(4-trifluoromPthn~ryphenyl)piperazine (S)-(VI) is obtained, Rf = 0.54 (ethyl acetate/hPY~ne, 70/30); [a]D = -42~ (c = 1.1, eth~nol; IR (neat) 2825, 1513, 1281, 1263, 1240, 1204, 1184, 1157, 1112, 1106 cm~l; NMR (300 MHz, CDCl3) 7.29 (d, lH,J=8.3 Hz, aromatic H), 7.27 (s, lH, aromatic H), 7.11 (d, 2H, J=9 Hz, aromatic H's), 6.97 (d, lH, J=8.2 Hz, aromatic H), 6.87 (q, 2H, J=9.1 Hz, two aromatic H's), 4.78 (m of d, lH, J=6.0 Hz, PhC-H), 4.11 (m, lH, PhCH2CH-H), 3.75 (m, lH, PhCH2CH-H), 3.18 (t, 4H, J=4.8 Hz, four of pip-H), 3.00 (m, lH, NCH-H), 2.76-2.45 (several m's, 7H, four pip-H, two PhCH-H, and NCH-H), 2.14 (m, lH, PhCHCH-H~, 2.02 (m, lH, PhCHCH-H) ~; CMR (75 MHz, CDCl3) 150.0, 136.5, 135.5, 131.5, 129.2, 126.3, 121.9, 120.1, 116.4, 74.1, 62.7, 54.9, 53.1, 49.1, 33.0 and 28.7 8; HRMS c~ l for C22H24N2O2F3Brl (+1) = 486.0954, found = 486.0956.
Step 3: (S)~-)-1-[2-[4~4-TrifluoromPthr.Yyphenyl)-l-piperazinyl]ethyl]-N-methylisochroman-6-c~ Y~ le (S)-(IX) Following the general p~vcedu~e of EXAMPLE 5, Step 3 and m~kin~ non-critical variations but using (S)-(-)-1-[2-(6-bromni~o~hlv an-1-yl)-ethyl]-4-(4-trifluoromPthnYyphenyl)piperazine (S) (VI) the product is obtained. Recrysts~ tinn from hot ethyl acetate and hexane gives (S)~-)-1-[2-[4~4-trifluorom~thmryphenyl)-1-piperazinyl]ethyl]-N-met~ylisodl-v lan-6-carbr~Y~mi-lP (S)-(IX), Rf = 0.20 mPthslnol/methylene ~hlnric~e, 5/95); IR (mull) 1636, 1614, 1572, 1551, 1513, 1450, 1270, 1238, 1157, 1107 cm~l; NMR (300 MHz, CDCl3) 7.54 (s, 2H, aromatic H's), 7.15 (d, lH, J=8.6 Hz, aromatic H), 7.11 (d, 2H, d=8.9 Hz, two aromatic H's), 6.87 (q , 2H, J=8.9 Hz, two aromatic H's), 6.19 (broad d, lH, C(O)N-H), 4.86 (m of d, lH, J=6.0 Hz, PhC-H), 4.13 (m, lH, PhCH2CH-H), 3.77 (m, lH, PhCH2CH-H), 3.18 (t, 4H, J=4.8 Hz, four of pip-H), 3.00 (d, 3H, J=4.9 Hz, C(O)NHC-H3), 3.00 (m, lH, CA 0222~282 l997-l2-l9 W O 97/02259 PCTrUS96/08681 NCH-H), 2.76-2.45 (several m's, 7H, four pip-H, two PhCH-H, and NCH-H), 2.14 (m,lH, PhCHCE-H), 2.02 (m, lH, PhCHCH-H) o; CMR (75 MHz, CDCl3) 167.8, 149.8, 144.7, 141.3, 134.3, 132.6, 127.5, 124.8, 124.3, 121.8, 116.5, 86.2, 74.3, 62.8, 54.54, 53.4, 48.9, 32.9, 28.9 and 26.7 S; HRMS ç~lr~ t~rl for C24HN303F3 = 463.2083, found = 463.2086.
~AlVlPLE 18 (S)-(-)-1-[2-[4-(4-Ethylphenyl)-l-piperazinyl]ethyl]-N-methyl-isochroman-6-ca~ 1e (S)-(IX) Step 1: (S)-(-)-1-[2-(6-Broml~iRo-~hroman-l-yl)acetyl]-4-(4-ethylphenyl)-piperazine (S)-(V) Following the general procedure of ~AlVrPLE 1, Step 3 and making non-critical variations but using 4-ethylphenylpiperazine, (S)-(-)-1-[2-(6-BromoiRorhrom~n-l-yl)acetyl]-4-(4-ethylphenyl)piperazine (S)-(V) is obtained, Rf =
0.70 (ethyl ~ret~t~/hPY~n~, 70/30); [~]D = -81~(c = 0.7, ethanol); IR (neat) 1640, 1614, 1516, 1482, 1462, 1444, 1428, 1232, 1108 and 826 cm~l; NMR (300 MHz, CDCl3) 15 7.27 (m, 2H, aromatic H's), 7.11 (d, 2H, J=8.4 Hz, aromatic H's), 7.0 (d, lH, J=8.2 Hz, aromatic H), 6.86 (d, 2H, J=8.2 Hz, aromatic H's), 5.25 (m of d, lH, J=6.5 Hz, PhC-H), 4.08 (m, lH), 3.89 (m, lH), 3.80-3.59 (m, 4H), 3.11 (t, 4H, J=5.0 Hz), 3.03-2.89 (1~118, 2H), 2.77 (d of d, lH, Ja=3.6 Hz, Jb=14.9 Hz), 2.66 (m, lH), 2.57 (q, 2H, J=7.6 Hz, PhC-H2), 1.20 (t, 3H, J=7.6 Hz, PhCH2C-H3) o; CMR (75 MHz, CDCl3) 20 169.0, 149.0, 136.5, 136.3, 131.8, 129.4, 128.6, 126.5, 120.4, 116.9, 73.5, 63.5, 50.3, 49.8, 46.1, 41.9, 39.9, 28.8, 27.9 and 15.7 o.
Step 2: ($)~-)-1-[2-(6-BromniRorhroman-l-yl)-ethyl]-4~4-ethylphenyl)-piperazine (S)-(VI) Following the general procedure of EXAMF~LE 1, Step 4 and making non-25 critical variations but using (S)-(-)-1-[2-(6-brom~iRorhroman-l-yl)acetyl34-(4-ethylphenyl)-piperazine (S)-(V), (S)~-)-1-[2-(6-BromoiRorhroman-l-yl)-ethyl]-4-(4-ethylphenyl)-piperazine (S)-(VI) i~ obtained, Rf = 0.61 (ethyl acetate/h.~Yzln~, 30/70);
IR (mull) 2960, 2929, 2819, 1516, 1481, 1379, 1237, 1143, 1111 and 822 cm~l; NMR(300 MHz, CDCl3) 7.29 (d, lH, J=8.3 Hz, aromatic H), 7.27 (8, lH, aromatic H), 7.09 30 (d, 2H, J=8.6 Hz, aromatic H's), 6.98 (d, lH, J=8.2 Hz, aromatic H), 6.87 (d, 2H, J=8.6 Hz, aromatic H's), 4.77 (m of d, lH, J=6.0 Hz, PhC-H), 4.13 (m, lH, PhCH2CH-H), 3.75 (m, lH, PhCH2CH-H), 3.17 (t, 4H, J=4.8 Hz, four of pip-H), 3.00(m, lH, NCH-H), 2.70-2.53 (several m's, 9H, four pip-H, two PhCH-H, PhC-H2, and NCH-H), 2.14 (m, lH, PhCHCH-H), 2.02 (m, lH, PhCHCH-H), 1.20 (t, 3H, J=7 6 35 Hz, PhCH2C-H3) o; CMR (75 MHz, CDCl3) 149.4, 137.1, 136.3, 135.6, 131.6, 129.3, 128.4, 126.5, 120.0, 116.3, 74.3, 62.8, 54.7, 53.5, 49.6, 33.2, 30.3, 28.9, 27.9 and 15.7 CA 0222~282 1997-12-19 W O 97/022S9 PCTrUS96/08681 o; HR~S calculated for C23H29N201Brl = 430.1444, found = 430.1443.
Step 3: (S)-(-)-1-[2-[4-(4-Ethylphenyl)-l-piperazinyl]ethyl]-N-methyl-isochroman-6-carb- YAm~ (S)-(lX) Following the general pl~cedu~,a of EXAMPLE 5, Step 3 and mPking non-critical variations but using (S)-(-)-1-[2-(6-bromr iRocl-roll,an-l-yl)-ethyl]-4-(4-ethylphenyl)-piperazine (S)-(VI) the desired product is obtained. Recryst~ 7Ation from hot ethyl acetate and hexane gives (S)-(-)-1-[2-[4-(4-ethylphenyl)-1-pipelazhlyl]ethyl]-N-methyl-isochroman-6-ca~L.~Y~ 1e (S)-(IX), mp = 138-140~; Rf =
0.28 (m~t~An~l/methylene chloride, 5/95); [a]D = -50~ (c = 0.93, m~t~Annl/methylene chloride, 50/50); IR (mull) 3321, 1635, 1614, 1539, 1518, 1405, 1312, 1238, 1107 and 822 cm~l; NMR (300 MHz, CDCl3) 7.B4 (s, 2H, aromatic H's), 7.15 (d, lH, J=8.6 Hz, aromatic H), 7.09 (d, 2H, J=8.5 Hz, 2 aromatic H's), 6.86 (d, 2H, J=8.5 Hz, 2 aromatic H's), 6.14 (broad d, lH, C(O)N-H), 4.86 (m of d, lH, J-6.0 Hz, PhC-H), 4.13 (m, lH, PhCH2CH-H), 3.77 (m, lH, PhCH2CH-H), 3.17 (t, 4H, J=4.8 Hz, four of pip-H), 3.00 (d, 3H, J=4.9 Hz, C(O)NHC-H3), 3.00 (m, lH, NCH-H), 2.76-2.45 (several m's, 9H, four pip-H, two PhCH-H, PhC-H2, and NCH-H), 2.14 (m, lH, PhCHCH-H), 2.02 (m, lH, PhCHCH-H), 1.20 (t, 3H, J=7.6 Hz, PhCH2C-H3) o; CMR (75 MHz, CDC13) 168.0, 149.3, 141.6, 135.7, 134.5, 132.7, 128.4, 127.7, 125.0, 124.4, 116.3, 62.9, 54.7, 53.4, 49.6, 33.1, 29.1, 27.9, 26.8 and 15.7 ~; HR~IS rA~ At,e(l for C25H33N3~3 = 407-2573, found = 407.2581.
EXAMPLE 19 (S)-(-)-1-[2-[4-(4-EthoYyphenyl)-l-piperazinyl]ethyl]-N-methyl-isochroman-6-c~ . L. .~ le (S)-(IX) Step 1: (S)-(-)-1-[2-(6-BromoiRo~ ,an-l-yl)acetyl]-4-(4-ethoxyphenyl)-piperazine (S)-(V) Following the general p-~ ce~lu-~e of EXA~LE 1, Step 3 and mAkinF non-critical variations but using 4-ethoxyphenylpiperazine, (S)-(-)-1-[2-(6-Brom~iRorhroman-l-yl)acetyl]4-(4-ethoxyphenyl)piperazine (S)-(V) is obtained, Rf =
0.60 (ethyl AcetAt~ YAne, 70/30); [a]D = -78~ (c = 0.82, et~An~l); IR (neat) 1627, 1515, 1478, 1441, 1429, 1250, 1230, 1102, 1031 and 821 cm~l; NMR (300 MHz, CDC13) 7.28 (m, 2H, aromatic H's), 7.0 (d, lH, J=8.2 Hz, aromatic H), 6.86 (d, 4H, J=8.2 Hz, aromatic H's), 5.25 (m of d, lH, J=6.5 Hz, PhC-H), 4.11 (m, lH), 3.99 (q, 2H, J=7.0 Hz, PhOC-H2), 3.89 (m, lH), 3.80-3.59 (m, 4H), 3.05 (t, 4H, J=5.0 Hz),3.03-2.89 (m's, 2H), 2.77 (d of d, lH, Ja=3.6 Hz, Jb=14.9 Hz), 2.66 (m of d, lH,J=16.4 Hz), 1.39 (t, 3H, J=7.0 Hz, PhCH2C-H3) ~; CMR (75 MHz, CDC13) 168.9, 153.5, 145.2, 136.3, 136.2, 131.6, 129.3, 126.4, 118.7, 115.1, 73.3, 63.7, 63.4, 51.2, 50.7, 46.1, 41.9, 39.8, 28.7 and 14.8 ~; HRMS ÇA~ lAt~d for C23H27N2O3Br =

W O 97/022S9 PCTrUS96/08681 458.1205, found = 458.1203.
Step 2: (S)-(-)-1-[2-(6-BromniRochroman-l-yl)-ethyl]-4-(4-ethoxyphenyl)-piperazine (S)-(VI) Following the gener~l plvce~ e of EXAMPLE 1, Step 4 and making non-5 critical variations but using (S)-(-)-l-[Z-(6-br moi~orhroman-1-yl)acetyl]-4-(4-ethoxyphenyl)piperazine (S)-(V) gives (S)-(-)- 1-[2-(6-brom ni cof~h roman 1-yl)-ethyl]-4-(4-ethoxyphenyl)-piperazine (S)-(VI), mp = 8~-87~; Rf = 0.28 (ethyl acetate/n-h~Y~n~, 30/70); [a]D = -46~ (c = 0.60, ethanol); IR (neat) 1516, 1476, 1261, 1246, 1196, 1130, 1117, 1104, 1060 and 932 cm~l; N~ (300 MHz,CDCl3) 7.29 (d, lH, J=8.3 Hz, 10 aromatic H), 7.27 (s, lH, aromatic H), 6.97 (d, lH, J=8.3 Hz, aromatic H), 6.85 (q, 4H, J=9.7 Hz, aromatic H's), 4.78 (m of d, lH, J=6.1 Hz), 4.144.07 (m, lH), 3.97 (q, 2H, J=7.0 Hz, PhOC-H2), 3.76-3.69 (m, lH), 3.10 (t, 4H, J=4.9 Hz, four of pip-H), 2.95 (m, lH), 2.70-2.50 (m's, 7H, four pip-H, two PhCH-H, a~d NCH-H), 2.13 (~n, lH, PhCHCH-H), 2.02 (m, lH, PhCHCH-H), 1.38 (t, 3H, J=6.9 Hz, PhOCH2C-H3) o;
15 CMR (75 MHz, CDCl3) 153.1, 145.6, 137.1, 136.3, 131.6, 129.3, 126.5, 1120.0, 118.1, 115.2, 74.3, 62.8, 55.6, 53.5, 50.6, 33.2, 28.9 and 15.0 o.
Step 3: (S)-(-)-1-[2-t4~4-Ethoxyphenyl)-l-piperazinyl]ethyl]-N-methyl-isochroman-6-ca~ (S)-(IX) Following the gener~l procedure of FXAMPLE 5, Step 3 and making non-20 critical v~ri~ti~ n~ but using (S)-(-)-1-[2-(6-brnmni~o~ ,.an-1-yl)-ethyl]-4~4-ethoxyphenyl)piperazine (S)-(VI) gives (S)-(-)-1-[2-[4~4-ethoxyphenyl)-1-piperazinyl]ethyU-N-methyl-isochroman-6-calL..~ 1P (S)-(IX). Recrygt~ t~n from hot ethyl acetate and hexane gives purified product, mp = 156-157~; Rf = 0.20 (m~t~ls3nol/methylene ~.hlnri~e, 5/95); [a]D = -48~ (c = 0.94, m~t~l~nol/methylene 25 chloride, 50/50); IR (mull) 3334, 1633, 1536, 1515, 1310, 1245, 1237, 1146, 1108 and 1050 cm~l; NMR (300 MHz, CDCl3) 7.54 (s, 2H, aromatic H's), 7.15 (d, lH, J=8.5 Hz, aromatic H), 6.85 (d of d, 4H, Ja=9.2 Hz, Jb=19.2 Hz, four aromatic H's), 6.15 (broad d, lH, C(O)N-H), 4.85 (m of d, lH, J=6.0 Hz, PhC-H), 4.13 (m, lH, PhCH2CH-H), 3.97 (q, 2H, J=7 Hz, PhOC-H2), 3.77 (m, lH, PhCH2CH-H), 3.10 (t, 4H, J=4.8 Hz, 30 four of pip-H), 3.00 (d, 3H, J=4.9 Hz, C(O)NHC-H3), 3.00 (m, lH, NCH-H), 2.76-2.45 (several m's, 7H, four pip-H, two PhCH-H, and NCH-H), 2.14 (m, lH, PhCHCH-H), 2.02 (m, lH, PhCHCH-H), 1.37 (t, 3H, J=7.0 Hz, PhOCH2C-H3) 8; CMR (75 MHz, CDCl3) 168.0, 153.1, 145.6, 141.6, 134.5, 132.7, 127.7, 126.3, 125.0, 124.4, 118.1, 115.2, 74.5, 63.8, 62.9, 54.7, 53.5, 50.6, 33.2, 29.1, 26.8 and 15.0 ~; HRMS r~lclllz3t~e~
35 for C25H33N3~3 = 4~-3 ~ found = 423.26l8 ~XANIPLE 20 (S)~-)-1-[2-[4-(4-Phenylmethyloxyphenyl)-l-pi~ ziLlyl]ethyl]-N

CA 0222F7282 l997-l2-l9 W O 97/02259 PCTnUS96/08681 methylisochrvL.lan-6-ca~ Y ~3 l . . i d P (S)-(IX) Step 1: (S)-(-)-1-[2-(6-Brom~i7~o~hroman-1-yl)acetyl]-4~4-phenylmethyloxyphenyl)piperazine (S)-(V) Following the general pl'OCedU~e of EXAMPLE 1, Step 3 and making non-critical v~ri~t;on~ but using 4-phenylmethyloxyphe~yl~ .dzine (3.38 g, 12.6 mmol), the product is obtained. This m~tPri~l is purified by HPLC on a single silica gel cartridge eluting with ethyl~et~tA/hexane (70/30) to give (S)-(-)-1-[2-(6-bromni,~or,hroman-l-yl)acetyl]-4-(4-phenylmethyloxyphenyl)piperazine (S)-(V), Rf =
0.30 (ethyl ~ret~t~/h~Y~n~, 50/50); [a]D = -34~ (c = 0.50, m~tl~nol); NMR (300 MHz, CDCl3) 7.35 (m, 7H, aromatic), 6.96 (d, lH, J=8.2 Hz, aromatic), 6.90 (m, 4H, aromatic), 5.26 (brdd, lH, J=5.4 Hz, mPthinP), 5.02 (s, 2H, Ph-CH2-0), 4.09 (m, lH, OCH2a ), 3.89 (m, lH, O=C-N-CH2a), 3.81-3.64 (m, 4H, OCH2b, O=C-N-CH2bCd), 3.05 (m, 4H, Ph-N-CH28), 3.00-2.89 (m, 2H, Ph-CH2a & N-C=O-CH2a), 2.76 (dd, lH, J=14.9 Hz & 3.6 Hz, N-C=O-CH2b), 2.66 (brdd, lH, J=16.4 Hz, Ph-CH2b) ~; CMR
(75 MHz, CDCl3) 169.0, 153.6, 145.5, 137.3, 136.6, 136.3, 131.8, 129.4, 128.6, 127.9, 127.5, 126.5, 120.4, 118.8, 115.7, 76.7, 73.5, 70.5, 63.5, 51.3, 50.7, 46.2, 42.0, 40.0 and 28.8 ~.
Step 2: (S)~-)-1-[2-(6-Brom-.ico~hroman-l-yl)-ethyl]-4~4-phenylmethyloxyphenyl)piperazine (S)-(VI) Following the general p~ocedu~e of EXAMPLE 1, Step 4 and m~king non-critical v~ri~tionc but using (S)~-)-1-[2~6-bromoicorh.v,~.an-l-yl)acetyl]-4~4-phenylmethyloxyphenyl)piperazine (V, 5.96 g, 11.4 mmol) gives (S)-(-)-1-[2~6-brom~ ochl~an-1-yl)-ethyl]-4-(4-phenylmethyloxyphenyl)-~ .d~hle (S)-(VI), Rf =
0.40 (ethyl ~cet~tP/hPY~n~ 50/50); [a]D = -63~ (c = 0.925, mPt~l~nol); NMR (300 MHz, CDCl3) 7.27 (m, 7H, aromatic), 6.91 (d, lH, J=8.3 Hz, aromatic), 6.83 (8, 4H, aromatic), 4.94 (8, 2H, Ph-CH2-O), 4.73 (brdd, lH, J=5.7 Hz, mPthinP), 4.03 (m, lH, OCH2a), 3.67 (m, lH, OCH2b), 3.05 (t, 4H, J=4.8 Hz, Ph-NCH2s), 2.88 (m, lH, Ph-CH2a), 2.60 (m, 7H, Ph-NC(H2)-CH2S-NCH2 & Ph-CH2b), 2.05 (m, lH, C(H)-CH2a), 1.97 (m, lH, C(H)-CH2b) ~; CMR (75 MHz, CDCl3) 153.1, 145.8, 137.4, 136.9, 136.3, 131.7, 129.3, 128.5, 127.9, 127.5, 126.5, 120.1, 118.2, 115.6, 70.5, 62.9, 54.6, 53.4, 50.4, 32.9 and 28.9 ~.
Step 3: (S)-(-)-1-[2-[4~4-Phenylmethyloxyphenyl)-1-piperazinyl]ethyl]-N-methyl-isochroman-6-ca,l,~Y ~ P, (S)-(IX) Following the general pl~ cedu~e of EXAMPLE 5, Step 3 and making non-critical v~ri~ti~nc but using (S)-(-)-1-[2-(6-bromoicorhroman-1-yl)~thyl]-4-(4-phenylmethyloxyphenyl)piperazine (S)-(VI, 5.08 g, 11.4 mmol) gives the product.

CA 02225282 l997-l2-l9 W O 97/022S9 PCT~r~/~ e 6~1 Thi8 m~tf~ri~l is purified by LC (silica gel, 230-400 mesh, 270 g; ethyl acetate) and le. ~y~ from ethyl acetate to give (S)~ 1-[2-[4-(4-phenylmethyloxyphenyl)-1-piperazinyl]ethyl]-N-methyl-isochroman-6-call,..x,1...ide (S)-(IX), mp = 164-167~; Rf =
0.40 (m~th~nnl/ethyl~retst~, 5/95); [a]D = -40~ (c = 0.9323, m~+ls~nol); IR (mull) 5 3302, 1639, 1544, 1515, 1498, 1314, 1291, 1272, 1252, 1153, 1138, 1111, 818, 735 and 695 cm~l; NMR (300 MHz, CDCl3) 7.53 (m, 2H, aromatic), 7.54 (m, 2H, aromatic), 7.43-7.23 (m, 5H, aromatic), 7.14 (d, lH, J=8.6 Hz, aromatic), 6.89 (s, 4H, aromatic), 6.19 (brdm, lH, NH), 5.01 (s, 2H, Ph0-CH2), 4.86 (brdd, lH, J=6.9 Hz,m~hinf~,), 4.14 (m, lH, OCH2a), 3.76 (m, lH, OCH2b), 3.10 (t, 4H, J=4.8 Hz, Ph-N-10 CH28), 3.00 (d, 4H, J=4.8 Hz, N-CH3 & Ph-CH2a), 2.76-2.49 (m, 7H, Ph-NC(H2)-CH28-NCH25, Ph-CH2b), 2.14 (m, lH, C(H)-CH2a), 2.04 (m, lH, C(H)-CH2b) ~; CMR
(75 MHz, CDCl3) 168.0, 153.0, 145.9, 141.6, 137.4, 134.5, 132.7, 128.5, 127.9, 127.7, 127.5, 125.0, 124.4, 118.0, 115.6, 74.5, 70.5, 63.0, 54.7, 53.5, 50.5, 33.2, 29.1 and 26.9 ~; MS (EI, m/z) = 485; HRMS (EI) c~ t~l for C30H35N303 = 485-2678, found =
15 486.2675.
EXAMPLE 21 (R)~+)-1-[2-[4-(4-Ethoxyphenyl)-l-piperazinyl]ethyl]-N-methyl-i~ocl~l~ ,an-6-carbnY~mi-le (R)-(IX) Step 1: (R)~+)-1-[2-(6-Brqmni~orhroman-l-yl)acetyl]4-(4-ethoxyphenyl)-piperazine (R-V) Following the general p.~ce~ of EXAMPLE 2, Step 2 and m~kinF non-critical v~ri~ti~ n~ but using 4-ethoxyphel~yl~ c~dzine gives (R)-(+)-1-[2-(6-bromoico. ~ an-l-yl)acetyl]-4-(4-ethoYyphenyl)piperazine (R-V), Rf = 0.60 (ethylacetate/h~Y~n~, 70/30); [a]D = +76~ (c = 0.71, eth~nol); IR (neat) 1626, 1515, 1478, 1442, 1249, 1246, 1230, 1102, 1030 and 821 cm~l; NMR (300 MHz, CDC13) 7.28 (m, 2H, aromatic H's), 7.0 (d, lH, Jz8.2 Hz, aromatic H), 6.86 (d, 4H, J=8.2 Hz, aromatic H's), 5.25 (m of d, lH, J=6.5 Hz, PhC-H), 4.11 (m, lH), 3.99 (q, 2H, J=7.0 Hz, PhOC-H2), 3.89 (m, lH), 3.80-3.59 (m, 4H), 3.05 (t, 4H, J=5.0 Hz), 3.03-2.89 (m's, 2H), 2.77 (d of d, lH, Ja=3.6 Hz, Jb=14.9 Hz), 2.66 (m of d, lH, J=16.4 Hz), 1.39 (t, 3H, J=7.0 Hz, PhCH2C-H3) ~; CMR (75 MHz, CDCl3) 168.9, 153.6, 145.0, 136.4, 136.2, 131.6, 129.3, 126.4, 120.2, 118.7, 115.1, 73.3, 63.7, 63.55, 63.47, 63.4, 51.2, 50.7, 46.0, 41.8, 39.8, 28.7 and 14.8 o; HRMS calculated for C23H27N2O3Br (on Br 81 ion) =
460.1185, found = 460.1179.
Step 2: (R)-(+)-1-[2-(6-Bromni~orhroman-l-yl)-ethyl]-4-(4-ethoxyphenyl)-pi~ e (R-VI) Following the general pL.,ce.lu~e of F~XAlvlPLE 2, Step 3 and m~kinF non-critical v~ri~t;~n~ but using (R)-(+)-1-[2-(6-brnmoi~orhroman-1-yl)acetyl]-4-(4-CA 0222~282 l997-l2-l9 W O 97/022S9 PCTrUS96/08681 ethoxyphenyl)piperazine (R-V) gives (R)-(+)- 1-[2-(6-br~m oi ~o~h roman- 1-yl)-ethyl]-4-(4-ethoxyphenyl)piperazine (R-VI), Rf = 0.25 (ethyl ~-et~t~/n-h~Y~ne, 30/70); [a]D =
+43~ (c = 0.73, eth~nol); IR (neat) 2820, 1511, 1478, 1446, 1250, 1225, 1116, 1108, 1047 and 825 cm~l; NMR (300 MHz,CDCl3) 7.29 (d, lH, J=8.3 Hz, aromatic H), 7.27 (s, lH, aromatic H), 6.97 (d, lH, J=8.3 Hz, aromatic H), 6.85 (q, 4H, J=9.7 Hz, aromatic H's), 4.78 (m of d, lH, J=6.1 Hz), 4.14-4.07 (m, lH), 3.97 (q, 2H, J=7.0 Hz, PhOC-H2), 3.76-3.69 (m, lH), 3.10 (t, 4H, J=4.9 Hz, four of pip-H), 2.95 (m, lH), 2.70-2.50 (m's, 7H, four pip-H, two PhCH-H, and NCH-H), 2.13 (m, lH, PhCHCH-H), 2.02 (m, lH, PhCHCH-H), 1.38 (t, 3H, J=6.9 Hz, PhOCH2C-H3) ~; CMR (75 10 MHz, CDCl3) 153.1, 145.6, 137.1, 136.3, 131.6, 129.3, 126.5, 1120.0, 118.1, 115.2, 74.3, 62.8, 55.6, 53.5, 50.6, 33.2, 28.9 and 15.0 o; HRMS cAl~lllAtecl for C23H29N2O2Brl = 444.1413, found = 444.1413.
Step 3: (R)-(+)-1-[2-[4-(4-Etho~gphenyl)-l-piperazinyl]ethyl]-N-methyl-isochroman-6-carbnY~mi-le (R-IX) 15Following the general procedure of EXAMPLE 5, Step 3 and making non-critical variations but using (R)-(+)-1-[2-(6-bromoi~o~hroman-1-yl)-ethyl]-4-(4-ethoxyphenyl)piperazine (R-VI) gives (R)-(+)-1-[2-[4-(4-ethoxyphenyl)-1-piperazinyl]ethyl]-N-methylisochroman-6-call,.,Y;1..,il1e (R-IX), Rf = 0.20 (mPtl~n~l/methylene chloride, 5/95); [a]D = +49~ (c = 0.93, m~ nol/methylene 20 rhlnritlç, 50/50); IR (mull) 3334, 1633, 1536, 1515, 1310, 1245, 1237, 1146, 1108 and 1050 cm~l; NMR (300 MHz, CDCl3) 7.54 (s, 2H, aromatic H's), 7.15 (d, lH, J=8.5 Hz, aromatic H), 6.85 (d of d, 4H, Ja=9.2 Hz, Jb=19.2 Hz, four aromatic H's), 6.15 (broad d, lH, C(O)N-H), 4.85 (m of d, lH, J=6.0 Hz, PhC-H), 4.13 (m, lH, PhCH2CH-H), 3.97 (q, 2H, J=7 Hz, PhOC-H2), 3.77 (m, lH, PhCH2CH-H), 3.10 (t, 4H, J=4.8 Hz, 25 four of pip-H), 3.00 (d, 3H, J=4.9 Hz, C(O)NHC-H3), 3.00 (m, lH, NCH-H), 2.76-2.45 (several m's, 7H, four pip-H, two PhCH-H, and NCH-H), 2.14 (m, lH, PhCHCH-H), 2.02 (m, lH, PhCHCH-H), 1.37 (t, 3H, J=7.0 Hz, PhOCH2C-H3~ ~; CMR (75 MHz, CDCl3) 168.0, 153.1,145.6, 141.6, 134.5, 132.7, 127.7,126.3,125.0, 124.4,118.1, 115.2, 74.5, 63.8, 62.9, 54.7, 53.5, 50.6, 33.2, 29.1, 26.8 and 15.0 ~; HRMS c~ te~l 30 for C25H33N3~3 = 4~3 ~5~ found = 423.2516.
EXAMPLE 22 1-[2-[4-(3-Trifluoromethylphenyl)-l-piperazinyl]ethyl]-N-methylisochroman-6-calL..~J'...;~ (IX) Step 1: 1-[2-[4-(3-Tri~uoromethylphenyl)-l-piperazinyl]ethyl]-N,N-di-t-butylo~y~ ~I.ollylisochlulllan-6-carbn~r~mi-le (VIII) 35Following the general procedure of F~AlvlpLE 3, Step 1 and making non-critical v~ri~t~ but using 1-[2-[4-(3-trifluoromethylphenyl)-1-pip~L~zi~yl]ethyl]-isochroman-6-c~l,--Y~ gives crude product. This mslt~ l is purified by LC (silica gel, 230-400 mesh, 60 g; ~e+ona/haY~na, 25/75) to give 1-[2-[4-(3-trifluoromethylphenyl)-1-piperazinyl]ethyl]-N,N-di-t-butyloxycarbonylisochroman-6-ca~ x~lllitle (VIII), Rf = 0.37 (~etonalhaY~na, 25/75).
Step 2: 1-[2-[4-(3-Trifluoromethylphenyl)-1-piperazinyl]ethyl]-N-methyl-isochroman-6-carb~ Y~mi~la (~) Following the general ploceduse of F'XAl\/IPLE 3, Step 2 and making non-critical v~ri~tior ~ but using l-[a-[4-(3 t~fll~oromethylphenyl)-1-pi~la~ yl]ethyl]-N~N-di-t-butylu~y~ ùllylisûclllulllan-6-c~Ll~x~ (VIII, 1.13 g, 10 1.8 mmol) gives crude product. This m~t~ri~ll i8 purified by LC (silica gel, 230~00 mesh, 66 g; ~- etor~PY~n~ 50/50) to give 1-[2-[4-(3-trifluoromethylphenyl)-1-piperazinyl]ethyl]-N-methylisochroman-6 carL-.Y~ (IX) which is rec..~ lli7~c from ethyl~et~t~/h-oY~ne, mp = 142-143~; Rf = 0.33 (~cetonplh~yslnf~ 50/50); IR
(mull) 3307, 1637, 1612, 1606, 1558, 1443, 1311, 1290, 1247, 1151, 1136, 1122, 1109, 16 1099 and 951 cm~l; NMR (300 MHz, CDCl3) 7.55 (m, 2H, arv ,a~ic), 7.33 (t, lH, J=8.0 Hz, aromatic), 7.12 (d, lH, J=8.6 Hz, aromatic), 7.06 (m, 4H, aromatic), 6.14 (brdm, lH, NH), 4.87 (brdd, lH, J=5.9 Hz, mat~lina)~ 4.14 (m, lH, OCH2a), 3.76 (m, lH, OCH2b), 3.24 (t, 4H, J=5.0 Hz, Ph-N-CH28), 3.00 (d, 4E, J=4.9 Hz, N-CH3 & Ph-CH2a), 2.76-2.48 (m, 7H, Ph-NC(H2)-CH2B-NCH2s, Ph-CH2b), 2.15 (m, lH, C(H)-CH2a), 2.05 (m, lH, C(H)-CH2b) ~; CMR (75 MHz, CDCl3) 168.0, 151.4, 141.6, 134.5, 132.7, 131.4 (qrt, JCF=32 Hz), 129.5, 127.7, 125.0, 124.4, 118.6, 115.7 (d, JCF=4 Hz), 112.1 (d, JCF=4 Hz), 74.4, 63.0, 54.6, 53.2, 48.7, 33.2, 29.1 and 26.9 o; HR~qS (EI) tA~ for C24H28F3N3~2 = 447.2133, found = 447.2132.
EXAMPLE 23 1-[2-[4-(4-Met~ylsulfonylphenyl)-l-piperazinyl]ethyl]N-methylisochroman-6-carb~ mi~l.s (IX) Step 1: 1-[2-[4-(4-Methylsulfonylphenyl)-1-piperazinyl]ethyl]-N,N-di-t-butylo~ &bullyLsochroman-6-c~l~ le (VIII) Following the general p,~,cedu~ of EXAMPLE 3, Step 1 and making non-critical v~ri~ nc but using 1-[2-[4-(4-methylsulru..yl~henyl)-1-30 piperazinyl]ethyl]-isochroman-6-c~hl,,.~;-le (825 mg, 1.9 mmol) gives crude product. This m~ l is purified by LC (silica gel, 230-400 mesh, 58 g;
~etonP/haY~na, 45/55) to give 1-[2-~4-(4-methylsulfonylphenyl)-1-piperazinyl]ethyl]-N,N-di-t-butylo~ycall,onylisochroman-6-ca~ e (VIII), Rf = 0.20 (~eton~ Y~n.q, 40/60).
Step 2: 1-[2-[4-(4-Methylsulfonylphenyl)-1-~i~e~ yl]ethyl]-N-methyl-isochroman-6-carboY~mi~e (IX) CA 0222~282 1997-12-19 W O 97/022S9 PCTrUS96/08681 Following the general procedure of EXAMPLE 3, Step 2 and making non-critical v~ri~t;onA but using 1-[2-[4-(4-methylsulfonylphenyl)-1-piperazinyl]ethyl]-N,N-di-t-butylu~ ~bu-lylisochroman-6-carbnY~mi-le (VIII, 660 mg, 1.0 mmol) gives crude product. This material is purified by LC (silica gel, 5 230-400 mesh, 71 g; mPtl~nnl/dichlorompth~np~ 5/95) to give 1-[2-[4~4-methylsulfonylphenyl)-l-piperazinyl]ethyl]-N-methylisochroman-6-carb- Y~mide (IX), Rf = 0.30 (mPth~n~)l/dichloromPth~nP~ 5/95); IR (mull) 1645, 1612, 1593, 1571, 1545, 1508, 1496, 1409, 1296, 1249, 1145, 1106, 1095, 957 and 780 cm~l; NMR (300 MHz, CDCl3) 7.73 (d, 2H, J=8.9 Hz, aromatic), 7.55 (m, 2H, aromatic), 7.15 (d, lH, J=7.9 10 Hz, aromatic), 6.91 (d, lH, J=8.9 Hz, aromatic), 6.14 (brdd, lH, J=4.4 Hz, NH), 4.86 (brdd, lH, J=6.2 Hz, m~t~lin~), 4.12 (m, lH, OCH2a), 3.75 (m, lH, OCH2b), 3.35 (t, 4H, J=4.9 Hz, Ph-N-CH28), 2.99 (brds, 7H, N-CH3, OCH3, Ph-CH2a), 2.75-2.46 (m, 7H, Ph-NC(H2)-CH2S-NCH2s, Ph-CH2b), 2.14 (m, lH, C(H)-CH2a), 2.02 (m, lH, C(H)-CH2b) o; CMR (75 MHz, CDCl3) 167.9, 154.3, 141.4,134.5, 132.7, 129.1, 128.6, 15 127.7, 124.9, 124.5, 113.8, 74.3, 63.0, 54.5, 52.9, 47.3, 45.0, 33.1, 29.1 and 26.8 ~;
HRMS (EI) ~~lr~ t-od for C24H31N304S = 457.2035, found = 457.2032; KF. Water =
0.87%; Melt Solvate = 0.53% ethyl acetate and 0.34% hPYstnP.
~XAlvl PLE 24 1-[2-[4~4-M~th- Yyphenyl)-l-,ui,ue..lzillyl]ethyl]isocl,lu,.lan-6-Step 1: 1-[2~6-Br ml~iAo~hroman-l-yl)acetyl]-4-(4-methoxyphenyl)-piperazine (V) Following the general plucedulc: of F~ANlpLE 1, Step 3 and m~king non-critical v~ri~t;on~ but using racemic 6-br moi~o- hroman-1-yl-acetic acid (IV) and 4-mPthl ~ryphenyl~i,u~azine gives 1-[2-(6-bromn.i~ochroman-1-yl)acetyl]~-(4-methoxyphenyl)piperazine (V), Rf = 0.26 (ethyl ~ret~t~p/hpy~np~ 70/30); IR (mull) 1639, 1512, 1446, 1439, 1249, 1214, 1112, 1030, 1028 and 820 cm~l; NMR (300 MHz,CDCl3) 7.32-7.26 (m, 2H, aromatic H's), 7.0 (d, lH, J=8.2 Hz, aromtic H), 6.88 (d, 4H, aromatic H's), 5.27 (m of d, lH, J=5.9 Hz, ArC-H), 4.164.07 (m, lH), 3.89 (m, lH), 3.80-3.60 (m, 4H), 3.77 (s, 3H, -OC-H3), 3.05 (m, 4H, four of pip-H), 2.97-2.90 (m, 2H), 2.76 (d of d, lH, Ja=3.7 Hz, Jb=14.9 Hz), 2.65 (m of d, lH, J=16.4 Hz) ~;
CMR (75 MHz, CDCl3) 168.9, 154.3, 145.2, 136.5, 136.2, 131.7, 129.3, 126.4, 120.3, 118.8, 114.4, 73.4, 63.4, 55.5, 51.3, 50.7, 46.1, 41.9, 39.9, 28.7 o.
Step 2: 1-[2-(6-Brom~ o~hroman-l-yl)ethyl]-4-(4-methoxy-phenyl) piperazine (VI) The general P~Ced~LLe of ~A~ PLE 1, Step 4 and m~king non-critical v~ri~tion~ but using 1-[2-(6-brom- i~ocl .l u ~an-1-yl)acetyl]-4-(4-methoxyphenyl)-CA 02225282 l997-l2-l9 W O 97/02259 PCTrUS96/08681 piperazine (V) gives 1-[2-(6-bromoisochroman-1-yl)ethyl]~-(4-met~oxyphenyl)-piperazine (VI), Rf = 0.23 (ethyl acetate); IR (neat) 1518, 1479, 1266, 1250, 1155, 1140, 1112, 1103, 1041 and 818 cm~l; NMR (300 MHz,CDC13) 7.29 (d, lH, J=8.3 Hz, aromatic H), 7.27 (s, lH, aromatic H), 6.97 (d, lH, J=8.3 Hz, aromatic H), 6.85 (q, 5 4H, J=9.7 Hz, aromatic H's), 4.78 (m of d, lH, J=6.1 Hz), 4.14-4.07 (m, lH), 3.76-3.69 (m, lH), 3.76 (s, 3H, -OC-H3), 3.10 (t, 4H, J=4.9 Hz, four of pip-H), 2.95 (m, lH), 2.70-2.50 (m's, 7H), 2.13 (m, lH, pipCH-H), 2.02 (m, lH, pipCH-H) o; CMR (75 MHz, CDCl8) 163.5, 146.5, 136.8, 136.0, 131.4, 129.0, 126.3, 119.7, 117.9, 114.2, 74.1, 62.5, 55.3, 54.4, 53.3, 50.4, 32.9 and 28.6 o.
Step 3: 1-[2-[4-(4-MPthnYyphenyl)-l-piperazinyl]ethyU-isochroman-6-A dry 100 mL round bottom flask is charged with THF (18 mL) and cooled to -78~ with a dry ice/A~etone bath. t-Butyllit~illm in h~Y~n~ (1.7M, 5.4 ml~ 9.2 mmol) is added at once. After stirring for 5 minutes, a llliX~U~ 1-[2-(6-15 bromoi~orhroman-1-yl)ethyl]-4-(4-mPtl~oYyphenyl)piperazine (VI) in THF (20 m L) is added via canula. After stirring for 15 minllte~ at -78~, trimethylsilyl isocyanate (0.88 mL, 6.55 mmol) and ~inY~ne (3.52 mL) are added via srying r~e~ liv~ly. After 15 _in. the cooling bath is removed and the reaction is stirred at 20-25~ for 1.5 hrs.
The reaction lllixLu-~a is qll~nr~hetl with sa~urdted aqueous Ammonillm ~hlnriclç, the 20 volatiles are removed under reduced pressure, and the residue is b~cifiPrl with aqueous sodium hydroxide. The crude basic SOlllt;On iB extracted with methylene chloride. The organic extracts are comhinP~, dried with sodium sulfate, filtered and con~entrated. The crude mAteriAl is purified by flash chromAt,o~.dphy (silica gel, 25 g; using a gradient of 0-10% mpt~nol/ethyl acetate to give 1-[2-[4-(4-25 mpt~nxyphenyl)-l-pipel~zill~l]ethyl]-isochroman-6-carhnyAmi~e (VII), mp = 180-182~;
Rf = 0.27 (m~t~Anol/ethyl Acet~te~ 10/90); IR (mull) 3366, 3198, 1628, 1642, 1602, 1514, 1437, 1245, 1109 and 815 cm~l; NMR (300 MHz,CDCl3) 7.61-7.58 (m, 2H, aromatic H's), 7.18, (d, lH, d=8.6 Hz, aromatic H), 6.85 (q, 4H, J=9.2 Hz, aromatic H's), 5.90 (very broad d, 2H, C(O)N-H2), 4.86 (m of d, lH, J=5.8 Hz, PhC-H), 4.18-30 4.11 (m, lH), 3.80-3.72 (m, lH), 3.76 (s, 3H, PhOC-H3), 3.10 (t, 4H, J=4.8 Hz, four of pip-H), 2.99 (m, lH), 2.73 (m of d, lH, J=16.4 Hz), 2.66-2.49 (m's, 6H), 2.15 (m, lH, pipCH-H), 2.04 (m, lH, pipCH-H) o; CMR (75 MHz, CDCl3) 168.7, 153.5, 145.4, 142.0, 134.3, 131.0, 127.9, 124.8, 124.6, 117.8, 114.1, 74.2, 62.6, 55.2, 54.3, 53.2, 50.3, 32.8, 28.7 and 27.2 ~; HRMS cAl~lllAte~l for C23H29N303 = 395.2209, found:
35 395.2219.
F'XAMPLE 25 1-[2-[4-(4-Mot~nYyphenyl)-l-piperazinyl]ethyl]-N-propyl-CA 02225282 1997-12-lg W O 97/022S9 PCT~US96/08681 isochroman-6-csrboY~mi-le (IX) Step 1: 1-[2-[4-(4-MPt~ ~Yyphenyl)-1-piperazinyl]ethyl]-N,N-di-t-butylo,.ycsLl,onylisochroman-6-caLI,..Y~ e (VIII) Follovving the genersl P1UCedULe of EX~MPLE 3, Step 1 and m~king non-5 critical v~ri~ti~nR but starting with 1-[2-[4-(4-methnYyphenyl)-1-piperazinyl]ethyl]-isochroman-6-c~Lb~-Y~ irle (VII, Ti~AMPLE 24), 1-[2-t4-(4-mPthnYyphenyl)-1-piperazinyl]ethyl]-N,N-di-t-butykJ~yc~l,ollylisochroman-6-cslL...Y~niclP. (VIII) is obtained.
Step 2: 1-[2-[4-(4-M~t~oYyphenyl)-1-piperazinyl]ethyl]-N-propyl-isochroman-6-caLL~.Ys.. icle (IX) An oven-dried 100 mT- lCC~V~l~ flask eq~upped with spinbsr is chsrged with 1-[2-[4-(4-mPt~oyyphenyl)-l-piperazinyl]ethyl]-N~N-di-t-butyl~ y~Lonylisochroman-6-cs l,..Y~...icle (VIII, 566 mg, 0.95 mmol) and 20 mL dichlorompth~na~ This ~;.cLuL~:
is trested with propylsmine (0.78 mL, 9.5 mmol). After 16 hr, the volatiles are 15 removed under reduced Pre~ULe to the crude product. This m~t~ris~l is purified by LC (silica gel, 230-400 mesh, 30 g; mpt~n~l/ethyl~cet~t~ 5/95) to give 1-[2-[4-(4-methoxyphenyl)-l-piperazinyl]ethyU-N-propylisochroman-6-caLI,~ le (IX), mp =
147-149~; Rf = 0.37 (mPtl~nnl/ethyl~et~t~e~ 5/95); IR (mull) 3302, 2815, 1639, 1639, 1515, 1320, 1310, 1293, 1278, 1247, 1153, 1112, 1107, 1041 and 824 cm~l; NMR (300 20 MHz, CDCl3) 7.54 (m, 2H, aromatic), 7.16 (d, lH, J=8.6 Hz, aromatic), 6.87 (m, 4H, aromatic), 6.16 (brdt, lH, NH), 4.87 (brdd, lH, J=6.0 Hz, m~t~ine)~ 4.14 (m, lH,OCH2a), 3.76 (m, 4H, OCH3& OCH2b), 3.42 (qrt, 2H, J=6.3 Hz, N(H)-CH2), 3.10 (t, 4H, J=4.8 Hz, Ph-N-CH28), 3.00 (m, lH, Ph-CH2a), 2.77-2.53 (m, 7H, Ph-NC(H2)-CH2B-NCH2s, Ph-CH2b), 2.17 (m, lH, C(H)-CH2a), 2.05 (m, lH, C(H)-CH2b), 1.63 25 (sxt, 2H, J=7.4 Hz, C(H3)-CH2), 0.98 (t, 3H, J=7.4 Hz, CH3-C(H2) ~; CMR (75 MHz, CDCl3) 167.1, 153.6, 145.5, 141.3, 134.3, 132.7, 127.4, 124.8, 124.2, 117.9, 114.2, 74.3, 62.8, 55.4, 54.5, 53.3, 50.4, 41.5, 33.0, 28.9, 22.8 and 11.3 ~; MS (EI, m/z) =
437.
EX~MPLE 26 1-[2-[4-(4-MPt~ll Yyphenyl)-1-~ yl]ethyl]-N-allyl-isochroman-6-caLL.. ~.nicie (IX) Following the general procedure of ~AMPLE 25, Step 2 and m~king non-critical v~t~n~ but using allylamine (0.69 mL, 9.1 mmol) give crude product.
This material is purified by LC (silica gel, 230-400 mesh, 30 g; m~~nol/ethyl acetate 3/97) to give product which is 1~ L~ ed from ethyl acetate/hPY~nP-, mp =
35 146-148~; Rf = 0.34 (me~nr)llet,hyl~et~tP, 5/95); IR (mull) 3295, 2814, 1640, 15~6, 1515, 1494, 1443, 1310, 1281, 1246, 1148, 1107, 1037, 923 and 823 cm~l; NMR (300 MHz, CDCl3) 7.57, 7.17, 6.85, 6.20, 5.92, 5.26, 5.19, 4.87, 4.08, 3.76, 3.11, 3.01, 2.78-2.50, 2.18 and 2.05 o; CMR (75 MHz, CDCl3) 167.1, 153.8, 145.7, 141.8, 134.6, 134.2, 132.5, 127.8, 125.1, 124.5, 118.2, 116.8, 114.4, 74.6" 63.0, 55.6, 54.7, 53.5, 50.7, 42.5, 33.2 and 29.1 o; MS (EI, m/z) = 435; HRMS (EI) cSIlc~ tP~l for C26H33N3O3 =
435.2522, found = 435.2516.
VrPLE 27 1-[2-[4-(4-Methoxy-phenyl)-l-piperazinyl]ethyl]-N-eth isochroman-6-ca~Ln~ 1P (IX) Following the general procedure of EXAMPLE 25, Step 2 and making non-critical variations but using ethylamine (approx 2 mL, cr~n~lPnce~ at 0~) gives crude product. This m~t~ri~l is purified by LC (slicia gel, 230-400 mesth, 30 g;
mPt~l~nol/ethyl ~-~et~te, 5/95) to give product. This material is LL;Lurdled with ethyl acetate~hexane to give 1-[2-[4-(4-mP~hn~yphenyl)-l-piperazinyl]ethyl]-N-ethyl-isochroman-6-calL~ e (IX), mp = 127-129~; Rf = 0.30 (mPt~l~nol/ethyl ~cehte, 5/95); IR (mull) 3308, 2815, 1640, 1540, 1514, 1442, 1359, 1312, 1298, 1283, 1246, 1149, 1112, 1037 and 826 cm~l; NMR (300 MHz, CDCl3) 7.55 (m, 2H, aromatic), 7.16(d, lH, J=8.6 Hz, aromatic), 6.87 (m, 4H, aromatic), 6.12 (brdt, lH, NH), 4.87 (brdd, lH, J=8.1 Hz, mPthinP), 4.15 (m, lH, OCH2a), 3.77 (m, 4H, OCH3& OCH2b), 3.49 (qt, 2H, J=7.2 Hz, N(H)-CH2), 3.11 (t, 4H, J=4.8 Hz, Ph-N-CH2s), 3.00 (m, lH, Ph-CH2 ) 2.77-2.50 (m, 7H, Ph-Nc(H2)-cH2s-NcH28~ Ph-CH2b)~ 2-15 (m~ lH~ C(H) CH2a), 2.05 (m, lH, C(H)-CH2b), 1.25 (t, 3H, J=7.2 Hz, CH3-C(H2) ~; CMR (75 MHz,CDCl3) 166.9, 153.4, 145.4, 141.2, 134.1, 132.5, 127.3, 124.7, 124.1, 117.8, 114.1, 74.2, 62.6, 55.2, 54.3, 53.2, 50.3, 34.6, 32.9, 28.7 and 14.6 o; MS (EI, m/z) = 423.
EXA~LE 28 1-[2-[4~4-MPthnYyphenyl)-l-piperazinyl]ethyl]-N-pr~pal~yl-isochroman-6-c~Ln ~ P. (IX) Following the general procedure of EXAMPLE 25, Step 2 and m~king non-critical variations but using plu~al~ylamine (1.6 mL, 23.0 mmol) gives crude product. This m~ri~l is purified by LC on 75 g (230-400) silica gel eluting withethyl acetate to give the product which is 1G~Y~I~11;7eCI from ethyl acetate/hexane to give l-t2-[4~4-mPt~ typhenyl)-l-piperazinyl]ethyl]-N-propar~yl-isochroman-6-30 c~.L-cii-le (IX), mp = 162-164~; Rf = 0.40 (mpt~l~n~l/ethyl ~.~etste 5/95); IR (mull) 3287, 1643, 1636, 1611, 1535, 1515, 1495, 1443, 1303, 1283, 1246, 1147, 1107, 1033 and 822 cm~l; NMR (300 MHz, CDCl3) 7.57 (m, 2H, aromatic), 7.17 (d, lH, J=8.6 Hz, aromatic), 6.85 (m, 4H, aromatic), 6.35 (brdt, lH, NH), 4.88 (brdd, lH, J=8.0 Hz, mPt~inP), 4.25 (dd, 2H, J=5.2 Hz & J=2.5 Hz, N(H)-CH2), 4.12 (m, lH, OCH2a ), 3.76 (m, 4H, OCH3& OCH2b), 3.10 (t, 4H, J=4.8 Hz, Ph-N-CH28), 3.01 (m, lH, Ph-CH2a), 2.78-2.50 (m, 7H, Ph-NC(H2)-CH2s-NCH2S, Ph-CH2b), 2.29 (t, lH, J=2.5 Hz, alkyne), W O 97/02259 PCTrUS96/08681 2.18 (m, lH, C(H)-CH2a), 2.05 (m, lH, C(H)-CH2b) 8; CMR (75 MHz, CDC13) 166.7, 153.6, 145.5, 142.0, 134.4, 131.6, 127.6, 124.9, 124.4, 118.0, 114.2, 79.3, 74.3, 71.8, 62.7, 55.4, 54.5, 53.3, 50.4, 33.0, 29.6 and 28.8 8; MS (EI, m/z) = 433; HRMS (EI) t~-l for C26H31N303 = 433.2365, found = 433.2367.
F~AMPLE 29 1-[2-[4-(4-MPthnyyphenyl)-l-pipe~ yl]ethyl]-N-(4 m~thnYyphenylmethyl)-isochroman-6-carboy~m~
Following the general procedure of ~xAMpLE 25, Step 2 and making non-critical variations but using 4-m~thnYyphenylmethylamine (1.2 mL, 9.2 mmol) gives crude product. The crude is purified by flash chrom~graphy on 67 g silica gel using m~th~nol/ethyl acetate (10/90) as the eluent to give 1-[2-[4-(4-methoxyphenyl)-1-piperazinyUethyl]-N-(4-methoxyph~llyLllet~lyl)isochroman-6-c~L~ P (IX), mp 5 162-163~; Rf = 0.40 (mPth~n~l/ethyl ~etstç, 10/90); [a]D = -40~ (c = 0.98, eth~n-)l);
IR (mull) 3306, 1642, 1540, 1515, 1313, 1251, 1244, 1235, 1110, 1036 cm~l; NMR
(300 MHz, CDCl3) 7.57 (m, 2H, aromatic H's), 7.28 (d, 2H, J=8.7 Hz, aromatic H),7.16 (d, 2H, J=8.7 Hz, aromatic H), 6.92-6.82 (m's, 6H,aromatic H's), 6.27 (m, lH, C(O)N-H), 4.86 (m of d, lH, J=5.8 Hz, PhC-H), 4.18-4.11 (m, lH), 3.80 (s, 3H, PhOC-H3), 3.80-3.72 (m, lH), 3.76 (8, 3H, PhOC-H3), 3.10 (t, 4H, J=4.8 Hz, four of pip-H), 2.99 (m, lH), 2.73 (m of d, lH, J=16.4 Hz), 2.66-2.49 (m's, 6H), 2.15 (m, lH, pipCH-H), 2.04 (m, lH, pipCH-H) 8; CMR (75 MHz, CDC13) 166.9, 145.7, 141.7, 134.5, 132.4, 130.2, 129.3, 127.7, 125.0, 124.5, 118.2, 114.4, 114.2, 74.5, 62.9, 55.5, 55.3, 54.6, 53.5, 50.6, 43.6, 33.1, 29.0 8; HRMS calculated for C31H37N304 = 515.2784,found = 515.2806.
EXAMPLE 30 1-[2-[4~4-MPthnyyphenyl)-l-piperazinyl]ethyl]-N-phenylmeth isochroman-6 c~ Y~ e (IX) An oven dried 15 mL micro vial, equipped with a claisen c. n~en~r~ water cooled condenR~r, and hose adapter, is charged with 1-(2-(6-br~mni~o~hl~lllan-1-yl)-ethyl)-4~mPt~nYyphenyl)-pipelazi~e (VI, 646 mg, 1.5 mmol), p~ lm (II) acetate (98%, 17.2 mg, 0.075 mmol) and 1,3-bis-diphenylphosFhinnpropane (97~o, 38.3 mg, 0.09 mmol). Carbon mnnnYi~e ~tmosphpre is PqtshliRh~l in the vial. To the react;ion vessel is introduced via syringe D~ (3.75 mT.),phenyl~t~ yl amine (1.15 mT~ 10.5 mmol) and diisu~v~ylethylamine (0.52 mL, 3 mmol). The ll~i~ is heated to 100~ over 10 hours. After cooling to 20-25~, it sepala~ed into two phases.
The reaction lllixLula is poured into ethyl ~cetote. The llli~ is washed one time with aqueous sodium hydroxide (lN). The organic layer is then con~ dted under reduced ple~ to remove excess solvents and r~ct~ntc to give a crude product which is purified by flash chrom~t~graphy on 100 g silica gel using ethyl acetate as CA 02225282 l997-l2-l9 W O 97t02259 PCT~US96/08681 the eluent to give 1-C2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-N-phenylmethylisochroman-6-carbn~mif~f~ (IX), mp = 153.0-153.5~; Rf= 0.25 mf~th~n-~l/ethyl ~cePte, 10/90); IR (mull) 3263, 2819, 1640, 1543, 1513, 1245, 1234, 1112, 1039 and 826 cm-1; NMR (300 MHz,CDCl3) 7.68 (d, 2H, J=6.9 Hz, aromatic 6 H's), 7.36-7.28 (m's, ~H, aromatic H's), 7.16, (d, lH, J=8.7 Hz, aromatic H), 6.86 (q, 4H, J=9.2 Hz, aromatic H's), 6.42 (t, lH, C(O)N-H), 4.86 (m of d, lH, J=5.8 Hz, PhC-H), 4.64 (d, 2H, J=5.7 Hz, PhC-H2), 4.17-4.10 (m, lH), 3.80-3.72 (m, lH), 3.76 (6, 3H, PhOC-H3), 3.10 (t, 4H, J=4.8 Hz, four of pip-H), 2.99, 2.73 (m of d, lH, J=16.4 Hz), 2.66-2.49 (m's, 6H), 2.15 (m, lH, pipCH-H), 2.04 (m, lH, pipCH-H) ~; CMR (75 ~Iz, 10 CDCl3) 189.7, 167.1, 153.8, 145.7, 141.8, 138.2, 134.5, 132.4, 128.8, 127.9, 127.8, 127.6, 125.1, 124.6, 74.5, 62.9, 55.6, 54.6, 53.5, 50.6, 44.1, 33.1, Z9.0 o; HRMS
c~lr~ t~d for C30H35N3O3 = 485.2678, found = 485.2664.
EXA~LE 31 1-[2-[4-(4-Mf~hnYyphenyl)-1-piperazinyl]ethyl]-N-butyl-isochroman-6-ca~l,.-x~...iflf~ (IX) Following the general procedure of F~AMT'LE 30 and m~kin~ non-critical variations but using n-butylamine (1.04 nnT.~ 10.5 mmol) gives crude product which is purified by flash chrom~ .dphy on 100 g silica gel using ethyl acetate as theeluent to give product which is rG~ ql~ t;nn from hot ethyl acetate to give the title ~u~ uu~d~ mp = 158.5-159.5~; Rf = 0.28 (ethyl acetate); IR (mull) 3301, 2816, 20 1637, 1537, 1515, 1444, 1308, 1244, 1111 and 823 cm~l; NMR (300 MHz,CDC13) 5.53, 7.16, 6.87, 6.10, 4.85, 3.80-3.67, 3.76, 3.45, 3.11, 3.10, 2.73, 2.66-2.49, 2.15, 2.04, 1.59, 1.43, 0.96 o; CMR (75 MHz, CDCl3) 167.3, 153.8, 145.7, 141.5, 134.5,132.9, 127.6, 125.0, 124.4, 118.2, 114.4, 74.5, 63.0, 55.6, 54.7, 53.5, 50.6, 40.0, 39.8, 33.2, 31.8, 29.1, 20.2, 13.8 ~.~5 li'XAMPLE 32 1-[2-[4-(4-Mf~t~ fnryphenyl)-l-piperazinyl]ethyl]-N-[(R)-a methylphenylmethyl]-isochroman-6-cOlL. .~ 1 e (IX) Following the general procedure of EXAMPLE 30 and m~kinF non-critical v~ri~t;~n~ but using (R)-(+)-a-methylphenylmethylamine (98~o, 0.90 mL, 7 mmol) gives crude product which is purified by flash chrom~tography on 100 g silica gel 30 using a gradient of 0 4% mf~th~nnl in ethyl ~- etqt~. The product is lG"~ i7f,.l from hot methylene rhlnri.l~ethyl acetate/~exane to give 1-[2-[4-(4-mf~ f~yphenyl)-1-pipwdziuyl]ethyl]-N-[(R)-a-methylphenylmethyl]isochroman-6-ca~ .x,~ le (IX) asa ~ lule of dia!i~eLGomers, mp = 140.5-141.0~; Rf = 0.28 (ethyl acetate); [~]D +25~ (c 0.94, eth~nol); IR (mull) 3310, 1636, 1630, 1514, 1495, 1275, 1148, 1110, 700 cm~1;
35 NMR (300 MHz,CDCl3) 7.58 (d, 2H, J=6.9 Hz, aromatic H's), 7.41-7.28 (m's, 5H,aromatic H's), 7.16, (d, lH, J=8.7 Hz, aromatic H), 6.85 (q, 4H, J=9.2 Hz, aromatic CA 0222~282 1997-12-19 W O 97/02259 PCT~US96/08681 H's), 6.29 (d, lH, J=7.8 Hz, C(O)N-H), 5.34 (quintet, lH, J=7.2 Hz, PhC-H), 4.86 (m of d, lH, J=5.8 Hz, PhC-H), 4.17-4.10 (m, lH), 3.80-3.72 (m, lH), 3.76 (B, 3H, PhOC-H3), 3.10 (t, 4H, J=4.8 Hz, four of pip-H), 2.99 (m, lH), 2.73 (m of d, lH, J=16.4 Hz), 2.66-2.49 (m's, 6H), 2.15 (m, lH, pipCH-H), 2.04 (m, lH, pipCH-H), 1.61 (d, 3H, 5 J=6!9 Hz, PhC(H)C-H3) ~; CMR (75 MHz, CDCl3) 166.2, 153.7, 145.7, 143.0, 141.7, 134.5, 132.6, 128.7, 127.6, 127.4, 126.2, 125.0, 124.5, 118.1, 114.4, 74.5, 62.9, 55.5, 54.6, 53.4, 50.5, 49.1, 33.1, 29.0, 21.6 o.
EXAMPLE 33 1-[2-[4-(4-MPt~n~ryphenyl)-l-piperazinyl]ethyl]-N-[(S)-a-methylphenylmethyl]isochroman-6-cd~ . . ,itle (IX) Following the general prucedu~ of EXAMPLE 30 and m~kinE non-critical v~ri~tinnR but using (S)-(-)-a-methylphenylmethylamine (98%, 0.90 mL, 7 mmol) give~ crude product which is purified by flash chrom~t~graphy on 100 g silica gel using a gradient of 0-7% m~th~nol in ethyl ~et~te~ The product is l'eC~y~ i7.eclfrom hot methylene chloride/ethyl acetate/hexane to give 1-[2-[4-(4-methoxyphenyl)-15 1-pi~ ~yl]ethyl]-N-[(S)-a-methylphenylmethyl]isochroman-6-c~ubf.~ le (IX) as a ll~ixLu~ of diastereomers, mp = 141.0-141.5~; Rf = 0.28 (ethyl acetate); [a]D -24~ (c 0.98, et~nol); IR (mull) 3310, 1636, 1530, 1514, 1495, 1275, 1148, 1110, 700 cm~l;
NMR (300 MHz,CDCl3) 7.58 (d, 2H, J=6.9 Hz, aromatic H's), 7.41-7.28 (m's, 5H, aromatic H's), 7.16, (d, lH, J=8.7 Hz, aromatic H), 6.85 (q, 4H, J=9.2 Hz, aromatic 20 H's), 6.29 (d, lH, J=7.8 Hz, C(O)N-H), 5.34 (quintet, lH, J=7.2 Hz, PhC-H), 4.86 (m of d, lH, J=5.8 Hz, PhC-H), 4.174.10 (m, lH), 3.80-3.72 (m, lH), 3.76 (s, 3H, PhOC-H3), 3.10 (t, 4H, J=4.8 Hz, four of pip-H), 2.99 (m, lH), 2.73 (m of d, lH, J=16.4 Hz), 2.66-2.49 (m's, 6H), 2.15 (m, lH, pipCH-H), 2.04 (m, lH, pipCH-H), 1.61 (d, 3H, J=6.9 Hz, PhC(H)C-H3) ~; CMR (75 MHz, CDCl3) 166.2, 153.7, 145.7, 143.0, 141.7, 25 134.5, 132.6, 128.7, 127.6, 127.4, 126.2, 125.0, 124.5, 118.1, 114.4, 74.5, 62.9, 55.5, 54.6, 53.4, 50.5, 49.1, 33.1, 29.0, 21.6 ~.
P'XANIPLE 34 1-[2-[4-(4-M.othnYyphenyl)-l-pipe~ lyl]ethyl]-N-phenyl-isochroman-6 ca.L.--~....icle (IX) Following the general procedure of P~AMPLE 30 and m~king non-critical 30 v~rint;~ n~ but using aniline (0.64 mL, 7 mmol) gives crude product which is purified by LC on 29 g (230~00) silica gel eluting with ethyl acetate/hexane (75/25) to give 1-[2-[4-(4-m~t~ nyyphenyl)-l-piperazinyl]ethyl]-N-phenylisochroman-6-c~~ ;de (IX), Rf = 0.25 (ethyl ~et~t~ Y~ne, 75/25); IR (mull) 2817, 1652, 1599, 1531, 1513, 1442, 1320, 1298, 1246, 1145, 1112, 1038, 823, 754, 693 cm~l; NMR (300 MHz, 35 CDCl3) 7.87 (s, lH, NH), 7.63 (m, 4H, aromatic), 7.37 (t, 2H, J=7.7 Hz, aromatic~, 7.21 (d, lH, J=7.9 Hz, aromatic), 7.18 (t, lH, J=6.3 Hz, aromatic), 6.85 (m, 4H, CA 02225282 l997-l2-l9 W 097/022S9 PCTnUS96/0~i81 aromatic), 4.86 (brdd, lH, J=6.0 Hz, mPt~linQ), 4.15 (m, lH, OCH2a), 3.76 (m, 4H, OCH3& OCH2b), 3.11 (t, 4H, J=4.9 Hz, Ph-N-~H28), 3.00 (m, lH, Ph-CH2a), 2.70-2.50 (m, 7H, Ph-NC(H2)-CH2S-NCH28, Ph-CH2b), 2.15 (m, lH, C(H)-CH2a), 2.05 (m, lH, C(H)-CH2b) o; CMR (75 MHz, CDCl3) 165.6, 153.8, 145.7, 142.2, 137.9, 134.8, 5 133.0, 129.1, 127.8, 125.3, 124.6, 124.5, 120.2, 118.2, 114.4, 74.5, 62.9, 55.6, 54.7, 53.5, 50.6, 33.2, 29.1 o.
EXAMPLE 35 1-[2-[4-(4-MPt~ yphenyl)-l-piperazinyl]ethyl]-N-phenylmethyl-N-methyl-isochroman-6-carb- Yslmi-1e (IX) Following the general procedure of EXAMPLE 30 and mAking non-critical 10 variations but using phenylmethylmethylamine (1.4 mL, 10.5 mmol) give~ crude product which is purified by LC on 77 g (230-400) silica gel eluting with ~eton~/hexane (40/60) and gradually increa~ing to ~ceton~hexane (60/40) to give product. Thi8 material is disolved in ether and treated with gaseous hy-lLochloric acid resulting in the formation of a solid. Freebase Rf = 0.30 (At~etonP/hPYAnp715 40/60); bi~q salt IR (mull) 3423, 2352, 2192, 1627, 1513, 1495, 1400, 1331, 1310, 1294, 1259, 1193, 1106, 1073, 1028 cm~l; NMR of freebase (300 MHz, CDC13) 7.26 (m, 8H,aromatic), 6.84 (m, 4H, aromatic), 4.84 (bs, lH, mPthinQ), 4.75 (bs, lH, Ph-CH2a-N), 4.54 (m, lH, Ph-CH2b-N), 4.12 (m, lH, OCH2a), 3.76 (m, 4H, OCH3& OCH2b), 3.08 (t, 4H, J=4.7 Hz, Ph-N-CH28), 3.02-2.88 (m, 4H, NCH3 & Ph-CH2a), 2.64 (m, 7H, Ph-20 NC(H2)-CH2s-NCH2~, Ph-CH2b), 2.15 (m, lH, C(H)-CH2a), 2.05 (m, lH, C(H)-CH2b) ~; HRMS (EI) ~ ~lclllAt,Qd for C31H37N303 = 499.2835, found = 499.2842.
Ti'XAlVlPLE 36 1-[2-[4-(4-M~thr.Yyphenyl)-l-pipe~dziuyuethyl]-N~N-dimeth isochru~an-6 c~b.~Y~ le (IX) A flame-dried 50 mL flask equipped with spinbar and ~ltliti~n funnel is 25 charged with freshly ~iFt;ll~ tetrahydivru~ (6 mL), cooled to -78~, and treated with a 1.7 M solllti~ n of tert-butyllithillm (3.0 mL, 5.0 mmol). The r~slllting ~i~u~e is treated drop-wise over 10 min. with a solllt;~n of 1-(2-(6-br moi~o~ hroman-1-yl)-ethyl)-4-(4-mPthmryphenyl)piperazine (VI, 1.08 g, 2.5 mmol) and 7 mL
tetrahyd~uru~dn (507 mg, 3.3 mmol). The aryl lithillm is stirred 10 min and is 30 treated with carbon dioxide (bone dry). After an ~ 1itinn 10 min, the aryl ca~l,u,.ylate is warmed to 20-25~ with the gas ~lflititm 8ll~pend-p~ The l~ U~: is treated with dimel~lyl~u~ miclP (2 drops) followed by oxalyl chloride (0.33 mT., 3.76 mmol) with copious gas evolution and a rls~ lg in color. After 45 min, the ~L2~Lu~ts is treated with dimethylamine gas. After 20 min, the amine ~ lition iS35 sllcpen-l~d and the reaction ~ u~e i8 diluted with 40 mT 5M sodium hydroxide and extracted twice with ethyl acetate (40 mL). The comhin~d organics are washed once CA 0222~282 l997-l2-l9 W O 97/02259 PCT~US96/08681 with saline (30 mL), dried over m~gnPRi~lm sulfate, filtered, and con~ dted to give product which is purified by LC on 63 g (230-400) 8 ica gel eluting with ~cetonP/hexane (50/50) to give 1-[2-[4-(4-mPth--xyphenyl)-l-pipt.a,iinyl]ethyl]-N,N-dimethylisochroman-6-carb~Y~mi-le (IX), mp = 94-96~; Rf = 0.31 (~etonR/hPY~nR, 5 50/50); IR (mull) 2808, 2792, 1624, 1610, 1513, 1488, 1444, 1414, 1275, 1253, 1231, 1152, 1109, 1036, 833 cm~l; NMR (300 MHz, CDC13) 7.19 (m, 2H, aromatic), 7.12 (d, lH, J=7.9 Hz, aromatic), 6.85 (m, 4H, aromatic), 4.85 (brdd, lH, J=6.0 Hz, mPthinR), 4.13 (m, lH, OCH2a), 3.76 (m, 4H, OCH3& OCH2b), 3.13-3.00 (m, llH, NCH3s, Ph-NCH2s, Ph-CH2a), 2.65 (m, 7H, Ph-NC(H2)-CH28-NCH2 & Ph-CH2b), 2.17 (m, lH, 10 C(H)-CH2a), 2.05 (m, lH, C(H)-CH2b) ~; CMR (75 MHz, CDCl3) 171.2, 153.5, 145.5, 139.4, 134.2, 134.0, 127.5, 124.6, 124.4, 117.9, 114.2, 74.3, 62.7, 55.3, 54.5, 53.3, 50.4, 39.4, 35.1, 33.0, 28.8 ~; HRMS (EI) c~lculated for C25H33N3O3 = 4~3 ~5~ found =
4~ 0.
EXAMPLE 37 1-[2-[4-(4-MPth-.Yyphenyl)-l-piperazinyl]ethyl]-N-methyl-isochroman-6-carb~Y~mi-le (IX) Following the general pl~cedura of EXAMPLE 36 and m~king non-critical v~ i~t;~nR but using methylamine gas and kPeping amount of other rPngent~ the same gives 1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-N-methylisoch~ an-6-carb-~Y~mide (IX) which is re~;.y~ 7~ from ethyl acetate to give the title 20 compound, mp = 174-176~; Rf = 0.40 (mPt~n~l/dichloromp~ nR~ 5/95); IR (mull) 3270, 1639, 1543, 1515, 1418, 1319, 1260, 1248, 1235, 1152, 1141, 1112, 1037, 832 and 820 cm~l; NMR (300 MHz, CDCl3) 7.53 (m, 2H, aromstic), 7.16 (d, lH, J=8.6 Hz, aromatic), 6.87 (m, 4H, aromatic), 6.19 (brdm, lH, NH), 4.86 (brdd, lH, J=5.9 Hz, mPthinP), 4.14 (m, lH, OCH2a), 3.76 (m, 4H, OCH3& OCH2b), 3.10 (t, 4H, J=4.825 Hz, Ph-N-CH28), 3.00 (d, 4H, N-CH3 & Ph-CH2a), 2.77-2.49 (m, 7H, Ph-NC(H2)-CH28-NCH28, Ph-CH2b), 2.14 (m, lH, C(H)-CH2a), 2.05 (m, lH, C(H)-CH2b) o; CMR
(75 MHz, CDCl3) 168.0, 153.8, 145.7, 141.6, 134.5, 132.7, 127.7, 125.0, 124.4, 118.2, 114.4, 74.5, 62.9, 55.6, 54.6, 53.5, 50.6, 33.1, 29.1, 26.8 o; HRMS (EI) c~ tpfl for C24H3lN3O3 = 409.2365, found = 409.2366.
30 ~XAlVrPLE 38 1-t2-[4-(4-Chlorophenyl)-l-pip~ yl]ethyl]-N-methyl-isoclllu~an-6-carbnYS-mi-lR (IX) Following the general pl'OCedu~ of EXAMPLE 36 and mQking non-critical variations but using 1-t2-(6-brom oi corh roman- 1-yl)-ethyl]4~4-chlorophenyl)-piperazine (VI, EXAMPLE 8, Step 2, 188 mg, 0.43 mmol) and methylamine gives 35 product which is purified by LC on 10 g (230-400) silica gel eluting with 40%~cetonP~hexane tû give 1-[2-[4-(4-chlorophenyl)-1-piperazinyl]ethyl]-N-methyl-W 097/02259 PCTrUS96/08681 isochroman-6-carb--~rRmi-le (IX), mp = 158-160~; Rf = 0.21 (40% R-eton~/hexane); IR
(mull) 3319, 3263, 1639, 1613, 1597, 1571, 1545, 1497, 1334, 1314, 1239, 1150, 1139, 1109, 816 cm~l; N~ (300 ~Iz, CDCl3) 7.54 (brd~, 2H, aromatic), 7.16 (m, 3H, aromatic), 6.84 (d, 2H, J=9.0 Hz, aromatic), 6.21 (brdm, lH, NH), 4.86 (brdd, lH, J=6.0 Hz, mPthine), 4.12 (m, lH, OCH2a), 3.77 (m, lH, OCH2b), 3.17 (t, 4H, J=4.8Hz, Ph-N-CH28), 3.00 (d, 4H, J=4.9 Hz, N-CH3 & Ph-CH2a), 2.77-2.45 (m, 7H, Ph-NC(H2)-CH2s-NCH28, Ph-CH2b), 2.18 (m, lH, C(H)-CEI2a), 2.05 (m, lH, C(H)-CH2b) ~; CMR (75 MHz, CDCl3) 167.7, 149.7, 141.3, 134.2, 132.4, 128.7, 127.4, 124.7, 124.2, 124.1, 116.9, 74.2, 62.7, 54.3, 53.0, 48.9, 32.9, 28.8, 26.6 o; HRMS (EI)~Rlc~ t~d for C23H28ClN3O2 = 413.1870, found = 413.1867.
~xAlvrPLE 39 1-[2-[4-(4-Chlorophenyl)-1-piperazinyl]ethyl]-N,N-dimethyl-isochroman-6-carb- YRmi-1~ (IX) Following the general procedure of EXAMPLE 36 and mRking non-critical vRriRfion~ but using 1-[2-(6-brom-i~o~ an-1-yl)-ethyl]-4-(4-chlorophenyl)-piperazine (VI, EXAMPLE 8, Step 2, 188 mg, 0.43 mmol) and dimethylamine gave 50 mg (27~o) of 1-[2-[4~4-chlorophenyl)-1-piperazinyl]ethyl]-N,N-dimethylisochroman-6-caLl,~ e (IX) as product. This mRtPr~Rl is co~lvtlled to the bis hyd~chloride salt with gaseous hyd~cllloric acid and ~e~ lli7e~1~ mp =
119-122~; Rf = 0.41 (40% ~cet~n~/hexane); bis salt IR (mull) 3411, 2507, 2421, 2336, 1628, 1570, 1496, 1397, 1334, 1286, 1263, 1170, 1110, 1095, 1057 cm~l; free baseNMR (300 MHz, CDCl3) 7.20 (m, 4H, aromatic), 7.12 (d, lH, J=7.9 Hz, aromatic), 6.83 (d, 2H, J=9.1 Hz, aromatic), 4.85 (brdd, lH, J=6.0 Hz, m~hine)~ 4.13 (m, lH, OCH2a), 3.76 (m, lH, OCH2b), 3.18 (t, 4H, J=4.9 Hz, Ph-NCH2~), 3.10-3.00 (m, 7H,NCH3s & Ph-CH2a), 2.60 (m, 7H, Ph-NC(H2)-CH2E,-NCH2 & Ph-CH2b), 2.14 (m, lH, - 25 C(H)-CH2a), 2.02 (m, lH, C(H)-CH2b) o; CMR (75 MHz, CDCl3) 171.3, 149.7, 139.3, 134.3, 134.1, 128.8, 127.5, 124.7, 124.5, 124.3, 117.0, 74.3, 62.8, 54.4, 53.0, 48.9, 39.4, 35-2, 32-9, 28-8 o; HRMS (EI) calculated for C24H30ClN302 = 427.2026, found =
427.2020.
F'XAMPLE 40 1-t2-[4-Phenylpipelazillyl]ethyl]isochroman-6-carbmrRmi(le (VII) Step 1: 1-[2-(6-BromniRochroman-1-yl)acetyl]-4-phe"yl~ .dzine (V) Following the general procedure of EXAMPLE 1, Step 3 and making non-critical vAriRt;~n~ but using racemic 6-bromr~i~orhroman-l-yl-acetic acid (IV, F'XAlVlPLE 7, Step 1) and N-phenylpiperazine gave 1-[2-(6-br m~ orhroman-1-yl)acetyl]-4-ph~yl~i~e~ e (V), Rf = 0.20 (40% ethyl acetate/hexane); IR (mull) 1641, 1599, 1495, 1482, 1442, 1406, 1329, 1278, 1232, 1171, 1156, 1107, 1027, 760, 694 cm~l; NMR (300 MHz, CDCl3) 7.29 (m, 4H, aromatic), 7.00 (d, lH, J=8.2 Hz, W O 97/02259 PCT~US96/08681 aromatic), 6.91 (m, 3H, aromatic), 5.26 (brdd, lH,J=5.8 Hz,m~thin~),4.11(m,1H, OCH2a),3.91 (dt, lH,J=13.6 Hz & J=5.1 Hz,O=C-N-CH2a), 3.72 (m, 4H,O=C-N-CH2bcd,OCH2b),3.18 (t, 4H,J=4.9 Hz,Ph-NCH2s),2.95(m,2H,Ph-CH2a & N-CO-CH2a),2.76(dd,lH,J=14.8 Hz & J=3.7 Hz,N-CO-CH2b),2.65 ~d, lH,J=16.4 Hz, Ph-CH2b)~;C~IR(75~DHz,CDCl3)168.8,150.7,136.2,136.1,131.5,129.2,129.0, 126.2,12~.2,120.1,116.3,73.2,63.3,49.5,49.0,45.8,41.6,39.7,28.5~;HR~S(EI) c~lr~llA~d for C21H23BrN202 = 414.0943, found = 414.0937.
Step 2: 1-[2-(6-BromoiRorhroman-l-yl)-ethyl]-4-phenylpiperazine~) Following the general ~rocedul~ of Ti~xAMpLE 1, Step 4 and m~kinF non-10 critical v~ri~tinnR but using 1-[2-(6-bromniRorhroman-1-yl)acetyl]-4-phenylpiperazine (V) gives 1-[2~6-bromoiRorhroman-1-yl)-ethyl]-4-phellyl~i~eL~i..e (VI) which is disolved in ether (30 mL) and treated with gaseous hyd~ocllloric acid. This crude salt is le~ ~y~ d from ethyl acetate/h~Y~nP, mp =241-242~;Rf=0.25(40% ethyl acetate~exane); bis salt IR (mull) 2532,2510,2482,2348,2205,1596,1494,142~, 1407,1112,1100,980,884,764,694cm~l; freebase N~R(300 MHz,CDCl3)7.26 (m, 4H, aromatic), 6.94 (m, 3H, aromatic), 6.85 (t, lH,J=7.3 Hz, aromatic), 4.78 (brdd, lH,J=5.8 Hz, m~thin~), 4.11 (m, lH,OCH2a),3.74 (m, lH,OCH2b),3.20 (t, 4H, J=4.9 Hz,Ph-NCH2s),2.93 (m, lH,Ph-CH2a),2.65 (m, 7H,Ph-NC(H2)-CH2B-NCH2 & Ph-CH2b),2.09 (m, lH,C(H)-CH2a),2.00 (m, lH, C(H)-CH2b) o; CMR (75 MHz, CDC13)151.6,137.8,136.3,131.6,129.3,129.1,126.5,120.0,119.6,116.0,74.3,62.8, 54.6,53.4,49.1,33.2,28.8~;MS (EI, m/z) = 400.
Step 3: 1-[2-[4-phellyl~i~el~inyl]ethyl]-isochroman-6-carbn~m (VII).
A flame-dried 10 ml flask e.lui~ped with spinbar and ~ ;0T~ funnel is charged with freshly ~ t;ll~d tetrahyd.uru~An(2 mL), cooled to -78~, and treatedwith a solll*-n of tert-butyllithinm (1.7 M,1.3 mL, 2.3 mmol). The resllltin~
ll~Luie is stirred 5 min and drop-treated with a solnti~n of 1-[2-(6-bromniRorhroman-l-yl)-ethyl]4-phe~ erazine(VI,431 mg, 1.1 mmol) in 6 mT-tetrahy-l,uru-an. The aryl lit~ lm is stirred 10 min and is added via ç~nnlll~ to a flame-dried 25 mL flask e~uipped with spinbar contS~ininF freshly ~
+rim~thylsilylisocyanate(0.22 mL, 1.6 mmol) and 2 mT tetrahydluru-~l also cooledto -78~. The rPRlllting ~ Lule is warmed to 20-25~ for 2 hours, diluted with 25 mL
saLu ated ~mmnnillm chloride, the volatiles removed under reduced pl'.,S~iU' e, adjusted topH = 13, and extracted twice with ethyl acetate (35 mT ). The comhin~organic e~L~cLs are washed once with saline(25 mT.), dried over m~gn~Rillm suffate, filtered, and con-e~ aLed. This m~t~ri~l is purified by LC on 27 g (230~00) silica W O 97/022S9 PCT/U~,.5.'E~'Yl gel eluting with 5% m~th~nollethyl acetate to give 1-[2-[4-phenyl~i~elazinyl]ethyl]isocl.lulllan-6-car~uY~ e (VII), IR (mull) 3350, 3189, 3067, 1663, 1600, 1570, 1503, 1496, 1427, 1336, 1238, 1143, 1110, 760, 692 cm~l; NMR
(300 MHz, CDCl3) 7.599 (m, 2H, aromatic), 7.26 (t, 2H, J=8.2 Hz, aromatic), 7.18 (d, 5 lH, J=8.5 Hz, aromatic), 6.93 (d, 2H, J=7.9 Hz, aromatic), 6.85 (t, lH, J=7.2 Hz, aromatic), 6.10 (brds, lH, NH), 5.75 (brds, lH, NH), 4.88 (brdd, lH, J=5.9 Hz, m~ in~), 4.15 (m, lH, OCH2a), 3.77 (m, lH, OCH2b), 3.21 (t, 4H, J=4.9 Hz, Ph-N-CH28), 3.02 (m, lH, Ph-CH2a), 2.79-2.50 (m, 7H, Ph-NC(H2)-CH2~-NCH2~" Ph-CH2b), 2.16 (m, lH, C(H)-CH2a), 2.05 (m, lH, C(H)-CH2b) ~; CMR (75 MHz, CDC13) 10 169.0, 151.3, 142.4, 134.6, 131.3, 129.1, 128.2, 125.1, 124.9, 119.7, 116.0, 74.5, 62.9, 54.6, 53.4, 49.1, 33.1, 29.0 ~; HRMS (EI) c~lr~ te~l for C22H27N302 = 365.2103, ~ound = 365.2108.
EXAMPLE 41 1-[2-[4-(3,4-Dichlorophenyl)-l-piperazinyl]ethyl]isochroman-6- ca l~n~J....i-le (VII) Step 1: 1-[2-(6-BromniQorhroman-l-yl)acetyl]-4-(3,4-dichlorophenyl)-piperazine (V) Following the general procedure of EXAMPLE 1, Step 3 and m~kinF non-critical variations but using racemic 6-bromf.iQorhroman-l-yl-acetic acid (IV, EXAMPLE 7, Step 1) and 3,4-dichlorophenyl~i~e~ e gives 1-[2~6-brnmniRorhroman-l-yl)acetyl]-4-(3~4-dichlorophenyl)piperazine (V), IR (mull) 1640, 1592, 1482, 1448, 1406, 1275, 1234, 1206, 1140, 1107 cm~l; NMR (300 MHz, CDCl3) 7.32-7.26 (m, 3H, aromatic H's), 7.01 (d, lH, J=8.2 Hz, aromatic H), 6.96 (d, lH, J=2.8 Hz, aromatic H), 6.74 (d of d, lH, Ja=2.8 Hz, Jb=8.9 Hz, aromatic H), 5.24 (m of d, lH, J=9.6 Hz), 4.11 (m, lHj, 3.94 (m, lH), 3.79-3.60 (m's, 4H), 3.16 (m, 4H), 3.09-2.89 (m, 2H), 2.77 (d of d, lH, Ja=3.6 Hz, Jb=14.8 Hz), 2.65 (d, lH, J=10.3 Hz) o; CMR (75 MHz, CDCl3) 168.0, 150.1, 136.2, 132.8, 131.7, 130.5, 129.4, 126.4, 123.0, 120.8, 117.7, 115.7, 73.5, 63.5, 48.5, 47.9, 45.2, 41.5, 39.9, 28.7 o;
Step 2: 1-[2-(6-Bromoisochroman-l-yl)-ethyl]-4-(3,4-dichlorophenyl)-piperazine (VI) Following the general pl~,ceduLc of ~AlvlpLE 1, Step 4 and making non-critical variations but using 1-[2-(6-bromni#orhroman-1-yl)acetyl]4-(3,4-dichlorophenyl)-piperazine (V) gives l-t2-(6-bromni#orhroman-1-yl)-ethyl]-4-(3,4-dichlorophenyl)-piperazine (VI), which after flash chrom~tr.~ .hy on 100 g of silica gel using a gradient of 40% to 50% ethyl acetate in h~Y~n~, Rf = 0.25 (ethyl acetate/h~Y~n~-, 25/75); IR (neat) 2825, 1593, 1483, 1467, 1455, 1449, 1380, 1239, 1142, 1111 cm~l; NMR (300 MHz,CDCl3) 7.32-7.24 (m, 2H, aromatic H's), 6.98 (m, CA 0222~282 l997-l2-l9 W O 97/02259 PCT~US96/08681 2H, aromatic H), 6.73 (d of d, lH, Ja=2.9 Hz, Jb=8.9 Hz, aromatic H's), 4.78 (m of d, lH, J=5.8 Hz), 4.12 (m, lH), 3.73 (m, lH), 3.16 (t, 4H, J=5.0 Hz), 3.00-2.90 (m, lH), 2.7-2.48 (m, 7H), 2.12 (m, lH), 2.02 (m, lH) o; CMR (75 MHz, CDCl3) 150.2, 137.1, 136.0, 132.2, 131.4, 130.1, 129.0, 126.2, 121.8, 120.0, 116.9, 114.9, 73.9, 62.6, 54.2, 5 52.8, 48.4, 32.9, 28.6 ~; HRMS c~ t~l for C21H23N201BrlCl2 = 468.0371, found = 418.0363.
Step 3: 1-[2-[4-(3~4-Dichlorophenyl)-l-pip~azillyl]ethyl]isochroman-6 carbn~mi-l~ (VII) Following the general procedure of h~AlvrpLE 40, Step 3 and m~king non-10 critical variations, but using 1-[2-(6-bromni~orl,~ ,lan-1-yl)-ethyl]-4-(3,4-dichlorophenyl)piperazine (VI) gives 1-[2-[4-(3,4-dichlorophenyl)-1-piperazinyl]ethyl]-isochroman-6-ca.LuY~ le (VII), Rf = 0.13 (ethyl acetate); NMR (300 MHz, CDCl3) 7.59 (m, 2H, aromatic H's), 7.24 (2 m, 3H, aromatic H's), 6.94 and 5.74 (two d, lH, aromatic H) 5.90 (broad d, 2H, PhC(O)N-H2), 4.87 (m of d, lH, J=6.0 Hz, PhC-H), 15 4.15 (m, lH, PhCH2CH-H), 3.77 (m, lH, PhCH2CH-H), 3.18 (t, 4H, J=4.8 Hz, four of pip-H), 3.00 (m, lH, NCH-H), 2.76-2.45 (several m's, 7H, four pip-H, two PhCH-H,and NCH-H), 2.15 (m, lH, PhCHCH-H), 2.03 (m, lH, PhCHCH-H) ~; CMR (75 MHz, CDCl3) 168.3, 152.0, 142.7, 135.2, 133.0, 130.7, 129.0, 125.0, 117.5, 115.0, 74.8, 63.0, 54.5, 53.0, 48.6, 33.0, 28.8 ~; HRMS c~ t~-l for C22H26N3F102 = 433.1324, 20 found = 433.1325.
~XAMPLE 42 1-[2-[4-(4-Fluorophenyl)- l-piperazinyl]ethyl]isochroman-6-CA - l.~
Step 1: 1-[2-(6-Bromoi~orhroman-l-yl)acetyl]-4-(4-fluorophenyl)piperazine (V) Following the general ~l~cedul~ of P:~AlVlPLE 1, Step 3 and m~kinE~ non-critical variations but using racemic 6-brnmni~ochroman-l-yl-acetic acid (IV, EXAMPLE 7, Step 1) and 4-fluorophellyl~ w~ille gives 1-[2-(6-brnmniRochroman-l-yl)acetyl]4-(4-fluorophenyl)piperazine (V), IR (neat) 1641, 1510, 1482, 1464, 1444, 1278, 1232, 1107, 827, 817 cm~l; N~ (300 MHz, CDC13) 7.32-7.26 (m, 2H, aromatic H's), 6.99 (m, 3H, aromatic H's), 6.92-6.86 (m, 2H, aromatic H's), 5.26 (m of d, lH, J=9.6 Hz), 4.11 (m, lH), 3.94 (m, lH), 3.79-3.60 (m'~, 4H), 3.08 (m, 4H), 2.99-2.89 (m, 2H), 2.77 (d of d, lH, Ja=3.6 Hz, Jb=14.8 Hz), 2.65 (d, lH, J=10.3 Hz) o; CMR (75 MHz, CDCl3) 168.0, 147.2, 136.2, 131.7, 129.2, 126.2, 120.2, 118.3, 118.2, 115.6, 115.3, 73.2, 63.3, 50.6, 50.1, 45.2, 41.5, 39.7, 28.5 ~; HRMS c~ t"~l for C21H22N2O2FBr = 432.0843, found = 432.0849.
Step 2: 1-[2-(6-Brnmni~o~-hroman-l-yl)ethyl]-4~4-W O 97/02259 PCTrUS96/08681 fluorophenyl)piperazine (VI) Following the general pl~ocedu~ of EXAMPLE 1, Step 4 and making non-critical variations but using 1-[2-(6-bromni~orhroman-1-yl)acetyU-4-(4-fluorophenyl)-piperazine (V) gives 1-[2-(6-brom oi .corh roman- 1-yl)ethyl]-4~4-fluorophenyl)piperazine 5 (VI) which after flash chrom~tography on 100 g of silica gel using a gradient of 40%
to 50% ethyl acetate in h~Y~n~, Rf = 0.26 (25% ethyl acetate in hexane); IR (neat) 2952, 2820, 1510, 1481, 1456, 1379, 1235, 1144, 1109, 817 cm~1; NMR (300 MHz,CDC13) 7.31-7.26 (m, 2H, aromatic H's), 6.98-6.86 (m, 5H, aromatic H's), 4.78 (m of d, lH, J=5.8 Hz), 4.14-4.07 (m, lH), 3.78-3.69 (m, lH), 3.16 (t, 4H, J=5.0 Hz), 10 3.00-2.90 (m, lH), 2.7-2.48 (m, 7H), 2.12 (m, lH), 2.02 (m, lH) o; CMR (76 MHz, CDCl3) 158.3, 156.2, 148.2, 137.3, 136.9, 131.7, 129.3, 126.5, 117.8, 117.7, 115.6, 115.4, 74.3, 62.8, 54.6, 53.4, 50.2, 33.2, 28.9 o; HRMS calculated for C21H24N2OlBrlFl = 418.1056, found = 418.1057.
Step 3: 1-[2-[4-(4-Fluorophenyl)-l-piperazinyl]ethyl]i~ochroman-6-16 carb~ Y~micle (VII) Following the general procedure of F:~AlvlpLE 40, Step 3 and making non-critical variations but using 1-[2-(6-br~m-i~orhroman-1-yl)ethyl]-4-(4-fluorophenyl)-piperazine (VI) gives 1-[2-[4-(4-fluorophenyl)-1-piperazinyl]ethyl]isochroman-6-c~b~ ...i(le (VII), Rf = 0.09 (ethyl acetate); NMR (300 MHz, CDCl3) 7.59 (m, 2H,aromatic H's), 7.17 (m, lH, aromatic H), 6.87 (m, 4H, aromatic H's), 6.21 (broad s, 2H, PhC(O)N-H2), 4.87 (m of d, lH, J=6.0 Hz, PhC-H), 4.15 (m, lH, PhCH2CH-H), 3.77 (m, lH, PhCH2CH-H), 3.13 (t, 4H, J=4.8 Hz, four of pip-H), 3.00 (m, lH, NCH-H), 2.76-2.45 (several m's, 7H, four pip-H, two PhCH-H, and NCH-H), 2.16 (m, lH,PhCHCH-H), 2.03 (m, lH, PhCHCH-H) o; CMR (76 MHz, CDC13) 169.1, 158.3, 155.5, 147.5, 142.0, 134.4, 131.2, 128.0, 124.9, 124.8, 117.6, 117.5, 115.4, 115.1, 74.3, 62.7, 54.4, 53.1, 499.9, 32.8, 28.8 o; HRMS cAlrlllAt,e(1 for C22H26N3F102 =
383.2009, found = 383.2010.
EXAMPLE 43 1-[2-[4-(3-Ethoxyphenyl)-l-piperazinyl]ethyuisochroman-6 c~l,.~ 1e (VII) Step 1: 1-[2-(6-Brom-iRorhroman-1-yl)acetyl]-4-(3-ethoxyphenyl)piperazine (V) Following the general plwedL~,2 of EXAMPLE 1, Step 3 and mAking non-critical variations but using racemic 6-brom-~i~o-l . . vlllan-l-yl-acetic acid (IV, F'XAlVlPLE 7, Step 1) and 3-ethoxyph~llyl~ ,e~azine give 1-t2-(6-bromoi~orhromanyl)acetyl]4~3-ethoxyphenyl)piperazine (V) which after flssh chromAt~graphy on 200 g of silica gel u~ing 25% ethyl acetate in h~Y~nf-, Rf = 0.28 (50% ethyl acetate in CA 0222~282 1997-12-19 W O 97/02259 PCT~US96/08681 hexane); IR (neat) 1641, 1501, 1480, 1445, 1241, 1225, 1108, 1040, 1031, 748 cm~l;
NMR (300 MHz,CDCl3) 7.32-7.26 (m, 2H, aromatic H's), 7.03-6.98 (m, 2H, aromatic H's), 6.94-6.86 (m, 3H, aromatic H's), 5.28 (m of d, lH, J=7.4 Hz), 4.16-4.05 (m, 4H), 3.98-3.91 (m, lH), 3.83-3.65 (m, 4H), 3.08-2.91 (m, 6H), 2.80-2.64 (m, 2H), 1.46 (t, 5 3H, J=6.9 Hz, -CH3) 8; CMR (75 MHz, CDCl3) 178.5, 152.0, 140.0, 157.0, 156.5, 131.7, 129.4, 126.5, 123.3, 121.0, 120.0, 118.4, 112.6, 73.4, 63.6, 63.5, 60.0, 51.0, 50.5, 46.4, 42.2, 40.0, 28.8, 14.9 o; HRMS calculated for C23H27N2O3Br1 = 458.1205, found = 458.1215.
Step 2: 1-t2-(6-Bromoisochroman-l-yl)ethyl]-4-(3-ethoxyphenyl)piperazine (VI) Following the general procedure of EXAMPLE 1, Step 4 and making non-critical variations but using 1-[2-(6-brom.ni~orhroman-1-yl)acetyl]-4-(3-ethoxyphenyl)-piperazine (V) gives 1-[2-(6-bromoi~orhroman-1-yl)ethyl]4-(3-ethoxyphenyl)piperazine (VI) which after flash chrom~o~.~phy on 100 g of silica gel using a gradient of 40% to 50% ethyl acetate in hpy~ne~ Rf = 0.30 (50% ethyl acetate in hexane); IR (neat) 2816, 1501, 1480, 1448, 1240, 1143, 1124, 1046, 1110, 748 cm~
1; NMR (300 MHz,CDCl3) 7.31-7.26 (m, 2H, aromatic H's), 7.00-6.90 (m, 4H, aromatic H's), 6.85-6.83 (m, lH, aromatic H), 4.78 (m of d, J=5.9 Hz, lH), 4.14-4.03 (m, 3H), 3.78-3.70 (m, lH), 3.13 (broad s, 4H), 3.00-2.90 (m, lH), 2.69-2.52 (m, 7H), 2.13 (m, lH), 1.99 (m, lH), 1.45 (t, 3H, J=7.0 Hz) ~; CMR (75 MHz, CDCl3) 151.37, 141.19, 137.0, 136.1, 131.5, 129.1, 126.4, 122.5, 120.8, 119.8, 117.9, 112.2, 74.2, 63.4, 62.6, 54.6, 53.5, 50.4, 33.0, 28.7, 14.8 o; HRMS C~ tr~l for C23H29N202Brl e 444.1413, found = 444.1400.
Step 3: 1-[2-[4-(3-Ethoxyphenyl)-l-piperazinyl]ethyl]isochroman-6-carboY~micle (VII) Following the general procedure of ~AMPLE 36 and m~king non-critical variations, but using 1-[2-(6-brom~ orhroman-l-yl)ethyl]-4-(3-ethoxy-phenyl)-piperazine (VI) gives the product which is col~vt:,ied into the hydLuchloride salt using ethereal hyd~û~loric acid to give 1-[2-[4-(3-ethoxyphenyl)-1-piperazinyl]ethyl]-isochroman-6-c~lJ~ P (VII), mp = 208-210~; Rf = 0.14 (10% mpt~nol in ethyl acetate); IR (mull) 2417, 2365, 1611, 1520, 1489, 1476, 1448, 1260, 1121, 152 cm~l;
NMR (300 MHz, CDCl3) 7.60 (m, 2H, aromatic H's), 7.18 (d, lH, J=8.5 Hz, aromaticH), 6.94 (m, 3H,aromatic H's), 6.84 (m of d, lH, J=8.2 Hz, aromatic H), 6.00 (broad d, 2H, PhC(O)N-H2), 4.86 (m of d, lH, J=6.0 Hz, PhC-H), 4.13 (m, lH, PhCH2CH-H),4.06 (q, 2H, 6.9 Hz, Proc-H2), 3.77 (m, lH, PhCH2CH-H), 3.13 (broad s, 4H, four of pip-H), 3.00 (m, lH, NCH-H), 2.76-2.45 (several m's, 7H, four pip-H, two PhCH-H, and NCH-H), 2.16 (m, lH, PhCHCH-H), 2.02 (m, lH, PhCHCH-H), 1.45 (t, 3H, J=7.0 Hz, PhOCH2C-H3) ~; CMR (75 MHz, CDCl3) 151.2, 142.0, 141.2, 134.1, 131.3, 147.6, 125.0, 124.9, 121.2, 117.9, 112.2, 74.1, 63.0, 62.8, 54.8, 53.3, 50.3, 3Z.5, 31.5, 27.2, 22.2, 14.5 o; HR~IS c~ tP~ for C24H3lN303 = 409.2365, found = 409.2364.
EXAMPLE 44 (S)-(-)-1-[2-[4-(4-MPth.~.~yphenyl)-1-piperidinyl]ethyl]-N-methylisochroman-6-carbnY~Tni~P. (S)-(IX) Step 1: (S)-(-)-1-[2-(6-Bromoiqo~hroman-1-yl)acetyl]-4~4-methoxyphenyl)-piperidine (S)-(V) Following the general procedure of EXAMPLE 1, Step 3 and m~kinF non-critical variations but using 4-methoxyphenylpiperidine (421 mg, 2.2 mmol) givescrude produce which i6 purified by LC on 53 g (230-400) silica gel eluting with 40%
ethyl ~etst~Jhexane to give (S)-(-)-1-[2-(6-br~ moiqo~hroman-l-yl)acetyl]-4-(4-methoxy-phenyl)piperidine (S)-(V), Rf = 0.26 (505~ ethyl ~cet~te~hexane); [a]D -86 (c 0.4975, mPt~l~n~l); IR (liq.) 2933, 1638, 1612, 1513, 1481, 1463, 1446, 1283, 1268, 1247, 1179, 1106, 1036, 1005, 830 cm~l; NMR (300 MHz, CDCl3) 7.28 (m, 2H, aromatic), 7.11 (dd, 2H, J=8.6 Hz & J=3.4 Hz, aromatic), 7.03 (m, lH, aromatic),6.85 (d, 2H, J=8.6 Hz, aromatic), 5.29 (brds, lH, O-CH), 4.85 (m, lH, Ph-CH) , 4.10 (m, 2H, OCH2a & O=C-N-CH2a), 3.79 (m, 4H, OCH3 & OCH2b), 3.15-2.66 (m, 7H, ~=C-N-cH2bcd~ Ph-CH2a~ N-CO-CH28, Ph-CH2b)~ 1.90-1.50 (m, 4 , 2s o; CMR (75 MHz, CDCl3) 168.9, 168.8, 158.2, 137.5, 136.8, 136.3, 131.7, 129.4, 127.6, 126.6, 126.3, 120.3, 114.0, 73.5, 63.4, 55.3, 46.8, 42.8, 41.9, 40.2, 40.0, 34.2, 33.2, 33.0, 28.9 o.
Step 2: (S)-(-)-l-t2-(6-Br. moiqo-~hroman-l-yl)ethyl]-4-(4-methoxyphenyl)-pirPritline (S)-(VI) Following the general procedure of EXAMPLE 1, Step 4 and m~king non-critical variations but using (S)~-)-1-[2-(6-bromoiqo~hr" ,an-1-yl)acetyl]-4-(4-mPth~Yyphenyl)pir~ri~lin~ (S)-(V) gives prodict which is purified by LC on 47 g (230-400) silica gel eluting with 75% ethyl acetate/hexane to give (S)~-)-1-[2-(6-brom~iqochroman-l-yl)ethyl]-4~4-mPtl-o~ry~henyl)pireri~lin-p (S)-(VI), Rf = 0.28 (75~o ethyl acetate/hexane); [a]D = -46 (c = 0.6677, mptl~nnl); IR (liq.) 2932, 2847, 2832, 2805, 1513, 1481, 1466, 1378, 1274, 1247, 1179, 1127, 1109, 1039, 828 cm~1; NMR
(300 MHz, CDCl3) 7.29 (m, 2H, aromatic), 7.14 (d, 2H, J=8.6 Hz, aromatic), 6.97 (d, lH, J=8.2 Hz, aromatic), 6.83 (d, 2H, J=8.7 Hz, aromatic), 4.77 (brdd, lH, J=5.7 Hz, m~thinP), 4.10 (m, lH, OCH28), 3.78 (s, 3H, OCH3), 3.71 (m, lH, OCH2b), 3.04 (m,2H, NCH2ab), 2.95 (m, lH, Ph-CH2a), 2.70-2.40 (m, 4H, Ph-CH, NCH2Cd, Ph-CH2b), 2.04 (m, 4H, O-C(H)-CH28, NCH2ef), 1.79 (m, 4H, Ph-C(H)-CH28) o; CMR (75 MHz, CA 0222~282 1997-12-19 W O 97/022S9 PCTrus96/08681 CDCl3) 158.2, 140.3, 137.5, 136.4, 136.2, 131.7, 129.5, 127.7, 126.6, 120.2, 113.9, 74.2, 63.1, 55.3, 54.8, 54.5, 53.9, 41.1, 32.5, 32.0, 28.8) o; HRMS (EI) ~ t~--l for C23H28BrNO2 = 429.1304, found = 429.1286.
Step 3: (S)-(-)-1-[2-t4-(4-M~t~o~yphenyl)-1-piperidinyl]ethyl]-N-methyl-isochroman-6-carbnY~mi-l~ (S)-(IX) r Following the general procedure of ~.~AMPLE 5, Step 3 and making non-critical variations but using (S)-(-)-1-[2-(6-br m~i~orhroman-l-yl)ethyl]-4~4-methoxyphenyl)piperidine (S)-(VI, 445 mg, 1.03 mmol) gives product which is purified by LC on 24 g (230-400) silica gel eluting with 75% ~eton~lhexane to give (S)-(-)-1-t-2-[4-(4-methoxyphenyl)-1-piperidinyl]ethyl]-N-methylisochroman-6-carb-Y~mi-le (S)-(IX), Rf = 0.36 (75% ~cetone/hexane); IR (liq.) 3291, 2934, 1636, 1612, 1571, 1551, 1514, 1496, 1467, 1315, 1293, 1247, 1179, 1109, 1036 cm~l; NMR(300 MHz, CDCl3) 7.54 (m, 2H, aromatic), 7.116(m, 3H, aromatic), 6.84 (d, 2H, J=8.7 Hz, aromatic), 6.20 brdm, lH, NH), 4.85 (m, lH, O-CH), 4.13 (m, lH, OCH2a ), 3.78 (m, 4H, OCH3 & OCH2b), 3.00 (m, 6H, Ph-CH2a, NCH3, Ph-CH2b, Ph-CH), 2.77-2.40 (m, 4H, N-CH2S), 2.10-1.94 (m, 4H, N-CH2S & O-C(H)-CH28), 1.80 (m, 4H, Ph-C(H)-CH2S) o; HRMS (EI) cAl~ t,ed for C25H32N203 = 408.2413, found = 408.2414.
h~AMPLE 45 (S)-(-)-1-[2-[4-(4-l~uoromethylphenyl)-1-pi~e.~ l]ethyl]-N,N-dimethylisochroman-6-c~l,..~ (S)-(IX) Following the general ~ cedu-~ of ~!~AMPLE 6, Step 4 and making non-critical v~ri~t;~n~ but using (S)-(-)-1-[2-(6-bromoiRo-hroman-l-yl)-l-ethyl]4-(4-trifluoromethylphenyl)piperazine (S)-(VI, EXAMPLE 5, Step 2, 21.17 g, 45.1 mmol)gives product which is purified by LC on 780 g (230-400) silica gel eluting with 3%-5% m~t~ noVdichlorom~tl~n~ to give (S)-(-)-1-[2-[4-(4-trifluoromethylphenyl)-1-piperazinyl]ethyl]-N,N-dimethylisochroman-6-cd.L,n~ l.q (S)-(IX), mp = 149-151~;Rf = 0.34 (5% m~th~nnl/dichlorom~+~n~); [a]D = -46~ (c = 0.988, m~t~nol); IR
(mull) 1627, 1617, 1527, 1414, 1337, 1315, 1294, 1241, 1160, 1152, 1143, 1135, 1107, 1072, 824 cm~l; NMR (300 MHz, CDCl3) 7.46 (d, 2H, J=8.7 Hz, aromatic), 7.20 (m, 2H, aromatic), 7.11 (d, lH, J=7.9 Hz, aromatic), 6.90 (d, 2H, J=8.7 Hz, aromatic), 4.86 (brdd, lH, J=5.9 Hz, m~thine), 4.12 (m, lH, OCH2a), 3.75 (m, lH, OCH2b), 3.28 (t, 4H, J=5.0 Hz, Ph-N-CH28), 3.09 (brds, 3H, NCH3), 2.99 (brds, 4H, NCH3 & Ph-CH2a), 2.74-2.48 (m, 7H, Ph-NC(H2)-CH2S-NCH2,,~, Ph-CH2b), 2.12 (m, lX, C(H)- ~
CH2a), 2.04 (m, lH, C(H)-CH2b) o; CMR (75 MHz, CDCl3) 171.4, 153.3, 139.5, 134.5, 134.3, 127.7, 126.6, 126.3 (d, JCF=4 Hz), 126.2, 124.8, 124.6, 120.4 (qrt, JCF=33 Hz), 114.4, 74.4, 63.0, 54.6, 53.1, 48.0, 39.6, 35.4, 33.2, 29.0 o; MS (EI, m/z) = 461.
EXAMPLE 46 1-(4-M~t~ln~yphenyl)-4-[2-[6-(5-methyloY~ole-2-yl)isochroman-1-CA 02225282 1997-12-l9 .
W O 97/022S9 PCT~US96/08681 yl)ethyl]piperazine (P-2) An oven-dried 25 mL flask equipped with spinbar and reflux conclpn~çris charged with 1-[2-[4-(4-mPth- ~yphenyl)-l-piperazinyl]ethyl-N-propargylisochroman-6-carbnYAmi~le (IX, EXAMPLE 28, 433 mg, 1.0 mmol) and mercuric acetate (19 mg, 5 0.06 mmol). The ~l~Lula is diluted with 12 mL acetic acid and heated to reflux.
After 3 hr, the reaction is cooled to 20-25~, volatiles removed under reduced p~_~.u.~, residue diluted with 35 mL lM sodium hydroxide, and extracted twice with ethyl acetate (30 mL). The comhine-l organic extracts are washed once with saline (20 mL), dried over mAenP~ium sulfate, filtered and oonrPntrated. This 10 material is comhin~l with the crude mAteriAl from an i~l~nti~Al 0.25 mmol scale reaction and purified by LC on 41 g (230-400) silica gel eluting with 25%
A~etone/hexane to give 1-(4-m~th~yyphenyl)-4-[2-t6-(5-methylrlyA~ol~--2-yl)isochr~lllan-1-yl)ethyl]piperazine (P-2) which is l~e~ YI ~lli7ecl from ethylacetate/hPYAnP mp = 129-130~; Rf = 0.40 (50% A-et~.ne/hexane)~~5 EXAMPLE 47 1-[2-(6-Aminoi~ochroman-1-yl)-ethyl]-4-(4-methoxyphenyl)-piperazine (Z-1) A 10 mL oven dried two neck round bottom under argon Atmn~ph~re is charged with a sollltion of 1-[2-(6-br~moi~o~hroman-1-yl)-ethyl]4-(4-methoxyphenyl)piperazine (VI, 406 mg, 0.94 mmol) in THF (2 mL). The ll~ula is 20 cooled to -78~ and t-butyl lithium (1.7 M in pentane, 1.081 mL, 1.83 mmol) is added dropwise. After stirring at -78~ for 15 min, the aryl lithillm is added dropwise via a canula to a sollltinn of diphenylrh-sph-rylazid (98%, 0.188 mT, 0.85 mmol) in THF
(9 mL) at -78~. The reaction l~ Lu~a is mAintAinptl at -78~ for two hours then warmed to -20~ over 40 min, and then recooled to -78~. Sodium bis(2-25 methoxyethoxy)All~minum hydride (3.4 M in tolllen~, 1.11 mL, 3.77 mmol) is addedslowly via syringe. As the reaction is warmed to 0~, e~.~ascence of nitrogen is obsel ~,~d. The reaction lllib~l~U~e: iS stirred at 0~ for two hours and then at 20-25~ for 30 min. After cooling to 0~, the reaction is qll~nr~hecl very slowly with water. After e~ vesc~llce sllhcitle~l, the crude is warmed to 20-25~, and filtered on a glass frit, 30 alternatively washing with water and ethyl acetate until no more product is ob&t~ d by TLC in the filtrate. The comhinPcl filtrates were transferred to a separatory funnel, salted out with sopdium ~hl--ri~e, shaken and the layers wereseparated. The organic layer is washed one time with 1% aqueous sodium hydroxideand one time with saline, dried with sodium sulfate, filtered and cor.~P~ ted. After 35 two flash chr~m~ al)hies on 20 g silica gel using 5~O mptl~Anol in methylene chloride as the eluent, 1-[2-(6-Aminoi~o-~hroman-l-yl)-ethyl]-4-(4-CA 0222~282 l997-l2-l9 W O 97/02259 PCT~US96/08681 methoxyphenyl)piperazine (Z-l) is obtained, Rf = 0.18 (5% m~~hAn- l in methylenechloride); IR (neat) 2951, 2828, 1625, 1511, 1456, 1262, 1244, 1104, 1037, 824 cm~l;
NMR (300 MHz, CDC13) 6.85 (m, 5H, aromatic HIB), 6.53 (d of d, lH, Ja=2.4 Hz, Jb=8.2 Hz, aromatic H), 6.43 (d, lH, J=2.2 Hz, aromatic H), 4.75 (m of d, lH, J=5.8 Hz, PhC-H), 4.09 (m, lH, PhCH2CH-H), 3.76 (~, 3H, OC-H3), 3.71 (m, lH, PhCH2CH-H), 3.67 (broad s, 2H, N-H2), 3.11 (t, 4H, J=4.9 Hz, four pip-H), 2.89 (m, lH, PhCH-H), 2.60 (m's, 7H, PhCH-H, NC-H2 and four pip-H), 2.10 (m, lH, PhCHCH-H), 2.00 (m, lH, PhCHCH-H) o; CMR (75 MHz, CDCl3) 153.8, 145.7, 144.6, 134.9, 129.6, 128.2, 125.7, 120.2, 118.2, 115.6, 114.9, 114.4, 113.6, 74.6, 63.2, 55.6, 54.9, 53.5, 50.6, 33.3, 29.2 o; HRMS calculated for C22H29N3O2 = 367.2260,found = 367.2255.
EXAMPLE 48 (S)-(-)-1-[2-(6-~minoiRo~hroman-l-yl)-ethyl]4-(4-methoxyphenyl)piperazine (S)-(Z-l) Following the general plocedula of EXAMPLE 47 and mAking non-critical variations but using (S)-(-)-1-[2-(6-brom~liRochroman-l-yl)-ethyl]-4-(4-methoxyphenyl)~ elazi~e (S)-(VI) gives (S)-(-)-1-[2-(6-Amin--iRo~hroman-l-yl)-ethyl]-4 (4_mPth~xyphenyl)piperazine (S)-(Z-l), Rf = 0.18 (5% m~thAnol in methylene ~hlr~rille); [a]D = -53~ (c = 1.04, ethAnol); IR (neat) 2951, 2828, 2819, 1625, 1511, 1262, 1244, 1104, 1037, 824 cm~l; NMR (300 MHz, CDCl3) 6.85 (m, 6H, aromatic H's), 6.53 (d of d, lH, Ja=2.4 Hz, Jb=8.2 Hz, aromatic H), 6.43 (d, lH, J=2.2 Hz, aromatic H), 4.75 (m of d, lH, J=5.8 Hz, PhC-H), 4.09 (m, lH, PhCH2CH-H), 3.76 (s, 3H, OC-H3), 3.71 (m, lH, PhCH2CH-H), 3.57 (broad s, 2H, N-H2), 3.11 (t, 4H, J=4.9 Hz, four pip-H), 2.89 (m, lH, PhCH-H), 2.60 (m's, 7H, PhCH-H, NC-H2 and four pip-H), 2.10 (m, lH, PhCHCH-H), 2.00 (m, lH, PhCHCH-H) o; CMR (75 MHz, CDCl3) 153.8, 145.7, 144.6, 134.9, 129.6, 128.2, 125.7, 120.2, 118.2, 115.5, 114.9, 114.4, 113.6, 74.6, 63.2, 55.6, 54.9, 53.5, 50.6, 33.3, 29.2 ~; HRMS cAl-~lllAt,e~l forC22H29N3O2 = 367.2260, found = 367.2258.
EXAMPLE 49 (S)-(-)-N-[Isochroman-1-[2-[4-(4-methnxyphenyl)piperazin-1-yl]ethyU-6-yl]formAmicle (S)~Z-2) Acetic anhydride (0.32 mL, 3.43 mmol) is cooled to 0~. Acetic formic anhydride is generated by the dropwise Atl~iti~n of 98% formic acid (0.20 mL, 5.2 mmol) to the acetic anhydride. The llli~ Ul~ iS heated to 55~ for 2 hours and then cooled to 0~. THF (1 mL) is added via syringe, followed by a solllt;nn of (S)-(-)-1-[2-(6-AminoiRo-hroman-l-yl)-ethyl]-4-(4-m~h-.xyphenyl)piperazine (S)-(Z-l, 600 mg, 1.63 mmol) in THF (2 mL). The reaction i8 warmed to 20-25~ and stirred for 3 hours. The reaction is cQnc~t-dted and purified by flash chrtmAt~ hy to give (s)-~-)-N-[i6oclllul~an-l-[2-[4-(4-methoxypheny~ a~ -yl]ethyl]-6-yl]form~mi~la (S)-(Z-2), Rf = 0.20 (5% mPth~n--l in methylene ~hl~ri~e); IR (mull) 1692, 1616, 1539, 1~12,1306,1292,1266,1245,1107,825 cm-l; ~nMnR (300 ~DHZ, CDC13) 8.65 (d, ~2 H
(rûtomer), J=11.4 Hz, NC(O)-H), 8.36 (d, 1/2 H (rotomer), J=1.7 Hz, NC(O)-H), 7.91 (broad d, 1/2 H (rotomer), J=11.4 Hz, N-H), 7.43 (broad B, lJ2 H (rûtomer), N-H), 7.24 (m, lH, aromatic H), 7.07 (d of d, lH, Ja=8.4 Hz, Jb=10.9 Hz, aromatic H), 6.84 (q and m, 5H, J=9.2 Hz, aromatic H's), 4.80 (m of d, lH, J=5.8 Hz, PhC-H), 4.10 (m, lH, PhCH2CH-H), 3.76 (s, 3H, OC-H3), 3.71 (m, lH, PhCH2CH-H), 3.11 (t,4H, J=4.9 Hz, four pip-H), 2.95 (m, lH, PhCH-H), 2.60 (m's, 7H, PhCH-H, NC-H2 and 10 four pip-H), 2.18 (m, lH, PhCHCH-H), 2.06 (m, lH, PhCHCH-H) o; HRMS
~ ~k,~ t~l for C23H29N303 = 395.2209, found = 395.2210.
EXAMPLE 50 (S)-(-)-N-[Isochroman-1-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-6-yl]~et~mi-le (S)-(Z-2) A 25 mT round bottom flask is charged with (s)-(-)-l-[2-(6-~min~ico~hroman 15 1-yl)-ethyl]-4~4-m~th.~Yyphenyl)piperazine (S)~Z-1, 200 mg, 0.54 mmol) and 4-dimethylaminopyridine (6.7 mg, 0.054 mmol). Methylene ~~hl~lritla (7 mL) is added via syringe and the reaction vessel is cooled to 0~. Triethylamine (0.114 mL, 0.82 m mol) and acetyl chloride (0.042 mL, 0.60 mmol) are then added r~ e~livl ly viasyringe. The ice bath is removed after 15 min. and the reaction is stirred at 20-25~
20 for 1.5 hours. The reaction is then partitionpd b~Lween 0.5 M aqueous sodium hydroYide and methylene ~hl-)ricle The layers were s~palaLed and the aqueous portion is ~ ed one more time with methylene rhlor~ The organics were c~mhina-l, dried with sodium sulfate, filtered and con~F ~l d~ed. The con-antrate is chr~m~to~-aphed on 17 g silica gel using 5% mpth~n~l in methylene ~hlori~la as the 25 eluent to give (S)-(-)-N-[isochroman-1-[2-[4-(4-mPth--Qyphenyl)piperazin-1-yl]ethyl]-6-yl]~et~mi-le (S)-(Z-2), Rf = 0.18 (5% mpth~nnl in methylene chloride); [a]D -44~(c 0.93, 50% eth~nol in methylene chlnri~le); IR (mull) 1667, 1615, 1599, 1546, 1512, 1421, 1333, 1312, 1247, 1036 cm~1; NMR (300 MHz, CDC13) 7.35, 7.21, 7.15, 7.04, 6.80, 4.80, 4.10, 3.76, 3.71, 3.11, 2.95, 2.60, 2.16, 2.10, 2.02 o; CMR (75 MHz, CDCl3) 30 168.3, 153.8, 145.7, 136.0, 134.9, 134.1, 125.3, 120.1, 118.2, 118.0, 114.5, 74.5, 63.1, 55.6, 54.8, 53.5, 50.6, 33.2, 29.2, 24.6 o; HRMS c~lc~ tP~l for C24H31N303 =
409.2365, found = 409.2358.
FXAlVlPLE 51 (S)-(-)-N-[Isochroman-1-[2-[4~4-mathl Yyphenyl)piperazin-1-yUethyl]-6-yl]ban7~mi(1P (S)-(Z-2) Following the general procedure of EXAMPLE 50 and m~king non-critica~
v~ri~t;on~ but using benzoyl chl~ri-l~ gives (S)-(-)-N-[isochroman-1-[2-[4~4-CA 0222~282 1997-12-19 W O 97/02259 PCTrUS96/08681 methoxyphenyl)piperazin-1-yl]ethyl]-6-yl]ben~mi-le (S)-(Z-2), Rf = 0.30 (5%
mf~th~nol in methylene chloride); [a]D = 40~ (c = L0, 50% ethanol in methylene ~hl~rk~e); IR (mull) 3282, 1651, 1516, 1505, 1339, 1312, 1280, 1244, 1108, 694 cm~l;
NMR (300 MHz, CDCl3) 7.86 (d, 2H, J=6.8 Hz, aromatic H's), 7.80 (broad s, lH, 5 PhN-H), 7.50 (m, 4H, aromatic H's), 7.36 (d, lH, J=8.3 Hz, aromatic H), 7.10 (d, lH, J=8.3 Hz, aromatic H), 6.86 (q, 4H, J=9.2 Hz, aromatic H's), 4.84 (m of d, lH, J=5.8 Hz, PhC-H), 4.13 (m, lH, PhCH2CH-H), 3.76 (s, 3H, OC-H3), 3.76 (m, lH, PhCH2CH-H), 3.12 (t, 4H, J=4.6 Hz, four pip-H), 2.99 (m, lH, PhCH-H), 2.68 (m's,7H, PhCH-H, NC-H2 and four pip-H), 2.10 (m, lH, PhCHCH-H), 2.02 (m, lH, 10 PhCHCH-H) o; HR~IS c~ t~ for C29H33N303 = 471.2522, found = 471.2525.
~XANI PLE 52 (S)-(-)-N-tIsochroman-1-[2-[4-(4-m.oth-1~ryphenyl)piperazin-l-yl]ethyl]-6-yl]propion~mi-le (S)-(Z-2) Following the general procedure of ~AlvlpLE 50 and m~kin~ non-critical variations but using propionyl chloride (S)-(-)-N-[isochroman-1-[2-[4-(4-15 methoxyphenyl)piperazin-l-yl]ethyU-6-yl]propior1~mide (S)-(Z-2) is obtained, Rf =
0.22 (5% m~th~nol in methylene ~hlnr--le); [a]D = -44~ (c = 0.97, 50% eth~nnl inmethylene chloritle); IR (mull) 3306, 1659, 1590, 1515, 1421, 1245, 1214, 1110, 1036, 821 cm~l; NMR (300 MHz, CDCl3) 7.76 (s, lH, aromatic H), 7.36 (broad s, lH, PhN-H), 7.24 (d, lH, J=8.3 Hz, aromatic H), 7.00 (d, lH, J=8.3 Hz, aromatic H), 6.80 (q, 20 4H, J=9.2 Hz, aromatic H's), 4.77 (m of d, lH, J=5.8 Hz, PhC-H), 4.06 (m, lH,PhCH2CH-H), 3.76 (s, 3H, OC-H3), 3.71 (m, lH, PhCH2CH-H), 3.07 (t, 4H, J=4.9 Hz, four pip-H), 2.85 (m, lH, PhCH-H), 2.60 (m's, 7H, PhCH-H, NC-H2 and four pip-H), 2.33 (q, 2H, J=7.5 Hz, PhNHC(O)C-H2), 2.14 (m, lH, PhCHCH-H), 2.00 (m, lH, PhCHCH-H), 1.19 (t, 3H, J=7.5 Hz, PhNHC(O)CH2C-H3) o; CMR (75 MHz, CDC13) 25 172.5, 153.7, 145.8, 136.3, 134.7, 133.8, 125.2, 120.2, 118.1, 114.5, 74.4, 63.0, 55.6, 54.8, 53.5, 50.6, 33.3, 30.6, 29.2 and 9.8 ~.
~XANIPLE 53 (S)~-)-N-[Isochroman-1-[2-[4-(4-m~th- xyphenyl)piperazin-l-yl]ethyl]-6-yl]acrylamide (S)-(Z-2) Following the general procedul~ of EXAMPLE 50 and m~king non-critical 30 v~ri~t;-~n~ but using acryl chloride gives (S)-(-)-N-[isocl..~....an-1-[2-[4~4-m~-Yyphenyl)piperazin-l-yl]ethyl]-6-yl]acrylamide (S)-(Z-2), Rf = 0.22 (5%
m~t~nol in methylene chloride); [a]D = -40~ (c = 0.79, 50% eth~nol in methylene chloride); IR (mull) 3266, 1661, 1592, 1536, 1512, 1422, 1244, 1218, 1109, 822 cm~l;
NMR (300 MHz, CDCl3) 7.46 (broad s, lH, PhN-H), 7.26 (s, lH, aromatic H), 7.06 (d, 35 lH, J=8.4 Hz, aromatic H), 6.85 (q, 4H, J=9.2 Hz, aromatic H's), 6.43 (d of d, lH, Ja=1.3 Hz, Jb=16.8 Hz, one acryl-H), 6.23 (m, lH, one acryl-H), 5.76 (d of d, lH, CA 0222~282 1997-12-19 W O 97/022S9 PCT/u~r~l~8~l Ja=1.3 Hz, Jb=10 Hz, one acryl-H), 4.81 (m of d, lH, J=5.8 Hz, PhC-H), 4.11 (m, lH, PhCH2CH-H), 3.76 (8, 3H, OC-H3), 3.75 (m, lH, PhCH2CH-H), 3.11 (t, 4H, J=4.9 Hz, four pip-H), 2.96 (m, lH, PhCH-H), 2.60 (m's, 7H, PhCH-H, NC-H2 and four pip-H), 2.14 (m, lH, PhCHCH-H), 2.03 (m, lH, PhCHCH-H) ~; CMR (75 MHz, CDC13) 5 163.5, 153.8, 145.8, 135.9, 134.9, 134.4, 131.1, 127.9, 125.4, 120.2, 118.2, 118.0, 114.4, 74.5, 63.0, 55.6, 54.8, 53.5, 50.6, 33.2, 29.2 ~; HRMS calculated for C*25H31N3O3 = 421.2365, found = 421.2358.
EXAMPLE 54 (S)-(-)-N-[Isochroman-1-[2-[4-(4-m~t~-xyphenyl)piperazin-1-yl]ethyl]-6-yl]isob uly~ d~l~ide(s)-(z-2) Following the general procedure of EXAMPLE 50 and m~kin~ non-critical variations but using i-butyryl chloride gives (S)-(-)-N-[Isochroman-1-[2-[4-(4-mPtl ~Yyphenyl)~i~. ,dzi~-l-yl]ethyl]-6-yl]isol)uLyl~l.ide (S)-(Z-2), Rf = 0.27 (5%
mf~t~nnl in methylene chloride); [a]D = -42~ (c = 0.94, 50% et~nol in methylene chloride); IR (mull) 3289, 1660, 1589, 1524, 1515, 1451, 1422, 1243, 1109, 822 cm~l;
15 NMR (300 MHz, CDCl3) 7.43 (s, lH, aromatic H), 7.23 (d, lH, J=8.4 Hz, aromatic H), 7.13 (broad s, lH, PhN-H), 7.04 (d, lH, J=8.3 Hz, aromatic H), 6.84 (q, 4H, J=9.2 Hz, aromatic H's), 4.80 (m of d, lH, J=5.8 Hz, PhC-H), 4.10 (m, lH, PhCH2CH-H), 3.76 (s, 3H, OC-H3), 3.71 (m, lH, PhCH2CH-H), 3.10 (t, 4H, J=4.9 Hz, four pip-H), 2.96 (m, lH, PhCH-H), 2.60 (m's, 8H, PhCH-H, NC-H2, 20 PhNHC(O)C-H) and four pip-H), 2.14 (m, lH, PhCHCH-H), 2.00 (m, lH, PhCHCH-H), 1.24 (d, 6H, J=6.9 Hz, two of PhNHC(O)CHMeC-H3) ~; CMR (75 MHz, CDC13) 175.2, 153.8, 145.8, 136.2, 134.9, 133.9, 125.3, 120.0, 118.2, 117.8, 114.4, 74.5, 63, 1, 60.8, 55.6, 54.8, 53.5, 50.6, 36.7, 33.2, 29.3, 19.6 ~; HRMS ~s~lc~ for C26H35N3O3 = 437.2678, found = 437.2680.~5 EXA~LE 55 (S)-(-)-1-[2-(6-Ethyl~minoiRochroman-l-yl)-ethyl]-4-(4-mPt~loYyphenyl)piperazine (S)-(Z-4) Following the general procedure of EXAMPLE 5, Step 2, and m~king non-critical v~ri~t;onR but using (S)-(-)-N-[isochroman-1-[2-[4-(4-mPt~Yyphenyl)piperazin-l-yl]ethyl]-6-yl]F~ret~mi-lP~ (S)-(Z-2, F~AlvlpLE 50) as the 30 substrate gives (S)-(-)-1-[2-(6-ethyl~min-iAochroman-l-yl)-ethyl]-4-(4-mPt~l~Yyphenyl)piperazine (S)-(Z4), Rf = 0.32 (5% mpt~nol in methylene chloride);
[a]D = -46~ (c = 0.54, 50% et~l~nol in methylene chloride); IR (neat) 2953, 2825, 2819, 1616, 1512, 1268, 1244, 1147, 11104, 824 cm~l; NMR (300 MHz, CDCl3) 6.86 (m, 5H, aromatic H's), 6.47 (d of d, lH, Ja=2.4 Hz, Jb=8.2 Hz, aromatic H), 6.34 (d, 35 lH, J=2.2 Hz, aromatic H), 4.76 (m of d, lH, J=5.8 Hz, PhC-H), 4.09 (m, lH, PhCH2CH-H), 3.76 (s, 3H, OC-H3), 3.71 (m, lH, PhCH2CH-H), 3.13 (t and q CA 0222~282 l997-l2-l9 W O 97/02259 PCTrUS96/08681 overlapping, 6H, four pip-H, and PhNC-H2), 2.91 (m, lH, PhCH-H), 2.62 ~m's, 7H, PhCH-H, NC-H2 and four pip-H), 2.10 (m, lH, PhCHCH-H), 2.00 (m, lH, PhCHCH-H), 1.25 (t, 3H, J=7.1 Hz, PhNHCH2C-H3) o; CMR (75 MHz, CDCl3) 153.8, 146.8, 145.8, 134.8, 126.8, 125.6, 118.2, 114.4, 112.2, 111.6, 74.6, 63.4, 55.6, 54.9, 53.5, 50.5, 5 38.6, 33.3, 29.5, 15.0 o; HRMS ç~ ted for C24H33N302 = 395.2573, found:
395.2573.
~:~AMPLE 56 (S)-(-)-1-(4-M~th- ~yphenyl)-4-[2-(6-propyl~min-iRochroman-1-yl)-ethyl]piperazine (S)-(Z-4) Following the general procedure of EXAMPLE 5, Step 2, and making non-10 critical variations but using (S)-(-)-N-[isochroman-1-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-6-yl]propion~midP (S)-(Z-2, EXAMPLE MDE45) as the substrate gives of (S)-(-)-1-(4-mPth~ryphenyl)-4-[2-(6-propyl~minsi~orhroman l-yl)-ethyl]piperazine (S)-(Z-4), Rf = 0.52 (50% ~cetonP in hexane); [a]D = 41~ (c =
0.69, 50% et~ ~n-l in methylene chloride); IR (neat) 2812, 2804, 1614, 1514, 1271, 15 1254, 1247, 1105, 1034, 830cm~l; NMR (300 MHz, CDC13) 6.86 (m, 5H, aromatic H'B), 6.47 (d of d, lH, Ja=2.4 Hz, Jb=8.2 Hz, aromatic H), 6.34 (d, lH, J=2.2 Hz, aromatic H), 4.76 (m of d, lH, J=5.8 Hz, PhC-H), 4.09 (m, lH, PhCH2CH-H), 3.76 (s, 3H, OC-H3), 3.71 (m, lH, PhCH2CH-H), 3.64 (broad s, lH, PhN-H), 3.09 (t and q overlapping, 6H, four pip-H, and PhNC-H2), 2.91 (m, lH, PhCH-H), 2.62 (m's, 7H, 20 PhCH-H, NC-H2 and four pip-H), 2.10 (m, lH, PhCHCH-H), 2.00, 1.63, 1.25 o;
HRMS ~ tPtl for C25H35N302 = 409.2729, found = 409.2722.
T1~XAMPLE 57 (S)-(-)-1-(4-MPth-.Yyphenyl)-4-[2-(6-methyl~minni~orhroman-1-yl)-ethyl]piperazine (S)-(Z-4) Acetic anhydride (0.32 mL, 3.43 mmol) is cooled to 0~. Acetic formic 25 anhydride is generated by the dropwise ~ tior~ of 98~o formic acid (0.20 mL, 5.2 mmol) to the acetic anhydride. The ~i~ e is heated to 55~ for 2 hours and then cooled to -15~ with an ethylene glycol/carbon dioxide bath. THF (10 mL) is addedvia syringe, followed by a ssllltion of (S)-(-)-1-[2-(6-~minoico-~hroman-1-yl)-ethyl]-4-(4-methoxyphenyl)piperazine (S)-(Z-1, EXA~LE 48, 1.99 g, 5.41 mmol) in THF (10 30 mL). The reaction stirred for 2 hours at -15~. The reaction warmed to 20-25~ and volatiles removed under reduced ~ S~ leaving a yellow oil. A solllti~ n of the crude in THF (30 mL) is charged into a 250 mL round bottom equipped with a reflux cc~nrlPn~Pr. The ~ ure is cooled to 0~ and borane methyl sulfide comrlP~ (lOM, 1.73 mL, 17.3 mmol) is added slowly via syringe. The ice bath is removed when 35 e~ sc~ .lce sllhRide~l The ~i~Lu~: is then heated to gentle reflux for 3 hours, ~then at 20-25~ for three days. The reaction is cooled to 0~ and mPth~nol (30 mT)iS added CA 02225282 l997-l2-l9 W O 97/02259 PCTnUS96/08681 dropwise (e~ esce~ce) then stirred for 1 hour at 20-25~, followed by reflux for 2 hours. After cooling to 20-25~, the volatiles are removed under reduced l,.es~
and the aqueous residue is b~cifiP~ with aqueous sodium hydroxide and extracted 80 mL ethyl acetate (three times). The organic extracts are comhin~ dried with sodium sulfate, filtered and con~enl-d~d to give a crude product. The crude ms~tAris3li6 purified by flash chrrlm~tography using 25% Areton~ in hexane as the eluent to give (s)-(~ -(4-m~t7lclxyphenyl)-4-[2-(6-methyl~minoi~o~hroman-l-yl)-ethyl]piperazine (S)-(Z-4), IR (neat) 2933, 2831, 2817, 1616, 1513, 1275, 1246, 1107, 1038, 826 cm~l; NMR (300 MHz, CDCl3) 6.86 (m, 6H, aromatic H's), 6.47 (d of d, lH, Ja=2.4 Hz, Jb=8.2 Hz, aromatic H), 6.35 (d, lH, J=2.2 Hz, aromatic H), 4.76 (m of d, lH, J=5.8 Hz, PhC-H), 4.09 (m, lH, PhCH2CH-H), 3.76 (s, 3H, OC-H3), 3.71 (m, lH,PhCH2CH-H), 3.58 (broad s, lH, N-H), 3.11 (t, 4H, four pip-H), 2.92 (m, lH, PhCH-H), 2.82 (s, 3H, NHC-H3), 2.62 (m's, 7H, PhCH-H, NC-H2 and four pip-H), 2.10 (m,lH, PhCHCH-H), 2.00 (m, lH, PhCHCH-H) 8; CMR (75 MHz, CDCl3) 153.8, 147.7, 145.8, 134.8, 126.9, 125.5, 118.2, 114.4, 111.8, 111.3, 74.64, 63.3, 55.6, 54.9, 53.5, 53.4, 50.6, 33.4, 30.9, 29.5 8; HRMS calculated for C23H31N302: 381.2416. Found:381.2415.
~AMpLE 58 ($)-(-)-1-(4-MPthnYyphenyl)-4-[2-(6-dimethyl~min~icorhroman-1-yl)-ethyl]piperazine (S)-(Z-7) From the preparation described in ~xAlvlpLE 57 is also i~nl~te(l (S)-(-)-1-(4-m~tho~yphenyl)4-[2-(6-dimethyl~minoiRo-hroman-l-yl)ethyl]~i~e~ e (S)-(Z-7), I2f = 0.22 (~- et~nP/h~y~n~ 25/75); NMR (300 MHz, CDCl3) 6.99-6.81 (m's, 5H, aromatic H's), 6.62 (d of d, lH, Ja=2.4 Hz, Jb=8.2 Hz, aromatic H), 6.46 (d, lH, J=2.2 Hz, aromatic H), 4.78 (m of d, lH, J=5.8 Hz, PhC-H), 4.10 (m, lH, PhCH2CH-H), 3.76 (6, 3H, OC-H3), 3.71 (m, lH, PhCH2CH-H), 3.11 (q, 4H, four pip-H), 2.95 (m, lH, PhCH-H), 2.92 (s, 6H, two of NC-H3), 2.62 (m's, 7H, PhCH-H, NC-H2 and four pip-H), 2.10 (m, lH, PhCHCH-H), 2.00 (m, lH, PhCHCH-H) 8; CMR (75 MHz, CDCl3) 153.8, 149.2, 145.8, 134.6, 126.3, 125.4, 118.1, 114.4, 112.5, 112.1, 111.4, 74.6, 63.4, 55.6, 55.0, 53.5, 50.6, 46.8, 40.7, 33.4, 29.7 8.
F~xAMpLE 59 (S)-(-)-l-t2-(6-Ethylmethyl~minoi~o~hroman-l-yl)-ethyl]4~4-m~t~rlYyphenyl)piperazine (S)-(Z-7) From the process described in EXAMPLE 57 is also i~ol~te (S)-(-)-1-[2-(6-ethylmethyl~minoi~o~hroman-1-yl)-ethyl]-4~4-mPth~ ~yphenyl)piperazine (S)-(Z-7), Rf = 0.22 (~-~eton~/hPY~n~, 25/75); [~]D = -54~(c = 0.83, et~ ~nrl/methylene ~hlnri-le 50/50); IR (mull) 2815, 1611, 1515, 1256, 1245, 1236, 1107, 1095, 1037 and 824 cm~l; NMR (300 MHz, CDCl3) 6.97-6.81, 6.59, 6.42, CA 0222~282 1997-12-19 W O 97/02259 PCT~US96/08681 4.77, 4.10, 3.76, 3.71, 3.37, 3.11, 2.95, 2.88, 2.62, 2.10, 2.00 and 1.11 o; CMR (75 MHz, CDCl3) 153.8, 147.6, 145.8, 134.6, 125.7, 125.5, 118.1, 114.4, 112.1, 111.0, 74.7, 63.5, 55.6, 55.0, 53.5, 50.6, 46.8, 37.5, 33.5, 29.7 and 11.3 o.
EXAMPLE 60 (S)-(-)-N-[Isochroman-1-[2-[4-(4-mPth- xyphenyl)~ Ldzi yl]ethyl]-6-yl]-N-methyl~et~mi~e (S)-(Z-5) Following the general procedure of EXAMPLE 50 and m~king non-critical variations but using (S)-(-)-1-(4-mPth~ yphenyl)-4-[2-(6-methyl~min~ orhroman-1-yl)ethyl]piperazine (S)-(Z-4), the title compound is obtained, Rf = 0.26 (mPth~nf l/methylene chloride 5/95); [a]D = -38~(c = 0.69, ethnn~l/methylene chloride (50/50)); IR (mull) 1669, 1661, 1513, 1448, 1445, 1275, 1248, 1109, 1036 and 826 cm~
l; NMR (300 MHz, CDCl3) 7.13, 6.98, 6.86, 4.83, 4.13, 3.76, 3.76, 3.23, 3.10, 2.97, 2.61, 2.14, 2.02 and 1.87 o; CMR (75 MHz, CDCl3) 170.6, 153.8, 145.7, 142.7, 137.8, 135.7, 127.2, 126.1, 124.8, 118.2, 114.4, 74.5, 62.8, 61.2, 55.6, 54.8, 53.5, 50.7, 37.2, 33.3, 29.0 and 22.5 ~.
EXAMPLE 61 (S)-(-)-N-[Isochl~an-1-t2-[4-(4-mPth- ~yphenyl)piperazin-1-yl]ethyl]-6-yl]-N-methylisG'Gul,y~de (S)-(Z-5) Following the general pl~cedu~ of ~xAMpLE 54 and m~kinF non-critical variation but using (S)-(-)-1-(4-mPthnYyphenyl)-4-[2-(6-methyl~minoi~o~ u...an-1-yl)-ethyl]piperazine (S)-(Z-4) gives (S)-(-)-N-[isochroman-1-[2-[4-(4-20 methoxyphenyl)piperazin-1-yl]ethyl]-6-yl]-N-methylisobuLy~ ide (S)-(Z-5), Rf = 0.33 (5% mPt~nol in methylene l~hlr~ricle); [a]D = -34~ (c = 0.80, 50% eth~nnl in methylene ~hlnri~le); IR (mull) 2962, 1658, 1512, 1468, 1457, 1386, 1245, 1109, 1038, 825 cm~l; NMR (300 MHz, CDCl3) 7.13 (d, lH, J=8.2 Hz, aromatic H), 6.98 (d, lH, J=8.2 Hz, aromatic H), 6.86 (m and q, 5H, J=9.2 Hz, aromatic H's), 4.83 (m of d, lH, 25 J=5.8 Hz, PhC-H), 4.13 (m, lH, PhCH2CH-H), 3.76 (s, 3H, OC-H3), 3.76 (m, lH, PhCH2CH-H), 3.22 (s, 3H, NC-H3), 3.10 (t, 4H, J=4.6 Hz, four pip-H), 2.97 (m, lH, PhCH-H), 2.61 (m's, 8H, NC(O)CMe2-H, PhCH-H, NC-H2 and four pip-H), 2.14 (m, lH, PhCHCH-H), 2.02 (m, lH, PhCHCH-H), 1.03 (d, 6H, J=6.5 Hz, two of NC(O)CHC-H3) o; CMR (75 MHz, CDCl3) 177.4, 153.8, 145.7, 142.4, 137.8, 135.7, 30 127.4, 126.1, 125.0, 118.2, 114.5, 74.5, 62.8, 55.6, 54.8, 53.5, 50.7, 37.5, 33.3, 31.0, 29.0, 19.8 o; HRMS c~ qte~l for C27H37N303 = 451.2835, found = 451.2827.
EXAMPLE 62 (S)-(-)-N-[Isochroman-1-[2-[4~4-methoxyphenyl)piperazin-1-yl]ethyl]-6-yl]-m~th~ne~lllf n~mitle (S)-(Z-3) (S)-(-)-1-[2-(6-~minoi~orhroman-1-yl)-ethyl]-4-(4-m~thr.Yyphenyl)-pi~ zi~e 35 (S)-( Z-1) (200 mg, 0.54 mmol) and 4-dimethylaminopyridine (6.7 mg, 0.054 mmol) are mixed. Pyridine (2 mL) is added via syringe, the ~lu~e is cooled to 0~, and CA 02225282 l997-l2-l9 W O 97/02259 PCTrUS96/08681 mf~thslne sulfonyl chloride (.045 mL, 0.60 mmol) is introduced. The ice bath is removed after 15 min. and the reaction i8 stirred at 20-25~ for 1.5 hours. The reaction is diluted with water and extracted two times with ethyl ~cet~te. The organics were combined, washed one time with an saturated aqueous copper sulfate5 ~0ll7t;~n then with water, dried over m~E~n~illm sulfate, filtered and co~cPntrated.
The concentrate is chr m~tographed on 25 g silica gel using 50% acetone in hexane as the eluent to give (S)-(-)-N-[isochroman-1-[2-[4-(4-mPt~Yyphenyl)piperazin-1-yl]ethyl]-6-yl]-metll~nPslllfor ~mi~1e (S)-(Z;-3), Rf = 0.21 (5% mPt~ ~nol in methylene chloride); [a]D = -43~ (c = 0.89, 50% ethanol in methylene rhl~ri~); IR (mull) 1512, 1339, 1319, 1295, 1244, 1152, 1106, 1037, 973, 826 cm~l; NMR (300 MHz, CDCl3) 7.06 (m's, 3H, aromatic H's), 6.87 (q, 4H, J=9.0 Hz, aromatic H's), 4.80 (m of d, lH, J=5.8 Hz, PhC-H), 4.11 (m, lH, PhCH2CH-H), 3.76 (s, 3H, OC-H3), 3.71 (m, lH, PhCH2CH-H), 3.10 (t, 4H, J=4.6 Hz, four pip-H), 3.0 (s, 3H, NHSO2C-H3), 2.95 (m,lH, PhCH-H), 2.60 (m's, 7H, PhCH-H, NC-H2 and four pip-H), 2.11 (m, lH, PhCHCH-H), 2.01 (m, lH, PhCHCH-H) o; CMR (75 MHz, CDC13) 153.8, 145.7, 135.8, 135.6, 134.8, 126.1, 121.2, 119.0, 118.2, 114.5, 74.4, 62.9, 55.6, 54.8, 53.5, 50.6, 39.4, 33.2, 29.1 O; HRMS c~ for c23H3lN3o4sl = 445-2035~ found =
445.2031.
EXAMPLE 63 (S)-(-)-6-Amino-1-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]isochroman, methyl urea (S)-(X-6) (S)~-)-1-[2-(6-~min- i~ochroman-1-yl)-ethyl]-4-(4-mPt~- xyphenyl)piperazine (S)-(Z-l, 376 mg, 1.0 mmol) is added to ~et~nitril~ (4 mL). Methyl isocyanate (0.091mL, 1.53 mmol) is added slowly via syringe. ~lition~l ~cet~nitrilp (7 mL) is added and the reaction is stirred for 3 hours at 20-25~. The pre~ipit~te is filtered and 25 rinsed successively with ethyl acetate and hexane to give crude product which is purified by flash chrom~tography using 5% mPtl~nol in methylene ~hlf~ri~le to give (S)-(-)-6-amino-l-t2-[4-(4-methoxyphenyl)piperazin-1-yUethyl]isochroman, methyl urea (S)-(X-6), Rf = 0.07 (5% mPtl~n-.l in methylene chloride); [a]D = -43~ (c = 0.75, 50~o et~l~nol in methylene chloride); IR (mull) 3312, 1645, 1614, 1597, 1567, 1512, 30 1421, 1310, 1244, 1109 cm~l; NMR (300 MHz, CDCl3) 7.11 (s, lH, aromatic H), 7.02 (m, 2H, aromatic H's), 6.84 (q and m, 5H, J=9.2 Hz, aromatic H's), 5.09 (m of d, lH, J=5.5 Hz, C(O)NMe-H), 4.77 (m of d, lH, J=5.8 Hz, PhC-H), 4.07 (m, lH, PhCH2CH-H), 3.76 (8, 3H, OC-H3), 3.71 (m, lH, PhCH2CH-H), 3.09 (t, 4H, J=4.9 Hz, four pip-H), 2.90 (m, lH, PhCH-H), 2.79 (d, 3H, J=4.7 Hz, C(O)NHC-H3), 2.60 (m's, 7H, 35 PhCH-~I, NC-H2 and four pip-H), 2.10 (m, lH, PhCHCH-H), 2.02 (m, lH, PhCHCH-H) o; CMR (75 MHz, CDCl3) 156.8, 153.8, 145.7, 136.8, 135.0, 133.5, 125.5, 121.2, CA 0222~282 l997-l2-l9 W O 97t02259 PCTrUS96/08681 119.1, 118.2, 114.5, 74.5, 63.1, 55.6, 54.8, 53.5, 50.6, 33.2, 29.2, 27.0 o; HRMS
ç~lr~ t*-i for C24H32N403 = 424.2474, found = 42473.
EXAMPLE 64 (S)-(-)-6-Amino- 1-[2-[4-(4-methoxyphenyl)~i ~uel azi yl]ethyl]isochroman, t-butylcarbamate (S)-(X-6) (S)-(-)-1-[2-(6-Aminoi~qochroman-1-yl)-ethyl]-4-(4-methn~yphenyl)piperazine (S)-(Z-1, 200 mg, 0.54 mmol) and sodil~m h~Y~mPthyl~ n~ (200 mg, 1.09 mmol) are mixed. THF (2 mT ) i8 added via syringe and the reaction i8 stirred for 15 min. Di-t-butyl pyloc~l,onate (108 mg, 0.50 mmol) is added as a sollltion in 1~ (2 mL). The ll~ixl,u~è is 6tirred at 20-25~ for 20 hours. The reaction is poured into water (40 mL).
The volatiles are removed under reduced p.e8~ule, and the aqueous residue is extracted with ethyl acetate (2 x 50 mL). The O~ ';CS were comhin~l, dried with sodium sulfate, filtered and con-~nl ~ted. The conc~..t-a~ is chrom~tographed on30 g silica gel using 5% m~t~nol in methylene chloride as the eluent to give (S)-(-)-6-amino- 1-[2-[4-(4-m ~tll nYyphenyl)piperazin- l-yl]ethyl]isochroman, t-butylcarbamate 15 (S)-(X-6), Rf = 0.38 (5% m~tl~nol in methylene chloride); [a]D = -39~ (c = 0.65, 50%
ethanol in methylene chloride); IR (mull) 1694, 1522, 1515, 1423, 1367, 1286, 1243, 1167, 1109, 1058 cm~l; NMR (300 MHz, CDCl3) 7.24 (8, lH, aromatic H), 7.02 (m, 2H, aromatic H's), 6.86 (q, 4H, J=9.0 Hz, aromatic H's), 6.44 (broad s, lH, N-H), 4.79 (m of d, lH, J=5.8 Hz, PhC-H), 4.10 (m, lH, PhCH2CH-H), 3.76 (s, 3H, OC-H3), 3.71 20 (m, lH, PhCH2CH-H), 3.10 (t, 4H, J=4.6 Hz, four pip-H), 2.94 (m, lH, PhCH-H),2.60 (m's, 7H, PhCH-H, NC-H2 and four pip-H), 2.11 (m, lH, PhCHCH-H), 2.01 (m, lH, PhCHCH-H), 1.52 (8, 9H, three of CC-H3) ~; CMR (75 MHz, CDCl3) 153.8, 152.8, 145.8, 136.5, 134.8, 132.8, 125.3, 118.6, 118.2, 116.8, 114.4, 80.6, 63.1, 61.1, 55.6, 54.8, 53.5, 50.6, 33.3, 29.3, 28.4 o.~5 EXAMPLE 65 1-(4-M~tl~. Yyphenyl)-4-t2-(6-methyl~minomPtl~ylisochroman-1-yl)ethyl]piperazine (BB-2) Following the general procedure of li'XAMPLE 1, Step 4 and m~king non-critical variations but using 1-[2-[4-(4-m~t~lnYyphenyl)-1-pipe.~.zi~yl]ethyl]-N-methyl-isochroman-6-cdll,u~ (IX, ~AMPLE 37) gives crude product. This 30 m~t~ri~l is purified by LC on 13 g (230400) silica gel eluting with 5% 3M Amm~)ni~
in m~t~nol/dichlorom~ne to give 1-(4-m~t~lnxyphenyl)-4-[2-(6-methyl~minh..,~l~lylisochroman-1-yl)ethyUpiperazine (BB-2), mp = 74-76~; Rf = 0.36 (5% 3M NH3in m~ot~l~nn]/dichlornm~t~l~n~); IR (mull) 2788, 1512, 1291, 1276, 1253, 1232, 1180, 1151, 1132, 1107, 1051, 1035, 1012, 927, 831; NMR (300 MHz, CDCl3) J
7.08 (m, 3H, aromatic), 6.85 (m, 4H, aromatic), 4.85 (brdd, lH, J=6.0 Hz, m~t~in~), 4.15 (m, lH, OCH2a), 3.77 (m, 4H, OCH3& OCH2b), 3.71 (s, 2H, Ph-CH2-N), 3.11 (t, 4H, J=4.9 Hz, Ph-N-CH2s), 2.97 (m, lH, Ph-CH2a), 2.72-2.50 (m, 7H, Ph-NC(H2)-CH2B-NCH28, Ph-CH2b), 2.46 (s, 3H, NCH3), Z.14 (m, lH, C(H)-CH2a), 2.04 (m, lH, C(H)-CH2b) ~; CMR (75 MHz, CDCl3) 153.6, 145.6, 137.9, 136.7, 133.9, 128.5, 126.0, 124.7, 118.0, 114.3, 74.5, 63.0, B5.6, 55.4, 54.7, 50.5, 35.9, 33.2, 29.0 o; HRMS (EI) rs3~ tetl for C24H33N3O2 = 395-2573~ fou F'XAMPLE 66 1-(4-Mf~hnYyphenyl)-4-[2-(6-dimethyl~minom~thylisochroman-1-yl)ethyl]piperazine (BB-2) Following the general procedure of Ti~AMPLE 1, Step 4 and making non-critical v~ri~t;o~ but using 1-[2-t4-(4-methoxyphenyl)-l-piperazinyl]etlhyl]-N~N-dimethylisochroman-6-c~b.~ e (IX, EXAMPLE 36) gives crude product which is purified by LC on 13 g (230-400) 6ilica gel eluting with 100~o dichlc.L~ n~ and gradually increasing polarity to 5% 3M ~mmoni~ in mPth~nnl/dichloromPth~nP to gie 1-(4-mPthnYyphenyl)-4-[2-(6-dimethyl~minnm~t.hylisochroman-1-yl)ethyl]piperazine(BB-2), mp = 95-98~; Rf = 0.33 (5~o 3M slmmnni&~ in mpt~nol/dichlorom~t~l~n~); IR
(mull) 2809, 2791, 2770, 2762, 1512, 1442, 1277, 1253, 1232, 1179, 1150, 1107, 1045, 1037, 832 cm~l; NMR (300 MHz, CDCl3) 7.07 (m, 3H, aromatic), 6.87 (m, 4H, aromatic), 4.83 (brdd, lH, J=6.4 Hz, m~hine)~ 4.11 (m, lH, OCH2a), 3.76 (m, 4H, OCH3& OCH2b), 3.40 (s, 2H, Ph-CH2-N), 3.11 (t, 4H, J=4.9 Hz, Ph-NCH2s), 2.97 (m,lH, Ph-CH2a), 2.65 (m, 7H, Ph-NC(H2)-CH28-NCH2 & Ph-CH2b), 2.26 (8, 6H, NCH3~,), 2.18 (m, lH, C(H)-CH2a), 2.05 (m, lH, C(H)-CH2b) o; CMR (75 MHz, CDCl3) 153.8, 145.8, 137.0, 136.6, 133.9, 129.5, 127.1, 124.6, 118.2, 114.4, 74.6, 64.0, 63.2, 55.6, 54.9, 53.5, 50.6, 45.3, 33.3, 29.1 o; HRMS (EI) cf~ qt~Cl for C25H35N3O2 = 409.2729, found = 409.2733.
EXAMPLE 67 1-[2-[4-(4-M~tlt nYyphenyl)- 1-piperazinyl]ethyl]-isochroman-6-carboxylic acid, ethyl ester (X) An oven-dried 10 mT- flask e.lui~ped with spinbar, reflux con-lPn~Pr, and 3-way adapter is charged with 1-[2-(6-bromoi~o~ an-1-yl)ethyl]4~4-methoYyphenyl)-piperazine (VI, Ti~xAMpLE 24, Step 2, 431 mg, 1.0 mmol), p~ m II acetate (11 mg, 0.05 mmol), 1,3-bis(diphenylrho~phino)propane (25 mg, 0.06 30 mmol), 2.5 mL dimelhylruL~mitlP, diisop~ ,ylethylamine (0.35 mL, 2.0 mmol), and elhs~nol (1.2 mL, 20 mmol). The r~slllt;ng ~xLu~: is purged 8iX timeB with carbon mnnoYi~P/under reduced ~ tUL~ followed by he~tinF to 100~. After 18 hours, the ~ixLul~ is cooled to 20-25~, conc~ ated under high V~ u~, diluted with 20 mL
lM sodium hydroxide, and e~L~c~oLt d twice with ethyl acetate (20 mL). The ~nmhin~ organics are washed once with saline (20 mL), dried over m~n~ lm sulfate, filtered, and conrenl-~ted to give product. This m~teri~l is purified by LC

CA 0222~282 1997-12-19 W O 97/022S9 PCTrUS96/08681 on 22 g (230400) silica gel eluting with 30% ~cetonP/hexane to give 1-[2-[4~4-methoxyphenyl)-l-piperazinyl]ethyl]-isochroman-6-carboxylic acid, ethyl ester (X), mp = 117-119~; Rf = 0.45 (35% AretonP~hexane); IR (mull) 1712, 1513, 1422, 1286,1260, 1246, 1187, 1145, 1140, 1108, 1053, 1037, 1023, 818, 767 cm~1; NMR (300 5 MHz, CDCl3) 7.84 (d, lH, J=8.2 Hz, _romatic), 7.80 (8, lH, _romatic), 7.17 (d, lH, J=8.1 Hz, aromatic), 6.85 (m, 4H, aromatic), 4.85 (brdd, lH, J=6.0 Hz, mPthin~), 4.36 (qrt, 2H, J=7.1 Hz, CO2CH2), 4.15 (m, lH, OCH2a), 3.76 (m, 4H, OCH3& OCH2b), 3.10 (t, 4H, J=4.7 Hz, Ph-N-CH2S), 3.00 (m, lH, Ph-CH2a), 2.79-2.50 (m, 7H, Ph-NC(H2)-CH26-NCH2s, Ph-CH2b), 2.15 (m, lH, C(H)-CH2a), 2.06 (m, lH, C(H)-CH2b), 10 1.39 (t, 3H, J=7.1 Hz, C(H2)-CH3 o; CMR (75 MHz, CDCl3) 166.2, 153.5, 145.4, 142.9, 133.9, 129.8, 128.2, 126.9, 124.5, 117.8, 114.1, 74.3, 62.6, 60.6, 55.2, 54.3, 53.2, 50.3, 32.8, 28.7, 14.0 o.
Ti~Al\/rPLE 68 6-Acetyl-1-[2-[4~4-mPt~n ~yphenyl)-1-piperazinyl]ethyl]-isochroman, hydrochloride salt (X~V) An oven-dAed 10 mL flask equipped with spinbar _nd reflux cnntl~Pn~qri6 charged with 1-[2-(6-bromni~ocl~l olllan-1-yl)ethyl]4-(4-mPt~nYyphenyl)-pi~eL~lzi~e (VI, EXAMPLE 24, Step 2, 431 mg, 1.0 mmol), pAllA~ lm II acetate (11 mg, 0.05 mmol), 1,3-bis(diphenylrhosphinn)propane (25 mg, 0.06 mmol), tl7Allinm II acetate (290 mg, 1.1 mmol), 3.0 mL dimeLhylrul...Ami-lP, triethylamine (0.28 mL, 2.0 mmol), and vinyl butylether (0.65 mT-, 5.0 mmol). The ~Lule iB heated to 100~ and after20 hours, the ~Lule is cooled to 20-25~, treated with hyLucllloric acid (lM, 6 mL) and is stirred for 1 hour. The ~ Lu~e is con~ ted under high v~( ~LU~, diluted with 20 mL 5M sodillm hydroxide, and extracted twice with ethyl acetate (20 mL).The comhinP~ organics are washed once with sAline (20 mT-), dried over mAgnp~iumsulfate, filtered and cnnl~,e~.t~dLed. This mAteriAl is purified by LC on 27 g (230400) silica gel eluting with 25% AretonP~PY~np~ This mAt~riAl is dissolved in a ~Luleof ethyl ~ret~t~mPt~l~nnl and is treated with gaseous hydluchloric acid resulting in the formation of a solid that is re~1Y~ C1 from ethyl acetate/mP~l~Annl to give 6-acetyl-1-t2-[4-(4-mP~l~nYyphenyl)-l-piperazinyl]ethyl]-isochroman~ hy~loride salt (XXIV), mp = 195-197~; Rf = 0.15 (30% AcetonP/hexane); bis salt IR (mull) 2560, 2516, 2487, 2462, 1675, 1511, 1~, 1425, 1359, 1290, 1265, 1245, 1113, 1035, 837 cm~l; freebase NMR (300 MHz, CDC13) 7.78 (d, lH, J=8.1 Hz, aromatic), 7.72 (s, lH, r aromatic), 7.20 (d, lH, J=8.1 Hz, aromatic), 6.87 (m, 4H, aromatic), 4.89 (brdd, lH, J=6.0 Hz, mPt~inP), 4.15 (m, lH, OCH2a), 3.76 (m, 4H, OCH3& OCH2b), 3.11 (t, 4H,J=4.8 Hz, Ph-N-CH28), 3.00 (m, lH, Ph-CH2a), 2.80-2.55 (m, 10H, Ph-NC(H2)-CH28-NCH2~, Ph-CH2b, COCH3), 2.15 (m, lH, C(H)-CH2a), 2.06 (m, lH, C(H)-CH2b) o;

CMR (75 MHz, CDCl3) 197.8, 153.7, 145.6, 143.5, 135.2, 134.4, 128.9, 126.1, 125.0, 118.1, 114.3, 74.5, 62.9, 55.5, 54.6, 53.4, 50.5, 33.0, 29.0, 26.5 o; HR~IS (EI) tP-l for C24H30N2O3 = 394.2256, found = 394-2262-EXAMPLE 69 6-Formyl-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-isochroman (AA-1) 1-[2-(6-Bromoi~orhroman-l-yl)ethyl]-4-(4-methoxyphenyl)piperazine (VI, FXAl\/rPLE 24, Step 2, 2.80 g, 6.5 mmol) and freshly t~ tillP-l tetrahy~L~ru~dn (16 mL) are mixed followed by cooling to -78~. The ~ is treated with a 1.7 M
soll7tion of tert-butyllithillm (7.7 mT, 13.0 mmol). After 15 min, the aryl lithiillm is 10 treated with dimeLllylru~ mi-l~ (1.0 mL, 13 mmol). The reaction i8 warmed to 20-25~ over 1.5 hours then is diluted with 75 mL water and extracted twice with ethyl acetate (75 mL). The comhin~(l organics are washed once with saline (50 mL), dried over mAEnP~ m sulfate, filtered, and conce.ll ~al~d to give crude product. Thi~
material iB purified by LC on 160 g (230-400) silica gel eluting with 30~o 15 ~ceton~/hexane to give 6-formyl-1-[2-[4-(4-mPth~Yyphenyl)-1-piperazinyl]ethyl]-isochroman (AA-1), Rf = 0.28 (30% ~etonP/hexane); IR (liq.) 2949, 2819, 1698, 1608, 1512, 1464, 1456, 1291, 1285, 1244, 1143, 1124, 1110, 1038, 824 cm~l; N~ (300 ~Iz, CDCl3) 9.97 (s, lH, CHO), 7.69 ( d, lH, J=8.0 Hz, aromatic), 7.60 (8, lH, aromatic), 7.28 (d, lH, J=7.7 Hz, aromatic), 6.85 (m, 4H, aromatic), 4.90 (brdd, lH, 20 J=6.0 Hz, m~thinP~), 4.16 (m, lH, OCH2a), 3.76 (m, 4H, OCH3& OCH2b), 3.10 (t, 5H, J=5.0 Hz, Ph-N-CH2s & Ph-CH28), 2.83-2.50 (m, 7H, Ph-NC(H2)-CH2E,-NCH2E~, Ph-CH2b), 2.16 (m, lH, C(H)-CH2a), 2.07 (m, lH, C(H)-CH2b) ~; CMR (75 MHz, CDCl3) 192.0, 153.8, 145.7, 145.2, 135.0, 134.7, 130.4, 127.4, 125.6, 118.2, 114.4, 74.6, 62.8, 55.6, 54.6, 53.5, 50.6, 33.1, 29.0 o; HRMS (EI) c~ tecl for C23H28N203 =
25 380.2100, found = 380.2098.
F~AMlpLE 70 2-[Isochroman-1-[2-[4-(4-methoxyphenyl)~ a~i~-1-yl]ethyl]-6-yl]~-et~mi~P (AA-4) Step 1: 1-[2-(6-Hyd.ul~y..~ethylisochroman-1-yl)-ethyl]-4-(4-mPtl~mryphenyl)piperazine (AA-2) 6-Formyl-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethylisochroman (AA-1, EXA~LE 71, 2.51 g, 6.6 mmol) and 25 mL mpth~nol are mixed followed by cooling to 0~. The ~ Lu~ is treated with a single portion of sodium borohydride (500 mg,13.2 mmol). The reaction is gradually warmed to 20-25~ over 2 hours and is diluted with 75 mL water and extracted twice with ethyl acetate (75 mL). The comhinç-1 organics are washed once with saline (50 mL), dried over m~gnP~illm sulfate, filtered and conc~ t-a~ed. This m~t~ is purified by LC on 130 g (230-400) silica CA 02225282 l997-l2-l9 W O 97/022S9 PCT~US96/08681 gel eluting with mPtl-~no]/dichloromPth~nP (5/95) to give 1-[2-(6-hy~l~u~ylllethylisûchroman-l-yl)ethyl]-4-(4-methûxyphenyl)piperazine (AA-2), Rf =
0.15 (35% ~retonP~hexane); IR (mull) 1513, 1445, 1428, 1292, 1279, 1248, 1186, 1152, 1140, 1107, 1057, 1034, 1011, 928, 826 cm~l; NMR (300 MHz, CDCl3) 7.17 ( d, lH, 5 J=8.0 Hz, aromatic), 7.09 (m, 2H, arcmatic), 6.86 (m, 4H, aromatic), 4.82 (brdd, lH, J=6.3 Hz, mPthinP), 4.64 (8, 2H, Ph-CH2-O), 4.12 (m, lH, OCH2a), 3.76 (m, 4H, OCH3& OCH2b), 3.10 (t, 4H, J=4.8 Hz, Ph-N-CH2S) 2.97 (m, lH, Ph-CH2a), 2.72-2.50 (m, 7H, Ph-NC(H2)-CH2S-NCH2s, Ph-CH2b), 2.10 (m, 2H, C(H)-CH2S) ~; MS
(EI, m/z) = 382.
Step 2: 1-[2-(6-Cy~nl mpt~ylisochroman-l-yl)ethyl]-4~4 mPtho~yphenyl)-piperazine (AA-3) 1-[2-(6-IIyL u~ylllethylisochroman- 1-yl)-ethyl]-4-(4-methoxyphenyl)piperazine (AA-2, 2.33 g, 6.1 mmol), 61 mL dichloromPth~ne and triethylamine (1.3 mL, 9.1 mmol) are mixed followed by cooling to 0~. The ~ Lu~e i8 treated with mPth~np~ fonylrhl~ e (0.52 mmol, 6.7 mmol). The reaction i8 warmed to 20-25~
over 1.5 hours and con- e~ at~d under reduced pL~ . The crude mesylate i8 diluted with 31 mT.dimethyl8lllfr~ P and treated with sodium cyanide (896 mg, 18.3 m~ol). This ,~ is heated to 60~. After 2 hours, the volatiles are removed under high V~ Ulll with the resulting residue diluted with 100 mL water and ~ ct~d twice with ethyl acetate (75 mL). The c- mhinP~1 organics are washed oncewith saline (75 mT,), dried over m~gnP~illm sulfate, filtered and conre~ dted. This m~t~risll is purified by LC on 88 g (230400) silica gel eluting with 35%
~ret~nP/hexane to give 1-[2-(6-cy~nnmPthylisochroman-1-yl)ethyl]-4~4-methoxyphenyl)piperazine (AA-3), mp = 118-119~; Rf = 0.36 (35% ~qcetone/hexane);IR (mull) 2810, 2790, 1512, 1444, 1275, 1253, 1232, 1182, 1151, 1111, 1107, 1058, 1051, 1031 and 831 cm~1; NMR (300 MHz, CDCl3) 7.10 (m, 3H, aromatic), 6.87 (m, 4H, aromatic), 4.82 (brdd, lH, J=6.3 Hz, mpthine)~ 4.14 (m, lH, OCH2a), 3.76 (m,4H, OCH3& OCH2b), 3.74 (s, 2H, NC-CH2), 3.11 (t, 4H, J=4.8 Hz, Ph-N-CH2S) 2.98 (m, lH, Ph-CH2a), 2.73-2.50 (m, 7H, Ph-NC(H2)-CH28-NCH2s, Ph-CH2b), 2.18 (m, lH, C(H)-CH2a), 2.04 (m, lH, C(H)-CH2b) o; CMR (75 MHz, CDCl3) 153.8, 145.8, 138.1, 135.1, 128.4, 127.9, 125.8, 125.6, 118.2, 117.9, 114.3, 74.462.9, 55.6, 54.7, 53.5, 50.6, 33.3, 29.0, 23.2 o; MS (EI, m/z) = 391.
Step 3: 2-[Isochroman-1-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-6-yl]ncc~ P (AA-4) 1-[2-(6-Cy~n~mPthylisûchroman-1-yl)ethyl]-4-(4-methoxyphenyl)piperazine (AA-3, 785 mg, 2.0 mmol), 5.0 mL dime~lylru~ mi-le and pot~ lm carbonate (39 W O 97/022S9 PCT/U~r~ 6~1 mg, 0.28 mmol) are mixed. The l~Lu~e is treated with a 30% 6Olllt;~m of Lyd~o~n peroxide (0.24 mL, 2.3 mmol). After 20 hours, the reaction is diluted with 100 mL
dichloromPt~nP and washed once with water (20 mL), once with sali~e (20 mL), dried over m~gnP~ lm sulfate, filtered and con~ ed. This mslt~ris~l is 5 ~ lli7gd from ethyl acetate/hexane to give 2-[isochroman-1-[2-[4-(4-mPt~ ryphenyl)piperazin-l-yl]ethyl]-6-yl]slcet~mitle (AA-4), mp = 159-161~; Rf = 0.15 (6% mPt~n~l/dichloromPtl~n~); IR (mull) 3381, 3208, 2791, 1658, 1633, 1613, 1444, 1293, 1275, 1255, 1231, 1150, 1108, 1032, 833 cm~l; NMR (300 MHz, CDCl3) 7.09 ( 8, 2H, aromatic), 7.02 (s, lH, aromatic), 6.86 (m, 4H, aromatic), 5.59 (brds, lH, NH), 10 5.43 (brds, lH, NH), 4.81 (brdd, lH, J=6.0 Hz, mPthine)~ 4.12 (m, lH, OCH2a), 3.76 (m, 4H, OCH3& OCH2b), 3.53 (8, 2H, O=C-CH2), 3.10 (t, 4H, J=4.9 Hz, Ph-N-CH28) 2.96 (m, lH, Ph-CH2a), Z.72-2.56 (m, 7H, Ph-NC(H2)-CH29-NCH28, Ph-CH2b), 2.13 (m, lH, C(H)-CH2a), 2.03 (m, lH, C(H)-CH2b) o; CMR (75 MHz, CDCl3) 173.4, 153.8, 145.7, 137.4, 134.7, 132.8, 129.8, 127.2, 125.4, 118.1, 114.4, 74.B, 55.6, 54.8, 15 53.5, 50.6, 42.8, 33.2, 29.0 o; MS (EI, m/z) = 409.
EXAMPLE 71 2-tIsochroman- 1-[2 -[4-(4-methoxyphenyl)piperazin- 1-yl]ethyl]-6-yl]-N-methykl~etqmi-lP (AA-5) Following the general procedure of EXAMPLE 3, Step 1 and making non-critical v~ri~t;~n~ but using 2-[isochroman-1-[2-[4~4-mPt~-~Yyphenyl)piperazin-l-20 yl]ethyl]-6-yl]~ce~ le (AA4, 446 mg, 1.09 mmol) crude product is obtained. This mslt,çri~l is purified by LC on 40 g (230400) silica gel eluting with 50%
ethyl ~ ~et o t~/hexane to give 2-[isochroman- 1-[2-[4~4-m Pt~ ~.Yyphenyl)~ipe~ dZi~- 1-yl]ethyl]-6-yl]-N,N-di-t-butylu~y.,~bù~yl~cetqmi-lP, Rf = 0.45 (60%
ethyl~- etqtP/hexane). This m~t~ri~l is reacted with methylamine according to the 25 general ,uluce~ of EXAMPLE 3, Step 2 and m~kinF non-critical v~ri~ti~n~ to give the desired product which is purified by LC on 13 g (230-400) silica gel eluting with 60% ~- etonP/hexane to give 2-[isochroman-1-[2-[4-(4-mPt~l-.Yyphenyl)piperazin-l-yl]ethyl]-6-yl]-N-methylAcet~...i-lP (AA-5), mp = 147-148~; Rf = 0.20 (50%
~-eton~/hexane); IR (mull) 3309, 1652, 1550, 1515, 1442, 1426, 1412, 1354, 1251,30 1228, 1153, 1147, 1114, 1036, 826 cm~l; NMR (300 MHz, CDCl3) 7.09 ( m, 2H, aromatic), 7.01 (s, lH, aromatic), 6.87 (m, 4H, aromatic), 5.45 (brds, lH, NH), 4.83 (brdd, lH, J=6.0 Hz, mPtl~ine), 4.15 (m, lH, OCH2a), 3.77 (m, 4H, OCH3& OCH2b), 3.53 (s, 2H, O=C-CH2), 3.12 (t, 4H, J=4.8 Hz, Ph-N-CH2s) 2.95 (m, lH, Ph-CH2a), 2.77 (d, 3H, J=4.9 Hz, NCH3), 2.72-2.56 (m, 7H, Ph-NC(H2)-CH2S-NCH2s, Ph-CH2b), 35 2.15 (m, lH, C(H)-CH28), 2.04 (m, lH, C(H)-CH2b) o; C~R (75 MHz, CDCl3) 17f.6, 153.8, 145.7, 137.3, 134.7, 132.9, 130.0, 127.3, 125.4, 118.2, 114.4, 74.5, 63.0, 55.6, W O 97/02259 PCTrUS96/08681 54.9, 53.6, 50.6, 43.3, 33.3, 29.0, 26.5 ~; MS (EI, m/z) = 423.
EXAMPLE 72 1-[2-[4-(4-Hyd~vAy~henyl)-1-piperazinyl]ethyl]-isochroman-6-c&~L..~ lP (CC-2) 1-[2-[4-(4-PhenylmethyloAyphenyl)-l-piperazinyl]ethyl]isochroman-6-carbl~Y~mi-1e (CC-1, EXAMPLE 9, 0.42 mmol, 200 mg), p~ m on carbon (10%, 20 rmg), eth~n~ l (5 mL) and methylene chloride (2 mL) are çomhin~-l After four daysthe starting material is consumed. The reaction llli~Lu~è is filtered on a bed of celite and rinsed several times ~ltern~tively with ethanol, mpth~nol~ methylene chloride and ethyl ~et~t~ The hltrates are comhinel:3 and conre~" ~aLed. The crude ms~t,erisil 10 is le~;~y~L~ s~l from hot etl~n~l with some mPth~nol to give 1-[2-[4-(4-hyvfuAy~uhenyl)-l-piperazinyuethyuisochroman-6-c~L~ (CC-2), IR (mull) 3300, 3255, 3206, 1672, 1615, 1513, 1444, 1426, 1366, 1256 cm~l; NMR (300 ~Iz, DMSO) 7.85 (d, lH, J=8.2 Hz, aromatic H), 7.82 (s, lH, aromatic H), 7.43 (d, lH,J=8.2 Hz, aromatic H), 6.96 (d, 2H, J=8.8 Hz, aromatic H's), 6.81 (d, 2H, J=8.8 Hz, 15 aromatic HIB), 5.00 (broad d, lH), 4.18 (m, 2H), 3.85 (m, lH), 3.68 (m, 4H), 3.46-3.0 (several broad m, 6H), 2.85 (broad d, 2H, J=16 Hz) 2.37 (broad m, lH) ~; HRMS
~k~ t,ecl for C22H27N303 = 382.2131, found = 382.2136.
liXAlVlPLE 73 ' (S)~-)-1-[2-[4~4-HydlvAy~henyl)-1-~i,ue~ yl]ethyl]-N-methyl-isochrvl..an-6-carbnY~mi~P (S)~CC-2) A Parr flask is charged with (S)~-)-1-[2-[4-(4-phenylmethylûAyphenyl)-1-piperazinyl]ethyl]-N-methylisochroman-6 ca~L..~ (S)~CC-l, EXAMPLE 20) 50 mL mPth~n~l, 25 mL tetral,yv~c,ru~,..., and 10% p~ rlillm on carbon (200 mg). The resulting black suspension is placed under 40 psi hyv~u~ll and ~h~kPn After 60 hours, the ~res~ e had fallen to 27 psi hyd~o~ and the reaction llliALule is 25 filtered through celite and con~ ted. The con-~Pntrae is le~y~ 7e~1 from mPths~nr~l/ethyl~cet~tJ~ to give (S)-(-)-1-[2-[4-(4-LyLvAy,uhenyl)-1-piperazinyl]ethyl]-N-methylisochromsn-6-c~ u~ e (S)-(CC-2), mp = 154-162~; Rf = 0.11 (5~o mPth~nollethyl~et~tç); [a]D = -53~ (c = 0.9681, mpth~nr~l); IR (mull) 3350, 3200, 3174, 2811, 1642, 1573, 1542, 1517, 1300, 1271, 1248, 1243, 1232, 1104, 825, cm~1;
30 NMR (300 MHz, DMSO-d6) o 8.81 (s, lH, OH), 8.37 (brdd, lH, J=4.6 Hz, NH), 7.61 (m, 3H, aromatic), 7.27 (d, lH, J=8.1 Hz, aromatic), 6.76 (d, 2H, J=8.9 Hz, aromatic), 6.63 (d, 2H, J=8.9 Hz, aromatic), 4.78 (brdd, lH, J=6.0 Hz, mpthinp)~ 4.03 (m, lH, OCH2a), 3.66 (m, lH, OCH2b), 2.93 (m, 4H, Ph-N-CH2B), 2.76 (d, 4H, J=4.5 Hz, N-CH3 & Ph-CH28), 2.49 (m, 6H, Ph-NC(H2)-CH28-NCH2~), 2.35 (m, lH, Ph-CH2b), 35 2.15 (m, lH, C(H)-CH2a), 1.85 (m, lH, C(H)-CH2b) o; CMR (75 MHz, DMSO-d6) 166.4, 150.8, 144.2, 141.2, 133.7, 132.3, 127.5, 124.8, 124.6, 117.6, 115.4, 73.6, 62.2, W O 97/022S9 PCTrUS96/08681 54.2, 53.1, 50.0, 32.5, 28.5, 26.2 o; HRMS (EI) calculated for C23H29N303 =
395.2209, found = 395.2212; KF. Water = 4.28~a EXAMPLE 74 (S)-(-)-1-[2-[4-(4-TrifluoromPth~nesulfonyloxyphenyl)-1-piperazinyl]ethyl]-N-methyl-isochro.llan-6-call,..Y~ (S)-(Cc-3) (S)-(-)-1-[2-[4-(4-lly~lo~yl~henyl)-1-piperazinyl]ethyl]-N-methyl-isochroman-6-c~l~ (S)-(CC-2, 959 mg, 2.4 mmol), 24 mL dichloromPth~n~, and N-phenyl I ~ ;n ~.oromethane-slllfonimi~e (910 mg, 2.5 mmol) are mixed. The ~l~ib~Lu~e is cooled to 0~ and treated with triethylamine (0.51 mL, 3.6 mmol) with no visible 10 change o-,-,u..;~g. After 16 hours, the llli~u~e is diluted with 75 mL lM sodium hydroxide and extracted twice with dichloromPth~ne (75 mL). The comhine~
organics are washed once with saline (50 mT.)~ dried over m~n~inm sulfate, filtered and conc~ ted. This m~t~ri~l is purified by LC on 88 g (230-400) silica gel eluting with 5% mPth~nol/dichloroTn~th~ne to give (S)-(-)-1-[2-[4-(4-~5 trifluorom~h~ne~ulfonyloxyphenyl)-l-piperazinyl]ethyl]-N-methylisocll~vlllan-6-le (S)-(CC-3), Rf = 0.34 (5~0 mPth~nol/dichloromPth~n~); [a]D = -39~ (c =
0.9447, m~+hs~nol); IR (mull) 1641, 1571, 1548, 1505, 1417, 1310, 1297, 1240, 1210, 1209, 1141, 1110, 885, 826, 609 cm~1; N~ (300 MHz, CDC13) 7.55 (m, 2H, aromatic), 7.14 (m, 3H, aromatic), 6.87 (d, 2H, J=9.4 Hz, aromatic), 6.18 (brdd, lH, 20 J=4.6 Hz, NH), 4.85 (brdd, lH, J=5.8 Hz, m.othin~), 4.13 (m, lH, OCH2a), 3.75 (m, lH, OCH2b), 3.22 (t, 4H, J=4.9 Hz, Ph-N-CH2S), 3.00 (d, 4H, J=4.9 Hz, N-CH3 & Ph-CH2a), 2.75-2.49 (m, 7H, Ph-NC(H2)-CH2s-NCH28 & Ph-CH2b), 2.15 (m, lH, C(H)-CH2a), 2.04 (m, lH, C(H)-CH2b) o; CMR (75 MHz, CDCl3) 168.0, 150.9, 142.1, 141.5, 134.5, 132.7, 127.7, 125.0, 124.5,121.9, 116.3, 74.4, 63.0, 54.5, 53.2, 48.7, 33.2, 29.1, 25 26.9; HRMS (FAB) calculated for C24H28F3N3O5S+H1 = 528.1780, found =
528.1791.
EXAMPLE 75 (S)-(-)-1-[2-[4-(4-Acetylphenyl)-1-piperazinyl]ethyl]-N-methylisochroman-6-ca~ ", i~le (S)-(IX) ($)-(-)-1-[2-[4~4-l~uoromPth~nP~lllfonyloxyphenyl)-l-piperazinyl]ethyl]-N-30 1~eLhylisochroman-6-carb~ mi~le (S)-(CC-3, 527 mg, 1.0 mmol), p~ illm II acetate (11 mg, .05 mmol), 1,3-bis(diphenylphosE!hinn)propane (25 mg, .06 mmol), 3.5 mL
dim~lhylr.,....~mide, triethylamine (0.28 mL, 2.0 mmol), and bu~ylvi~.ylether (0.65 mL, 5.0 mmol) are comhinPtl The resulting ~ e is heated to 50~. After 16 hours, the reaction is cooled to 20-25~, treated with 8 mT lM hydlochloric acid, and 35 i8 stirred for 1 hour. This acidic ~ is conr~ntrated under reduced p~ uue~
diluted with 15 mL lM sodium hydroxide, and extracted twice with dichlornmpth~n~

CA 02225282 l997-l2-l9 W O 97/022S9 PCT~US96/08681 (25 mL). The comhinPtl organics are washed once with saline (15 mL), dried over mslgnr~illm sulfate, filtered, and csn~ dted. This m~t~ri~l is purified by LC
36 g (230-400) silica gel eluting with 50% ~reton~/hexane to give (S)-(-)-1-[2-[4-(4-scetylphenyl)-l-pipelazin~l]ethyl]-N-methylisochroman-6-ca l,..~...itl~ (S)-(CC-4) 5 which upon . cc, ~ lli7~tion from ethyl acetate/hPY~ne, mp = 156-157~; Rf = 0.20 50% ~retone~hexane); [a]D = ~1~ (c = 0.8481, mpth~nnl); IR (mull) 3331, 1662, 1598, 1570, 1550, 1519, 1427, 1415, 1311, 1284, 1239, 1196, 1150, 1107, 609 cm~l; NMR
(300 MHz, CDCl3) 7.85 (d, 2H, J=8.9 Hz, aromatic), 7.55 (m, 2H, aromatic), 7.14 (d, lH, J=8.5 Hz, aromatic), 6.84 (d, 2H, J=8.9 Hz, aromatic), 6.24 (brdd, lH, J=4.6 Hz, 10 NH), 4.86 (brdd, lH, J=5.8 Hz, m~hin~), 4.12 (m, lH, OCH2a), 3.76 (m, lH, OCH2b), 3.35 (t, 4H, J=5.0 Hz, Ph-N-CH2~,), 3.00 (d, 4H, J=4.9 Hz, N-CH3 & Ph-CH2a), 2.75-2.53 (m, 7H, Ph-NC(H2)-CH28-NCH28 & Ph-CH2b), 2.50 (s, 3H, O=C-CH3), 2.16 (m, lH, C(H)-CH2a), 2.02 (m, lH, C(H)-CH2b) o; CMR (75 MHz, CDCl3) 196.6, 168.0, 154.2, 141.5, 134.5, 132.7, 130.4, 127.7, 127.6, 125.0, 124.5, 113.4, 74.4, 63.0, 54.5, 53.0, 47.3, 33.2, 29.1, 26.9, 26.1 ~; HRMS (EI) r~lr,~ t~l for C25H31N303 = 421.2365, found = 421.2365.
EXAMPLE 76 (S)-(-)-3-[Isochroman-1-[2-[4~4-mrth~.Yyphenyl)piperazin-l-yl]ethyl]-6-yl]-N,N-dimethylacrlyamide (S)-(XVIII) (S)-(-)-1-[2-(6-Brsmsi~orhroman-l-yl)-ethyl]-4~4-m~thnyyphenyl)-~ui~ut~zi~e 20 (S) (VI) (431.4 mg, 1.0 mmol), p~ lim (II) acetate (98%, 11.4 mg, 0.05 mmol) and 1,3-bis-diphenylrho~phinopropane (97%, 24.7 mg, 0.06 mmol) are comhin~ Argon sltTn9~3rh~re is er~hli~h~l To the reaction vessel is introduced via syringe D~
(4.1 mL), clilllelllylacrylamide (0.72 mL, 7.0 mmol), and diisu,ulu~ylethylamine (0.35 mL, 2.0 mmol). The l~Lule is heated to 100~ over 18 hours. After cooling to 20-25 25~, the reaction is diluted with aqueous sodium hydroxide and extracted threetimes with ethyl ~re~t~ The organics are cnmhin~-l and con~ d~ed. Re~i-lnsll D~ is le wvGd under high vacuum. The crude m~tJ~ri~l is purified by flash chrom~i,o~-d~hy on 80 g silica gel using 5~o m~th~nsl in methylene rhlsrirl~ as the eluent to give a solid which is Ic~;~y~ from hot ethyl acetate/hexane to give 30 (S)-(-)-3-[isoch~ llan-1-[2-[4-(4-m~nYyphenyl)piperazin-l-yl]ethyl]-6-yl]-N~Ndimethyla.;lly~,ide (S)-(XVIII), mp = 120-121~; Rf = 0.30 (5% m~t~nnl in methylene chloride); NMR (300 MHz,CDCl3) 7.62 (d, lH, J=15.4 Hz, aromatic H), 7.34 (d, lH, J=8.0 Hz, aromatic H), 7.10, (d, lH, J=8.0 Hz, aromatic H), 6.85 (d of d and m, 4H and lH respectively, Ja=9.1Hz, Jb=21.4 Hz, aromatic H's), 4.83 (m of d, 35 lH, J=6.0 Hz, PhC-H), 4.13 (m, lH, PhCH2CH-H), 3.75 (m, lH, PhCH2CH-H), 3.75 (s, 3H, PhOC-H3), 3.17 (s, 3H, NMeC-H3), 3.10 (t and s, 4H and 3H respectively, W O 97/OZ2S9 PCTrUS96/08681 J=4.8 Hz, four of pip-H and one of NMeC-H3), 2.94 (m, lH, NCH-H), 2.76-2.45 (several m's, 7H, four pip-H, two PhCH-H, and NCH-H), 2.14 (m, lH, PhCHCH-H), 2.02 (m, lH, PhCHCH-H) ~; CM~ (76 MHz, CDCl3) 166.7, 153.8, 146.7, 142.0, 139.8,134.5, 133.6, 128.3, 126.6, 126.2, 118.1, 117.1, 114.4, 74.6, 63.0, 56.6, 64.8, 53.5, 50.6, 5 37.4, 35.9, 33.2 and 29.1 8.
PLE 77 (S)-(-)-1-(4-M.~tllnYyphenyl)4-[2-[6-(1,2,4-triazol-3-yl)-isochroman-l-yl]ethyl]piperazine (S)-(0-2) Step 1: (S)-(-)-1-[2-[4-(4-M~tl nYvphenyl)-l-piperazinyl]ethyU-N-dimethyl~minnmf~yleneisochroman-6-carbnY~mid~ (S)-(O-l) (S)-(-)-1-[2-[4-(4-m~thnYyphenyl)-l-piperazinyl]ethyl]isochroman-6-ca b..~ le (S)-(VII, 395.6 mg, 1 mmol) and N,N-~ ,e~lylL~ mid~im~t~ylacetal (94~o, 0.34 mL, 2.4 mmol) and toluene (1 mL) are comhin~-l The reaction ~lu~e isheated to 90~ for 1.5 hours. After cooling to 20-26~, the volatiles are l~ ..ovt~d under reduced ple~u~. pllrifi~tinn of the crude material by flash chr~m~tography on 90g silica gel using 5% m~thnnol in methylene l~hlori~l~ as the eluent gives (S)~-)-1-[2-[4~4-m~tl~nyyphenyl)-l-piperazinyl]ethyl]-N-dimethyl~minl~mptl~yl~n~iRot~hroman-6 call~uY~---i(le (S)-(O-l), mp = 134-135.5~; Rf = 0.28 (5~o m~t~nnl in methylene chloride); [a]D = -47~ (c = 0.96, 50% methylene chloride in eth~nnl); IR (mull) 1647, 1608, 1693, 1612, 1446, 1417, 1329, 1269, 1247, 1108 cm~l; NMR (300 MHz, CDCl3) 8.63 (s, lH, NMe2C-H), 8.07 (d, lH, J=8.1 Hz, aromatic H), 8.02 (s, lH, aromatic H), 7.14 (d, lH, J=8.0 Hz, aromatic H), 6.85 (d of d, 4H, Ja=9.2 Hz, Jb=21.6 Hz, aromatic H's), 4.88 (m of d, lH, J=5.1 Hz, PhC-H), 4.13 (m, lH, PhCH2CH-H), 3.76(m, lH, PhCH2CH-H), 3.75 (s, 3H, OC-H3), 3.21 (8, 3H, NMeC-H3), 3.18 (s, 3H, NMeC-H3), 3.10 (t, 4H, J=4.9 Hz, four pip-H), 2.98 (m, lH, PhCH-H), 2.76 (m of d, lH, J=16 Hz, PhCH-H), 2.60 (m's, 6H, NC-H2 and fûur pip-H), 2.15 (m, lH, PhCHCH-H), 2.05 (m, lH, PhCHCH-H) ~; CMR (75 MHz, CDCl3) 177.6, 160.8, 153.7, 145.8, 142.0, 134.9, 133.7, 130.3, 127.6, 124.5, 118.1, 114.4, 74.8, 63.1, 55.6, 54.7, 53.5, 50.6, 41.4, 35.3, 33.2 and 29.2 o.
Step 2: (S)-(-)-1-(4-M~thnYyphenyl)4-[2-[6-(l~2~1 t~ ol-3-yl)isochroman-l-yl]ethyl]piperazine (S)-(0-2) (S)-(-)-1-[2-[4-(4-M~thnYyphenyl)-l-piperazinyl]ethyl]-N-dimethyl~minom~t~ylen~i~o~hroman-6-carbny~m~ (S)-(O-l, 208 mg, 0.46 mmol) and glacial acetic acid (1 mT ) are cnmhin.o-l under argon ~tmn~rh~re. IIydls.7i~e monohyd~a~ (0.045 mL, 0.92 mmol) is added dropwise via syringe with vigorous 35 8tirring It i~ stirred at 20-25~ for 24 hours. The reaction ~I u~a is diluted with water and partitir~n~l between saturated aqueous sodium bicarbonate and CA 0222~282 1997-12-19 W O 97/02259 PCTrUS96/08681 methylene ~hlm itle T}~e organics are comhin~, dried with sodium sulfate, filtered and cQnc~ ed. The con~ entrate is purified by flash chrom~graphy on 6 g silica gel using 5% m~oth~n~l in methylene chloride as the eluent to give (S)-(-)-1-(4-methoxyphenyl)-4-[2-[6-(1,2,4-triazol-3-yl)isochroman-1-yl]ethyl]piperazine (S)-(0-2), 5 mp = 195.5-196~; Rf = 0.11(5% m~t~nol in methylene chloride); NMR (300 MHz, CDCl3) 8.18 (s, lH, triazoleC-H), 7.81 (d, lH, J=7.7 Hz, aromatic H), 7.8 (s, lH, aromatic H), 7.15 (d, lH, J=8.0 Hz, aromatic H), 6.85 (d of d, 4H, Ja=9.2 Hz, Jb=21.6 Hz, aromatic H's), 4.87 (m of d, lH, J=5.1 Hz, PhC-H), 4.13 (m, lH, PhCH2CH-H), 3.76 (m, lH, PhCH2CH-H), 3.75 (s, 3H, OC-H3), 3.12 (t, 4H, J=4.9 Hz, four pip-H), 10 2.98 (m, lH, PhCH-H), 2.76-2.59 (several m's, 7H, PhCH-H, NC-H2 and four pip-H), 2.15 (m, lH, PhCHCH-H), 2.05 (m, lH, PhCHCH-H) ~; CMR (75 MHz, CDCl3) 159.4, 153.9, 146.9, 145.6, 139.8, 134.7, 127.3, 127.0, 125.3, 124.2, 118.2, 114.5, 63.1, 55.6, 54.7, 53.4, 50.6, 33.0, 29.0 ~.
~.~AMPLE 78 (S)-(-)-1-(4-M~thn~yphenyl)-4-[2-[6-(2-methyl-1,2,4-triazol-3-yl)-isochroman-l-yl]ethyl]piperazine (S)-(0-2) Following the general proce.lure of EXAMPLE 77, Step 2 and mslking non-critical variations, but using methyl hydl~zi~le gives (S)~-)-1-(4-methoxyphenyl)-4-t2-[6-(2-methyl-1,2,4-triazol-3-yl)isochroman-1-yl]ethyl]piperazine (S)-(0-2), Rf = 0.17 (5% mf.tl~nt)l in methylene chloride); NMR (300 MHz, CDC13) 8.04, 7.47, 7.46, 7.24, 6.85, 4.89, 4.16, 3.99, 3.80, 3.75, 3.10, 2.98, 2.77, 2.67-2.59, 2.18, 2.07 ~; CMR (75 MHz, CDC13) 154.4, 153.8, 160.7, 145.7, 140.4, 134.9, 129.3, 126.2, 125.9, 125.3, 118.1, 114.4, 74.5, 62.9, 55.6, 54.7, 53.5, 50.6, 37.0, 33.2, 29.0 o.
EXAMPLE 79 (S)-(-)-1-(4-M~t~r Yyphenyl)-4-[2-[6-(2-phenylmethyl-1,2,4-triazol-3-yl)isochroman-1-yl]ethyl]piperazine (S)-(0-2) Following the general ~l~ce~ e of EXAMPLE 77, Step 2 and mslking non-cAtical variations but u~ing phenylmethyl hydrazine gives (S)-(-)-1~4-methoYyphenyl)-4-[2-[6-(2-phenylmethyl-1,2,4-triazol-3-yl)isochroman-1-yl]ethyl]piperazine (S)-(0-3), Rf = 0.28 (5% m~t~ nol in methylene chloride); NMR
(300 MHz, CDC13) 8.01 (s, lH, triazoleC-H), 7.37-7.30 (m's, 5H, aromatic H's), 7.19-7.15 (m's, 3H, aromatic H's), 6.86 (d of d, 4H, Ja=9.2 Hz, Jb=21.6 Hz, aromatic H's), 5.43 (s, 2H, PhC-H2), 4.87 (m of d, lH, J=5.1 Hz, PhC-H), 4.14 (m, lH, PhCH2CH-H), 3.79 (m, lH, PhCH2CH-H), 3.78 (s, 3H, OC-H3), 3.10 (t, 4H, J=4.9 Hz, four pip-H), 2.97 (m, lH, PhCH-H), 2.73-2.52 (several m's, 7H, PhCH-H, NC-H2 and four pip-H), 2.16 (m, lH, PhCHCH-H), 2.05 (m, lH, PhCHCH-H) o; CMR (75 MHz, CDC13) 156.0, 153.8, 151.3, 145.7, 140.5, 135.9, 134.9, 129.4, 129.0, 128.1, 126.9, 126.2, 12~.8, 125.3, 118.2, 114.4, 74.4, 62.9, 55.6, 54.7, 53.~, 52.8, 50.6, 33.2, 29.0 o.

CA 02225282 l997-l2-l9 W O 97/022S9 PCTrU$96/08681 EXAMPLE 80 (S)-(-)-1-(4-MPt~lYyphenyl)-4-[2-[6-(1,2,4-QY~ ol-5-yl) isochroman-1-yl]ethyl]piperazine (S)-(0-2) Hydroxylamine h~ vchloride (83.4 mg, 1.2 mmol) in a ""Ai.U~, of 6N
aqueous sodium hydroxide (0.24 mT, 1.2 mmol), 70~o acetic acid (1.2 mL) and (S)-(-)-5 1-[2-[4-(4-methoAyphenyl)-1-piperazinyl]ethyl]-N-dimet~ylAminomp+~ylpnpi~o~hroman-6-c~~ y~ p (S)-(O-l, EXAMPLE 77, Step 1, 450.6 mg, 1.0 mmol) are added at once. The mixture is stirred at 20-25~ for a total of 70 minutes. The reaction is diluted with water and the pH is raised to 8 withsaluldted aqueous sodium bicarbonate. The aqueous llliXlUl~ iS extracted twice with 10 methylene chloride. The organics are comhinP~, dried with sodium sulfate, filtered and con~ t ~ ~ed. This mA+~riAl (Rf = 0.18 (5% mPthAn~l in methylene chloride)) is dissolved in a ~iA~Ul~ of anhydrous acetic acid (2 mL) and anhydrous p rli~YAn~ (2 mL). Argon ~tm~sphPre is Pst~hli~hP~l and the reaction is heated to 90~ for two hours. After cooling to 20-26~, the reaction is diluted with water and the pH is15 raised to 8 with sa~ d aqueous sodium bicarbonate. The aqueous ~Lule is ~A~ ,Led twice with methylene ~hlo~lP The organics were comhinprl, dried with sodium sulfate, filtered and cc~n~qntrated. Pllrifir~ti~ n of the ccmcçntrate by flash chrnmAtc~.dl,hy on 50 g silica gel using 4% m~ n~l in methylene chloride as the eluent gives (S)-(-)-1-(4-methoxyphenyl)-4-[2-t6-(1,2,4-oY~ ol~5-yl)isocl~lvlllan-1-20 YUethYl]~iPelc zine (S)-(0-2), mp = 126-127~; Rf = 0.36 (5% mpth~nol in methylene chloride); NMR (300 MHz, CDCl3) 8.47 (s, lH, rys~ c-H)~ 7.95 (d, lH, J=8.1 Hz, aromatic H), 7.92 (s, lH, aromatic H), 7.28 (d, lH, J=8.1 Hz, aromatic H), 6.86 (d of d, 4H, Ja=9.1 Hz, Jh=21.2 Hz, aromatic H's), 4.90 (m of d, lH, J=5.1 Hz, PhC-H), 4.17 (m, lH, PhCH2CH-H), 3.81 (m, lH, PhCH2CH-H), 3.76 (s, 3H, OC-H3), 25 3.11 (t, 4H, J=4.9 Hz, four pip-H), 3.03 (m, lH, PhCH-H), 2.80 (m of d, lH, J=16.4 Hz, PhCH-H), 2.66-2.51 (several m's, 6H, NC-H2 and four pip-H), 2.18 (m, lH, PhCHCH-H), 2.07 (m, lH, PhCHCH-H) 8; CMR (75 MHz, CDC13) 175.3, 157.8, 153.8, 145.7, 143.6, 135.3, 128.7, 125.8, 125.7, 122.0, 118.2, 114.4, 74.5, 62.8, 55.6, 54.6, 53.5, 50.6, 33.1, 29.0 8.
30 ~AMpLE 81 (S)-(-)-N-Methyl-1-[2-[4~4-propionylphenyl)-1-pipel~z~yl]ethyl]isochroman-6-c~uL..Y~ (S)-(IX) Step 1: (S)-(-)-6-Bromo-1-(2-hyd~vAy~ yl)isochroman (S)-(S-1) (S)-(-)-(6-Brnmoi~o~hroman-1-yl)acetic acid (S)-(XI, ~AMPLE 1, Step 2, 16.27 g, 60 mmol) and 100 mL tetrahy-l~vru~ are comhin~-i This ~ is treated 35 with a 10M 8- lnti~n of borane methyl sulfide (18.0 mL, 0.18 mol) while ms~int~i~iin 20-25~ with a water bath. After 1 hour, the ~ is cooled to 0~ and 810wly W O 97/02259 PCTrUS96/08681 qllRn~hR~l with 160 mL mP~nnl Note: An in~ln~ n period of app~ tP~ly 1-2 ...i..~l~ is noticed before a rapid and sudden generation of hyd-v~.-. The ~1~Al~U~e i8 warmed to 20-25~ and volatiles removed under reduced ~,~e. -.~e. The re~slllt;
ll~A~u~e iB diluted with lM sodium hydroxide (150 mL) and extracted three times 5 with ethyl acetate (100 mL). The comhinR~l organics are washed once with saline (100 mL), dried over m~FnRRium sulfate, filtered and conre~,l-dted. This m~t~ri~l is Y~ Pfl from ethyl ~cPtstP/hexane to give (S)-(-)-6-bromo-1-(2-hy-LvAyt~ yl)-isochrom~n (S)-(S-l), mp = 95-96~; Rf = 0.28 (30% ~- etonR/hexane); [a]D = -107~ (c =
0.4069, m~t~nol); IR (mull) 3237, 3022, 1482, 1422, 1326, 1277, 1114, 1053, 1026, 10 972, 905, 894, 880, 816, 788, cm~l; NMR (300 MHz, CDCl3) 7.28 (m, 2H, aromatic), 6.92 (d, lH, J=8.2 Hz, aromatic), 4.92 (brdd, lH, J=6.8 Hz, m.othinR), 4.15 (m, lH, OCH2a), 3.81 (t, 2H, J=5.5 Hz, HO-CH2), 3.74 (m, lH, OCH2b), 3.00 (m, lH, Ph-CH2a), 2.66 (dt, lH, J=16.4 Hz & J=3.1 Hz, Ph-CH2b), 2.45 (brds, lH, HO), 2.18 (m, lH, C(H)-CH2a), 2.02 (m, lH, C(H)-CH2b) o; CMR (75 MHz, CDCl3) 136.5, 136.1, 15 131.8, 129.4, 126.3, 120.2, 75.9, 63.4, 60.8, 37.5, 28.8 o; MS (EI, m/z) = 256.
Step 2: (S)-(-)-1-(2-Hyd~uAy~lllyl)isoclllu an-6 c~l,u~ylic acid, methyl ester (S)-(S-2) (S)~-)-6-Bromo-1-(2-l.ydlvAyt lhyl)isochroman (S)~S-l, 5.14 g, 20.0 mmol), ps~lls~ lm II acetate (225 mg, 1.0 mmol), 1~3-bis(diphenylrhocFhino)propane (49520 mg, 1.2 mmol), 40.0 mT- dimell.ylru~ mitle~ diisu~ ylethylamine (10.5 mL, 60.0 mmol), and mP~ nol (16 mL, 0.40 mol mmol) are comhinp~l The rR~lllt;n~ A~ e is purged six times with carbon mon~n~ p~reduced ples~ followed by hP~tinF to 76~ quickly. The reaction ~ AI~U~e: is stirred for 19 hours. At this time, the ll~Alu~
is cooled to 20-25~, diluted with 200 mL water, and extracted twice with 25 dichlorom~'~ne (200 mT ). The comhinR-l organics are washed once with water (100 mL), once with saline (100 mL), dried over m~nP~inm sulfate, filtered and cor.~ ted. This m~ri~l is purified by LC on 300 g (230-400) silica gel eluting with 50% ethyl ~-et~te/hexane to give (S)-(-)-1-(2-l~yd~uAyt~l~-yl)isochroman-6-C~lJ~AY1iC acid, methyl ester (S)-(S-2), mp = 56-58~; Rf = 0.23 (60~ ethyl 30 acetate/hexane); [a]D = -114~ (c = 0.8773, mPt~l~nol); IR (mull) 3407, 3336, 1718, 1434, 1418, 1296, 1274, 1261, 1250, 1195, 1112, 1055, 1022, 997, 754 cm~l; NMR
(300 MHz, CDCl3) 7.79 (m, 2H, aromatic), 7.11 (d, lH, J=8.0 Hz, aromatic), 4.97 (brdd, lH, J=6.8 Hz, mPtl inR), 4.15 (m, lH, OCH2a), 3.88 (8, 3H, CH3), 3.82 (t, 2H, J=5.5 Hz, HO-CH2), 3.75 (m, lH, OCH2b), 3.01 (m, lH, Ph-CH2a), 2.71 (dt, 2H, 35 J=16.8 Hz & J=3.3 Hz, Ph-CH2b & HO), 2.21 (m, lH, C(H)-CH2a), 2.03 (m, lH, C(H)-CH2b) ~; CMR (75 MHz, CDCl3) 166.9, 142.8, 134.1, 130.3, 128.3, 127.4, 124.8, WO 97/022S9 PCT/US96/0868l 75.8, 63.4, 60.6, 52.1, 37.6, 28.9 ~.
Step 3: (s)~ -(2-IIy~lru~y~lyl)-N-methyli~ûchroman-6-carbc~y~m (S)-(S-3) (S)-(-)-1-(2-HyLu~y~:Ulyl)isochroman-6-c~l~u~ylic acid, methyl ester (S)-(S-2, 5 473 mg, 2.0 mmol) and 8.0 mT~ 6M methylamine in mPth~nol are comhin~l The reaction vessel is sealed with a telon 6c~ ,ap and the ~Lula is heated to 75~.After 20 hûurs, the resction ~ixLu~e is cûoled to 20-25~, cont~ ed under reducedples~ula and ~ ated with hexane to give (S)-(-)-1-(2-h~,Lu.~y~ yl)-N-methyl-isochroman-6-c~Lu~ le (S)-(S-3), mp = 99-101~; Rf = 0.20 (5'ro m~th~nnl/dichlûrom~th~nP); [a]D = -119~ (c = 0.8674, mPth~nnl); IR (mull) 3350, 3274, 1648, 1614, 1572, 1564, 1422, 1336, 1320, 1156, 1107, lû78, 1058, 1045, 718, cm~l; NMR (300 MHz, CDCl3) 7.53 (m, 2H, aromatic), 7.08 (d, lH, J=8.7 Hz, aromatic), 6.32 (brds, lH, NH), 4.97 (brdd, lH, J=6.7 Hz, m~lllinP), 4.16 (m, lH, OCH2a), 3.82 (t, 2H, J=5.4 Hz, HO-CH2), 3.74 (m, lH, OCH2b), 3.02 (d, 4H, J=4.9 15 Hz, NCH3 & Ph-CH2a), 2.71 (dt, 2H, J=16.4 Hz & J=3.2 Hz, Ph-CH2b & HO), 2.21 (m, lH, C(H)-CH2a), 2.03 (m, lH, C(H)-CH2b) ~.
Step 4: (S)-(-)-1-(2-M~t~ ~ne~ f nylc.,.yt~ yl)-N-methyli~ûcllLv~ n-6-carbnY~mi~l~ (S)-(T-2) (S)-(-)-1-(2-Hyv~u~.y~:Lhyl)-N-methylisocLlu ,an-6 c~L~ P (S)~S-3, 383 20 mg, 1.6 mmol), 16 mL dichloromPt~nP and triethylamine (0.34 mL, 2.4 mmol) areco~hinP-l followed by cooling to 0~. The ~Lu~. is treated with mP~nP~l1lfonyl chloride (0.15 mL, 1.95 mmol). After 15 min, the reaction is diluted 10 mL
dichlor~mP~ ~ne and washed once with 16 mL water, once with 15 mL saline, dried over m~FnP~illm sulfate, filtered and conre-.l-dLed to give (S)~-)-1-(2-25 mp~h~np~uLfonylc~y~ yl)-N-methyl-isochroman-6-c~~ 1e (S)-(T-2), Rf = 0.35(60% ~cetonP/hexane); NMR (300 MHz, CDCl3) 7.53 (m, 2H, aromatic), 7.11 (d, lH, J=7.9 Hz, aromatic), 6.23 (brds, lH, NH), 4.90 (brdd, lH, J=7.4 Hz, mP~hine)~ 4.46 (m, lH, OCH2a), 4.34 (m, lH, MsO-CH2a), 4.12 (m, lH, MsO-CH2b), 3.76 (m, lH, OCH2b), 3.00 (m, 7H, NCH3, S-CH3, Ph-CH2a), 2.73 (dt, lH, J=16.1 Hz & J=3.2 Hz, 30 Ph-CH2b), 2.42 (m, lH, C(H)-CH2a), 2.14 (m, lH, C(H)-CH2b) o.
Step 5: (S)-(-)-N-Methyl-1-[2-[4-(4-propionylphenyl)-1-pipe~ lyl]ethyl]-isochroman-6-carboY~micle (S)-(IX) A ~i~ e of (S)-(-)-1-(2-m~th~nP,alllfonylu,.y~Ulyl)-N-metlhyl-isochroman-6-carb~ Y~mi-l~ (S)~T-2, 509 mg, 1.5 mmol), 4'-piperazinopropiophPnonP (393 mg, 1.8 35 mmol), and potsQaillm carbonate (622 mg, 4.5 mmol) in ~etonitrile (7.5 mL) isheated to 50~ overnight, then l~:nu~ed for an n~l~lit;~n~l 5 hours. The reaction W O 97/022S9 PCT~US96/08681 ~I ~ue is then cooled to 20-25~ and conce~lt~ d~ed to a residue, which is part;t;nned between water and dichloromPt~nR. The aqueous layer is extracted twice more with dichloromPt~nR and the cnmhinRfl organic layers are washed once with water,once with saline, dried over m~gnPRillm sulfate, filtered and coll~~l~t d~d. This 5 m~t,~rizll i8 purified by LC on 36 g (230~00) silica gel eluting with 60%
~cetomP/hPY~ne This m~teri~l is re"ly~ li7erl from mpth~nol/ethyl acetate to give (S)-(-)-N-methyl-1-[2-[4-(4-propionylphenyl)-1-piperazinyl]ethyl]-i~odl~ ulllan-6-carbnY~mic~e (S)-(IX), mp = 160-161~; Rf = 0.20 (60% ~cetor~P/hexane); IR (mull)3274, 1669, 1640, 1607, 1543, 1522, 1415, 1407, 1315, 1233, 1200, 1156, 1142, 1111, 10 798 cm~1; NMR (300 MHz, CDCl3) 7.87 (d, 2H, J=9.0 Hz, aromatic), 7.55 (m, 2H,aromatic), 7.14 (d, lH, J=8.6 Hz, aromatic), 6.85 (d, 2H, J=9.0 Hz, aromatic), 6.24 (brdd, lH, J=4.6 Hz, NH), 4.86 (brdd, lH, J=5.7 Hz, m~thinR), 4.13 (m, lH, OCH2a), 3.76 (m, lH, OCH2b), 3.34 (t, 4H, J=5.0 Hz, Ph-N-CH28), 3.00 (d, 4H, J=4.9 Hz, N-CH3 & Ph-CH2a), 2.90 (qrt, 2H, J=7.4 Hz, O=C-CH2), 2.75-2.46 (m, 7H, Ph-NC(H2)-15 CH28-NCH28 & Ph-CH2b), 2.14 (m, lH, C(H)-CH2a)~ 2-02 (m~ 1H~ C(H)-CH2b), 1-19(t, 3H, J=7.4 Hz, C(H2)-CH3) o; CMR (75 MHz, CDCl3) 199.3, 168.0, 154.1, 141.5, 134.5, 132.7, 130.0, 127.7, 127.3, 125.0, 124.5, 113.5, 74.4, 63.0, 54.5, 53.0, 47.4, 33.2, 31.2, 29.1, 26.8, 8.9 o; MS (EI, m/z) 435.
~AMPLE 82 (S)~-)-1-[2-[4-(4-Trifluo~o~ce,~yl~henyl)-1-pi~tLdzillyl]ethyl]-N- elllylisocllrc lan-6-c~L~ ~r~irle (S)-(IX) Following the gener~l p~uce-lu~ of ~!~AMPLE 81, Step 5 and mslking non-critical v~ri~ti~n~ but using 4'-piperazinotrifllloromethylrhRn-nR (504 mg, 1.95 mmol) gives crude product. This material is purified by LC on 59 g (230-400) silica gel eluting with 50~ etonR/hexane to give (S)-(-)-1-[2-[4-(~ ' rifln~7roacetylphenyl) 25 piperazinyUethyl]-N-methylisochroman-6-carbnY~mi~le (S)-(IX), Rf = 0.20 (60%
etonP/hexane).
~XAMPLE 83 1-[1-[2-[4-(4-MPt~nyyphenyl)-l-piperazinyl]ethyl]-isochroman-6 yl]calLollyl]pyrrolidine (IX) Following the general p~ucedu~ of F~xAMpLE 30 and ms-king non-critical 30 v~ri~ti~nc but using pyrrolidine (1.26 mL, 15.0 mmol) gives crude product. The crude is purified by flash chrom~t~Eraphy on 100 g silica gel using a gradient of 5-10~ mPt~l~nol in ethyl acetate as the eluent to give purified product.
Recrys~ t;~n from methylene chloride and hexane gives 1-[1-[2-[4~4-mP~l~nYyphenyl)-1-pi~.dzillyl]ethyl]-i~ûchro an-6-yl]c~L,o~ yl]pyrrolidine (IX), mp =
35 156.0-156.5~; Rf = 0.35 (10~o mPt~nnl in ethyl acetate); IR (mull) 1615, 1609, 1563, 1514, 1441, 1254, 1234, 1154, 1106, 825 cm~l; N~ (300 M~z,CDCl3) 7.32 (d, lH, W O 97/02259 PCTnUS96/08681 J=8.0 Hz, aromatic H), 7.29 (8, lH, aromatic H), 7.12 (d, lH, J=7.9 Hz, aromatic H), 6.85 (q, 4H, J=9.2 Hz, aromatic H's), 4.85 (m of d, lH, J=5.8 Hz, PhC-H), 4.17-4.10 (m, lH), 3.80-3.72 (m, lH), 3.76 (s, 3H, PhOC-H3), 3.64 (t, 2H, J=6.7 Hz, C(O)NC-H2), 3.11 (t, 2H, J=6.6 Hz, C(O)NC-H2), 3.11 (t, 4H, J=4.8 Hz, four of pip-H), 2.99 5 (m, lH), 2.73 (m of d, lH, J=16.4 Hz), 2.66-2.49 (m's, 6H), 2.15 (m, lH, pipCH-H), 2.04 (m, lH, pipCH-H), 1.99-1.85 (two slightly overlapping ~luint~L~, 4H, J=7.0 Hz, two of C(O)NCH2C-H2) o; CMR (75 MHz, CDC13) 169.4, 153.6, 145.6, 139.7, 135.2, 134.0,127.7, 124.7, 124.4, 118.0, 114.3, 74.4, 62.9, 55.4, 54.6, 53.4, 50.5, 49.5, 46.1, 33.0, 28.9, 26.3, 24.3 o.
10 li'XAMPLE 84 (+/-)-1-[2-(4-Phenyl-1-pir~ri-linyl)ethyl]isochroman-6-c~
Step 1. (+/-)-2-(6-BromniRorhroman-1-yl)acetic acid A ~LI,uL2 of ethyl (+/-)-2-(6-bromoicorhroman-1-yl)~ret~ts (III, EXAMPLE 1, step 1; 0.77 g, 2.58 mmol), sodium hydroxide (2N, 1.9 mT,) and etl~nol (5 mL) is15 stirred for 75 min, at which time eth~nol is removed under reduced ~ie~
Several millilit~rs of water are added to the residue, followed by hyd~cllloric acid (4N) sl~fflrir-nt to bring the pH of the ~Lu.~ to about 2. The llPi~Lul~ is ~-Ll..~ led with ether and the organic layers are dried with m~E~n~cinm sulfate and ~.~..r_..t-dted to give (+/-)-2-(6-brnmniRorhroman-l-yl)acetic acid (IV), NMR (CDC13) 20 2.69 - 2.97, 3.83, 4.16, 5.18, 6.94 and 7.32 o.
Step 2. (+/-)-2-(6-Brrmri~orhroman-1-yl)ethyl alcohol To (+/-)-2-(6-bromni~orh-~.".an-1-yl)acetic acid (IV, Step 1; 0.82 g, 3.0 mmol) in dry THF (20 mT-) is added borane-methyl sll1fide (0.86 g, 9.1 mmol). After stirring for 2.5 hr, m~~h~nnl is added and the ~Lu~e is cor..~e..l-d~ed under reduced 25 ~}e8~ule. M~t~nnl is again added and the ~i~L~ cnnre~lt c~ed twice more. The residue is then partitionP-l between dichlorrmrth~n~ and aqueous sodium bicarbonate and the organic layers are dried with sodium sulfate and con~ -aLed to give (+/-)-2-(6-bromni~o~ .vll,an-1-yl)ethyl alcohol (S-1), N~ (CDCl3) 2.0, 2.2, 2.64, 2.69, 3.02, 3.70-3.79, 3.82-3.86, 4.15, 4.92, 7.28 S.
Step 3. (+/-)-1-[2-(6-Lr.~.. ~iRocl.-~an-1-yl)ethyl]-4-phe~.ylpi~e.;dine l~/r~~h~nrRlllfi~nyl rhlnri~lr~ (0.22 mT., 2.84 mmol) is added to an ice water-cooled ~Lus~ of (+/-)-2-(6-bromoiRorhroman-1-yl)ethyl alcohol (S-1, step 2; 0.599 g, 2.33 mmol), 4-dimethylaminopyridine (0.016 g, 0.131 mmol), diisopl~pylethylamine(0.49 mL, 2.81 _mol) and dry T~D? (7.5 mL). The ice water bath is removed and the 35 ~ is allowed to warm to 20-25~. When the mesylation is cnmp1~t~ (by TL~), ethylene gycol (2.4 mL), diisopl~ylethylamine (1.0 mL, 5.7 mmol) and 4-W O 97/02259 PCTrUS96/08681 phenylluipel;dine (0.452 g, 2.80 mmol) are added and the l~ Ule is heated overnight at 80~. After cooling, the ~ e is poured into water and eYtracted withdichloromPt7~flnP The comhinP~7 organic layers are dried over sodium sulfate andcnnc~.lt-dted under reduced pre~ule. The residue is chromf7t~graphed (silica gel;
m~lhflnt~l/dichloromPthf7ne, 2/98) to give (+/-)-1-[2-(6-bromoi~o-hroman-1-yl)ethyl]-4-phenylpiperidine (VI), NMR (CDCl3) 1.85, 1.99-2.17, 2.46-2.60, 2.65-2.71, 2.95, 3.09, 3.74, 4.10, 4.77, 6.99 and 7.17-7.32 o.
Step 4. (+/-)-1-[2-(4-Phenyl-1-piperidinyl)ethyl]isochroman-6-carbnYz7midP
A lllil~l,Ule of (+/-)-1[2-(6-bromoi~o-hroman-1-yl)ethyl]4-phe.lyl,ui~el;dine (VI, step 1; 0.422 g, 1.05 mmol), DMF (2.7 mL), 1~ 3~3~3-hr~YflmPt7lylrliRilfl7flne (Aldrich; 1.6 mL, 7.58 mmol), diisoplouylethylamine (0.38 mL, 2.18 mmol), pfllk7~7il7m (II) acetate (0.012 g, 0.053 mmol) and 1,3-bis(diphenylrhosrhino)propane (0.026 g, 0.064 mmol) is ~lPgflRRef7. siY. times under reduced p~ ule and released to carbon monoYi~r each time. The lr~l,ulo is heated at 90~ overnight and then the cooled lllixl,ul~ is poured into hydlocllloric acid (lN, 11 mL) and eYtracted with ether. The pH of the aqueous layer i8 adjusted to 12 using aqueous sodium hydroxide. The aqueous layer then is ~,~Ll~.cLed three times with ethyl acetate and the com70ine~7 organic layers are washed with saline, dried over mngnP~ m sulfate and conre .ll a~ed under reduced pi~ Ule. The residue is chromf7~graphed (si icagel; mPt~flnnl/dichloromPtl~f7nP~mmnnil7m hydroYide, 2/98/0.5) to give (+/-)-1-[2-(4-phenyl-1-piperidinyl)ethyl]isochroman-6-carboYf7mi-7P (VII), NMR (CDCl3) 1.83, 1.99-2.22, 2.51-2.62, 2.74-2.79, 2.97-3.08, 3.78, 4.14, 4.87, 5.63, 6.05, 7.19-7.33 and 7.59 o.
EXAMPLE 85 N-Methyl-1-[2-(4-phenyl-1-piperidinyl)ethyl]isochroman-6-c&L~Y~r~ e~ ma eic acid sa t Step 1. (+/-)-N-Bis(tert-butylu~y~;allJollyl)-l-[2~4-phen piperidinyl)ethyl]isochroman 6 car7QnYflmit7e Following the general procedure of l~xAlvl PLE 3, step 1, and mslking non-critica. variations, (+/-)-1-[2-(4-phenylpiperdin-l-yl)ethyl]isochroman-6-c. .l,-.x~ 7,P
(VII, EXAMPLE 84, 0.231 g, 0.634 mmol), 4-dimethylaminopyridine (0.0098 g, 0.0802 mmol) and di-tert-butyldicarbonate (0.312 g, 1.43 mmol) give (+/-)-N-bis(tert-butylu~yc~l onyl)-1-[2-(4-phenyl-1-piperdinyl)ethyl]isoclllu an-6-carbnY~mi-le (VIII) after chrom~t~;- ~hy (silica gel; mPt~l~nol/dichloromPth~np~ 2/98), NMR (CDCl3) 1.39, 1.84, 2.00-2.20, 2.44-2.63, 2.71-2.81, 2.94-3.15, 3.78, 4.14, 4.89, 7.20-7.30 and 7.60-7.65 ~.
Step 2. N-Methyl-1-[2-(4-phenyl-1-piperidinyl)ethyl]isochroman-6-carbnY~mi-le, maleic acid salt -Methyl amine gas is cc~nclenRe~l into a glass high pres:ju~: reaction vessel cooled at -78~ (under an argon ~t~mnsphPre) and co~ ing a LL~LuLa of ( I /-)-N-bis(tert-butylu"~ . aL l,onyl)- 1-[2-(4-phenyl- 1-piperdinyl)ethyl]isochroman-6-caLl,.~Y~1...irle (VIII, step 1, 0.2818 g, 0.499 mmol) and dichloromPth~nP (4 mL). After 5 several mLs of methylamine are concl~n~ecl into liquid, the vessel is sealed and the lure is allowed to warm to 20-25~, with stirring. After stirring overnight, the vessel is recooled to -78~ and the seal broken. After again warming to 20-25~, the L,L~uLa is conce..t- ~ted under reduced pressure and the rPSllltinF residue is chromatographed (silica gel; mPth~nl~l/dichlornmPth~nP, 3/97 to 5/95) to give N-10 methyl-1-[2-(4-phenyl-1-piperidinyl)ethyl~isochroman-6-carbr.Y~mide (IX).
N-Methyl-1-[2-(4-phenyl-1-piperidinyl)ethyl]isochroman-6-caLlJu~ lP. is treated with maleic acid (0.0360 g, 0.310 mmol) in dichlornmPth~nPlmpth~nol to give N-methyl-1-[2-(4-phenyl-1-piperidinyl)ethyl]isochroman-6-carb.~Y~mi-le, maleic acid salt (B-l[X), NMR (CDCl3) 1.84, 2.05-2.20, 2.52-2.66, 2.72-2.78, 3.01, 3.41, 3.49, 3.78, 15 4.13, 4.35, 6.12, 7.16-7.32 and 7.53 ~.
EXAMPLE 86 (+/-)-1-[2-[4-(2,4-Dichlorophenyl)-1-piperazinyl]ethyl]isochroman-6-c~.l,.~ e Step 1. 1-(2,4-Dichlorophenyl)piperazine A lnixlul~ of 1,3-dichloro-4-fluorobenzene (Q-2) (4.21 g, 25.5 mmol), 20 piperazine (Q-1, 11.0 g, 128 mmol) and dimethyl~et~mide (15 mL) i8 heated at 165~
for 6.8 ]hr, at which time the ~PLL~U a is cooled and partitionp~l between dichlorc~mPt~nP and aqueous sodium bicarbonate. The org~nic layers are dried with sodium sulfate and conre--l-d~ed under high vacullm to give 1-(2,4-dichlorophenyl)piperazine (Q-3), which was sllffl~ipntly pure to use in step 2 without 25 further purific~tion $tep 2. (+/-)-1-[2-(6-Bromni~orhroman-1-yl)ethyl]4-(2,4-dichlorophenyl)piperazine ]Following the general pl~cedula of EXAMPLE 84, step 3 and m~king non-critical variations, (+/-)-2-(6-bromni~ochlu lan-l-yl)ethyl alcohol (S-1) (EXAMPLE 84, 30 step 2; 0.60 g, 2.31 mmol), 4-dimethylaminopyridine (0.018 g, 0.147 mmol), diisu~ur~"uylethylamine (0.49 mL, 2.81 mmol), mpth~npsulfonyl chlorillP (0.22 mL, 2.84 mmol) and dry THF (7.5 mL) are collv~lad to the mesylate (T-1). The mesylate is treated with diisop.v~uylethylamine (1.0 mL, 5.7 mmol), 1-(2,4-dichlorophenyl)piperazine (Q-3, step 1; 0.65 g, 2.82 mmol) and ethylene glycol to 35 give, after chrnm~to~ uhy (silica gel; mpth~novdichloromptl~np~ 2/98) (+/-)-1-[2-(6-bromoi~o~hroman-1-yl)ethyl]-4-(2,4-dichlorophenyl)piperazine (VI), NMR (CDCl3) CA 02225282 l997-l2-l9 W O 97/022S9 PCTrUS96/08681 2.01, 2.10, 2.65-2.71, 2.95, 3.05, 3.74, 4.11, 4.78, 6.96, 7.18 and 7.26-7.36 ~.Step 3. (+/-)-1-[2-[4-(2,4-Dichlorophenyl)-1-piperazinyl]ethyl]isochroman-6-ca~
Following the general procedure of EXAMPLE 84, step 4, and making non-5 critical variations, (+/-)-1-[2-(6-brf~mni~ochroman-1-yl)ethyl]-4-(2,4-dichlorophenyl)piperazine (VI, step 1; 0.373 g, 0.794 mmol), gives 0.095 g of (+/-)-1-[2-[4-(2,4-dichlorophenyl)-1-piperazinyl]ethyl]isochroman-6-c~1.... ,1...i ~ (VII) after chrom~;. dphy (silica gel; mf~t~n- l/dichlorom-~thAne, 2/98), NMR (CDCl3) 2.05, 2.15, 2.50-2.80, 3.05, 3.78, 4.15, 4.87, 5.62, 6.04, 6.96, 7.19, 7.35 and 7.60 o.~0 F~Al\/IPLE 87 (+/-)-N-Methyl-1-[2-[4-(2,4-dichlorophenyl)-1-piperazinyl]ethyl]isochroman-6-call,n Y ~ . ";~
Step 1. (+/-)-N-Bis(tert-butyloAy~i~bonyl)-l-[2-[4-(2~4-dichlorophenyl) piperazinyl]ethyl]isochroman-6-carbf~ Y~mide Following the general proce-lule of EXAMPLE 3, step 1, and mAkinF non-16 critical vAriAtiorl~ (+/-)-1-[2-[4-(2,4-dichlorophenyl)-1-pipel~zillyl]ethyl]isochroman-6-c~b.~ (VI, EXAMPLE 86, step 2; 0.0854 g, 0.198 mmol), 4-dimethyl~minopyridine (0.0046 g, 0.0377 _mol) and di-tert-butyl dicarbonate (0.0982 g, 0.450 mmol) give, after chrnmAIo~.~phy (silica gel;
ml~t~nl~l/dichlorom~t~Ane, 2/98), (+/-)-N-bis(tert-butyluAy~ nyl)-1-[2-[4-(2,4-20 dichlorophenyl)-1-piperazinyl]ethyl]isochroman-6-c~ rifle (VIII), NMR (CDC13)1.40, 2.05, 2.17, 2.51-2.79, 2.95-3.05, 3.78, 4.15, 4.89, 6.96, 7.19, 7.35 and 7.60-7.66 o.
Step 2. (+/-)-N-Methyl-1-[2-[4-(2,4-dichlorophenyl)-1-piperazinyl]ethyl]igochlvluan 6 carbnY~mi~lA
Following the general p~ucedul c, of EXAMPLE 85, step 2, and mAkinE non-critical vAriAt;r~n~ (+/-)-N-bis(tert-butyloxycarbonyl)-1-[2-[4-(2,4-dichlorophenyl)-1-pi~e~ yl]ethyl]isochroman-6-c~l,nY,1...i-lA (VIII, step 1; 0.104 g, 0.164 mmol) gives after chrom~l,o~phy (silica gel; mPt~lAnol/dichlorompt)lAnA~ 1.5/98.5 to 3/97 to 5/95) a solid. This m~teri~l was cryst~lli7Ad from ~ret~nitrilPlheAane to give (+/-)-N-methyl-1-[2-[4-(2,4-dichlorophenyl)-1-piperazinyl]ethyl]isochroman-6-c ~ 1,. .Y ~ . . .i~F!
(IX), MS (m/z) = 447; IR (mineral oil; most intense peaks) 1637, 1478, 1572, 1558, 1450, 3289 and 1107 cm~1; NMR (CDCl3) 2.05, 2.16, 2.52-2.78, 3.03, 3.77, 4.13, 4.86, 6.10, 6.96, 7.17, 7.36 and 7.54 o.
~AMPLE 88 1-[2-[4-(3-Chloro-4-methoxyphenyl)-1- ., piperazinyl]ethyl]isochroman-6 carbnY~mi-1e Step 1. 1~3-Chloro-4-m~t~nYyphenyl)piperazine CA 02225282 l997-l2-l9 W O 97/02259 PCT~US96/08681 A ~llixLu~: of 3-chloro-p-~ni~i-linP (R-2, 0.633 g, 4.00 mmol), bis(2-chlc~l~el~s~ mine slydsocllloride (0.860 4.80 mlnol~, pot~CRillm carbonate (1.11 g, 8.00 mmol) and diméthyl~-~ehmi~lP (6 mL) is stirred at 100~ for 18 hr and then cooled. The ~ u~e ispartitinnpcl between dichloromPth~mP, water and aqueous 5 sodium bicarbonate and the organic layers are dried with sodium sulfate and concPntrated. The residue is chrom~t~u~c.phed (silica gel;
mPths~nnl/dichloromPtl-~ne, 8/92) to give 1-(3-chloro4-mpthnyyphenyl)piperazine (R-3), N~ (CDCl3) 3.05, 3.86, 6.80, 6.87 and 6.99 o.
Step 2. (+/-)-1-[2-(6-Br)mni~orhroman-l-yl)ethyl]4-(3-chloro4-methoxyphenyl)piperazine Following the general ~locedl~e of ~AMPLE 84, step 3, (+/-)-2-(6-bromni~orhroman-l-yl)ethyl alcohol (S-l, EXAMPLE 84, step 3, 0.450 g, 1.75 mmol), 4-dimethylaminopyridine (0.012g, 0.0990 mmol), diiso~ropylethylamine (0.32 mL, 1.84 mmol), mPt~nesulfonyl chloride (0.14 mL, 1.81 mmol) and d-y TED~ (5.6 mL) are eullv~sled to the mesySate. ~ it.icm~l portions of diisoproplyethylamine (0.18 mL, 1.03 mmol) and m~tl~nP~ fr,nyl rhlori~l~ (0.08 mL, 1.03 m~nol) are added to complete the form~tion of the me~ylate. To the mesylate then is added dii~u~ropylethylamine (0.65 mL, 4.26 msnol), 1-(3-chloro4-mPthnYyphenyl)piperazine (step 1; 0.398 g, 1.75 mmol) and ethylene glycol (1.8 mL). The s~Lu~e is stirred at 80~ for 3 hr and then overs~ight at 20-25~, after which the sllixl,us~ again is heated for 4 hr at 80~. A~ition~l 1-(3-chloro4-mPthnYyphenyl)piperazine (0.0443 g, 0.195 mmol) is added and the mi~ul~: is heated ~nn~lPr 3 hr. After cooling, the slliXl~Ule is parfftioned be~w~sl dichlorc mPth~nP and aqueous sodium bicarbonate and the organic layers are dried with sodium sulfate and conre~ d~ d. The residue is chrom~to~-aphed (silica gel; mPth~nol/dichlornmpth~ne~ 2/98) to give (+/-)-1-t2-(6-bromni~o~hroman-l-yl)ethyl]-4-(3-chloro-4-methoxyphenyl)piperazine (VI), NMR
(CDCl3) 2.01, 2.10, 2.52-2.71, 2.96, 3.10, 3.75, 3.85, 4.10, 4.78, 6.77-6.87, 6.98 and 7.29 o.
Step 3. (+/-)-l-t2-t4-(3-Chsoro-4-mPthn~s7phenyl)-l-pipesdzssl~l]etlhyl]isochroman-6-carbny~midp Following the general pr)celluse, of ~AMPLE 84, step 4, and m~king non-crstical v~ri~tinnR (+/-)-1-[2-(6-brnmoi~o~h-uslsan-1-yl)ethyl]-4-(3-chloro-4-metho~yphenyl)piperazine (VI, Step 2; 0.420 g, 0.902 mmol), DMF (2.3 mL), 3~3~3-hPy~mp-thyl~iRil~np (1.4 mL, 6.64 m_ol), diisu~su,uylethylamine (0.34 mL, 1.95 mmol), p~ m (II) acetate (0.0110 g, 0.049 mmol) and 1,3-bis(diphenylph~Rphino)propane (0.024 g, 0.0575 ~nol) give (+/-)-l-t2-[4-(3-chloro-4 W O 97/02259 PCTrUS96/08681 methoxyphenyl)- 1-piperazinyl]ethyl]isochru...an-6-ca~ . x ~ l P (VII) . After chrom~ phy (silica gel; mPtl~nnl/dichlornmpth~np~ 2/98), NMR (CDCl3) 2.06, 2.15, 2.53-2.64, 2.74-2.79, 3.02, 3.11, 3.77, 3.84, 4.14, 4.87, 5.60, 6.04, 6.77-6.87, 6.98, 7.18 and 7.60 8.
T'~x~ pLE 89 (+/-)-1-[2-[4-(3-Chloro-4-methn~yphenyl)-1-piperzinyl]ethyl]-N-methylisochroman-6-caL 1, ~ ~ X ~ ~ ~ ~ i d e Step 1. (+/-)-N-Bis(tert-butyloxycarbonyl)-1-[2-[4-(3-chloro-4-methoxyphenyl)-l-piperazinyl]ethyl]isochroman-6-carbn~r~mi~p Following the general p.ucedu~ of EXAMPLE 3, step 1, and making non-10 critical variations, (+/-)-1-t2-[4-(3-chloro-4-mPthn~yphenyl)-1-piperazinyl]ethyl]isochroman-6-carbnY~mi~e (VII, EXAMPLE 88, step 3; 0.153 g, 0.355 mmol), 4-dimethylaminopyridine (0.0086 g, 0.0704 mmol) and di-tert-butyldicarbonate (0.186 g, 0.853 mmol) give, after chrom~to~.aphy (silica gel;
mf~th~noVdichlorom~th~ne, 2/98), (+/-)-N-bis(tert-butyk,Ay. arbu..yl)-1-[2-[4-(3-chloro-15 4-mPthn~ryphenyl)-1-piperazinyl]ethyl]isocllrol..an-6 c~l.oY~...i~P (VIII). NMR
(CDCl3) 1.39, 2.03, 2.14, 2.48-2.64, 2.73-2.80, 3.00, 3.11, 3.78, 3.85, 4.14, 4.88, 6.80-6.88, 6.98, 7.20 and 7.60-7.65 8.
Step 2. (+/-)-N-Methyl-1-[2-[4-(3-chloro-4-mPthnyyphenyl) piperzinyl]ethyl]isochroman-6-call....,....i~le Following the general prùce-lu e of Ti~AMpLE 85, step 2, and m~king non-critical variations, (+/-)-N-bis(tert-butyluAycal~ullyl)-1-[2-[4-(3-chloro-4-methoxyphenyl)-l-pip~zi--yl]ethyl]isochroman-6-ca~ le (VIII, step 1; 0.183 g, 0.290 mmol) gives 0.118 g of product after chrom~tography (silica gel;
mPth~nol/dichloromPth~ne, 2/98). The product is cry~t~ p~l from ethyl acetate/mPth~nnl/hexane and then from ethyl acetate/dichloromPth~ne to give (+/-)-1-[2-[4-(3-chloro4-mPthn~ryphenyl)-l-piperzinyl]ethyl]-N-methylisGchro...anyl-6-c~bnxJ~ P (IX), MS (m/z) 443; IR (mineral oil, most intense peaks) 1508, 1642, 3266, 1112, 1548, 1274 and 949 cm~1; NMR (CDCl3) 2.09, 2.21, 2.58-2.77, 3.01, 3.15, 3.76, 3.85, 4.15, 4.88, 6.12, 6.77-6.88, 6.98, 7.17 and, 7.54 8.~0 T~'XAlVIPLE 90 N-(2-IIydluAyt~ yl)-1-[2-4~4-mptllnl~yphenyl) piperazinyl]ethyl]isochroman-6 c~l,..x~...i-le Step 1. (+/-)-1-2-(6-Bromni~ochroman-1-yl)acetyl-4~4-m~thnYyphenyl)piperazine A ~LuAluLe of (+/-)-2-(6-bromoisochroman-1-yl)acetic acid (IV, T~AMpLE 84, 35 step 1; 4.66 g, 0.0172 mol), dichloromPth~nP (18 mL), DMF (18 mT ), diethyl cyanophnsphon~ (3.4 mL, 0.022 mol), 1-(4-mPthnxyphenyl)piperazine hydrochloride CA 02225282 l997-l2-l9 W O 97/022S9 PCTnUS96/08681 (R-3) (Aldrich; 4.78 g, O.OZ1 mol) and triethylamine (6.5 mL, 0.047 mol) is stirred at 20-25~ for 2.5 hours. Satulated sodium bicarbonate sodium bicarbonate (100 mL) is added to the mixture and the l-~Lu~is allowed to stir for 20 min, at which time it is extracted with dichloromPt~Ane The comhimP~l organic layers are dried over ms~f~npRillnn sulfate and cnn.~ ted under reduced ~ e. The residue is washed twice with hexane (discard) and the residue again is conl~ntrated under reduced pressure. The residue is chromAt~ graphed (silica gel; ethyl acetate/hPYAnP~
50/50) to give (+/-)-1-2-(6-bromni~o~ .u.l.an-l-yl)acetyl4-(4-methûxyphenyl)piperazine (V), NMR (CDCl3) 2.63-2.69, 2.74-2.80, 2.90-3.08, 3.59-1û 3.96,4.11,5.26,6.87,7.01,7.31~.
Step 2. (+/-)-1-[2-(6-Bromoisochroman-1-yl)ethyl]-4-methoxyphenylpiperazine Following the general pl~Ce~ e of EXA~!LPLE 1, step 4, but using bor_ne-methyl sulfide (14 mL) in place of borane-THF, (+/-)-1-2-(6-bromni~o. l..u.~an-1-yl)acetyl-4-(4-mPtl~oYyphenyl)piperazine(V, step 1; 5.83 g,0.013 mol) gives 4.33 g of (+/-)-1-[2-(6-bromni~orhroman-l-yl)ethyl]-4-methoYyphe~lylpi~elazine (VI), N~
(CDCl3) 2.00, 2.12, 2.49-2.71, 2.95, 3.10, 3.75, 4.11, 4.78, 6.87, 6.97 and 7.29 o.
Step 3. (+/-)-l-t2-t4-(4-MPt~nyyphenyl)-l-piperazinyl]ethyl]i8ochr 6-carboYAmi~P
Following the general ~.u~edul~ of F~AMPLE 84, step 4, (+/-)-1-t2-(6-bromni.qGrh.u ~an-1-yl)ethyl]4-(methoxyphenyl)piperazine (VI, step 2; 4.29 g, 9.95 mmol) gives (+/-)-1-t2-[4-(4-methoxyphenyl)-1-pi~dzi~yl]ethyl]isochroman-6-carboYAmi-l~ (VII), NMR (CDCl3) 2.06, 2.16, 2.54-2.79, 2.99, 3.11, 3.77, 4.15, 4.87, 5.64, 6.06, 6.87, 7.19 and 7.59 o.
Step 4. (+/-)-N-Bis(tert-butylu,Ly~bu~lyl)-l-[2-t4-(methoxyphenyl) piperazinyl]ethyl]isochroman 6 car~oYAmi(l~
Follovring the general plocc:du~e of F'XAl\/IPLE 3, step 1, (+/-)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]isochroman-6-carbc.~r~mi(le (VII, step 3; 1.97 g, 4.97 mmLol), 4-dimethylaminopyridine (0.0816 g, 0.668 mmol) and di-tert-butyl-30 dicarbonate (2.56 g, 0.0117 mol) gives (+/-)-N-bis(tert-butylu~.y. ~bu~.yl)-1-[2-[4-mPt~nYyphenyl)-1-piperazinyl]ethyl]isochroman-6-c~b.-~A..-i-le (VIII), NMR (CDC13) 1.39, 2.03, 2.15, 2.53-2.78, 2.99, 3.11, 3.77, 4.13, 4.88, 6.85, 7.21 and 7.63 o.
Step 5. N-(2-hy-l~u.sy~Lllyl)-1-[2-4-(4-methoxyphenyl)-1-piperazinyl]ethyl]isoclllulllanyl-6-ca~L.~ le A ~ule of (+/-)-N-bis(tert-butylu,.. ~bù,lyl)-1-[2-t4-(mPtl~oYyphenyl)-1-piperazinyl]ethyl]isochroman-6-carbnY~mi-le (VIII, step 4; 0.216 g, 0.362 mmol), W O 97/022S9 PCTrUS96/08681 dichlorometh~ne (7 mT ) and eth~nol~min~ (0.2 ~, 3.31 Inol) is stirred overnightat 20-25~. The llliXLUlG i6 then partit;on~-l between water and dichlorom~th~n~
The comhin~l organic layers are dried over sodium sulfate and co~ dted under reduced 1;JIG~ U1G. The residue is chrom~t~graphed (silica gel;
5 m~ths~nol/dichlorom~ths3ne (4/96) to give product which is cry~t~ 7ecl from dichlorom~th~n~hexane/ethyl acetate to give 0.090 g of N-(2-hydroxyethyl)-1-[2-4~4-methoxyphenyl)-l-piperazinyl]ethyl]isochromanyl-6-carb--Y~mi-1~ (IX), MS (m/z) 439;
IR (mineral oil) (most intense peaks) 1514, 1631, 1554, 1031, 3293, 1249 and 1613 cm~1; NMR (CDCl3) 2.05, 2.15, 2.51-2.78, 3.01, 3.11, 3.63, 3.77, 3.85, 4.13, 4.86, 6.59, 10 6.87, 7.17 and 7.57 ~.
EXAMPLE 91 1-[2-[4-(4-M~oth ~Yyphenyl)- l-piperazinyl]ethyl]-N-(phenylmPthnyy)isochroman-6-cal1~ e A llliXl~UlG of (+/-)-N-bis(tert-butylu~y~Lùnlyl)-l-[2-[4-(4-m~thnyyphenyl)-l-piperazinyl]ethyl]isochroman-6-carl,.-~ le (VIII, EXA ret7, step 4; 0.206 g, 0.345 15 mmol), THF (7 mT.)~ O-benzylhyd-u~ylamine h ydlochloride (0.0645 g, 0.4041 mmol) and diiso~rv,uylethylamine (0.12 mL, 0.689 mmol) i8 are heated at reflux for 7 hours.
The llli~ then is stirred at 20-25~ for two days, at which time s~ ition~l O
benzyllly.l~u,~ylamine hydlo~ ri-l~ (0.323 g, 2.03 mmol) and diiso~.u~ylethylamine (0.35 mT-, 2.01 Inol) are added. After stirring overnight at 85-90~, THF is removed 20 by cc,~-r~ Lil-g under reduced plG~UlG and the residue is parfftion~-l between dichlorom~th~ne and water. The cc-mhine-l organic layers are dried over sodium sulfate and co..c~ ed under reduced ~llGI~ to give crude m~t~ri~l This ms~t,çri~l is chr~ ms~c~;.dphed (silica gel; mf~thsln-71/dichlorom~oth~n~ 4/96) to give the product which is cryst~ etl from h~Y~n~ethyl ~cetste/dichlorom~th~neim~th~nol to25 give the title compound, MS (m/z) 501; NMR (CDCl3) 2.03, 2.12, 2.48-2.75, 2.98, 3.10, 3.77, 4.11, 4.84, 5.05, 6.86, 7.14, 7.41 and 8.43 ~.
EXAMPLE 92 (+/-)-1-[1-[2-[4-(4-M~thnYyphenyl)-1-piperazinyUethyl]isochroman-6-yl]-4-mel.llyl,ui~erazine A ~ ule of (+/-)-N-bis(tert-butylc.~y. &.I.ùnyl)-1-[2-[4-(4-methoxyphenyl)-1-30 ~i,uelazillyl]ethyl]isochroman-6-c.~L~ (VIII, EXA ret7, step 4; 0.211 g, 0.355 mmol), THF (11 mT-), diisoproplyethylamine (0.6 mL, 3.44 mmol) and 1-methylpiperazine (0.4 mL, 3.6 mmol) is stirred over a weekend at 20-25~, after which THF is removed under reduced ples~ and the residue is partitioned between dichlorom~th~n~ and water. The comhin~ organic layers are dried over 35 ms~gn~ lm sulfate and con~e..l-dted under reduced p~ le to give crude product.
The crude product is chrom~twgraphed (silica gel; mpth~nol/dichlorom~th~ne~ 2/98 to W 097/022S9 PCT/U~,5.'~ 6~1 4/96). The p~u1ucl i8~ ~-t~ from ethyl acetate and hexane to give the title compound, a portion is le~ i7e~1 from ethyl o-~eto~e, MS (mJz) 478; N~
(CDCl3) 2.09, 2.32, 2.48-2.75, 2.99, 3.11, 3.47, 3.76, 4.13, 4.86, 6.86 and 7.18 ~.
- T~AlVlPLE 93 (+/-)-N-Hydlu~y-1-[2-[4-(4-mPthn~ryphenyl)-1-pipG~ yl]ethyl]-N-methylisochroman-6-ca~ or.,ide A ~ Llu. e of (+/-)-N-bis(tert-butyl~ yc~ ullyl)-l-[2-[4-(4-methoxyphenyl)-l-piperazinyl]ethyl]isocLluluan-6-ca~ P (VIII, EXA ret7, step 4; 0.205 g, 0.344 mmol), dichloromPtll-one (7 mL), N-methylhy~llu~ylo-mine hy~llucl~loride (0.271 g, 3.25 mmol) and dii6ùp.~0~ylethylamine (0.60 mL, 3.44 mmol) are stirred overnight at 20-25~. The ~ U~G then is parfftionP~ between dichlorompthone and water. The comhinP-l organic layers are dried over sodium sulfate and conc.~ ated under reduced ~rG-~u G. The residue i8chromAtographed (silica gel;
mPth~nol/dichlorompt~l~np) 2/98 to 4/96) to give the desired product which is upon cryst~lli7~t;~n from hexane/mPthAn~-l/dichlor ~mp~An~/ethyl acetate gives the title cu~ ou~d, MS (Jz) 425; NMR (CDC13) 2.05, 2.17, 2.54-2.77, 3.00, 3.11, 3.42, 3.77, 4.13,4.85,6.87,7.17and7.33~.
T~Al\/IPLE 94 (S)-(-)-1-[2-[4-[4-(ter~Butylu~,~l,onyl)phenyl]-1-piperazinyl]ethyl]-N-methylisochroman-6-c~ ,.,i-la (V-2) 8tep 1. 4-FluorobPn7oic acid, ter~butyl ester To a ~olllt;~n of 4-fluorobenzoic acid (18.7 g, 0.133 mol) in DMF (140 mT-) is added 1,1-ca~l,oll~kliimirlAl7ol-p (21.6 g, 0.134 mol). The lllib~ is heated for 1 hour at 40~, at which time t-butanol (26 mL, 0.272 mol) and DBU (20.5 mL, 0.137 mol) are added. After stirring overnight at 40~, the cooled ~lu~e is poured into ethyl ether (1300 mL) and washed with hydrochloric acid (10%, 250 mL), followed by water (250 mT) and then pot~ - carbonate (10%, 250 mT-). The ether layer is dried over sodium sulfate and concenhated under redllced ple~_u~e. The residue is chromA~ . aphed (silica gel; ethyl acetate/hPY~na, 10/90) to give 4-fluorobenzoic acid, tert-butyl ester (Q-2); MS (m/z) 196; N~ (CDC13) 1.59, 7.07 and 7.99 ~.
Step 2. 4~ri~ az~-1-yl)benzoic acid, tert-butyl ester A m-~Llu-~ of 4-fluorobenzoic acid, tert-butyl ester (Q-2) (step 1; 20.5 g, 0.105 mol), piperazine (52.8 g, 0.613 mol) and dimethylAcet-mi~e (121 mL) is heated at150-155~ for 160 ",;"l,lPs After CoolinF~ the solid i8 removed by filtration andwashed with hPY~ne The comhinPd filtrates are conrentrated under high vacuum and the residue is partit;~na~l between dichlor mPthAne and water. The comhinPc~organic layers are dried over sodium sulfate and concent~ated under reduced pIeooul~ The slightly solvent-wet solids are ~lllrrie~ in heYane and the solid is CA 02225282 l997-l2-l9 W O 97/022S9 PCTnUS96/08681 collecte-l and washed with h~Y~n~. The solids are dried at 20-25~ under reduced pressure to give the t-butyl 4-(piperazin-1-yl)bPn7o~te A-1-lition~1 product i8 obtained by conr9. .t ~ alion of the filtrate and chrom~t~Fraphy of the resulting residue (silica gel; m~th~n-~l/dichlorom~th~n~/~mmnnillm hydroxide, 3.5/96.5/0.5 to 719310.5) 5 to give 4-(pipe~ -1-yl)benzoic acid, t-butyl ester (Q-3); MS (m/z) 262; NMR
(CDCl3) 1.57, 3.01, 3.25, 6.84 and 7.87 o.
Step 3. (S)-(-)-4-[4-[2-(6-brom- iRorhroman-1-yl)ethyl]-1-piperazinyl]benzoic acid, tert-butyl ester (V-1) Following the general procedure of EXAMPLE 84, step 3, and m~king non-10 critical variations, (S)-(-)-2-(6-br?moiRochroman-1-yl)ethyl alcohol (S-1) (EXAMPLE
6, step 1; 4.95 g, 0.0193 mol) and 4-(piperazin-1-yl)benzoic acid, tert-butyl ester (Q-3) (step 2; 5.42 g, 0.0206 mol) gives the title culll,uuu~d, MS (m/z) 500; NMR (CDC13) 1.57, 2.02, 2.12, 2.50-2.70, 2.95, 3.32, 3.73, 4.10, 4.79, 6.85, 6.97, 7.29 and 7.86 o.
Step 4. (S)-(-)-1-[2-[4-[4-(tert-ButyL~y~ lJullyl)phenyl]-1-~ zi~lyl]ethyl]-N-methyli~ocllru~an-6-c~ul,u A l~lura of (S)-(-)-4-[4-[2-(6-brom- iRo-hroman-1-yl]ethyl]-1-piperazinyl]h~n7Oi~ acid, tert-butyl ester (V-1) (step 3; 2.63 g, 5.25 mmol) in dimethyl.lc~L ~ ide (45 mL) which has been tleg~RRe~l and released to argon is added to pQll~ lm (II) acetate (0.0616 g, 0.274 mmol), 1,3-bis(diphenylrh-)sphino)propane 20 (0.164 g, 0.396 mmol) and diisop~o~uylethylamine (1.8 mL, 0.0103 mol). The ll~i~lule is ~l~g~Re-l a second time, rele~RinF to argon. The llliXl~Ula is heated at 60-65~ while carbon monoY~ is bubbled into the ll~ u a. After several minllt~R methylamine isalso bubbled into the n~i~ula. After he~ting for 6.5 hours at 60-65~, the )~i~lu~a is stored overnight in the refrigerator. The lllLb~ula then i8 filtered through 25 ~ tom~eous earth and ~ ition~l portions of p~ illm (II) acetate (0.065 g, 0.290 mmol), 1,3-bis(diphenylphosphinn)propane (0.162 g, 0.392 mmol) and dusopropylethylamine (1.8 mL, 0.0103 mol) are added to the filtrate, which is heated at 60~ for 4 hr with the ~ it;on of carbon m~noy~ and methylamine gases, after which the ll~ Lula is cooled and co- c~ a~ed under reduced ~ . The residue 30 is partiti~n~ between dichlorom?~n~ and water. The comhin.o~l organic layers are washed with water and saline and dried over sodium sulfate and conce~ Led under reduced plah~u~:. The residue is chrom~ dphed (silica gel;
mA~h~nA,l/dichloromethane, 2/98 to 4/96). Impure fractions are comhine~l and rechrom~t4~.d~hed (silica gel; m~th~nnl/dichlor~A~m~h~n~s~ 2/98) to give the title 35 cvlll~vulld, MS (mlz) 479; NMR (CDCl3) 1.56, 2.03, 2.16, 2.48-2.79, 3.01, 3.32, 3.76, 4.14, 4.86, 6.08, 6.84, 7.15, 7.53 and 7.86 ~.

W O 97/02259 PCT/u~5l~s~l FXA MPLE 95 (+/~ -[2-[4-(4-MPt~nYyphenyl)-l-piperazinyl]ethyl]isochroman-6-ol, methyl carbamate ester (X-6) Step 1. (+/-)-2-(6-IIyd~u~yisochroman-1-yl)acetic acid, ethyl ester To an ice-cooled ~xture of 3-hydlv~yl~hPnethyl alcohol (X-1) (2.9 g, 21 mmol) 5 and ethyl 3,3-diethu~y~-vpionate (4.75 g, 25 mmol) in nitrom~t~np (5 mL) i8 added boron trifluoride etherate (3.44 mL). After the ~ liti~n is comrl~tP (about 5 min) the reaction is stirred for an A,l~litinn~l 60 min. The ...i,~u,.3 is then part;tionPcl between dichloromPth~nP and aqueous ~mm~nillm rhlorirlP The organic layers are dried vwith sodium sulfate and con(e..l.dled. The residue is chroTn~tographed (silica 10 gel; ethyl acetate/hPY~nP~ 10/90 to 30/70) to give (+/-)-2-(6-h~d~u~yisochroman-1-yl)acetic acid, ethyl ester (X-2), NMR (CDCl3) 1.28, 2.6-3.0, 3.79, 4.09, 4.21, 5.07, 5.19, 6.60, 6.67 and 6.91 o.
Step 2. (+/-)-2-(6-Hydroxyisochroman-l-yl)acetic acid To (6-hyd~v~yisochroman-1-yl)acetic acid, ethyl ester (X-2) (step 1; 2.38 g, 15 10.1 mmol) in eth~nol (10-15 mT-) is added sodium hydroxide (2N, 10 ~). The ...i,.l.~a is stirred overnight and eth~nol is then removed under reduced pl~S.i~e.
The rPRllltinE aqueous ~ is then diluted with several mLs of saline and ifiPd with llyd~u~l-loric acid (3N), and the ~ Le is ~ ..o~d with ethyl ether and conc~ d~ed. To remove rPm~ininE starting material, the residue is part;ti~n 20 between aqueous sodium bicarbonate and dichlorompt~ ~ne. The organic phase isremoved and the aqueous layer is ~ lifiP-l with con~e~ d~ed llyd~u~llloric acid and then extracted with ether. The ether layer is dried over m~EnQ~inm sulfate and conc~l dted. The conrPntrate is crystolli~P~l from THF/hPy~np~dichlorompth~n-p to give (+/-)-2-(6-hyd.u~yisoch.v~l~an-1-yl)acetic acid (X-3), NMR (CDCl3) 2.1-3.0, 3.81, 25 4.15, 5.2, 6.59, 6.68 and 6.90 o.
Step 3. (+/-)-1-2-(6-Hydroxyisochroman-1-yl)acetyl-4-(4-mPt~l~Yyphenyl)piperazine To a l~ e of (+/-)-2-(6-hyd~u~yisochlulllan-1-yl)acetic acid (X-3) (step 2;
0.361 g, 1.73 mm~ol), 1-(4-methoxyphenyl)piperazine dilly.Lu~hl-ri-lQ (0.458 g, 1.73 30 mmol), dichloromPt~ne (5 m~ ), and DMF (0.5 mT~) iS added triethylamine (0.80 mL, 5.72 mmol) and then diethyl cyanophosphon~t,P (0.29 mL, 1.91 mmol). After stirring for 50 min, water is added and the ~-~xLu~a is stirred for 1 hour. The ~xLu~a isthen extracted with dichlor mPth~ne and the organic layers are st,~alaLed, cnmhinpd and washed with aqueous sodium bicarbonate. The organic layers are dried with 35 sodium sulfate and con~-h~ Led. The residue is cryst~ ed from ethyl acetate-dichloromPthAnp-mpt~nol to give (+/-)-1-2-(6-hy~l~u~yisochroman-1-yl)acetyl4-(4-W O 97/022S9 PCT~US96/08681 methoxyphenyl)piperazine (X-4), NMR (DMSO) 2.57-2.63, 2.73-2.90, 2.97, 3.64, 3.69, 3.95, 5.03, 6.51, 6.57, 6.8-7.0 and 9.27 ~.
Step 4. (+/-)-1-[2-t4-(4-Mathn~yphenyl)-l-piperazinyl]ethyl]i6Ochroman-6-ol A ~i"~u. e of (+/-)-1-2-(6-hydroxynsochroman-1-yl)acetyl-4-(4-methoxyphenyl)piperazine (X-4) (step 3; 0.375 g, 0.98 mmol), borane methylsulfide (0.28 _L, 2.9 mmol), and TE~ (15 mL) is stirred overnight at 20-25~ and then at 80 for 2 hr. After cooling, the n~Al,u.e is treated with mpth~nol and co~cantrated under reduced ~U~c~S~Ule. The ~ tion of m.oth~nol and con-enl-dLion is repeated twice more and then the residue is stirred for 3 hr in hydrochloric acid/~cetone (4N, lJ9, 5 ml). The ~-~et~na is then removed under reduced p~e~uLe and the residue is part~tiona-l between dichlorom~t~nP and aqueous sodium bicarbonate. The organic layers are dried with sodium bicarbonate and con--e..t~dted. The residue is cryst~lli7e~ from dichlorom~th~n~/hexane to give (+/-)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]isochroman-6-ol (X-5), NMR (CDC13) 2.05, 2.21, 2.5-2.7, 2.94, 3.13, 3.70, 3.76, 4.10, 4.82, 6.41, 6.57 and 6.80-6.91 o.
Step 5. (+/-)-1-[2-[4-(4-M~thnYyphenyl)-l-piperazinyl]ethyl]isochroman-6-ol, methyl carbamate ester To a ~lliA~ule of (+/-)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]isoch.u .an-6-ol (X-5) (step 4; 0.064 g, 0.17 mmol) and DBU (0.032 g, 0.21 mmol) in dichlorom~th~na (2 mL) is added methylisocyanate (0.031 mL; 0.52 _mol). After sPr~ing for 1.5 hr, the ~ Lu~e is partioned between dichlorompth~n~and dilute sodium hydroxide. The organic layers are dried with sodium sulfate and cnnr.qnt~ ated. The residue is chrom~t~ hed (silica gel;
m~th~nol/dichlorom~ np~ 2/98) to give (+/-)-1-[2-t4-(4-methoxyphenyl)-1-piperazinyl]ethyl]isochroman-6-ol, methyl carbamate ester (X-6) which after cryst~lli7~t;~n from ether/h.oY~ne. MS (m/z) at 425; N~ (CDC13) 2.04, 2.12, 2.65, 2.90, 3.11, 3.75, 3.77, 4.11, 4.83, 4.98, 6.82-6.95 and 7.08 o.
EXAMPLE 96 (+/-)-1-[2-[4-[4-(~minnc~- Lollyl)phenyl]-l-pipelazi~lyl]ethyl]-N-methylisochromanyl-6-carbnY~mi~a Step 1. (+/-)-1-(2-Chlo~ueLllyl)isochroman-6-ol To a ~lu~e of 3-hyd~uAylJh~n~thyl alcohol (Y-l) (0.074 g, 0.537 mmol) and chlu~u~ o~)inn~ hyde diethyl acetal (0.107 g, 0.64 mmol) in nitromath~na (0.5 mL) is added boron trifluoride-etherate (0.007 mL, 0.054 mmol). After stirring for 100 min, water is added and the llliAllu~c: iS partit.ionarl between dichloromath~na, water and saline. The organic layers are dried with sodium sulfate and con~ntrated and the residue chrom~ .a,uhed (silica gel; ethyl acetate~hPY~ne, 10/90) to give (+/~
(2-chlùioeLllyl)isochroman-6-ol (Y-2) c~).,t~i..i..~ a small amount of (+/-)-1-(2-ethu~yel~lyl)isochroman-6-ol as an i~ U~;~y. This m~tf~ is used without further purifir~tinn in step 2, NMR (CDCl3) 2.15 - 2.38, 2.62, 2.68, 2.91, 3.6-3.8, 4.10, 4.89, 6 5.08, 6.59, 6.68 and 6.95 o.
Step 2. (+/-)-1-(2-Chlu~v~l~lyl)isochroman-6-ol, trifluoromPth~n~clllfon~te ester To a "';~I~U1e of (+/-)-1-(2-chl(JroeLllyl)isochroman-6-ol (Y-2, Step 1; 0.079 g, 0.371 mmol), triethylamine (0.0413 g, 0.408 mmol), 4-dimethylaminopyridine (0.0009 10 g, 0.0074 mmol) and dichlornmPt~np (1 ~) cooled at -78~ is added trifuoromPth~nP~ulfonic acid anhydride (0.069 g, 0.408 mmol). The cooling bath is then removed and the ~ lure is allowed to warm slowly to 20-25~. After stirring for a total of 60 min, the ~u~e is par~;tinn~ b~Lwe ~ dichlornm~ ne and aqueous ~mmnninm chloride. The organic layers are dried with sodium sulfate, 15 cnn-e..l-dted, and the residue chromAt4~.aphed (silica gel; ethyl acetate/hPYslnP
10/90) to give (+/-)-1-(2-chloloetLyl)isocl~l~an-6-ol, trifluorom~th~n~elllfon~t~ ester (Y-3), NMR (CDCl3) 2.24, 2.31, 2.73, 2.78, 3.00, 3.67, 3.80, 4.12, 4.94 and 7.05-7.18 .
Step 3. (+/-)-1-(2-Chloroethyl)-N-methylisochroman-6-carbnY~mitl~
A ~ u~e of (+/-)-1-(2-chlOloelllyl)isochroman-6-ol, trifluorol.. ~Lh~nP~lllf~n~tP
ester (Y-3, Step 2; 0.291 g, 0.844 mmol) in D~ (1.5 mT ) is de-gassed under reduced ,ule~u~e for five minllte~, after which p~ linm (II) acetate (0.019 g, 0.084 mmol) and 1,3-bis(diphenylrhn~rhinn)propane (0.52, 0.127 mmol) i8 added. Carbon mnnnYi~le gas i8 bubbled in and diisoplo,uylethylamine (0.29 mL, 1.69 mmol) is added. Methylamine gas is then bubbled in and the bath temperature is raised to 50~. The s~ lit;~)n of methylamine gas and carbon monnYi~ gas is cnntinll~i for 1 ~, at which time an ~ ition~l p~ linm acetate (0.010 g) and 1,3-bis(diphenylrho~phino)propane (0.025 g) are added. A~er an slrl~itin~l 4 hr the ~Lu~ is allowed to cool and then is partitionçd belwe~ ,l ether, aqueous ~mmonillm chloride, saline-~mmnnillm ~hlori~.q, and saline. The organic phases are separated, dried over m~gn~illm sulfate and cnn~ç~ ted. Chrom~tography of the residue (silica gel; m~l-~nol/dichlorom~t~l~n~, 2/98), gives (+/-)-1-(2-chloroethyl)-N-methylisochroman-6-c~L~ (Y-4), NMR (CDCl3) 2.20, 2.33, 2.73, 2.79, 2.97, 3.01, 3.65, 4.12, 4.95, 6.09, 7.14, 7.53 and 7.56 ~.
Step 4. (+/-)-1-[2-[4-[4-(~minoc~rbonyl)phenyl]-1-piperazinyl]ethyl]-N-methylisochromanyl-6-c~l,..~ ,.... i-W O 97/02259 PCT~US96/08681 A lllLl~llUL~ of (+/-)-1-(2-chloroethyl)-N-lllal~lyLsochroman-6 c~ 1e (Y~, step 3; 0.0937 g, 0.369 mmol), 4-(piperazin-l-yl)hPn7~mi~e (Q-3, PREPARATION 1, 0.114 g, 0.554 mmol), diisoplvpylethylamine (0.0716 g, 0.554 mmol), sodium iodide (0.007 g) and ethylene glycol (2 mL) is heated at 100~ for 6.5 hr, after which an 5 ~iti~nAl 0.056 g of 4-(piperazin-l-yl)bPn7~mi-1Q is added. After stirring for an s3rl~itinnAl 24 hr at 100~, the ll~LI,u.a is allowed to cool (with stirring for the rPm~inçr of the weekend). Water is then added and the l~lL~Lu~ is extracted withdichloromPth~ne The organic extracts are con~-..l ated and comhinecl with the gummy residue (from which the aqueous layer has been flPr~nt~-l). The comhinP(l 10 crude product is chrom~tographed (silica gel; mpth~n~vdichlorompth~ne~ 6/94) to give (+/-)-1-[2-[4-[4-(~minoc~rbonyl)phenyl]-1-piperazinyl]ethyl]-N-methylisochromanyl-6-carb~Y~mi-le (Y-5), NMR (CDC13) 2.05, 2.18, 2.5-2.8, 3.02, 3.32, 3.77, 4.13, 4.88, 4.8-6.0, 6.12, 6.89, 7.16, 7.54 and 7.72 o.
~XAMPLE 97 (R)-(+)-1-[2-[4-[4-(AminocA . bullyl)phenyl]-1-piperazinyl]ethyl]-N-methylisochromanyl-6-carbnY~mi~P
Separation of (+/-)-1-[2-[4-[4-(~minoc~rbonyl)phenyl]-1-piperazinyl]ethyl]-N-methylisocl.lu~anyl-6-caLl,n~ lP (Y-5, ~AlvlpLE 96) into its plu8 and minus ~n~nt;,lmf-rs is achieved by preparative chroms~ . d,uhy on a chiral phase pre-packed column using as solvent ethyl alcohoVisopLu~yl alcohoVtriethylamine in a ratio of 4/1/0.08 (V/V) and using ~iPtection at 295 nM. Peak 1, (S)-(-)-1-[2-[4-[4-(~minocslrbonyl)phenyl]-l-piperazinyl]ethyl]-N-methylisochromanyl-6-caLL
(F~AMPLE 6), eluted first, followed by Peak 2, R)-(+)-1-[2-[4-[4-(~mino~,~ ~ IJunyl)phenyl]-l-piperazinyl]ethyl]-N-methylisochromanyl-6-carb~y~mirle (Y-5), MS (m/z) 422.
~XAlVIPLE 98 (S)-(-)-1-[2-[4~4-Cyanophenyl)-1-piperazinyl]ethyl]-N-methylisochroman-6-carb--Yslmi.lP
Step 1. 1-(4-Cyanophenyl)piperazine A ~ure of 4-fluorobPn7~mifle (Q-2, 0.700 g, 5.78 mmol), piperazine (2.49 g, 28.9 mmol), and water (5 mL) is heated at 100~ for 85 min and then allowed to cool.
Water (5-10 mL) i8 added and the lllil~LUla is partiti~npcl b~waell ethyl ~et~t~aqueous sodium bicarbonate, and saline-aqueous sodium bicarbonate. The organic layers are dried over m~FnPRil1m sulfate and con--r~ dted to give 1-(4-cyanophenyl)piperazine (Q-3), NMR (CDCl3) 1.77, 3.02, 3.28, 6.85 and 7.49 o.
Step 2. (S)-(-)-2-(6-Br~moico~hroman-1-yl)ethyl alcohol Borane-methyl sulfide (3.1 mL, 33.2 mmol) i8 added to a l~u~a of (S)-(-j-2-(6-brom~icochroman-l-yl)acetic acid (XI, EXAMPLE 1, step 2; 3.0 g, 11 mmol) and CA 02225282 l997-l2-l9 W O 97/02259 PCT~US96/08681 l~ (40 mL). GaR evolution and a moderate exotherm ensue. After stirring for 2.5 hr, mPth~nol is slowly added to quench excess borane-methyl sulfide. The nuxl ule i8 then con. ~..l ated under reduced plesrlu.~ and m~th~nol is added to the residue.
The Illil~l,Ule again is conce..l-dted and m~th~ncll again added. After a final 5 cc...r~ -dtion from m~th~nnl, the residue is part~tion~(l between dichlorom~thsm~, aqueous hydlocllloric acid, and aqueous sodium bicarbonate. The organic layers are dried over sodium sulfate and conce--t ated. The residue is chromAtographed (silica gel; m~th~nol/dichlorl m~th~n~, 4/96) to give (S)-(-)-2-(6-bromniRorhroman-1-yl)ethyl alcohol (S-1), NMR (CDC13) 2.03, 2.20, 2.60-2.70, 3.02, 3.70-3.85, 4.16, 4.93, 6.93 and 10 7.29 ~.
Step 3. (S)-(-)-6-Bromo-1-(2-bromoethyl)isochroman To a llli~l,Ul13 of triphenylrhr~sphine (9.60 g, 36.6 mmol), carbon tetrabromide(6.06 g, 18.3 mmol), and dichlorom~th~n.o (25 mT, cooled to about 20~ to control the exotherm that occurs as the reagents are mixed) is added over 10 min (S)-(-)-2~6-15 bromoisochroman-1-yl)ethyl alcohol (S-l, step 2; 2.35 g, 9.1 mmol) in dichlorometh~ne (25 mL). The cooling bath is L~llWVt:d and the l~ ULe is stirredfor 40 min, at which time hexane is added dropwise until no more cloudiness appear6. The ~U~t is allowed to stand overnight in the refrigerator and then thesolids are removed by filtration. The solids are washed with ether and the comhin~-l 20 filtrates are con~ e~lt- àLed and the residue is chrom~tc.~. aphed (silica gel; ethyl slret~t~/heYs~n~o~ 10/90) to give (S)-(-)-6-bromo-1-(2-bromoethyl)isoclll.. an (T-1), N~ (CDC13) 2.22 - 2.46, 2.66, 2.71, 2.94, 3.51, 3.62, 4.09, 4.84, 6.94 and 7.29 o.
Step 4. (S)-(-)-4-[4-[2-(6-BromniRorhroman-1-yl)ethyl]-1-piperazinyl]ben7onitrilf.
A IlliX~,Ule of (S)-(-)-6-bromo-1-(2-bromoethyl)isochroman (T-1, step 3, 1.53 g,4.79 mmol), 1-(4-cyanophenyl)piperazine (Q-3, step 1, 0.987 g, 5.27 mmol), diisoplol~ylethylamine (0.681 g, 5.27 mmol), and ethylene glycol (5 mL) is heated at 95~ for 4 hr and then at 20-25~ overnight The IlliXl,Ul~ is parfitinn~l between dichlorom~th~ne and water and the organic layers are dried over sodium sulfate and conr~ l ~ I - àted. The residue is chrom~t~ . aphed (silica gel;
mF~th~n- l/dichlornm~th~n~ 2/98) to give (S)-(-)-4-[4-[2-(6-brnm- iRorhroman-l-yl)ethyl]-l-pipl .a~hlyl]b~n7onitrile (VI), N~ (CDCl3) 2.00, 2.12, 2.48-2.72, 2.95, 3.33, 3.73, 4.10, 4.80, 6.85, 6.96, 7.38 and 7.49 o.
Step 5. (S)-(-)-1-[2-[4-(4-Cyanophenyl)-1-pipel~i..yl]ethyl]-N-3B methylisochroman-6-c&~L.. ,~
Following the general pl~CedU~ of ~XAMPLE 6, step 4, and m~king non-W O 97/022S9 PCT~US96/08681 critical variations, (S)-(-)-4-[4-[2-(6-brom~iRochroman-l-yl)ethyl]-1-piperazinyl]bP-n~o~itril~ (VI, step 4, 1.61 g) is cvllvs~ d to (S)-(-)-1-[2-[4~4-cyanophenyl)-l-piperazinyl]ethyl]-N-methylisochroman-6-call,~.,c.1...itle (IX), MS (m/z) at 404; IR (mineral oil, most intense peaks) 1603, 1635, 2210, 1517 and 1553 cm~l;
5 NMR (CDCl3) 2.05, 2.18, 2.48-2.78, 3.00, 3.01, 3.34, 3.76, 4.12, 4.88, 6.08, 6.85, 7.15, 7.49, 7.53 and 7.54 o.
EXAMPLE 99 (S)-(-)-1-[2-[4-[4-(~min~Arbonyl)phenyl]-1-piperazinyl]ethyl]-N-methyl-N-(phenyl m Pth ~ ry)isochroman-6-cal 1, . . x ~ . . . i d e Step 1. (S)-(-)-1-[2-[(TetrPhy.lLv~yl~l-2-yl)oxy3ethyl]isochroman-6-c~LoAylic acid, methyl ester A l~ixLu-e of (S)-(-)-1-(hydlvAyel~lyl)isoclllulll_n-6-c~LvAylic acid, methyl ester (S-2, EXA~LE 81, step 2, 1.36 g, 5.76 mmol), dichloromPt~AnP (10 mL), p-toluene sulfonic acid monohydrate (0.0142, 0.0747 mmol) _nd 3,4-dihydro-2H-pyran(1.6 mL, 0.0175 mol) is stirred at 20-25~ for 45 minutes. The ~ALu~è then i6 partit;~.ned between aqueous sodium bicarbonate and dichloromethAne. The comhinP~l organic layers are dried over ~odium sulfate and con-~entrated under reduced ple~ . The residue is chromAt4~- aphed (silica gel; ethyl acetate/hPYAnP, 5/95 to 15t85) to give (S)-(-)-1-[2-[(tetrahyd.opyl~-2-yl)oxy]ethyl]isochroman-6-c&sbuAylic acid, methyl ester (W-2), NMR (CDCl3) 1.53, 1.69-1.80, 2.04, 2.23, 2.73-2.79, 2.98, 3.51-4.13, 4.60, 4.92, 7.18, 7.80 and 7.83 o.
Step 2. (S)~-)-1-[2-[(Tetrahyd,~"uy.dll-2-yl)oxy]ethyl]isochroman-6-c~LuAylic acid A ~Lb~U~ e of (S)-(-)- 1-[2-[(tetrahyvl o~yl ~-2-yl)oAy]ethyl]isochroman-6-c~buAylic acid, methyl ester (~7V-2, step 1, 1.55 g, 4.85 mmol), et~Anol (12 mL), sodium hydroxide (2N, 3.6 mL, 7.2 mmol) and water (1 mL) is stirred for 6.5 hours at 20-25~, at which time the ll iA~u~è is stored in the refrigerator overnight. The lliALule is then stirred an Arlflit;onAl 2.5 hours at 20-25~ and then is concPntrated under reduced plee. ule. Water (6 mL) i8 added and the re~lllt;ng ~ is cooled in an icetwater bath. The pH of the ~lliALule is adjusted to pH 5 using hydlu~loric acid (4N) and the r~lllffnE slurry is extracted with dichloromPt~An~. The cnmhinpd organic layers are dried over mAgnPRillm sulfate and co~ce.ll-dted under reducede~ e to give (S)-(-)-1-[2-[(tetrahydlv,uy.dll-2-yl)oYy]ethyl]isochroman-6-carboYylic acid (W-3), MS (m/z) = 306; N~ (CDCl3) 1.55, 1.70-1.84, 2.08, 2.26, 2.77-2.82, 3.01, 3.54, 3.66-4.17, 4.63, 4.96, 7.23 and 7.88 o.
Step 3. (S)-(-)-N-Methyl-N-(phenylmet~l- Yy)-1-[2-[(tetrahydr~,~yla,l-2-yl)oAy]ethyllisocl;llolllan-6-c&lL.~ le W O 97/02259 PCTrUS96/08681 1,1'-Carbonyl-liimi-1~7.olP (0.064 g, 0.39 mmol) is added to (S)-(-)-1-[2-[(tetrallyd~u~y.~l-2-yl)oxy]ethyl]isochroman-6-ca~Ly~ylic acid (W-3, step 2; 0.109 g, 0.356 mmol) and THF (2 mL). The llli~l,U~e iS stirred at 20-26~ for 2 hr and then N-methyl, O-benzylhydru~ylamine (Tetrahedron Letters, 30, 31-34 (1989), 0.054 g, 0.39 5 mmol) is added and the ~i~u~e: is stirred overnight at 60~. The ..--~lure then is corfentrated and the residue is partitinnP-l between dichlornmPth~ne, water and aqueous sodium bicarbonate. The organic layers are dried over sodium sulfate andconrP~n~rated. The residue is chrom~t~graphed (silica gel;
meth~nnl/dichlorQmPtl~nP 2/98) to give (s)-(-)-N-methyl-N-(phenylmpthnyy)-l-[2 10 t(tetrallyd.v,uy~an-2-yl)oxy]ethyl]isochroman-6-carbQY~mide (W4), NMR (CDCl3)1.50 - 1.65, 1.70-1.90, 2.07, 2.28, 2.67, 2.72, 2.92, 3.36, 3.53, 3.66-3.95, 4.02, 4.11, 4.62, 4.69, 4.92, 7.07-7.14, 7.30, 7.36 and 7.45 ~.
Step 4. (S)-(-)-1-(2-IIy-l~u2~.y~ yl)-N-methyl-N-phenylmpthnyyisochroman-6-carbnys~mitlp 16 (S)-(-)-N-methyl-N-(phenylmPthnYy)-1-[2-[(tetrallyd,u~yldn-2-yl)oxy]ethyl]isochroman-6-ca bn~1r..i~P (W-4, step 3; 0.131 g, 0.308 mmol) is stirred at 20-25~ in a ~-~u~e of acetic acid/THF/water (4/2/1, 5 mL) for 2 hr and then at 60~ for 4 hr, at which time it is stored in the refrigerator overnight. The solvents are then removed and the reslllting l~u~e is part tionpcl between dichlornmPth~nP
20 and water. The organic layers are dried with sodium sulfate and conf~..t-d~ed and the residue is chrom~ ;- dphed (silica gel; mPthAnnl/dichlorompth~np~ 2/98) to give crude product. NMR of this material in~ AtP~ the presence of tetrahyLopy,dr.yl (THP)-like protons, so mPth~nol (2 mL) and p-tolllPnf~ulfonic acid hy.l~d~e (0.006 g) are added and the l~ u~e is stirred overnight. The solvent is then removed under25 reduced pressure and the re~idue is partitinned between dichlorompth~ne and aqueous sodium bicarbonate. The organic layers are dried over sodium sulfate andconcentrated to give (S)-(-)-1-(2-hyd~ ye~}lyl)-N-methyl-N-phenylmPthnYyisochroman-6-c~l,..x~ 1P (W-5), NMR (CDCl3) 2.07, 2.25, 2.64, 2.70, 3.02, 3.38, 3.77, 3.86, 4.19, 5.01, 7.06, 7.08, 7.31, 7.37 and 7.46 o.
Step 5. (S)-(-)-1-[2-t4-[4-(~minncA-l,u.. yl)phenyl]-1-pipeld~ yl]ethyl]-N-methyl-N-(phenylmPth-.Yy)isochroman 6 carbmf~mir~e To an ice-cooled l~ LUL~ of (S)-(-)-1-(2-hydlu,~y~ yl)-N-methyl-N-phenylmPtl n-xyisochroman-6-carbny~mirle (W-5, step 4; 0.099 g, 0.290 mmol), diiso~Ouylethylamine (0.049 g, 0.377 mmol) and 4-dimethylaminopyridine (0.0018 g, ."
35 0.014 mmol) in dichlorr~mPthAnP (1.5 mL) is added mpthslnpsulfonyl ~-hlori~lP (0.0~3 g, 0.377 mmol) in dichloromPt~ne (0.5 mL). The llli2~u~ is stirred for 1.5 hr and CA 0222~282 1997-12-19 W O 97/02259 PCT~US96/08681 then part;tionPr7. between dichloromPthslne and aqueous sodium bicarbonate. The organic layers are dried with sodium sulfate and co7lrPntrated to give a mesylate (W-6). To the mesylate is added 4-(piperazin-l-yl)bçn7slmi~7,e (Q-3, PREPARATION 1,0.071 g, 0.348 mmol), diisu,u~v~uylethylamine (0.075 mL, 0.580 mmol), and ethylene glycol (0.3 mL). A smal amount of dichloromeths7ne is used to wash down the sides of the flask. The mixture is heated at 85~ for 2.5 hr and then cooled. Water is added and the ~ uLa is allowed to stand in the refrigerator overnight. The supç7~s7t~nt is then rlecS7ntefl and the rPmslining residue is chromsltographed (silica gel; methslnol/dichloromPthslne, 4/96 to 6/94) to give the title compound, NMR
(CDCl4) 2.08, 2.20, 2.5-2.75, 2.95, 3.34, 3.37, 3.76, 4.13, 4.69, 4.89, 5.7, 6.89, 7.10, 7.29, 7.47 and 7.72 o.
EXAMPLE 100 (S)-(-)-1-[2-[4-[4-(~mino~All,onyl)phenyl]-1-piperazinyl]ethyl]-N-hyll~ v2~y-N-methylisochroman-6-carbo~rslmirle A ~ Lula of (S)-(-)-1-[2-[4-[4-(s7minoc~l1,ollyl)phenyl]-1-piperazinyl]ethyl]-N-methyl-N-(phenylmPthn~y)isochroman-6-ca~ sl~ 7~e (W-7, ~XAlVIPLE 99, step 5, 0.067 g, 0.13 mmol), pslllslr7itlm on charcoal (10~, 0.0068 g) and mPths7nnl (3 mT ) is stirred under ap~ ; sltPly one slt nnsphPre of hyvlu~;~n gas for one hour, at which time ethyl acetate (1 mL) is added to aid in dissolving the starting material.
Stirring is continued under a llyd~ùgell sltmnsphpre~ and after 8 hr an sldr7iffnnSll pslllsln7illm on charcoal (10%, 0.0068 g) is added. When the starting material is consumed (about 28 hr) the psllls7~7il7m on charcoa. is filtered off and the filtrate i8 concf~ntrated. The residue is chromslt~graphed (si ica gel;
mPthslnnl/dichloromPt)lslnP, 8/92 to 15/85) to give (S)-(-)-1-[2-[4-[4-(slminof slrbonyl)phenyl]-l-piperazinyl]ethyl]-N-llydLu~y-N-methylisochroman-6-carbn~S7mide (W-8), NMR (DMSO) 1.89, 2.10, 2.45, 2.65-2.70, 2.85, 3.21, 3.66, 4.02, 4.77, 6.90, 6.98, 7.22, 7.36, 7.41, 7.68, 7.72 and 9.94 o.
EXAMPLE 101 (+/-)-1-[2-[4-[4-(Aminosu fonyl)phenyl]-1-piperazinyl]ethyl]-N-methy isochroman-6-carbn~rslmide Step 1. 4-(Piperazin-1-yl)ben7~nPslllfsnslmir7.e A llliXl.Ul~, of 4-fluorobPn7enP~lllfsnslmide (Q-2, 6.95 g) and piperazine (17.1 g) in water (30 mL) is heated at 100~ overnight. The solid is then collpcterl~ washed with water and tolllPne, and dried under reduced pla~iu~a to give 4-(piperazin-1-yl)bP-n7pneslllfonslmi~lp (Q-3), MS (m/z) = 241; IR (mineral oil, most intense peaks) 1160, 822, 1332, 608, 1593 and 1137 cm~l; NMR (DMSO) 2.81, 3.17, 2.3, 7.01, 7.07and 7.61 o.
Step 2. (+/-)-1-[2-[4-[4~Aminosulfonyl)phenyl]-1-piperazinyl]ethyll-N-W O 97102259 PCTrUS96/08681 methylisochroman-6-caL 1, ~ ~ x i1 r. . i /1~
Following the general procedure of EXAMPLE 96 ~nd m~kin~ non-critical variations, (+/-)-1-(2-Chloroethyl)-N-methylisochroman-6-carbnYslmi~la (Y-4 EXAMPLE 96, step 3, 0.024 g, 0.095 m-mol) and 4-(piperaziny-1-5 yl)ben7~n~sll1f~n~mi~a (Q-3, Step 1) gives (+/-)-1-[2-[4-[4-(~minnslllfonyl)phenyl]-1-piperazinyl]ethyl]-N-methylisochroman-6-carb~Y~mi~ (Y-5), NMR (CDCl3) 2.05, 2.19, 2.5-2.8, 3.01, 3.34, 3.42, 3.79, 4.16, 4.89, 6.41, 6.91, 7.18, 7.54, 7.56 and 7.76 ~.
Following the general procedure of EXAMPLE 94 (CHART V) and making non-critical variations and using the rç~rt~nt~ corresponding to the products, the 10 compounds of EXAMPLES 102-104 are obtained:
EXAMPLE 102 (S)-(-)-N-Methyl-1-[2-[4-[4-(methylaminocarbonyl)phenyl]-1-piperazinyl]ethyl]isochroman-6-carbnx~micla EXAMPLE 103 (S)-(-)-N-Methyl-1-[2-[4-[4-(dimethyl~minoc~rbonyl)phenyl]-1-piperazinyl]ethyl]isochroman 6 carbnYslmi.l.O
EXA ~ LE 104 (S)-(-)-N-Methyl-1-[2-[4-[4-(n-propyl~minoç~rbonyl)phenyl]-1-piperazinyl]ethyl]isochroman-6-caLI,.,x~...i~1a Following the general plocedu. e of EXAMPLE 100 and m~kin~ non-critical variations and using the re~t~nt~ corresponding to the products, the culllpou~lds of ~AMpLEs 105-108 are obtained:
EXAMPLE 105 (S)-(-)-N-hyLv~y-N-methyl-1-[2-[4-[4-(trifluoromethyl)phenyl]-1-pipelazillyl]ethyl]isochroman 6 carbn~ s~mi~la EXAMPLE 106 (S)-(-)-1-[2-t4-(4-Chlorophenyl)-1-piperazinyl]ethyl]-N-hyd~u~y-N-methylisochroman-6-c~uL~ 1e EXAMPLE 107 (S)-(-)-1-t2-t4-(4-Cyanophenyl)-l-piperazinyl]ethyl]-N-hydroxy-N-methylisochroman-6-carbnY~mi-le EX~PLE 108 (S)-(-)-N-Hydroxy-N-methyl-l-t2-t4-[4-(methylcarbonyl)phenyl]-1-piperazinyl]ethyl]isochroman-6-carbn~ ~micle Following the procedul~ of CHART DD and making non-critical vs~ tion~:
known to those skilled in t,he art the compounds of EXAMPLES109 thru 120 are obtained.
EX~PLE 109 (S)-4-[4-[2-t6-(1,2,4-Triazol-3-yl)-isochroman-1-yl]ethyl]-1-piperazinyl]ban7 slmitla li~xAlvlpLE 110 (S)-4-[4-[2-[6-(2-Methyl-1,2,4-triazol-3-yl)-isochroman-1-yl]ethyl]-l-pipeL~zirlyl]ban7~mi~a EXA ~ LE 111 (S)-4-[4-[2-[6-(1,2,4-OY~ 7Ol-5-yl)-isochroman-l-yl]ethyl]-l-piperazinyl]ben7 ~mi~le CA 0222~282 l997-l2-l9 W O 97/02259 PCT~US96/08681 lvrpLE 112 (S)-1-[2-[6-(1,2,4-Triazol-3-yl)isochroman-1-yl]ethyl~-4-[4-trifluoromethylphenyl] -piperazine EXAMPLE 113 (S)-1-[2-[6-(2-Methyl-1,2,4-triazol-3-yl)-isochroman-1-yl]ethyl]-4-[4-trifluoromethylphenyl]piperazine lil~AMpLE 114 (S)-1-[2-[6-(1,2,4-OY~ 7ol-5-yl)isochroman-1-yl]ethyl]-4-[4-trifluoromethylphenyl] -piperazine EXA~LE 115 (S)-1-[4-Acetylphenyl]-4-[2-[6-(1,2,4-triazol-3-yl)isochroman-1- yl]ethyl]piperazine EX~MPLE 116 (S)-1-[4-Acetylphenyl]-4-[2-[6-(2-methyl-1,2,4-triazol-3-yl)isochroman-1-yl]ethyl]piperazine EXAMPLE 117 (S)-1-[4-Acetylphenyl]-4-[2-[6-(1,2,4-~Y~ 7ol-5-yl)isochroman-l- yl]ethyl] -piperazine ~XANIPLE 118 3-[1-[2-[4-(4-Aminocarbonylphenyl)piperazin-1-yl]ethyl]isochroman-6-yl] -N,N-dimethylacrylamide EXAMPLE 119 3-[1-t2-[4-(4-Trifluoromethylphenyl)piperazin-1-yl]ethyl]isochroman-6-yl]-N,N-dimethylacrylamide ~AMPLE 120 3-[1-[2-[4-(4-Acetylphenyl)piperazin-l-yl]-ethyl]isochroman-6-yl]-N,N-dimethylacrylamide W O 97/022S9 PCTrUS96108681 Fo~ru~,~s OF TFr~ rPT.~ #) - R c , ~ H2N ~ H N~ ~

~N N~OCH3 N~N~OCH3 (-)-endl ILio, I ~er (+)-ena"~io" ,er H ~O

H3C~N~C --N N~OCH3 15H ~O (+)-ena'~tiu,"el ~/

~N N~OCH3 (-)-ena, lliGI "er E-3 ~N J~

~ IN' CH3 ~N~N~COI--NH2 25 H ~O S-(-) ena,lLio",er ~NAN~CF3 (-)-en~nLio",er\

30 H N--C--~ H2N,C [~

~--~N N~3CH3 N~N~CI

CA 02225282 l997-l2-l9 W O 97/02259 PCTrUS96/08681 H N~ C ~
0 ~0 H2N~ ~ ~N N~O ~CH3 10 H2N~ ~--N~N~O--CH

N N~ CH2--CH3 15 o E-11 R
I l H2N~ ~

H2N ~CH~-NA~ CH3 O H ~
H2N' =l N N~CH2--CH3 ~N N~CF3 (-)-enar,Li~l"er \_/ \=/

~l 3 ' IN~ ~

36 E 16\--J ~ ÇH3 W O 971022S9 PCTrUS96/08681 H3C~ N,C ~ ~7 ~ ~ \CF CH3 ~N~ ~

H3C~N~Q~ (-)-ena"li~",el ~/ ~ ~~

N N~O
E-l9 \--/ \=/ ~CH2--CH3 ~N~ ~C~ ~N~

--N~N~O E-22 E-21 ~CH2--CH3 1O, H2N' ~

H3C~N~C~ N N~OCH3 N N~ CH3 W O 97/022S9 PCT~US96/08681 R ~--N~ ~

S H ~ ~N~N~OCH3 N N~OCH3 E-25 \--/

3 H ~ H ~N N~OCH3 16 NN4~OCH3 E-27 --/o \=/

~NH ~

o N N~OCH3 CH30~N--C ~ E-30 \J \=/

N N ~OCH3 CH3 ~l ~J'''l~NH~ ~

H3C~--NH~C~ N N~OCH3 N N~OCH3 CA 02225282 l997-l2-l9 W O 97/02259 PCTrUS96/08681 CH~ R W E-34 \J ~OOH3 N N~OCH3 E-33 \J

~~ ~ ~N~N~OCH3 N N~OCH3 ~ 2 HCI E-35 \--J o ~N ~ ~

'Nb~ ~ ~N~N~CI

26 N N~OCH3 E-37 ~ N~ N~

O H2N~ J~~ E 40 H3C ~ ~
N N~CI
~ 2 HCI E-39 \--/

W O 97/02259 PCT~US96/08681 O O
ll ll H N'C~l Cl~O

~N N~CI ~N N~F
E-41 ~/ E-42 ~/

H ~
NH2-COl ICH3 N3~3OCH3 ~O O (-)-en~"li~r"el E-44 ~N N~
~ 2 HCI Cl I / \=/
~ .52 CH2CI E-43 ~.78 H20 H3C
~0 H3C ~ ~N N~OCH3 N N~CF3 (-)-enar~ "el E-4s H2N~ H2N~[~ ~3,OCH3 N N~OCH3 E-48 o H3C' --N~[~ ~N~O~CH3 H' 'NH~,~N~ 3 E-50 o H3C~C~N ~NJ~O'CH3 ~ N~J

15 ~ N ~ ~ ~CHs N~J
E-51 o H3C C~

o ~ H ~ ~N~O~CH3 2 ~ 'N~[~,N~ E-54 H3C~ ~ ~N~ ~CH3 H3C~NH~ ~ 3 E-56 CA 02225282 l997-l2-l9 W O 97/022S9 PCTrUS96/08681 H C'N~--N ~[~O~CH

S H3C~ ~, ~ o E-sa N~J C
10 H3C, E 57 H C' ~r~ ~N~o~CH3 / ~N~ E-60 E-59 '-~

H3C~C_ ~ ~N~J O~CH3 H3C H3C~3~N~ CH3 H3C o H3C~ ¦ l l H3C' ~O~ 'NH~N~O'CH3 R N~J
H3C'NH' 'NH~N~J E-34 CA 02225282 l997-l2-l9 W O 971022S9 PCTrUS96/08681 H3C~

H'N/--~ N N~OCH3 N N~OCH3 E-65 \--/

H3C' ~

H C~O~C~ E-56 OCH3 NA ~OCH3 E-67 \--/
R H2N~

H~C~ E-70 --/ ~OCH3 N N~OCH3 H N~C~
H3C--N ~ '~N~N~OH

E 71 \--/ ~OCH3 CA 02225282 l997-l2-l9 W O 97/022S9 PCTrUS96/08681 Il , O H =IO

H3C~N~C 1 ~N N~O-- --CF3 H ~o (~)~ena''liolller E-74 ~/ \=J' ~

(-)-ena,,liu,"er N~N~OH
o HaC~N,C~'IN~ ~ ~ ~ ~O'CH3 (-)-ena,lliel"er ~N~c~oH3 H3C~
N--N
HN--N N~ ~~~

'CH3 E 78 E-77 ~ ~O~

N~ J~ ~CH3 E-7s N ~J

O H ~O

H9C~N,C~ (-)-3nanlio",er ~ ~C/~CF3 N N~C//
(~)~ena''Liolller E 81--/ ~CH3 ~
~ NH2--~/N~C~ ~N~
16 N N4~OCH3 E-84 E-83 \--/ \=/
R

H ~ NH2--C~N~N~CI

N~ CH--COOH
CH--COOH

NH2--C~

H ~O ~N N~OCH3 ~-~ ~NN~ E-88 Cl E-87Cl 3~;

W O 97/02259 PCTrUS96/08681 o HO~H ~,0 3 ~N~ ~ ~N N~OCH3 ~N N~OcH3E-9o E-89 O Cl H C--N~N,C~

f~ 'N~ ~, E-92 ~N~N~OCH3 E-91 1 \~ ~OCH3 ao 1~ OH3 ~N N~Q--O--C--CH3 OH ~O S-(-)-el~ar,Liu,,,er CH3 ~N N~OCH3 N CH~mic E ~/ ~~--NH2 racemic N~N~30CH3 H~N~

CH3 ~N N~C--NH2 E-98 R-(+)-enanlior"er E97 ~/

CH~O
[~3~O~N~C~ S ( ) en~ al N~N~3C--NH2 O ~N N~CONH2 CH3 ~
racemic N N~S~2NH2 W O 97/02259 PCT~US96/08681 C~AR.T A

Br~ OH (II) Br ~ (III) Br ~

A /=~ Rl ~ HN\W1~ R2 ~~
2~ ~N~ ~W1~

Br ~

R1 (VI) N\W1 ~ R2 CA 02225282 l997-l2-l9 W 097/022S9 PCTrUS96/08681 C~AR.T B
Br ~

N A W1 ~ ~2 \ ~VI) H2N~
A ~ R~
N'JW' ~ R2 (VII) o o 1~ (C~3),CO ~ ~ ~
(CH3)3CO O N~ W~ R1 ~VIII) o al2 ~ R1 N W, ~ R2 (IX) O

Q13 - ~

N\--W1~ R2 (X) W O 97/02259 PCT~US96/08681 CT~AF~T C

6 ~ O (II) Br ~O t ~
CO H ~
2 (XII) CO2C2H5 ~AR.T n '' 5 ~ (VI) ~ ~ RR~
(CH3)3 Si ~

~o (XIII) ~ /--\ /=~ R, N~ Wl ~ R2 - ~-~ (XIV) N/--\ ~ RR~

(XV) Q1-2 ~

N~W1 ~ RR,2 W O 97/02259 PCTrUS96/08681 C~R.T ~.

Br / ~ R2 Q,~ - O ~ ~
~0 N W~ ~ (XVI) ~ ~ R~ ~VII) ~NJ~/~

1-2 N W,~ RR~ ~II) N W,~ R

C~AR.T F

Q.-3--~~

~--N/--\W ~ R2 ~

N~ W~ ~
(X~) o~
~N ~

N W,~ R, a, 3--~~

2~; N/--\W,~ (XXII) IQ,, ~N~

N/--\W,~ ~2 (X~II) W O 97/022S9 PCT~US96/08681 C~AR.T G

~0 1 ~ N Wl ~ F'~ \ (X) ll Q13--O~
R~
N\--W1~ R2 (XXIV) o Ql' ~ R
N~W, ~ R2 ~V) Q1~
C

N~W,~ R, C~AR.T ~
~,~

N~ ~ R~

'10 / 11~
NAW ~ R2 (XgVI) Ql 16 N-- 5~

N W,~ RR2 (XXVII) Ql-3--S~[~

I N W,~ RR~ (X2SVlll) 11~
N~Wl ~ R~

CA 02225282 l997-l2-l9 W O 97/02259 PCT~US96/08681 C~AR.T I

HOOC-- (CH2)n ~ -~ R2 10HOCH2 (CH2)n ~,~

~ N W~ ~ R ! (X~) 15BrcH2(cH2)n ~

N A w~ XXII) Q1 3SCH2 (CH2)n ~

A /=3~ R, (XXXI I 1) N'JW' ~ R2 Q~ 3SCH2 (CH2)n ~
0 ~~
~N W~ R, (~X2~V) CA 02225282 l997-l2-l9 W O 97/022S9 PCT~US96/08681 C~AR.T J

6SIcH2(cH2)n ~

N W~ R2 (XXXlI) o 10NaO--S--CH2(CH2)n ~
/--\ /=~ 1 N W~ ~ R2 1~l 15Cl- SCH2(CH2)n ~

NWl~ (2~Vl) o Q1-.
N-- SCH2 (CH2)n ~

Ql2 ~ ~~
~ ~ R~ (X~Vll) NW~ ~ R2 W O 97/022S9 PCTrUS96/08681 C~ART K

BrCH2 (CH2)n ~

~ ~ RR, ~I) Ql~
0 N~NH
\~ X X is-CH~or-N~
Ql-s N ~ N - CH2~C~2~n ~ D

lB \--/ ~ RR2 (X~Vlll) W O 97/022S9 PCT~US96/08681 ~,~AR.T T, C2H5O (CH2)n ~
b,~o (XXXIX) A /~ 1 N W, ~ R2 OH
N
~ ' Q16--C9 N

Q1~ N
\~ (CH2) ~--N~W, .~

W O 97/022S9 PCT~US96/08681 C~AR.T ~

BrCH2 (CH2)n ~

N W, ~ ~X~II) 0 N _ CCH2(CH2)n ~Z, N~W, ~ RR~(XLI) ~ CH2 (CH2ln ~

N~Wl ~ RR2(XLII) O , ~ ~ A R
N~W,~ R2 (XLIII) CA 02225282 l997-l2-l9 W O 97/022S9 PCTrUS96/08681 C~AR.T N

N - CCH (CH2)n ~

N~W,~ ll2 (XLI) NH

CCH2(CH2)n , R, (XLII) N ~W1 ~, R2 ~~
~ \>_ CH2 (CH2)n N~W, ~ R, (XLIII) / Q1-5 +

~ ~>--CH2 (CH2~n ~

2~; N W, ~ R2 CA 02225282 l997-l2-l9 W O 97/02259 PCT~US96/08681 C~AR.T O

H2NJ~ (VII) ~ N~ ~W

,~-5 0 3 ~ ,N NJ~

~N/--\ ~~R2 (0-1) Q
N--N

Q~ 5 N~

~N w,~ (0-2) --~ N'~C~
~N W, ~ 1 (0-3) \--/ R2 CA 02225282 l997-l2-l9 W O 97/02259 PCTnUS96/08681 CE~A RT P

Q1s H ~ (P-l) ~ 1 ~~R

~

N W, ~ (P-2) W O 97/022S9 PCTnUS96/08681 C~AR.T ~

H--N N--H (Q ) +

Br/F~EWG orBr/F~R2 (Q-2) EWG

It--N~N~EWG ortl--N~N~

C~RT R

R1 (R-l) O2N~
~R2 I

~ R1 H2N~R2 (R-2) I

HN N~
R2 (R-3) CA 02225282 l997-l2-l9 W O 97/022S9 PCT~US96/08681 C~R.T S

(S-l) OH

~ (S-2) OH

Q1 ~ ~ (S-3) OH

W O 97/022S9 PCT~US96/08681 C~AR.T T

COOH

Br~

~NJ~ (S-l) OH Br~C~
Q~-2 ~~ (S-3) ~ (X~ Br, OMs) OH

N~ Br~

(Vl) (X~ Br, OMs) ~

Ql 1 ~
N~

N Wl~

(IX) ~, PCTnUS96108681 C~A~T U

Br~ (U-l) COOH

l~o (U-2) COO-alkyl Q~lO (U-3) ~1, COO-alkyl Q~lO (Ul) J~ COOH

Q1-l'N ~'~ (U-5) OH

C~ART V

- 5~N~W~3 C--O-- (C~-G3)31kyl 0~N~N~W~ G--O-- (C~-C3)alhyl(V-2) 15H~N~N~W~OH

O

CH3~,N~W,~N--R
2~; R

W O 97/02259 PCT~US96/08681 C~AR.T W

alkyl-O~
~ ~ (W-l) O ~ ~OH
alkyl -O~

o ~ ~ O o (W-2) HO~, ~
O ~ O O
~ ~ ~ (W-3) alkyl-alkyl ~o o ~ ~ ~ ~ (W 4) ~~~ ~

~ O H (W-5) o alkyl-1 1 ~ (W-6) ~O'N ~ ~ W ~ (W-7) ~ N ~

HO~N ~ ~ w, (W-8) CA 02225282 l997-l2-l9 W O 97/02259 PCT~US96/08681 C~AR.T ~
HZ, ~,~OH
W (X-l) ~~
J~ CO2alkyl (X-2) 0 HZ, ~

(X-3) HZ~ ~

N~J(X-4) HZ~ R2 N~J

Q-2 Z2 ~ Z1 ~ ~W, (X-6) W O 97/02259 PCTrUS96/08681 C~ART ~

~0 ~ 1 ~A, (Vl) ~r H2N~

NW1 ~R1 (Z-1 ) H ~ \

Q~o2s ~C~

~ 1~ 1 N W, ~R, (Z-2) (Z-3) o,, --N~W,~~ CH2~N~W,~

(Z-5) ,Q-2 ~2 1 ~ Ql2--C~H2 ICH2 ~3Ço ICH2 ~0 30~N W1~R, Q--t ~NAW ~R, (Z-6) (Z-7) W O 97/022S9 PCT~US96/08681 C~AR~
Br ~

~ N W ~ ' (Vi) H ~

~N W ~R, (AA-l) \-- R2 HO--~
~N W,~ (A~-2) N~C~

N W, ~ (AA-3) H2N ~

N W, ~ (AA~) Q, ~ (AA-S) N W ~R' CA 02225282 l997-l2-l9 W O 97/022S9 PCTrUS96/08681 C~AR.T RR

Q1 1 ¦¦

Q--2 ~ (BB-l) N Wl ~ R2 ~ 10 16 N - CH2 - Xl ~ (BB-2) Q12 ~ O
~ 1~ RR

CA 02225282 l997-l2-l9 W O 97/022S9 PCTrUS96/08681 C~AR.T CC

Q1- Il ~N~N w,~ (CC-l) \ o~
Ph O
Q1 -1 ,~

16 Q- 2 N W~ R~ (CC-2) Q~ 1ll 1 ~0 Q--2 ~N W,~OSo2cF3 (CC-3) ~ IN~ ~ (lX) l-2 N W~ R, \--/ R2 -W O 97/02259 PCT~US96/08681 C~ART DD

o H2~ ~"
I

oP
0 M~2N NJ~ o (DD-2) OP
N--N N--O

15 Q15 N~ ~o (DD-3) Q1~ N ~[~o (DD-5) ~P

N--O
N--N //
Q1 ei N~ (DD 4) ~1-6 N~ (DD~) [--N~ W1~ N~JW1

Claims (38)

1. A 1,6-disubstituted isochroman of formula (I) (I) where:
(I) W1 is a nitrogen (-N-) or carbon (-CH-) atom;
(II) X1 is:
(A) -(CH2)n1- where n1 is 0 thru 3, (B) -CH=CH-;
(III) R1 is:
(A) -H, (B) -F, -Cl, -Br, -I, (C) C1-C8 alkyl, (D) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (E) C2-C8 alkynyl containing 1 or 2 triple bonds (=), (F) C3-C8 cycloalkyl, (G) -C1-C3 alkyl-C3-C8 cycloalkyl, (H) -N02, (I) -C=N, (J) -CF3, (K) -O-R1-1 where R1-1 is:
(1)-H, (2) C1-C8 alkyl, (3) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (4) C2-C8 alkynyl containing 1 or 2 triple bonds (=), (5) C3-C8 cycloalkyl, (6) -C1-C3 alkyl-C3-C8 cycloalkyl, (7) -CF3, (8) -SO2-CF3, (9) -(CH2)n2-~ where n2 is 0 thru 4 and where -~ is optionally substituted with one or two:
(a) -F, -C1, -Br, -I, (b) -C=N, (c) -CF3, (d) C1-C3 alkyl, (e) -O-R1 1A where R1-1A is -H, C1-C6 alkyl, -CF3 or -CH2-~
(f) -NR1-1AR1 1B where the R1 1A and R1 1B are the same or different and where R1 1B is -H, C1-C6 alkyl, -CF3 or -CH2-~, and where R1-1A is as defined above, (g) -CO-NR1-1AR1-1B where R1-1A and R1-1B are as defined above, (h) -S02-NR1-AR1-B where R1-1A and R1-1B are as defined above, (i) -NR1-1A-S02-R1-1B where R1-1A and R1-1B are as defined above, (j) -N02, (k) -O-SO2-CF3, (L) -N(R1-1)2 where the R1-1 can be the same or different and are as defined above, (M) -CO-N(R1-1)2 where the R1-1 are the same or different and are as defined above, (N) -S02-R1-3 where R1-3 is:
(1) -H, (2) -CF3, (3) C1-C8 alkyl, (4) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (5) C2-C8 alkynyl containing 1 or 2 triple bonds (=), (6) C3-C8 cycloalkyl, (7) -C1-C3 alkyl-C3-C8 cycloalkyl, (8) -(CH2)n2-~ where n2 is as defined above and -~ is optionally substituted with one or two:

(a) -F, -Cl, -Br, -I, (b) -C2N, (c) -CF3, (d) C1-C3 alkyl, (e) -O-R1 3A where R1-3A is -H, C1-C6 alkyl, -CF3 or -CH2-~
(f) -NR1-3AR1-3B where the R1-3A and R1-3B are the same or different and where R1-3B is -H, C1-C6 alkyl, -CF3 or -CH2-~, and where R1-3A is as defined above, (g) -CO-NR1-3AR1-3B where R1-3A and R1-3B are as defined above, (h) SO2-NR1-3AR1-3B where R1-3A and R1-3B are as defined above, (i) -NR1 3A-SO2-R1-3B where R1-3A and R1-3B are as defined above, (j) -NO2, (k) -O-SO2-CF3, (9) -0-R1-3A where R1-3A is as defined above, (10) -NR1-3AR1-3B where R1-3A and R1-3B are as defined above, (O) -NR1-1-SO2-R1-3 where R1-1 and R1-3 may be the same or different and are as defined above, (P) -(CH2)n2-~ where n2 is as defined above and where -~ is optionally substituted with one or two:
( 1) -F, -C1, -Br, -I, (2) -C=N, (3) -CF3, (4) C1-C6 alkyl, (5) -O-R1-1 where R1-1 is as defined above, (6) -N(R1-1)2 where the R1-1s are the same or different and are as defined above, (7) -CO-N(R1-1)2 where the R1-1s are the same or different and are as defined above, (8) -SO2-N(R1-1)2 where the R1-1s are the same or different and are as defined above, (9) -NR1-1-SO2-R1-1 where the R1-1s are the same or different and are as defined above, (10) -NO2, (11) -O-SO2-CF3;
(Q) -CO-R1-1 where R1-1 is as defined above, (R) -CO-O-Q1-2 where Q1-2 is defined below;
(IV) R2 is defined the same as R1,R2 can be the same or different than R1;
(V) Q1 is:
(A) -CO-NQ1-1Q1-2 where Q1-1 is (1) -H, (2) C1-C8 alkyl, (3) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (4) C2-C8 alkynyl containing 1 or 2 triple bonds (=), (5) C3-C8 cycloalkyl, (6) -C1-C3 alkyl-C3-C8 cycloalkyl, (7) -CF3, (8) -SO2-CF3, (9) -(CH2)n7-.PHI. where n7 is 0 thru 4 and where ~ is optionally substituted with one or two:
(a) -F, -C1, -Br, -I, (b) -C=N, (c) -CF3, (d) C1-C3 alkyl, (e) -O-Q1-1A where Q1-1A is -H, C1-C6 alkyl, -CF3 or -CH2-.PHI.
(f) -NQ1-1AQ1-1B where the Q1-1A and Q1-1B are the same or different and where Q1-1B is -H, C1-C6 alkyl, -CF3 or -CH2-.PHI., and where Q1-1A is as defined above, (g) -CO-NQ1-1AQ1-1B where Q1-1A and Q1-1B are as defined above, (h) -SO2-NQ1-1AQ1-B where Q1-1A and Q1-1B are as defined above, (i) -NQ1-1A-SO2-Q1-1B where Q1-1A and Q1-1B are as defined above, (j) -NO2, (k) -O-SO2-CF3,and where Q1-2 is:

(1) -H, (2) C1-C8 alkyl, (3) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (4) C2-C8 alkynyl containing 1 or 2 triple bonds (=), (5) C3-C8 cycloalkyl, (6) -C1-C3 alkyl-C3-C8 cycloalkyl, (7) -CF3, (8) -(CH2)n2-~ where n2 is as defined above and ~ is optionally substituted with one or two:
(a) -F, -C1, -Br, -I, (b) -C~N, (c) -CF3, (d) C1-C6 alkyl, (e) -O-Q1-2A where Q1-2A is:
(i) -H, (ii) C1-C6 alkyl, (iii) -CF3, (iV) -(CH2)~, (9) -(CH2)n9-Q1-2B(CH2)n10-Q1-2C where n9 and n10 are the same or different and are 0 thru 4, where Q1-2B is -O- or -NQ1-2D-, where Q1-2D is (a) -H, (b) C1-C8 alkyl, (c) C2-C8 alkenyl containing 1 thru 3 double bonds, (d) C2-C8 alkynyl containing 1 or 2 triple bonds, (e) C3-C8 cycloalkyl, (f) -C1-C3 alkyl-C3-C8 cycloalkyl, (g) -CF3, (h) -(CH2)n11-~ where n11 is 0 thru 4 and -~ is optionally substituted with one or two:
(i) -F, -Cl, -Br, -I, (ii) -C~N, (iii) -CF3, (iv) C1-C3 alkyl, (V) -O-Q1-2E where Q1-2E is -H, C1-C6 alkyl -CF3 or -CH2-~, (vi) NQ1-2EQ1-2F where the Q1-2E and Q1-2F are the same or different and where Q1-2F is -H, C1-C6 alkyl, -CF3 or -CH2-~, and where Q1-2E is as defined above, (vii) -CO-NQ1-2EQ1-2F where Q1-2E and Q1-2F
are as defined above, (viii) -SO2-NQ1-2EQ1-2F where Q1-2E and Q1-2F
are as defined above, (ix) -NQ1-2E-SO2-Q1-2F where Q1-2E and Q1-2F
are as defined above, (X) -NO2, (xi) -O-SO2-CF3, and where Q1-2C is defined the same as Q1-2D and the Q1-2C and Q1-2D can be the same or different, and where Q1-1 and Q1-2 are taken together with the attached nitrogen atom to form a 5 or 6 member ring which can include one additional nitrogen or oxygen atom;
(B) -SO2-NQ1-1Q1-2 where Q1-1 and Q1-2 are as defined above, (C) -CO-O-Q1-3 where Q1-3 is:
(1) -H, (2) -CF3, (3) C1-C8 alkyl, (4) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (5) C2-C8 alkynyl containing 1 or 2 triple bonds (=), (6) C3-C8 cycloalkyl, (7) -C1-C3 alkyl-C3-C8 cycloalkyl, (8) -(CH2)n7-~ where n7 is as defined above and -~ is optionally substituted with one or two:
(a) -F, -Cl, -Br, -I, (b) -C=N, (C) -CF3, (d) C1-C3 alkyl, (e) -O-Q1-3A where Q1-3A is -H, C1-C6 alkyl,-CF3 or -CH2-~
(f) -NQ1-3AQ1-3B where the Q1-3A and Q1-3B are the same or different and where Q1-3B is -H, C1-C6 alkyl, -CF3 or -CH2-~, and where Q1-3A is as defined above, (g) -CO-NQ1-3AQ1-3B where Q1-3A and Q1-3B are as defined above, (h) -SO2-NQ1-3AQ1-3B where Q1-3A and Q1-3B are as defined above, (i) -NQ1-3A-SO2-Q1-3B where Q1-3A and Q1-3B are as defined above, (j) -NO2, (k) -O-SO2-CF3, (D) -CO-Q1-3 where Q1-3 is as defined above, (E) -CO-imidazole, (F) -NQ1-1Q1-2 where Q1-1 and Q1-2 are as defined above, (F) -NQ1-1-CO-Q1-2 where Q1-1 and Q1-2 are as defined above, (G) -C(Q1-3)=N-O-Q1-4 where Q1-4 is defined the same as Q1-3 and Q1-3 is as defined above, the Q1-3 and Q1-4 can be the same or different, (H) -SO2-Q1-3 where Q1-3 is as defined above, (I) -N(Q1-1)-SO2-Q1-3 where Q1-1 and Q1-3 is as defined above, (J) 5-oxadiazole optionally substituted with one Q1-5 where Q1-5 is:
(1) -H, (2) -F, -Cl, -Br, -I, (3) C1-C8 alkyl, (4) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (5) C2-C8 alkynyl containing 1 or 2 triple bonds (~), (6) C3-C8 cycloalkyl, (7) -C1-C3 alkyl-C3-C8 cycloalkyl, (8) -NO2, (9) -C~N, (10) -CF3, (11) -O-Q1-5A where Q1-5A is (a) -H, (b) C1-C8 alkyl, (c) C2-C8 alkenyl containing 1 thru 3 double bonds, (d) C2-C8 alkynyl containing 1 or 2 triple bonds, (e) C3-C8 cycloalkyl, (f) -C1-C3 alkyl-C3-C8 cycloalkyl, (g) -CF3, (h) -SO2-CF3, (i) -(CH2)n7-~ where n7 is 0 thru 4, (12) -NQ1-5AQ1-5D where Q1-5A is as defined above, Q1-5D is:
(a) -H, (b) C1-C8 alkyl, (c) C2-C8 alkenyl containing 1 thru 3 double bonds, (d) C2-C8 alkynyl containing 1 or 2 triple bonds (=), (e) C3-C8 cycloalkyl, (f)-C1-C3 alkyl-C3-C8 cycloalkyl, (g) -CF3, (h) -(CH2)n7-~ where n7 is as defined above, (13) -CO-NQ1-5AQ1-5D where Q1-5A and Q1-5D are as defined above, (14) -SO2-Q1-5K where Q1-5K is:
(a) -H, (b) -CF3, (c) C1-C8 alkyl, (d) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (e) C2-C8 alkynyl containing 1 or 2 triple bonds (=), (f) C3-C8 cycloalkyl, (g) -C1-C3 alkyl-C3-C8 cycloalkyl, (h) -(CH2)n7~ where n7 is as defined above, (15) -NQ1-5A-SO2-Q1-SK where Q1-5A and Q1-5K may be the same or different and are as defined above, (16) -(CH2)n7~ where n7 is as defined above and where -~ is optionally substituted with one or two:
(a) -F, -C1, -Br, -I, (b) -C=N, (c) -CF3, (d) C1-C6 alkyl, (e) -O-Q1-5A where Q1-5A is as defined above, (f) -NQ1-5AQ1-5-D where Q1-5A and Q1-5D are as defined above, (g)-CO-NQ1-5AQ1-5D where Q1-5A and Q1-5D are as defined above, (h)-SO2-NQ1-5AQ1-5D where Q1-5A and Q1-5D are as defined above, (i)-NQ1-5A-SO2-Q1-5D where Q1-5A and Q1-5D are as defined above, (J) -N02, (k) -O-SO2-CF3;
(K) 3-oxadiazole optionally substituted with one Q1-5 where Q1-5 is as defined above, (L) triazole optionally substituted with one or two Q1-5 which may be the same or different, where Q1-5 is as defined above, (M) 5-thiadiazole optionally substituted with one Q1-5, where Q1-5 is as defined above, (N) 3-thiadiazole optionally substituted with one Q1-5 where Q1-5 is as defined above, (O) 2-oxazole optionally substituted with one or two Q1-5 which may be the same or different, where Q1-5 is as defined above, (P) 2-thiazole optionally substituted with one or two Q1-5 which may be the same or different where Q1-5 is as defined above, (Q) 2-imidazole optionally substituted with one, two or three Q1-5 which may be the same or different, where Q1-5 is as defined above, (R) 1-imidoazole optionally substituted with one, two or three Q1-5 which may be the same or different, where Q1-5 is as defined above, (S) tetrazole optionally substituted with one Q1-5, where Q1-5 is as defined above, (T) cyclobutenedione optionally substituted with one Q1-1 and one Q1-5 where Q1-1 and Q1-5 are as defined above, (U) 1-pyrimidinyl optionally substituted with one Q1-5,where Q1-5 is as defined above, (V) 2-pyridinyl optionally substituted with one Q1-5, where Q1-5 is as defined above, (W) 3-pyridinyl optionally substituted with one Q1-5, where Q1-5 is as defined above, (X) 4-pyridinyl optionally substituted with one Q1-5, where Q1-5 is as defined above, (Y) -Z1-CO-Z2-Q1-2 where Q1-2 is as defined above and Z1 is -O- or -NQ1-1- where Q1-1 is as defined above, where Z2 is -O- or -NQ1-1- where Q1-1 is as defined above, with the proviso that when X1 is -(CH2)n1-, where n1 is 0 and Q1 is:
-CO-NQ1-1Q1-2' -SO2-NQ1-1Q1-2 or -NQ1-1Q1-2' -NQ1-1-CO-Q1-2 then Q1-1 and Q1-2 cannot both be selected from:
-H, -C1-C6 alkyl, -C3-C7 cycloalkyl, -C1-C3 alkyl-(C3-C7) cycloalkyl and pharmaceutically acceptable salts thereof.

2. A 1,6-disubstituted isochroman (I) according to claim 1 where:
(I) W1 is a nitrogen (-N-) or carbon (-CH-) atom;
¦ ¦
(II) X1 is:
(A) -(CH2)n1- where n1 is 0 thru 3, (B) -CH=CH-;
(III) R1 is:
(A) -H, (B) -F, -C1, -Br, -I, (C) C1-C8 alkyl, (D) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (E) C2-C8 alkynyl containing 1 or 2 triple bonds (~), (F) C3-C8 cycloalkyl, (G) -C1-C3 alkyl-C3-C8 cycloalkyl, (H) -NO2, (I) -C~N, (J) -CF3, (K) -O-R1-1 where R1-1 is:

(1) -H, (2) C1-C8 alkyl, (3) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (4) C2-C8 alkynyl containing 1 or 2 triple bonds (~), (5) C3-C8 cycloalkyl, (6) -C1-C3 alkyl-C3-C8 cycloalkyl, (7) -CF3, (8) -SO2-CF3, (9) -(CH2)n2~ where n2 is 0 thru 4 and where -~ is optionally substituted with one or two:
(a) -F, -Cl, -Br, -I, (b) -C~N, (c) -CF3, (d) C1-C3 alkyl, (e) -O-R1-1A where R1-1A is -H, C1-C6 alkyl,-CF3 or -CH2-~
(f) -NR1-1AR1-1B where the R1-1A and R1-1B are the same or different and where R1-1B is -H, C1-C6 alkyl, -CF3 or -CH2-~, and where R1-1A is as defined above, (g) -CO-NR1-1AR1-1B where R1-1A and R1-1B are as defined above, (h) -SO2-NR1-1AR1-1B where R1-1A and R1-1B are as defined above, (i) -NR1-1A-SO2-R1-1B where R1-1A and R1-1B are as defined above, (j) -NO2, (k) -O-SO2-CF3, (L) -N(R1-1)2 where the R1-1 can be the same or different and are as defined above, (M) -CO-N(R1-1)2 where the R1-1 are the same or different and are as defined above, (N) -SO2-R1-3 where R1-3 is:
(1) -H, (2) -CF3, (3) C1-C8 alkyl, (4) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (5) C2-C8 alkynyl containing 1 or 2 triple bonds (=), (6) C3-C8 cycloalkyl, (7)-C1-C3 alkyl-C3-C8 cycloalkyl, (8) -(CH2)n2-~ where n2 is as defined above and -~ is optionally substituted with one or two:
(a) -F, -C1, -Br, -I, (b) -C=N, (C) CF3, (d) C1-C3 alkyl, (e) -O-R1-3A where R1-3A is -H, C1-C6 alkyl, -CF3 or -CH2-~
(f) -NR1-3AR1-3B where the R1-3A and R1-3B are the same or different and where R1-3B is -H, C1-C6 alkyl, -CF3 or -CH2~, and where R1-3A is as defined above, (g) -CO-NR1-3AR1-3B where R1-3A and R1-3B are as defined above, (h) -SO2-NR1-3AR1-3B where R1-3A and R1-3B are as defined above, (i) -NR1-3A-SO2-R1-3B where R1-3A and R1-3B are as defined above, (j) -NO2, (k) -O-SO2-CF3, (9) -O-R1-3A where R1-3A is as defined above, (10) -NR1-3AR1-3B where R1-3A and R1-3B are as defined above, (O) -NR1-1-SO2-R1-3 where R1-1 and R1-3 may be the same or different and are as defined above, (P) -(CH2)n2-~ where n2 is as defined above and where -~ is optionally substituted with one or two:
(1) -F, -C1, -Br, -I, (2) -C=N, (3) CF3, (4) C1-C6 alkyl, (5) -O-R1-1 where R1-1 is as defined above, (6) -N(R1-1)2 where the R1-1s are the same or different and are as defined above, (7) -CO-N(R1-1)2 where the R1-1s are the same or different and are as defined above, (8) -SO2-N(R1-1)2 where the R1-1s are the same or different and are as defined above, (9) -NR1-1-SO2-R1-1 where the R1-1s are the same or different and are as defined above, (10) -NO2, (11) -O-SO2-CF3;
(IV) R2 is defined the same as R1,R2 can be the same or different than R1;
(V) Q1 is:
(A) -CO-NQ1-1Q1-2 where Q1-1 is:
(1) -H, (2) C1-C8 alkyl, (3) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (4) C2-C8 alkynyl cnntaining 1 or 2 triple bonds (~), (5) C3-C8 cycloalkyl, (6) -C1-C3 alkyl-C3-C8 cycloalkyl, (7) -CF3, (8) -SO2-CF3, (9) -(CH2)n7-~ where n7 is 0 thru 4 and where -~ is optionally substituted with one or two:
(a) -F, -Cl,-Br, -I, (b) -C~N, (c) -CF3, (d) C1-C3 alkyl, (e) -O-Q1-1A where Q1-1A is -H, C1-C6 alkyl, -CF3 or -CH2-~
(f) -NQ1-1AQ1-1B where the Q1-1A and Q1-1B are the same or different and where Q1-1B is -H, C1-C6 alkyl, -CF3 or -CH2-~, and where Q1-1A is as defined above, (g) CO-NQ1-1AQ1-1B where Q1-1A and Q1-1B are as defined above, (h) -SO2-NQ1-1AQ1-B where Q1-1A and Q1-1B are as defined above, (i) -NQ1-1A-SO2-Q1-1B where Q1-1A and Q1-1B are as defined above, (j) -NO2, (k) -O-SO2-CF3, and where Q1-2 is:
(1) -H, (2) C1-C8 alkyl, (3) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (4) C2-C8 alkynyl containing 1 or 2 triple bonds (~), (5) C3-C8 cycloalkyl, (6) -C1-C3 alkyl-C3-C8 cycloalkyl, (7) -CF3, (8) -(CH2)n2-~ where n2 is as defined above and -~ is optionally substituted with one or two:
(a) -F, -Cl, -Br, -I, (b) -C~N, (c) -CF3, (d) C1-C6 alkyl, (e) -O-Q1-2A where Q1-2A is:
(i) -H, (ii) C1-C6 alkyl, (iii) -CF3, (iv) -(CH2)~, (9) -(CH2)n9-Q1-2B(CH2)n10-Q1-2C where n9 and n10 are the same or different and are 0 thru 4, where Q1-2B is -O- or -NQ1-2D-, where Q1-2D is:
(a) -H, (b) C1-C8 alkyl, (c) C2-C8 alkenyl containing 1 thru 3 double bonds, (d) C2-C8 alkynyl containing 1 or 2 triple bonds, (e) C3-C8 cycloalkyl, (f)-C1-C3 alkyl-C3-C8 cycloalkyl, (g) -CF3, (h) -(CH2)n11-~ where n11 is 0 thru 4 and -~ is optionally substituted with one or two:
(i) -F, -Cl, -Br, -I, (ii) -C~N, (iii) -CF3, (iv) C1-C3 alkyl, (V) -O-Q1-2E where Q1-2E is -H, C1-C6 alkyl,-CF3 or -CH2-~, (vi) -NQ1-2EQ1-2F where the Q1-2E and Q1-2F are the same or different and where Q1-2F is -H, C1-C6 alkyl, -CF3 or -CH2-~, and where Q1-2E is as defined above, (vii) -CO-NQ1-2EQ1-2F where Q1-2E and Q1-2F
are as defined above, (viii) -SO2-NQ1-2EQ1-2F where Q1-2E and Q1-2F
are as defined above, (ix) -NQ1 2E-SO2-Q1-2F where Q1-2E and Q1-2F
are as defined above, (X) -NO2, (Xi) -O-SO2-CF3, and where Q1-2C is defined the same as Q1-2D and the Q1-2C and Q1-2D can be the same or different, (B) -SO2-NQ1-1Q1-2 where Q1-1 and Q1-2 are as defined above, (C) -CO-O-Q1-3 where Q1-3 is:
(1) -H, (2) -CF3, (3) C1-C8 alkyl, (4) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (5) C2-C8 alkynyl containing 1 or 2 triple bonds (=), (6) C3-C8 cycloaLkyl, (7) -C1-C3 alkyl-C3-C8 cycloalkyl, (8) -(CH2)n7-~ where n7 is as defined above and -~ is optionally substituted with one or two:
(a) -F, -C1, -Br, -I, (b) -C=N, (C) -CF3, (d) C1-C3 alkyl, (e) -O-Q1-3A where Q1-3A is -H, C1-C6 alkyl, -CF3 or -CH2-~
(f) -NQ1-3AQ1-3B where the Q1-3A and Q1-3B are the same or different and where Q1-3B is -H, C1-C6 alkyl, -CF3 or -CH2~, and where Q1-3A is as defined above, (g) CO NQ1-3AQ1-3B where Q1-3A and Q1-3B are as defined above, (h) -SO2-NQ1-3AQ1-3B where Q1-3A and Q1-3B are as defined above, (i) -NQ1-3A-SO2-Q1-3B where Q1-3A and Q1-3B are as defined above, (J) -NO2, (k) -O-SO2-CF3, (D) -CO-Q1-3 where Q1-3 is as defined above, (E) -CO-imidazole, (F) -NQ1-1Q1-2 where Q1-1 and Q1-2 are as defined above, (G) -C(Q1-3)=N-O-Q1 4 where Q1-4 is defined the same as Q1-3 and Q1-3 is as defined above, the Q1-3 and Q1-4 can be the same or different, (H) -SO2-Q1-3 where Q1-3 is as defined above, (I) -N(Q1-1)-SO2-Q1-3 where Q1-1 and Q1-3 is as defined above, (J) 5-oxadiazole optionally substitutedd with one Q1-5 where Q1-5 is:
(1) -H, (2) -F, -C1, -Br, -I, (3) C1-C8 alkyl, (4) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (5) C2-C8 alkynyl containing 1 or 2 triple bonds (=), (6) C3-C8 cycloalkyl, (7) -C1-C3 alkyl-C3-C8 cycloalkyl, (8) -NO2, (9) -C=N, (10) -CF3, (11) -O-Q1-5A where Q1-5A is (a) -H, (b) C1-C8 alkyl, (c) C2-C8 alkenyl containing thru 3 double bonds, (d) C2-C8 alkynyl containing 1 or 2 triple bonds, (e) C3-C8 cycloalkyl, (f) -C1-C3 alkyl-C3-C8 cycloalkyl, (g) -CF3, (h) -SO2-CF3, (i) -(CH2)n7-~ where n7 is 0 thru 4, (12) -NQ1-5-AQ1-5D where Q1-5A is as defined above, Q1-5D is:
(a) -H, (b) C1-C8 alkyl, (c) C2-C8 alkenyl containing 1 thru 3 double bonds, (d) C2-C8 alkynyl containing 1 or 2 triple bonds (=), (e) C3-C8 cycloalkyl, (f) C1-C3 alkyl-C3-C8 cycloalkyl, (g) -CF3, (h) ~(CH2)n7~ where n7 is as defined above, (13) -CO-NQ1-5AQ1-5D where Q1-5A and Q1-5D are as defined above, (14) -SO2-Q1-5K where Q1-5K is:
(a) -H, (b) -CF3, (c) C1-C8 alkyl, (d) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (e) C2-C8 alkynyl containing 1 or 2 triple bonds (~), (f) C3-C8 cycloalkyl, (g) -C1-C3 alkyl-C3-C8 cycloalkyl, (h) -(CH2)n7~ where n7 is as defined above, (15) -NQ1-5A-SO2-Q1-5K where Q1-5A and Q1-5K may be the same or different and are as defined above, (16) -(CH2)n7~ where n7 is as defined above and where -~ is optionally substituted with one or two:
(a) -F, -C1, -Br, -I, (b) -C=N, (c) -CF3, (d) C1-C6 alkyl, (e) -O-Q1-6A where Q1-5A is as defined above, (f) -NQ1-5AQ1-5D where Q1-5A and Q1-5D are as defined above, (g) -CO-NQ1-5AQ1-5D where Q1-5A and Q1-5D are as defined above, (h) -SO2-NQ1-5AQ1-5D where Q1-6A and Q1-5D are as defined above, (i) -NQ1-5A-SO2-Q1-5D where Q1-5A and Q1-5D are as defined above, (J) -NO2, (k) -O-SO2-CF3;
(K) 3 -oxadiazle optionally substituted with one Q1-5 where Q1-5 is as defined above, (L) triazole optionally substituted with one or two Q1-5 which may be the same or different, where Q1-5 is as defined above, (M) 5-thiadiazole optionally substituted with one Q1-5, where Q1-5 is as defined above, (N) 3-thiadiazole optionally substituted with one Q1-5, where Q1-5 is as defined above, (O) 2-oxazole optionally substituted with one or two Q1-5 which may be the same or different, where Q1-5 is as defined above, (P) 2-thiazole optionally substituted with one or two Q1-5 which may be the same or different, where Q1-5 is as defined above, (Q) 2-imidazole optionally substituted with one, two or three Q1-5 which may be the same or different, where Q1-5 is as defined above, (R) 1-imidazole optionally substituted with one, two or three Q1-5 which may be the same or different, where Q1-5 is as defined above, (S) tetrazole optionally substituted with one Q1-5, where Q1-5 is as defined above, (T) cyclobutenedione optionally substituted with one Q1-1 and one Q1-5 where Q1-1 and Q1-5 are as defined above, (U) 1-pyrimidinyl optionally substituted with one Q1-5, where Q1-5 is as defined above, (V) 2-pyridinyl optionally substituted with one Q1-5, where Q1-5 is as defined above, (W) 3-pyridinyl optionally substituted with one Q1-5, where Q1-5 is as defined above, (X) 4-pyridinyl optionally substituted with one Q1-5, where Q1-5 is as defined above, with the proviso that when X1 is -(CH2)n1-, where n1 is 0 and Q1.is:
-CO-NQ1-1Q1-2, -SO2-NQ1-1Q1-2 or -NQ1-1Q1-2, -NQ1-1-CO-Q1-2 then Q1-1 and Q1-2 cannot both be selected from:
-H, -C1-C6 alkyl, -C3-C7 cycloalkyl, -C1-C3 alkyl-(C3-C7) cycloalkyl and pharmaceutically acceptable salts thereof.

3. A 1,6-disubstituted isochroman (I) according to claim 1 where W1 is a nitrogen atom.

4. A 1,6-disubstituted isochroman (I) according to claim 1 where W1 is a carbon atom.

5. A 1,6-disubstituted isochroman (I) according to claim 1 where X1 is -(CH2)n1-.

6. A 1-6-disubstituted isochroman (I) according to claim 5 where n1 is 0 or 1.

7. A 1,6-disubstituted isochroman (I) according to claim 1 where X1 is -CH=CH-.

8. A 1,6-disubstituted isochroman (I) according to claim 1 where R1 is -O-R1-1, -CF3, -CO-N(R1-1)2 and -CO-R1-1.

9. A 1,6-disubstituted isochroman (I) according to claim 7 where R1-1 is C1-C3 allkyl.

10. A 1,6-disubstituted isochroman (I) according to claim 1 where R2 is -H.

11. A 1,6-disubstituted isochroman (I) according to claim 1 where Q1 is selectedfrom the group consisting of -CO-NQ1-1Q1-2,-SO2-NQ1-1Q1-2 and -NQ1-1Q1-2.

12. A 1,6-disubstituted isochroman (I) according to claim 10 where Q1 is -CO-NQ1-1Q1-2.

13. A 1,6-disubstituted isochroman (I) according to claim 11 where the pharmaceutically acceptable anion salt is selected from the group consisiting ofmethanesulfonic hydrochloric hydrobromic, sulfuric, phosphoric, nitric, benzoic,citric, tartaric, fumaric, maleic, CH3-(CH2)n-COOH where n is 0 thru 4, HOOC-(CH2)n-COOH where n is as defined above.

14. A 1,6-disubstituted isochroman (I) according to claim 1 where R1 is (Q) -CO-R1-1 or -CO-O-Q1-2-

15. A 1,6-disubstituted isochroman (I) according to claim 14 where the 1,6-disubsituted isochroman is (S)-(-)-1-[2-[4-(4-trifluoroacetylphenyl)-1-piperazinyl]ethyl]
-N-methylisochroman-6-carboxamide.

16. A 1,6-disubstituted isochroman (I) according to claim 1 where Q1 is (Y) -Z1-CO-Z2-Ql 2

17. A 1,6-disubstituted isochroman (I) according to claim 16 where the 1, 6-disubstituted isochroman is selected from the group consisting of:
(S)-(-)-6-amino-1-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]isochroman methyl urea, (S)-(-)-6-amino-1-[2-[4-(4-methoxyyphenyl)piperazinyl]ethyl]isochroman t-butylcarbamate and (+/-)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]isochroman-6-ol methyl carbamate ester.

18. A 1,6-disubstituted isochroman (I) accordingg to claim 1 where Q1 is (F')

19. A 1,6-disubstituted isochroman (I) according to claim 18 where the 1, 6-disubstituted isochroman (I) is selected from the group consisting of:
(S)-(-)-N-[isochroman-1-[2-[4-(4-methoxyphenyl)piperazin-l-yl]ethyl]
-6- yl]benzamide and (S)-(-)-N-[isochroman-1-[2-[4-(4-methoxyphenyl)piperazin-l-yl]ethyl]
-6-yl]acrylamide.

20. A 1,6-disubstituted isochroman (I) according to claim 1 where Q1-1 and Q1-2 are taken together with the attached nitrogen atom to form a 5 or 6 member ring.

21. A 1,6-disubstitued isochroman (I) according to claim 20 where the 5 or 6 member ring is selected from the group consisting of pyrrolidine, piperidine, piperazine and morpholine.

22. A 1,6-disubstituted isochroman (I) according to claim 20 which is (+/-)-1-[1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]isochroman-6-yl]
-4- methylpiperazine.

23. A 1,6-disubstituted isochroman (I) according to claim 1 which is selected from the group consisting of:
1-[2-[4-(4-methylsulfonylphenyl)-1-piperazinyl]ethyl]isochroman -6-carboxamide, (S)-(-)-1-[2-[4-(4-trifluoromethoxyphenyl)-l-piperazinyl]ethyl]
-N-methisochroman-6-carboxamide, 1-[2-[4-(4-methylsulfonylphenyl)-1-piperazinyl]ethyl]-N-methylisochroman-6-carboxamide, 1-[2-[4-(4-methoxyphenyl)-l-piperazinyl]ethyl]-N-allylisochroman-6-1-[2-[4-(4-methoxoyphenyl)-l-piperazinyl]ethyl]-N-propargylisochroman-6 carboxamide, 1-[2-[4-(4-methoxyphenyl)-l-piperazinyl]ethyl]-N-(4-methoxyryphenylmethyl)isochroman 6 carboxamide, 1-[2-[4-(4-methoxyphenyl)-l-piperazinyl]ethyl]-N-phenylmethylisochroman-6-carboxamide, 1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-N-[(R)-.alpha.-methylphenylmethyl]-isochroman-6-carboxamide, 1-[2-[4-(4-methnxyphenyl)-1-piperazinyl]ethyl]-N-[(S)-.alpha.-methylphenylmethyl]isochroman-6-carboxamide, 1-[2-[4-(4-methoxyphenyl)-l-piperazinyl]ethyl]-N-phenylisochroman-6-carboxamide, 1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-N-phenylmethyl-N-methylisochroman-6-carboxamide, 1-(4-methoxyphenyl)-4-[2-[6-(5-methyloxazole-2-yl))isochroman-1-yl)ethyl]piperazine, (S)-(-)-N-[isochroman- 1-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-6-yl]-methanesulfonamide, 1-(4-methoxyphenyl)-4-[2 -(6-methylaminomethylisochroman-1-yl)ethyl]piperazine, 1-(4-methoxyphenyl)-4-[2-(6-dimethylaminomethylisochroman-1-yl)ethyl]piperazine, 1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]isochroman-6-carboxylic acid ethyl ester, 6-acetyl-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]isochroman, 6-formyl-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]isochroman, 2-[isochroman-1-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-6-yl]acetamide, 2-[isochroman-1-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-6-yl]-N-methylacetamide, (S)-(-)-3-[isochroman-1-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-6-yl]-N,N-dimethylacrlyamide, (S)-(-)-1-(4-methoxyphenyl)-4-[2-[6-(1,2,4-triazol-3-yl)-isochroman-1-yl]ethyl]piperazine, (S)-(-)-1-(4-methoxyphenyl)-4-[2-[6-(2-methyl-1,2,4-triazol-3-yl)-isochroman- 1-yl]ethyl]piperazine, (S)-(-)-1-(4-methoxyphenyl)-4-[2-[6-(2-phenylmethyl-1,2,4-triazol-3-yl)isochroman-1-yl]ethyl]piperazine, (S)-(-)-1-(4-methoxyphenyl)-4-[2-[6-(1,2,4-oxadiazol-5-yl)-isochroman-1-yl]ethyl]piperazine, 1-[1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]isochroman-6-yl]carbonyl]pyrrolidine, N-(2-hydroxyethyl)-1-[2-4-(4-methoxyphenyl)-1-piperazinyl]ethyl]isochroman-6-carboxamide, 1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-N-(phenylmethoxy)isochroman-6-carboxamide, (+/-)-N-hydroxy-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-N-methylisochroman-6-carboxamide, (S)-(-)-1-[2-[4-[4-(aminocarbonyl)phenyl]-1-piperazinyl]ethyl]-N-methyl-N-(phenylmethoxy)isochroman-6-carboxamide, (S)-(-)-1-[2-[4-[4-(aminocarbonyl)phenyl]-l-piperazinyl]ethyl]-N-hydroxy-N-methylisochroman-6 carboxamide, (S)-(-)-N-hydroxy-N-methyl-1-[2-[4-[4-(trifluoromethyl)phenyl]-1-piperazinyl]ethyl]isochroman-6-carboxamide, (S)-(-)-1-[2-[4-(4-chlorophenyl)-1-piperazinyl]ethyl]-N-hydroxy-N-methylisochroman-6-carboxamide, (S)-(-)- 1-[2-[4-(4-cyanophenyl)- 1-piperazinyl]ethyl]-N-hydroxy -N-methylisochroman-6-carboxamide, (S)-(-)-N-hydroxy-N-methyl-1-[2-[4-[4-(methylcarbonyl)phenyl]-l-piperazinyl]ethyl]isochroman-6-carboxyamide (S)-4-[4-[2-[6-( 1,2,4-triazol-3-yl)isochroman-1-yl]ethyl]-1-piperazinyl]benzamide, (S)-4-[4-[2-[6-(2-methyl-1,2,4-triazol-3-yl)isochroman-1-yl]ethyl]-1-piperazinyl]benzamide, (S)-4-[4-[2-[6-(1,2,4-oxadiazol-5-yl)-isochroman-l-yl]ethyl]-l-piperazinyl]benzamide, (S)-1-[2-[6-(1,2,4-triazol-3-yl)isochroman-1-yl]ethyl]-4-[4-trifluoromethylphenyl]piperazine, (S)-1-[2-[6-(2-methyl-1,2,4-triazol-3-yl)isochroman-1-yl]ethyl]-4-[4-trifluoromethylphenyl]piperazine, (S)-1-[2-[6-(1,2,4-oxadiazol-5-yl)isochroman-l-yl]ethyl]-4-[4 trifluoromethylphenyl]piperazine, (S)-1-[4-acetylphenyl]-4-[2-[6-( 1,2,4-triazol-3-yl)isochroman-1-yl]ethyl]piperazine, (S)-1-[4-acetylphenyl]-4-[2-[6-(2-methyl-1,2,4-triazol-3-yl)isochroman-1-yl]ethyl]piperazine, (S)-1-[4-acetylphenyl]-4-[2-[6-(1,2,4-oxadiazol-5-yl)isochroman-l-yl]ethyl]piperazine, 3-[1-[2-[4-(4-Aminocarbonylphenyl)piperazin-l-yl]ethyl]isochroman-6-yl]-N,N-dimethylacrylamide, 3-[1-[2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethyl]isochroman-6-yl]-N,N-dimethylacrylamide, 3-[1-[2-[4-(4-acetylphenyl)piperazin-1-yl]-ethyl]isochroman-6-yl]-N,N-dimethylacrylamide .

24. An aromatic bicyclic amine of the formula (ABA) (ABA) where: I
(I) W1 is (-N-) or -(CH)-(II) X1 is -(CH2)n1-, and n1 is 0, (III) Q1 is (A) -CO-NQ1-1Q1-2 where Q1-1 is:
(1) -H, (2) C1-C8 alkyl, (3) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (4) C2-C8 alkynyl containing 1 or 2 triple bonds (~), (5) -(CH2)n7-~ where n7 is 0 thru 4 and where -~ is optionally substituted with one or two:
(a) -F, -Cl, -Br, -I, (b) -C~N, (c) -CF3, (d) C1-C3 alkyl, (e) -O-Q1-1A where Q1-1A is -H, C1-C6 alkyl, -CF3 or -CH2-~, (f) -NQ1-1AQ1-1B where the Q1-1A and Q1-1B are the same or different and where Q1-1B is -H, C1-C6 alkyl, -CF3 or -CH2-~, and where Q1-1A is as defined above, (g) -CO-NQ1-1AQ1-1B where Q1-1A and Q1-1B are as defined above, (h) -SO2-NQ1-1AQ1-B where Q1-1A and Q1-1B are as defined above, (i) -NQ1-1A-SO2-Q1-1B where Q1-1A and Q1-1B are as defined above, (J) -NO2, (k) -O-SO2-CF3, and where Q1-2 is:
(6) C1-C8 alkyl, (7) C2-C8 alkenyl containing 1 thru 3 double bonds (=), (8) C2-C8 alkynyl containing 1 or 2 triple bonds (~), (9) -(CH2)n2-~ where n2 is as defined above and -~ is optionally substituted with one or two:
(a) -F, -C1, -Br, -I, (b) -C~N, (c) -CF3, (d) C1-C6 alkyl, (e) -O-Q1-2A where Q1-2A is:
(i) -H, (ii) C1-C6 alkvl, (iii) -CF3, (iV) -(CH2)~, (B) -SO2-NQ1 1Q12 where Q1-1 and Q1-2 are are defined above, (C) -NQ1-1Q1-2 where Q1-1 and Q1-2 are as defined above, (D) -NQ1-1-C°-Q1-2 where Q11 and Q12 are as defined above, (III) R1 is:
(A) -H, (B) -F, -Cl, -Br, -I, (C) C1-C8 alkyl, (D) -C~N, (E) -CF3, (F) -O-R1-1 where R1-1 is:
(1) -H, (2) C1-C8 alkyl, (3) -CF3, (4) -SO2-CF3, (5) -(CH2)n2-~ where n2 is 0 thru 4 (G) -N(R1-1)2 where the R1-1 can be the same or different and are as defined above, (H) -CO-N(R1-1)2 where the R1-1 are the same or different and are as defined above, (I) -SO2-R1-3 where R1-3 is:
(1) CF3, (2) C1-C8 alkyl, (3) -O-R1-3A where R1-3A is as defined above, (4) -NR1-3AR1-3B where R1-3A and R1-3B are as defined above, (J) -CO-R1-1 where R1-1 is as defined above;
(IV) R2 is defined the same as R1, R2 can be the same or different than R1;
and pharmaceutically acceptable salts thereof.

25. An aromatic bicyclic amine (ABA) according to claim 24 where W1 is (-N-).

26. An aromatic bicyclic amine (ABA) according to claim 24 where one of R1 and R2 is -H.

27. An aromatic bicyclic amine (ABA) according to claim 24 where Q1 is (A) -CO-

28. An aromatic bicyclic amine (ABA) according to claim 27 where Q1-1 is -H.

29. An aromatic bicyclic amine (ABA) according to claim 27 where Q1-2 is -CH3.

30. An aromatic bicyclic amine (ABA) accoldingg to claim 27 where the pharmaceutically acceptable anion salt is selected from the group consisting of methanesulfonic, hydochloric, hydrobromic, sulfuric, phnsphnric, nitric, benzoic, citric, tartaric, fumaric, maleic, CH3-(CH2)n-COOH where n is 0 thru 4, HOOC-(CH2)n-COOH where n is as defined above.

31. An aromatic bicyclic amine (ABA) according to claim 27 where the substitutedd amino compound is selected from the group consisting of (S)(-)-1-[2-[4(4-methoxyphenyl)-1-piperazinyl]ethyl]-N-methylisochroman-6 carboxamide, (R)-(+)-1-[2-[4(4-methoxyphenyl)-1-piperazinyl]ethyl]-N-methylisochroman-6-carboxamide, (S)-(-)-1[2-[4-(4-trifluoromethylphenyl)-1-piperazinyl]ethyl]-N-methyl-isochroman-6-carboxamide, (S)-(-)-1-[2-[4-[4-aminocarbonyl)phenyl]-l-piperazinyl]ethyl]-N-methylisochroman 6 carboxamide, 1-[2-[4-(4-ethoxyphenyl)-1-piperazinyl]ethyl]-N-methylisochroman-6-carboxamide, 1-[2-[4-(4-propoxyphenyl)- l-piperazinyl]ethyl]-N-methylisochroman -6-carboxamide, (S)-(-)-1-[2-[4-(4-ethylphenyl)-1-piperazinyl]ethyl]-N-methylisochroman-6-carboxamide, (S)-(-)-1-[2-[4-(4-ethylphenyl)-l-piperazinyl]ethyl]-N-methylisochroman-6-carboxamide, (S)-(-)- 1-[2-[4-(4-phenylmethyloxyphenyl)- 1-piperazinyl]ethyl]-N-methylisochroman-6-carboxamide, (R)-(+)-1-[2-[4-(4-ethoxyphenyl)-l-piperazinyl]ethyl]-N-methylisochroman-6-carboxamide, 1-[2-[4-(3-trifluoromethylphenyl)-1-piperazinyl]ethyl]-N-methylisochroman-6-carboxamide, 1-[2-[4(4-methoxyphenyl)-l-piperazinyl]ethyl]-N-propylisochroman-6-carboxamide, 1-[2-[4-(4-methoxyphenyl)-l-piperaziny]ethyl]N-ethylisochroman-6-carboxamide, 1-[2-[4-(4-methoxyphenyl)-l-piperazinyl]ethyl]-N-butylisochroman-6-carboxamide, 1-[2-[4-(4-chlorophenyl)-1-piperazinyl]ethyl]-N-methylisochroman-6-carboxamide, (S)-(-)-1-[2-[4-(4-methoxyphenyl)-l-piperidinyl]ethyl]-N-methylisochroman-6-carboxamide, (S)-(-)-1-[2-[4-(4-hydroxyphenyl)-l-piperazinyl]ethyl]-N-methylisochroman-6-carboxamide, (S)(-)-1-[2-[4-(4-trifluoromethanesulfonyloxyphenyl)-l-piperazinyl]ethyl]-N-methyl-isochroman-6-carboxamide, (S)-(-)-1-[2-[4-(4-acetylphenyl)-1-piperazinyl]ethyl]-N-methylisochroman-6-carboxamide, (S)-(-)-N-methyl-1-[2-[4-(4-propionylphenyl)-1-piperazinyl]ethyl]isochroman-6-carboxamide, N-methyl-1-[2(4-phenyl-1-piperidinyl)ethyl]isochroman-6 carboxamide, (+/-)-N-methyl-1-[2-[4-(2,4-dichlorophenyl)-1-piperazinyl]ethyl]isochroman-6-carboxamide, (+/-)-1-[2-[4-(3-chloro-4-methoxyphenyl)-l-piperzinyl]ethyl]-N-methylisochroman-6-carboxamide, (S)-(-)-1-[2-[4-[4-(tert-butyloxycaronyl)phenyl]-1-piperazinyl]ethyl]-N-methylisochroman-6-carboxamide, (+/-)-1-[2-[4-[4-(aminocarbonyl)phenyl]-1-piperazinyl]ethyl]-N-methylisochromanyl-6-carboxamide, (R)-(+)-1-[2-[4-[4-(aminocarbonyl)phenyl]-1-piperazinyl]ethyn-N-methylisochromanyl-6-carboxamide, (+/-)-1-[2-[4-[4-(aminosulfonyl)phenyl]-1-piperazinyl]ethyl]-N-methylisochroman-6-carboxamide, (S)-(-)-N-methyl-1-[2-[4-[4-(methylaminocarbonyl)phenyl]-1-piperazinyl]ethyl]isochroman-6-carboxamide, (S)-(-)-N-methyl-1-[2-[4-[4-(dimethylaminocarbonyl)phenyl]-1-piperazinyl]ethyl]isochroman-6-carboxamide, (S)-(-)-N-methyl-1-[2-[4-[4-(n-propylaminocarbonyl)pheny]-1-piperaziny]ethyl]isochroman-6-carboxamide.

32. An aromatic bicyclic amine (ABA) according to claim 31 where the substitutedamino compound is (S)-(-)-1-[2-[4(4 trifllloromethylphenyl)-l-piperazinyl]ethyl]-N-methyl-isochroman-6-carboxamide and (S)-(-)-1-[2-[4-[4-(aminocarbonyl)phenyl]-1-piperzinyl]ethyl]-N-methylisochroman-6-carboxamide.

33. An aromatic bicyclic amine (ABA) according to claim 27 where the substitutedamino compound is selected from the group consisting of 1-[2-[4(4-dhlorophenyl)-1-piperzinyl]ethyl]-N,N-dimethylisochroman-6-carboxamide and (S)-(-)-1-[2-[4-(4-trifluoromethylphenyl)-1-piperazinyl]ethyl]-N,N-dimethylisochroman-6-carboxamide.

34. An aromatic bicyclic amine (ABA) according to claim 24 where the substituted amino compound is selected from the group consisting of 1-[2-(6-aminoisochroman-l-yl)-ethyl]4-(4-methoxyphenyl)piperazine, (S)-(-)-1-[2-(6-aminoisochroman-l-yl)-et,hyl]4-(4-methoxyphenyl)piperazine, (S)-(-)-1-[2-(6-ethylaminoiochroman-l-yl)-ethyl]4-(4-methoxyyphenyl)piperazine, (S)-(-)-1-(4-methoxyphenyl)-4-[2-(6-propylaminoisochroman-l-yl)ethyl]piperazine, (S)-(-)-1-(4-metoxyphenyl)4-[2-(6-methylaminoischroman-1-yl)ethyl]piperazine, (S)-(-)-1-(4-methoxyphenyl)4-[2-(6-dimethylaminoisochroman-l-yl)ethyl]piperazine and (S)-(-)-1-[2-(6-ethylmethylaminoischroman-l-yl)ethyl]-4(4-methoxyphenyl)piperazine.

36. An aromatic bicyclic amine (ABA) according to claim 24 where the substitutedamino compound is selected from the group consisting of (S)-(-)-N-[isochroman-1-[2-[4(4-methoxyphenyl)piperazin-l-yl]ethyl]-6-yl]formamide, (S)-(-)-N-[isochroman-1-[2-[4(4-methoxyphenyl)piperazin-l-yl]ethyl]-6-yl]acetamide, (S)-(-)-N-[isochroman-1-[2-[4-(4-methoxyphenyl)piperazin-l-yl]ethyl]-6-yl]propinamide, (S)4)-N-[isochroman-1-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-6-yl]isobutyramide, (S)(-)-N-[isochroman-1-[2-[4(4-methoxyphenyl)piperazin-l-yl]ethyl]-6-yl]-N-methylacetamide and (S)(-)-N-[isochroman-1-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-6-y]-N-methylisobutryamide.

36. An aromatic bicyclic amine selected from the group consisting of (S)(-)-1-[2-[4-(4-methoxyphenyl)-l-piperazinyl]ethyl]isochroman-6-carboxamide, (R)-(+)-1-[2-[4(4-methoxyphenyl)-l-piperazinyl]ethyl]isochroman-6-carboxamide, 1-[2-[4(4-diethylaminophenyl)-1-piperazinyl]ethyl]isochroman-6-carboxamide, 1-[2-[4-(3-trifluromethylphenyl)-1-piperazinyl]ethyl]isochroman-6 carboxamide, (S)-(-)-1-[2-[4-(4-trifluoromethylphenyl)-1-piperazinyl]ethyl]isochroman-6-carboxamide, 1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]isochroman-6-carboxamide, 1-[2-[4-phenylpiperzinyl]ethyl]isochroman-6-carboxamide, 1-[2-[4-(4-hydroxyphenyl)-1-piperzinyl]ethyl]isochroman-6-carboxamide, (+/-)-1-[2-(4-phenyl-1-piperidinyl)ethyl]isochroman-6-carboxamide, (+/-)-1-[2-[4-(2,4-dichlorophenyl)-1-piperazinyl]ethyl]isochroman-6-carboxamide, 1-[2-[4-(3-chloro-4-methoxyphenyl)-1-piperazinynethy]isochroman-6-carboxamide.

37. An aromatic bicyclic amine according to claim 36 which is:
(S)-(-)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]isochroman-6-carboxamide, (R)-(+)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]isochroman-6 carboxamide,

38. An aromatic bicyclic amine according to claim 36 where the pharmaceutically acceptable anion salt is selected from the group consisting of methanesulfonic, hydrochloric hydrobromic, sulfuric, phosporic, nitric, benzoic, citric, tartaric, fumaric, maleic, CH3-(CH2)n-COOH where n is 0 thru 4, HOOC-(CH2)n-COOH
where n is as defined above.