CA2004617A1

CA2004617A1 - Therapeutic use of dihydropyrimidones and benzazepine and benzothiazepine derivatives

Info

Publication number: CA2004617A1
Application number: CA 2004617
Authority: CA
Inventors: Craig E. Crosson; Miguel A. Ondetti; David E. Potter; David M. Floyd; Gunnar Aberg
Original assignee: Individual
Current assignee: Houston Biotechnology Inc
Priority date: 1988-12-05
Filing date: 1989-12-05
Publication date: 1990-06-05
Also published as: AU4754790A; WO1990006123A1; CA2004616A1; AU4807790A; WO1990006118A1

Abstract

ABSTRACT OF THE DISCLOSURE
A method of treating a subject suffering from ischemia or edema of the retina or optic nerve which comprises administering to said subject a therapeutically effective amount of a calcium channel antagonist selected from the group consisting of dihydropyrimidones and benzazepines.

Description

200461'^~

TI~ Ul'IC . U8E OJ
ROPYRIMIDOt~58 A~D BENZA~SPINE~
BEN2:0TE~I~ZEPIN~ DER~ATIVEES

~NVEN~OR~;: C~.A~G ~ . CROSSON, D~VID E . POTTER, MIGU~
A. ONDE~TI, DAVID M. FLOY~D a~ GUNNM A13ERG .

~ he ~ 0Ct lnventlon, i~ dr~lwn to t~o u~e oi~
~ihydropyrl~ donel~ ana ben~ oplno an~ bel~zothia2epine d-lr~vative~ a4 c:alalum cha~el n~a~oni~ t- in t~
5 t~ea~cmen~ of ~o~ nal and op~ic slorvo dogene~:ation.
Ba,~ka~nd ~ e,~nven~
R~tin~l va~cular di~ea~o and 13ah~mia are a~ociAtod wlth m~lf~n~tlon o~ nourc~endocrino r~gulatlon and i`~.
~utoregulatl4n o~ tha ohoroldal an~ retlnal clrculAt~on~, 10 ~e~p-otlv-ly. It ha8 b-~n po~tulated thAt xc~8iv~ `
ol-vatio~ of ~ntraaellula~ ~alclum ~calolum ov~rload~ in retlnal bloo4 v s~ols an~ n~uron~ m-y bo l~volv-d in the .
p-tho~on~ o~ rotlnal ~aulopathy, i~ch ml~ ~nd . ultlmat-ly, r-tin~l d~mAg-. Some ~p-al~1~ p~thologl~
ev~nt~ trlg~-r~d by oxc-s~ int~ncollulnr a~lclu~ ions inalud-~ g-noratio~ o~ rrO- rndloal~, aotl~a~ion of prvt-a~e~ 40nu~10~ d lipaE~, and ~nt-r~er-nae wi~h en-r~y prodution ln mitochondria~ ,"-"i Blood flow to tho r~tlna 1~ ~u~pll~d by two ~ep~r~te val~cul~r ~y~t-m-~ th x~tinal v~ssel~ ~up~lyinq tho inner retlnal lay~x~ ~nd a~oroid~l ve~l~el~ ~upplying th~ ou~or ~ ~ :
r~tin~l layox~. ~n pri~t 3, appxoxImatel~ 35% of the to1;al r~tlnnl blood ~low 1l~ do:riv-d ~rom t~e r~tin~
v~el~, wh~le 64% 14 ~ro~ the choroidal : ~ .

2- :

A.lthough th~ cho.roidal bloc)t flow .i.~ of gxe~ter maqn:L~ude, retinal isc;homla 1~ u~u~lly~ a~lo~ ted ~it~.l a re~uct;Lon of flow irl the ln~ler retin~l.l v~ . Th:Ls greater ` ;`~
pro~onslty for isch~ lr.l th~- lnrler retina may re~lt ~ ::
5 from sever~l fac~orss (1) the hi~h rato o~ ~horoi~al ~ - 4 bloo~ ~low ove~ ~hat r~guir.et to meet the ~tabollc ~d~
o.c t~e outex reti.n~; ~2) the la.rge ~1lameter caplllarie~ ln ;.
~e choroid are le~s likely to bo occluded by omboli~ (3) the lack o~ ana~omo~e~ in tho ~tlnal ve~se~s; ~nd ~4~
0 th- l~g~r p~r~ontage of oxygen ext~ac~ed ~rom tho retinal arteriole~ca~illarie4 (35X) a8 con~ared to the choro~al clrculatlon (3-~%). To maintaln a~ ad-quate ~upply of nutr~ent~ to tho in~er xet~na under variou~ sy~t~m~c and ocular ¢ondltion~, blood ~low through normal r~tinal 15 V~8~01~ i~ hi~hly autoregul~tod by m~t~bollc (oxygnn ~nd carbon dioxid~), myo~onic and pos~ibly loaal hormonal ~aracr~no and ~utocrin~) f~ctor~
A numb~r of ey-t~mic nd ooul~r di~o~d-r~ h~vo b~-n ~-$ociat-d with i0ch~m~q condition~ o~ tho retina o~ optlc norv . Ocular manlf ~t-tlon~ o~ ey~tomic di~ord~r~
lnclud-- di~b-t-e, ~th ro~cloro~1-, hy~orlipid~m~ nd !'~,''~
hyp-rt n-ion. ~oclfia o~ula~ di-ordor~ includ r-tlniti- of AlD-, macular d~g~nora~ion, ant-rior l-ch-~ic optlc ~ urop-thy, ocular hyp~rt-n~lon, ql~ucom~
rot~nopathy o~ ~r~m~turlty, r-tin~l v08-ol occlu~ion, dl~b-tlc r-tinopathy ~nd hyp-rt~n~iv rotlnop-thy. In addltlon, d~mlc condl~ion~ o~ ~h- x-tln- or optic n-~o ~'"'""!":'~
ar~ ovld nc~d ~n d~ab-to-, hyport~nsion ~nd cy~toid m~cul-r ed~ w-r ovid~nco al-o ug~--t~ ~h-t ...
30 oxco~lv influx of c~laiu~ lon- into ~ascul~r and .;; :~.
n-u~onal tl~4u~ pri~ry contrlbutor to th ;~ ~
pa~hog-n~ of l~chomlc in~ury and th- d velo~m~nt of : ~ -v-oculopathy and nauropathy.
~t 1~ th~refo~- o~ ub-tanti~l int~re~t to identify - ~.d compound~ whlch ma~ b~ u~ed in t~ th~r-poutic treatm~nt of or prophyl~ctic tr-~tm~nt ~ainst ~-culopathie- ~nd n-uro~thi~ ociat d wlt~ th- ey~
:; ., . ~, : , .. . ..

,'~
,.,,,~",..~s . ,~..
.; -~,j..

- . - - ... . .

,2 0 04 617 -3- , ~

Fur~er, it i~ o~ clroat intero~t to dev~lop a ~.
roproducible ~nd s~nsitlve bioas~ly which i~ a good :~ -predicto~ ot. the utility of. a ~:ompound a~ a t~e~:a~eu~ic for variou~ ls~:hemic ro~inol~ath~-~. De~ir~blo characteri~tic~ o~ ~uch a bioa~ay a~e the u~,e o~
rala~lvqly E~mAll animal~ with ocular va~culAture an~
noural retina ~imilar to t.h~t of humans, ~rtlcula~ly rodontlao, which provi~e~ for con~titutl~vo roti~al dysfunctlon or the ability to reproducihly in~uc:o 5uch dy~function, oa~ o~ acce~,~ to the m-jos- art~rle~
~upplyincJ ~1~ retina, e~- of identlfying tho exi~tenco of the dy~unction ant tho eff~ct of addition of ~ candid~to com~ound on o¢currenco of uch dy~function o~ th~ cffect on progro~ion o~ auch dysrunction.
R-lev~nt Lltor~ur-The public-tlon- citod h r-in ~re incorporat-d by ref-renco a~ 1~ each publiaatlon w~re ~paoifia~lly a~
lndivi~u-lly ~ndlcat-~ to bo incorporat~d ~y ro~-ronce Chol ~1985) ~ouroqcl~nc~ or~ 5~s293-297, d~crib-d th calcium d p-nd~nc~ o gluta~e ~eurotoxlcit~ in ~ortlcal o~ll oultur ~ l~ru~ ~198S) '~
Cli~al 8c$~c- 68sll3-122, de-cribeo pot~ntial ther~p-utlc ~ tion~ of aAta~oni~t~ of excit~toL~ -~
a~iAo ac~d n~urotran~s~ltt-r~ Sinclalr t al , (19~2) ~ '~,~;,`.',!1.'~'."~'-' Am~ an ~c-d~y ~ ODh~-lmo~oqy ~7~-750, ~ Jcxlb~
r-~ln-l va-cular ~utox-~ula~lon ~n di~b~t~H moll~tu~
Rhio et al , (19~2) Di~t~s ~1~1056-1060, d-~rlb~
r-t~nal va~cular roactivlt~ to noro,Din phr~n nd `~
anglot-n~ in normale an4 ~abe~ic4 Flw kon~tein et all, ~198S) ~m J~ C~rd~ol~ S6 3H-14H, de~cribe th~ ~ ~
xperiment~l b~ ,of long~term th~ir~p,y of a~t-rlal ~ ~ r-;c hyp-xton-lon wlth calclum a~tagoni~t~ Fl~cken~tein et d al , (1987) Ib~ ~9tl77a-~87B, de~cribe ~uture directlons in th- u~o o~ e-lclum a~t~onl~s in tho tx~t~-nt of 35 c~rdiov~cul~ di~e-s- Godfraind (1987~ qi `
~sllB~23B, provld~ ~ cla~lficAt~on of c~lcium~
antagoni~to Fl-eken~t-in ot al~, (1987) T~P~ ~ 496-501, ,.

.. .

.... -. ;~

~4-d~scribe inve~ti~a~tion of the rol~ of calcium in t~lo ;:~
p~thogenc~ o~ o~peri~ntal a:c~erloscl~ro~ Katz and ~ach (l9a7~ J. Clin. ~ha~macol. ;'7:825-934, de~crib~ a t~erape~tic appl:Lcation of 1,~-di~ydro~yrldine calclum -~
channel blocXe~. aelm~r~ ot al., ~19~8) N. Enq~. J. ~
31~:203-207, ~e~c:ribe ~n investlg~tlon of nimodipin~ in a~ute ischemlc ~troke. Cook and Ho~ (19~8) Bx. J.
harmacol. 93:121-131, de-cribe th~ ca~d~ova~cular ~f~cts ;
o~ ap~Ln and s~ 34915 in xatc a~d rabbit~. Nihar~
( 19~ ) Analologv ~: 37-45, d~lacribe~ th~ effect of calclum-entry-blocker~ on artoriole~, cap.illaries flnd -.
v~nule~ o~ the xotina. Corbll-re, Fr-nch Patont No.
2,s~s,s7~ de~eribes tho ~- oi-- ocular ~harmac~utlcA~ ?!`
containlng ~nltroph~nyl)~ihyd~:o~yridinedi~arboxylate~
Triggle and Jani~ ~1987) _nn. Rov~ Pharma~o~. Toxieol 27:347-369, d se~i~e ~truetur--~une~tion rel~tion~hip~ for ealelum chann~l ' liq~ds, part~oul~rly ~.. ' 1,4-dihydropyr~dinoc. ,'".. ',,`".,-, ~tlel~ eonc-~ed wi~.~ r~t model~.fo~ ~hronie or `.;`.
acute r-tin~l ~y~unotlon inelud~ von Sallmunn and Gr~os (1974) ~v~tiaa~ve g b~b~lag~egy ~3-~010-1015s Fr~n~ et ~
198~) ~çl-ne~ 37~37~ ~nd St-~An~-on ~t Al., .. ~ ~`
(lg88) ~nv~t. .Oo~ Lmo~ . 8el. 29-1d,so-1055. ..
9y~RY Q_ T3E ~y~NTIQ~
A~h t~rocycl- c-lciu~ ntsy blo~k-rq are us-ful in - -~
th~ treat nt of 4u~ect~ ~uch a~ ~mmal~, lncluding m~n, u~ring ~rom i~ah-m~A or ~do~ o~ th r-ti~ or optic n-rv . Such c~lcium ntry block~r~ m~y b~ groupod a~
c~lclum chann l ~nt~goni~t~ nd ~oltatory ~mino acid ` 1 30 rocopto~ ~ntagoni~to. ~oci~ted wlth ~tlnal dys~u:nctton ~ Y~
ar~ t-chnigu~ ~or ~ ing neural r-t~n~1 funct~on. In ~d~ltlon, ~uch compound~ xhlbit prophylactic off-ct~ in pr~v-ntln~ 0uch condltion~. Motho~ ar~ ~urth r ~ovided ~or ~cr--nln~ compound~ a-~ocl~t-d with r~gul~t~on of :~
3S c~lcium chann~l- by omployin~ ln vi~2 bloa~y~ ucing rat4 wlSh induclbl- retin~l dy4~unction.

:
"''~

Z0 0~6 1~ .
-5- ;

DESC~IP~ION OF TEE~ SPECI`FIC EMBC~D~'NTS
Compot~ a~l~oclated, either d:Lre~tly or ind.ir~ct'Ly, with the modulatlon of c~lc~.um ~,nt~ ~xh~bit: ~ th~ap~utic or prophylactic e~feat to ~t~ect~ flu~f~ring f~om i~ch~mia or ~d~ma of the retina or ~ptlc nozvo. Such condltions ar~ evidenced ln tho sy~t~mic and ocular i~ch~ic a~d .,-ede~ic di~or~r~ c:itod ~ove.
These compo~ld~ may be divlde~ lnto two categoriee.
The fir~t are the ealciu~ c~hannel antagoni0ts, whlcn mAy be further divldod into ~ihydropyridine~
dihy~ropyrimidon ~, diphenylpl~er~zine~ be~zazepines and ben~othi-zopino~ d-rivatlve~. Th~ ooco~d cate~ory aro h ~xe$tatory ami~o acld a2st~0ni~t~, whlch lnclud~ NMDA, --~
guisquAlate ~n~ k~lnat- re~eptor ~nti~igoniots. ;`
Among dihydropyr~dlneo of lnt~r~st are nifedip~no.
ha~ing tha ~t~ucturAl fo2~1-:

COOC }~ CO~C~I~ ~ "`:': ~'';" ' ' '"''' "
~C ~C~ ~, ,.,~, '' ~'`~.

nl~odlp~n-, hAvin~ th~ ~tructural formulA~

~C~ifOOC~COOClt,-C~,-CC>~ ~

~ ......... :.

2 ~ 0-~6 ~7 .

nisol~lpin~, havi:l~g stru~tural l.o~m~la~

Nl CI~ CO~IC~ ,-,". ,.",.. -., ,~,' ~C ~C~C~

nitrendipln~, hav:l.ng ~t;ructural forntula: ~ ~

/~Ot ~ OCC ~ eo~c~ I ~nd 1,1-Dim-thyl-2-[N~(3,3-diph~ylpropyl)-N-metbyl- .:
5 amino~ethyl ~ot:hyl 1,4-dihydro~2,B-dim~thyl-4- :~
(3-nitrophenyl)-3,S-pyr~di~edica~boxyla~e hydrochloride, .
h~ving the st~uct~r~l f ~mula:

?004617 -7~
, ~ ,"" ,, ~
Among dlhydropyrir~iclone~ are~ tho~ o~ th~ ~ormul~
..
~_N~ ~-0~
X ~ N I"

an4 pha~maceutically ~ccoptable 4~1t~ thor~of wh-reln X 1E
oxyg~n or ~ulfur~ a~ i~ hydrogon~ slkyl, cycloalkyl, ~yl, or arylalkyl and ~ hydrog-n, alXyl, cyclo~lkyl, eryl, ~ jmt,~
5 h~t~roCyQ10, : - ---~ ~CE12 )n --Y2~ cH2 )p-- Ya or halo ub~tut~d ~lkyl, or R' an~ R'~ t~k-n tog-th~r `
wlth th- nitrog-n ~to~ to whic~ th~y aro ~tt-ch~d ax~
l-pyrrolldlnyl, l-p~p-ridlnyl, l-a~pinyl, 4-mo~holinyl, ~ ''','7,'' 4~th1~morphol~nyl, l-plp~r-~inyl, 4-~lkyl-1-plp-r-z~nyl, ` ;~
4-nryl~lkyl-1-pi~rarlnyl, ~-dia~ylalkyl-l-~ip-r-$~nyl or l-pyrrolldlnyl, l-~ipo~idinyl, or l--z~i~lnyl ~ub~tltuto~
wlth alkyl, alkoxy, ~lkylthio, halo, trl~luorom thyl or hydroxy) . .'' .,~.. ,,.' ',.
; 1- hy~ro~ n, l~yl, alk~yl, l~ynyl, cycloal~yl, - ~ (C~)n ~

or halo ~ub4tltut~ alkyl Rt~ 1~ hy~xo~on, ~l~yl, cycloalkyl, aryl, hot-roayclo, ~`~
., ~

2(~46~
- -8~

~ ' , ~ .,. . ' .
~'5 R~5 ;~
t~H9~n_ Y~ (C~a3;~

.~, . .. . .
o:r halo ~u~t$tuted alkyl; .-.,-,`;,,,-Rl~ is ~ryl or ~torocy~lo;
R'5 and Rl~ are cac~ ihde~ondently hydrog~n, alkyl, , (C~ aryl or --~C~Iy ~q-~--cycloalkyls ` `<
Yl ~ cyd oalkrl, aryl, het1rocyclot hydroxyl, alkoxy, ar~l - ( ca9 ~m - . merca~to, alkylthio, 10 aryl (CH2)m ~ - , 4mino, s~stitutod amino, `;~
c~rbamoyl, (Subst~tut~d amlno)~ et~rocyclo~ 2)m~~C~ : ``

lS carboxyl, ~lkoxycarbonyl, ~l~yl~ ryl-~CH2) ~lkyl-~ -o - or aryl-(C~2~m- d- O~
Y2 i~ cycloal~yl, aryl, h~terocyclo, ca~bamoyl, (oub~titut~ amino)-~, ca~boxyl, alkoxyc~rbonyl, q ~ . R ~
alkyl~ yl-(C~ c - or h~t-rocyclo-(C~)m ~ ~
Y~ 10 ~y~roxyl, al~oxy, ~r~yl ~ )m - o - , m~ro-pto, al~ylthio, ~ryl - ~CH~)m - S

~ lkyl~ o - , ~ryl-~CH~)m ~ ~ - O
amino or 4ubstltuted ~mlnot ~ ~
g $4 O, 1, ~ or 3t ~ . '`
~ is 0 or An int-~r o~ 1 to 6t 30 n i- O or an ~nt-gor o~ 1 to 5~ ~nd : ..
p ~- n lnto~or o~ 1 ~o S.

E-p-clally pr ~orrod i- (~ Arlnoc-rbonyl)-6-(3-chloro~hon~ ,2,3,6-t~tr-hydro-4~m~thyl-2-oxo-.. ; ....-... ., ;~j ~ 0 046 ~7 _9~, 5~pyrimidin~-carl:,oxyli~ ac:l.d, :L-m~t-~ylethy:l ester, havl~g the structux~l fclrmula~
#,~ Hr ;
~ c~ o~r N ~ N~2 .~; , C~3 0 ~ o A~on~ dl~h~yl~ipex~zine4 of lnt~ost are CinnariZ~ n~! and ~lunarl2inQ, havi~g ~truc~ural ~onmula~

;,H~ C ' C~ .
H C,H, ~n4 , ~ o~;

~ H f \ C
....~

In ~dditlon, ~h~ c~l elum entry blocke~ of th1 lnv-ntion ~-y lnclude ~uc~ calclu~ cbanh l ant-go~l~t~

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

--- 2(~04617 --- - 1 0~ ., .. "

phenylal~cyl~mln~ uch a~3 vorap,~m~l a~cl adi~mil, ; . .
b~nzoth~az~ine~, such ~ diltiaze~ nd benza~e~inea. .
Ben~zupine and benzothi~lzepine der.~atives o~
inter~t inaludo t ose of ~he fo~u:La~ ''.~'','~''.''~''''''~:~',~,',''''!,~'`,' , ,~ , ' , ,;` .~

an~ th-~ phax~aceut:Lcally ~cceptable 4alt~ ~hereo, whereins X 1~1 -UI2- 0~ -S~;

a~ CM or ~~Ya;

wh-n X ~ -C~ 2 i4 ~7'~ .' ?'~ ~

." " .",, "- ~ "
, ~-,,`"' ,'~

~00461~ :

C~2~
Y5~C~ ~CY~2 ;

Y4 ~)n~

~. ~

L~ )n ~ I
h~n X ~ , R~ 2) C~ 2) Y~Y~

~a ;~

.......... .. .

2(~046~7 ~ : : -, ~ ~ ". " ., .,: `, '''"''`'',.`,''''~' ;~'','' . :, ~ . . ': ' ':

Z ~ 0 4 6 ~ 7 ~13 ~

,r ~:
R3 and R~ ~re each iIIdepe!nd~ntly hydrogen, halogen, .
al~yl, ~lkoxy, ~ryloxy, arylalko~, arylalkyl, cyano, ~ ~ `
hydroxy, alkanoyloxy, ~ N
Q
S -0-~-NY9, ~luoro ~ubstituted alkoxy,. fluoxo ~ub4titutod alkyl, (cycloalkyl~alkolcy, -N~

: . . . ., ..:
-~Yl OYl ~ ~ -S (O)m~l~yl ~ ~S (O)mary~ -Yl 2 or --~-Y1~;
n ox n' a~e indep-ndently 0, 1, 2, or 3 m ~ 0, 1 or 2 Yl and Y~ axo ind~pend~n~ly hydrogen or Alkyl, Yl i8 `~
hydrogon and Y2 i~ alk nyl, alkynyl, aryl, hot-~oaryl, or cycloalkyl, or Yl and Y~ togethor ~ith the carbon atom to wh~ch they are attach-d ~rc cyclo~lkyl; .
Y~ i- hydsog~n, alkyl, alkanoyl, ~lk~nyl, ;~
~ arylcarbonyl, ;
het-roa~ylcarbonyl, or -~-NY~Y~
Y~ and Y0 ar- o~ch lnd-~ondently hydrog~n, dlkyl, .
aryl or aryl-lkyl, ~rov~dod that wh n both ar- pr -ent thoy ~r- not both hydro~n, and p~ovidcd ~urth-r that when .
- both ~r- ~ttached to ~h ~o o~rbon ~tom n~th r of them i~ hydro~ n~
Y~ and Y7 ar- ach in~o~en~-ntly hydrogon, ~lkyl, . '~
cycloalkyl or ~rylalkyl or Y~nd ~7 togoth r with th~
nltrogon atom to whlch thoy ~ro attachod re ~z-tid~nyl, -~
pyrrolldinyl, ~lp~idinyl, or morpholinyls Y~ ~nd Y~ aro ach lnd~pond n~ly hydrog ~, alkyl.
Aryl or hot~oaryl, or Y~ ~n~ Y~ to~th-r with tho ni~rog-n ~tom to whlch th y ~r- ~ttachod r~ pyrrolldinyl, -~
pip-rldinyl or morphollnyls ~h Y~O And Y~l ~r- o w h indopendently hydrog~n, ~lkyl, al~anoyl, ~ry~c~rbonyl, h~t-ro~rylcarbo~yl, ',~

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

2~04617 ; ~

Y~ 2 i8 hydroxy, allcoxy, a~yloxy, amlno, alkylamino or dlalkylamlno ~la i~ alkyl, alkoxy, or arylo~sy; and Y~ hydxogel~, hytroxy, all~oxy, a~yloxy or arylalkoxy. `
, .. . ., ,. . ~ ~
, , ~.~. ..
.. '~

, ~ .., .., . ~"

~, . ~, , ,,~

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

~ 0 ~6 ~7 :,..-., . -.
Liot~d below are d~in~ltion~ of vaxiou~ te~ns ull~d ~o d~wrlb~ t.h~ b~nzazeplne4 of thl~ vent:icn. Tho~o dofinltion~ apply to th- t~lrms a~ 1:hey aro u~ ous~hout th ~peci~icat~l on ~unle~- th~y are oth-rwl~o limlte~ ln 5 spociflc ~ tAnGe~) either lndividu~ly or a4 a ~art: o~ a ~ ., }
larger group.
Tho te~s "alkyl" ~d "alkoxy" refor ~o bo~ ~traight ..
ana `oranch~d chain gxoup~. ~hos- group- ha~ing 1 to 10 c~rbon ato~4 are preerrod.
Tho t~m "alkenyl" ~e~or~ to both tra~ght and braslohod c22~l1n grou~ o~e grou~ havln5~ 2 to 10 carbon atom~ are p~eforr~d.
Th term "-ryl" rofer- to ~onyl and ubatitutod .
~henyl. ~x~mplary ub~tit~t~d ph~nyl grou~ ar~ ph~nyl .
~rou~ ~ub~tltut~d w~th l, 2 or 3 amino ~-N~8 ) alkylumino, d~alkylum~no, nltro, ~alog ~, hydro~yl, txlfluoro~thyl, alkyl ~of 1 to 4 carbon atom-), alkoxy ~ ;
( Q~ 1 to 4 ~arbon ato~), alkylth~o, (of 1 to 4 c~rbon ~om-), alk~noyloxy, carbon~l, or c~rbo~yl ~roupo.
Tho t-~m ~-lk~noyl" r-~r- to group~ hav~A~ th~

~ormula ~lkyl~ ho~- alkanoyl qro~p~ h~v~ 2 to ~1 ~-rbon ~to~ aro ~rof ~-d.
The t~rm l'h-t-~oaryl" re~ x~ to ~n aro~tio 25 h torocycli~ group h~ving ~t l-~-t on- hot~ro-tom in ~he .
rlng. Pr-~orrod group~ ar- ~yridlAyl, pyrrolyl, .
i~idA~olyl, ~uryl, thionyl, o~Azolyl or thi~zolyl.
Th~ tor~ "cy~loAlkyl" ~ r- to grou~ h~vin~ 3, 4, 5, 6 or 7 a~bon ~tom~
Th t rm "h~log n" ro~ r~ to fluor~no, chlorin~, ' bromlno and io~n~. . ~ ~ ' m- t~m~ "~luoro ~ub~tituted alkyl" and ~luoro u~tituto~ alkoxy" r-~ r to ~lkyl nd ~lkoxy group~
d ~c~i~od abo~o) in which ono o~ mo~o hydrog na havo b~
ropl~c-d ~y ~luoxin ~tom~. Ex~mpl ry ~roup- ar~
tr~luoro~thyl, 2,2,2-trtfluoro-thyl, ~ta~luo~oo~hyl, ~luoromothoxy, dlfluo~om~thoxy, tc.

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

-- 2 ~ 046 ~

. ~
T~o cc~m~ourld~ of forDlula I ~o~m acid-addltlon salt~
wit~ inorg~lnlc ~nd organi~ ac~ds. Th~ acld-addition u~lt~ ~xeq~on~ly provide u8eful moan~ for ~olatin4 th~
produ~ts ~om r~a¢tion ~ixtur-s by form~n~ the ~al~ in S mediu~ in which it i~ insol~ble. Tho fre~ ba~- may thon ~
be obtalne~ by neutralization, ~ , w~th a baq~ ~uch as sodium hydroxl~e~ Any other aalt ~ay t~n b~ formed from the free ba~e nd t~ app~opxiato inorg~nic or or~anic 4cid. 211u~trAt~vo are tho bydroh~llde~, e~p-cially the ~' ~ ?~
h~drochloxldo a~d hydxobxomide, ~ulÇ~t-r nitx~te, pho~phat~, bor~to, ac-tater tartr~te, maleato, ~lt~ate, succinate, bon20at~, A~cor~at~, ~alicylate, t methan ul~onate, benzcne~lfonato, toluennsulfonate and ~ho c~rbon hto~s in the 3 ~ntl 4-posit$on~ o the benza~-pino nuclou~ and, carbon a~om4 in the Z ~n~
3-poslt~on- of th b~n~othi-zopine n~¢leu-, of th~
compound~ of th- formula I are a~yNmotric c~rbon~ Th-compound- of ~ormul~ ~, ther-foro, ~xi~t ln nantlo~e~ic '~
~0 and dla-tor~om rla form- and aa racomlc mixtUr-- th~r-o ~11 ar- wlthln th- ~cop- of thl~ lnv ntion. It i-b-ll-v~d that tho~- compound~ o~ formu~ ~ ~h~ch h-vo tho ç~ conf~gur~t~on ~r- th mo~t potont ~nd ~r- th r-~o~
p~f ~r-d. ~:~
2S P~rticul~rly p~o~-rrod a~ ~u Wbl- bons~-pin withl~ th~ lnvontlon a~o th~ compound~
[3Et~~1~8~ ~3~4~-]~~3~~Ac-tyloxy)-lr3~4~5-totr~yd~o-~
(4-m~thoxyphenyl)-1-(2-~yr~olldinyl-~othyl)~6- : :
~trl~luorom thyl)-2H-l-b-nza~pln-2-on , monohydrochloride ~nd [3R-(3~,4~)]-3-(Ae-tyloxy)-1,3,4,5-tetr~hy~ro~4-(4-methoxyph~ny~ (2-~l~othyla~ino~thyl-6-(trl~luoromothyl)-2~ benzax~ 2-ono (And the monohydro~hloxld th-~-o~), h~vin~ tructural ~ormula~

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

:; .' " . .,: -.,. ',':' .','' ' ,, ,j,.,,~ ~,``, : ~ ,;~: ,....

~. ,. .~ . .

~--a .'~,. ~

~.., .. ~

t P ~

, re~pectively.
Calcium channel antagc~ni~t~ whic~ may be employ~d in .
invontion ~ro produced. by ~o~entlonail rn~thod~ well known in the art. In p~rt:Lculelr tho benzot}~lazep~n- ~nd : .~.
benz~zopine ~es~i~at$ve~ ce~n ~o p~op~red ~rom t~o corraeponding compound~ h~ving t;he :~'on~ul~

P~ ~ ~
~h~ propAr~t~on of tho r~c~ic eu~d nonrace~a~c fo~ of the `~
compounds of formula I I when X lo CH2 i- ~e~crlb~d i~
Unlt~d statos Patont 4,752,645 l~uod ~ , "~ "".""" ,.
Jun~ 21, 19~8 for tho~ compound~ wh~rein R

~nd ir~ Unltod 9tato- Pat-nt 4,74~,239, ~-u~d M~ ~1, 19 or tho~o compound~ w~ro~n ~ O~ and ~ ~4 hyq~ogo~
Compound~ o~ ~or~ul~ I~ w~oro X 1~ S ~nd a~ 1~ Ya a~
pr-p~r-d ~J d-~cr~b~d in U ~ Pat-nt 3,S62,257 is-uod F~br~ry 9, 1971 y~
Compound~ o~ ~or~ul~ ~I whoro X i~ S and R~
ar- pr-par-d ~ de~crlbod ~n ~ ont ~,694,002, l~su~d Sept~mbor 15, 1987 Co~pound~ of formul~ tI Wh r~1n R~
-O-YJ n~ Y~ ~ otb-r than hydro~ n can be obtainod by alkylatlon or acyl~tlon ~u-ing con~ontional techni~ue~) of t~- correo~ondlng compound o~ th- formula I~ wh~ n R~

Th co~pound- o~ formula I~ ~here ~ OH cun be ~r-p~-d ~n nonr~c-~lc ~orm by r-actlng tho rac-mlc -~
compoun~ o~ ~ormul~ rI whero Rl 1~ O~ with a non~acomic ,: . , . , , . , ., - . - , ,. " ~ ., ~

~.'."; '''"',..'`'.""'.

.:. - . ~ .
: ~ ... ...

2 ~ 0~6 17 . .. --~

'." '.',. ''- '.~, 's' `,"
c:omprlse~ t~eating a cc~mpol~d o~ fo~m~la ~i with an a~kali n~etal hyclrid~ ~e.g., sod~m ~dritlo) in an in~rt solvent ~e.g., dim~thylfor~amide o:r dl~eth,yl~ulfoxlde) followed by reaction wlth a com~o n~ of th~ ~o~mula: .

IV~ C~n~ N
to obtAin ~he torre~pondinc~ co~ounc~havin~ the formul Reduction o~ a compound o~ fDrmula ~ u6ing, for exumplo, catalytic hydrogonatlon ~e.g., rhodium on `~
alumlna) yield- ~h- corr-~pond~ng product of ormul~
hav~ng th formul~

VI. ~ ~

- R~ductlv ~m~nat~on Or A CO~OU~ of ror~ula V~ with t~e appropri~to ~ld-hy~o or k~ton- u~inq ch~mlcal r~duain~
lS agont ~.g., ~od~um cyanoboro~y~r~do) ylold~ tho corr ~pondlng ~roduot of fo~mula ~ havlng th- ~ormulas VII. ~ ~

w~oroin ~t l-a-t on~ ~ Y~ ~n~ Y~ tban hydro~ n.

' '" ~' ':', ` ~.,'", 2(~04617 ~a~

A t~n~t1v 1~, :o ~ O or ~n~ul- I ~kr-ln can b- prep~red ~y fir4$ tr-~tlng ~ co~pound of fo~mula ~t -with an alX~li m~tAl hydride ~ r ~odiu~ hydrlde) in an lnert organic ~olv-nt (.~., di~ethyl~.nm~mid- or .
s ~imethyl4ulXo~id~ ) follow~d by re~c~ion with the ap~ro~r~te compound h~lng tho ~ormul~

V~ R~-L ;.

10 wh~rel~ Ra i~ Y~ y~ v~

. . . ' . i !~ ~
Q r~ul~nt co~poun~ ha- th formulas .
':. '. ." ..',",', `',"'.
IX. ~:
"'~,{~ , ~

nd c~ b- r act d with ozo~ ln ~n ln~r~ olv-~t (~.~., a h~logonat d hydroca~on) ~ollow d ~y r~duction (~.g., u-in~ a ch~mieal r~duclng agent ~uch a~ dlmethyl~ulfide) to y~-ld th- corr ~on~ing co~pound h~vln~ th- ~ormul~:

~,~

~004617 A compound c-~ formul~ X can ~e tre~tad wi1:h thu ~pp~opriate a~nlne hav~ n~ th~ fonqula X~. H~
5 ln tho presence of ~ re~ucing agent ~e.g., hydrogcn u~ing ~ cataly~t ~uch h~ pa~ladlum OZl cu~on, or a chomical r-d~cin~ agen~ ~u~h 4~ od~um cyAno~orohydri~-) to o~t~in tho corr-~pondlng produc~ o~ ~ormul~
It i~ o ~o-~ible to o~tain a:n ~nt~modi~te of `.
fo~mula X wh~o~n R~ Y"-CH-~-Y~ or ,~ ;

by r~actin~ a compound o~ ~or~ula I:r with A com~ound oE . ~
tho formulas . ~ i.. , 1~ - ' ';

.~, . ,, ~ .,.-, . ..

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

2~0~6~

~ o~poun~ of ~ormul~ I wher~.tn R~ is can bo ~ynthesl~ed by rea~tio~ of a ~ompound of formtlla I~
with an allcyla~n~ agent, such ~ ohloroace~onit:ril~ ~ to -~ ~-gi~e a compound of formul,~ ~ wh~r~in ~2 1B -C~N. The 5 xe4ultant c:om~ound Of ~or~lulq I w.he~ei~ R,, ~ -C~2CN car be re~cted wlth an ~lcohol, ~uCh a~ nol ln the ~-re~nce o~ ataly~t, ~luoh ~L8 hydrochloric acld o~
~odium ethoxlde to g~vo a c:ompoun~ of ~o~ula I ~here:ln R~
iB --C~28 N~. Tr~atmont 02~ ~hl6 compound w~th a d~amlno of 1he ~ormula E~2N-CH8(CH2~ e~ compou~

o~ forTnula I wher,~ln ~5~ i8 '.'~`' '''` `"'".'.''' "`"''`~'':'' : ., :: ~ - ., ., ..~ . .:

;~

~~~. 2(~a)46~
~;~3 :. ~,;.. ~;
Ex¢ltatory amino aclcl receptor sntagoni~t~ includ~
801, 2-~PV and CNQX, ha~ring th~ uctuxal fo~mulas ;. .; . ,-., . ,, . ;. ~;

"

~-~ `~"

~ b ~

aH3 "~

nd ' .

' 2N~X

r -p-ctlv ly.
P~rth-r, th ph-~m-c~utically acco~ta~ alt~ of ~y -~:~
of ~ bo~ n~d co~pound~ m~y b- ~mployod a~ tho ~lclum ont~y ~lock ~ ~n wcordance wi~h the i~vont~on Comb~ tlon~ o~ tho ~or~m-nt~onod ~o~ouna~ may l~kowl~e Calc~um ontry bloc~or~ of ~hic ~n~-~tlon mar bo '~$.
ad~lni-tor-~ orally, p~r-nt xall~ or topi~ally~ ~n acut-ltu~tlon-, p~-nte~al and~or toplcal dmlni~t~at~on i~
prof rr ~ ln ora r to mo~ ~apidly ~ntroduc- th- calcium , ~.

.. , ~,, ," "~-.2 0 04 6 17 ~ntry blocker to th~ targett ~i.ta. For ch~onio th-ra~y, oral ad~inil~tra~on i8 nor¢~ally~ pr~f~rr~d ~lnce it i~ mo~e eaaily a~min~t~red.
The compounde ~or u~ in thi- in~ntion ~r~ m.. ~-.
5 ~m~ ni~tered in their ~ure form or ~n adm~xtur- w~tA a ph~rmaceutia~l~y acceptable a~rrlox ~uch a~ an or~nic or `~
lnorganio ~olid or liquld oxcipiont ~dopendi~q on ~he deslred admln~trat~on). I~e ~harmacoutical preparatlon~
may thu~ b~ ~d~ni~t rod a8 a aol~d, ~omi~eolid, 10 lyophll~zod powder, liquld ~o~ge fonm, tablet~, pill~
a~psul~ owder~, solut~o~-, s~e~enelon~r emuloion~
croamo, lo~lon-, ointment-~ or qranulo~, a8 well ae injectable so1ution~. T~e naturo of the co~ouition in ~ r~
the ~harmaceut~cal carrier or d$1u~nt will, o~ cour~e, -15 de.p-nd upon ~he int-n~ d ro~t~ of ~dm~ni~tration. ~ .` When th~ ~h-r~acou~lcal co~positlon i~ ln the ~orm of ~ ~olution or ~u~pon~ion, ~xu~ple~ of Approprlate pharmac-uticAl carrl-x~ or dlluon~ (d ponding on tho intond-d rout- of adm~nl-t~at~on) includ ~or quoou~
20 ~yu~o~, wator~ for non-~ueou~ ~y-tem-, th-nol, ~lyc-xln, pro~ylono glycol, corn oil, olivo oll, yru~ `7 co~ton~-od oil, po nut oll, e~-mo o~ rain~ and mi~tur-~ th~r-o~ wlth wat rS a~d ~or olid ~y~t~m~, '~:~,,,,~,.~,,!.,.,,~,.~
lacto-e, kaol~n, munnltol, ~ucro~ ol-tln und ~gar.
. 25 ~n ~ditlon to convent~on~l ~har~ae-utlc~l c~rrlor~
or xel~l-nte, th~ pharmae-utlcal com~o~ltlon- ~y ~nclud- .~-.. ~ .
oth r ~dlcln~l ag~nt-, phar~ae-utlcal ~ nt~, ~d~uv-nt~, ;`~ : `.,~
Wbillzer-, ntl-o~d-nt~, ~ren-~v~tiv J, lubric~At~
qu-~ondlng ~g~nt-, nd vi~ao~ity modi~lor~, ~tc Tho do-~q l-vol o~ th cal~ium entry block~r within thl~ lnv~ntlon 1- d p~ndent upo~ th~ cond~tlon~ o the dl~-o to be tr-~t-d, th~ admlnl~tr~tlon rout~ ~mployod, tho ~ub~-ct und th~ ph~r~Acokln tlc and ph~rm~co~yAamic chax~ctor~tlc~ o~ th~ act~v~ lnqro~l-nt. Th ~os~g of tho aotlv- lnur-dl~nt i- g n~r~lly wlthln th~ ran~ from about 0.~ to bout 100 mg/kg ~d~ tor-d orally, p~r~ntor-lly or topic~lly.
,,~ , ,, ,'-""','"
'', 200~617 When admi~lster~d elt.h~ par~nt~rally or topically, th~ p~y~iological p~ i~ g-lnerally in the range o~ about pH 6.S to 8. .
M-thod~ ar~ further do~ribed for scr~oning oompound~
c~pablo of r~ver~lng ~ot~nal malfunctlon the ~Soct o~
r~tlnal dy~unc~ion, wh~re an 1~ vl~o bioat~ay i~ omployod lnvolvlng rat4 with ~nducible retinal dy~function.
s~eci~ic compoun~ for tr~tin~ rotin~l ~ysfunceion are pxovided a~oc~ated ~ith modul~tion o~ c~lalum ohann~
activity and~or the ~atlvatio~ o~ xcltatory a~$no ~cld rn¢eptors. Particul~rly, ~alolum chAnn~l ant~goni~t~ or ~ c~
o~her compound~ h~vln~ ogulvalent e~oct ~-~oitatory mino ~c~d antagonl~t~) c-n bQ u-ed in the tre~t~nt of r-tinal va~culopathy.
15on~ methodology involv ~ ~ho u-- of ~ahl -.`~
~alt-~en~tlv- (SS) rat~ whiah a~o available from ~arlan Sprague-D4wl~y. Th ra~s will gen~r~lly be in the ago group of th~-o to tw~nty weok~, u~u~lly ln tho ago group .
o~ ~our to tw-lvo w~ok~. Wh n plaaod on a h~gh ~alt diQt, the anlmal~ ~ap~dly d-v lo~ (2~4 ~o~X~) a y~t mlc hy~orton-lon Oth-r r-t~ wh~c~ m-y bo u-od ar~ nor~al 8~r~guo D~wloy (alblno) rat~, Tong Ev-n~ plgm nt d rat~ o~
~ont~n ou-ly hyp-rton-l~o (S~R) (alb~no) rat~
All o~ th -o rat~ ~ay bo e~ployot a~ modol- by 25 cro-tion of ~cuto r-tinal i~cho~ia ~n tho~r oyo~ Tbe 1; ~ {
l~ch mia m~y b- cro~t-~ by r-vor-lbly occlud~ng th ~hort ~o~t rlor clll~ry art rio~ th central rotinal ~rt xy Eloctror-tino~r~m- ar- rocord d prlor to, durin~ ~d aftor ooclu~on~ ~h~ ooclu~lon 1- r~vorsod ~ft~r a br~a~
p-riod, u-u-lly one minuto to th~oo hour-, pref~rably flve minut-- to two hour~ ~n~ r~p-r~u-ion occur~. ~uring".~ ' ~ '~;
r-p-rfuolon ~R~ ~ro taX~n to ~rovi~ ~n ind x o~ ~otin~
function, ~ollow d by ~ hl~tologic x~J~n~tlon to d-torm$no ch-ng~- in norm~l r-tln~i ~tructu~o.
3S Ophth~l~o~co~ic xAmln~tion of tho ye~ o ~ orm~d to docu~ont th abs-ne- of ~tlnal blood flow ~nd ~ro~
i~ch mlc d~a~ ru~ e ~icAcy i~ rol~tod to ~h ~bility , ~

- 2~046~7 .
o~ th~ candidate! ~ompo~it;Lon ~o .r~duco or preve~t~
pslthologic changes not~d ln ERG ~nd histolo~ic oxAmination3.
For hl~tological exami:nati~Dn, the eye~, may b~ fi~od 5 by cardiac perf~3ion wlth A ~ix~tivo, ~h a~ a combination of ~raformal~ehyde and glutar~ldehyde in an .
ap~o~iato buffer. Af~ar r~mov~1 of th- oye~, ~he cJlobe m~y be opened at ~he ora serra~- ~nd fixation contl~ued ~ B
for fou~ to tw-n~y-~our hou~. Sogment~ o~ th c~ntr~
10 and porlpherAl retin~l ~ro ~hen di~-ctod fxee, the tl~sue washo~ ~nd then po~t flxed ln an ~ppro~riat- ~xat~vs, e.g., o~lum t-troxid~. Followlng d hydr-tion, ~he ~amplo may b- ~ectioned in acco~dance with convent~onal techniques for li~ht and ol~ctron mlcro wopy. : `~
Ch~nges ~n thlck~e~ on tho rotlnal layor or number of c-ll bodl~ p-r unlt ~r-a ln th- inn~ ~nd outor nuclear l~y~r~ m4y ~h n bo ob~orv~d and ropo~tod. In -~
adaitlon, ~h r~ln~ may b- r~portod a~ ~norm~l", 1~ all -`~ Y~
1AYOr4 ar- lnt~ct with no ~bnormalltlo~ "mil~
d~gonoration~, lf thlnnln~ o~ th lnnor an~ outor ~-gmont#
or vi-~blo roduct~on ln coll bodl-~ of th lnn~r and outor nucl-ar l-y~r~ ha~ occur~-di ~nd "~ov~r~ dcgonor~tlon"~ l oxten~iv~ lo-- of any ind~vldu-l or multi~ y r~ of th ~tln- hao oocu~od. ;~
~o v~lu-to r-t~n~l ~unction, an ol-ctroro~lnog~-m :~
(~RG) m~y b~ mploy ~. Function~ o~omont o~ th~ lnn-r und outor lay~r~ o~ th- nou~al rot~n~ ~nd th non-noura~
retln- ~PE~ 1~ m~do by m ~n~ of ~uli fi-l~ ER4~. Th~
w~vo ~or~8 o~ tho ~Ra re~ul~ from tho ol-ctrophy~iological p~oce~o~ volv~d in vl~u~l txan~uatlon ln the r-tln~
Roduc~lon in tho~e w~v-~ provid~ a dlroc~ mo~-ur-mont of r~tin~l ~natlo~. Th~ in~ti~l n~ativ- do n-ctlon, t-rmod ,~
the "~-w~v-", o~iginatoe in tho photoroc~ptor-. Th~
ub~oqu~nt b-w~ pro~u~ed by th Mull~r nd bl~olar 35 c~lls ~om th inn~ t~n~. Th ~uch lowor ~o-itl~e .;
c-w~e AXi~- fro~ th ~E but 1~ gen~r~lly roduc-d or aboent ln adult ~lblno r~t~. Wh-r-~ th- ~otorec-ptor~

~'' ,',',"' '' '','`', ,~.:,: ~,:;'`.',`
',.~'..~

-d7- - :

and RP~ ar~ nour:i~hed by t~e ~horoidal el~culation, ~he lor and bi~oli~r cell~ a.~ noUr$~hed pri~a~ by the ;~
rutinal ve~ol~. An initi~ dicfl~ion a~ to tno ~it~ of retin~ chemla ~ay be reli~ted to ~electlve reduotlon~ in tl~e indlvidu~l wavo form~
Ba-e-llne ~RG~ may be o~t~lne~ prlor to lnduc~ion o~
rntinal i~ahemiA The~eA~ter, ~G~ ar- d-t-r~n-d at convenient interval-, e g hourly, daily or we~kly ~he~e ~ub~equ-nt ERC~ are thon normalized to p~ o~mic value~
anG ar- oxpr-~od ~ ~ho p~re-nt of con~o~
ba~ellne~ vAluec ~rlor to dark adaptatio~, the r~t ho~t rccelve~ an ophthalmos~opic ~amination to en~ur~
~b~onc- of c~taracts or oth r gro~ Abnormalitio~. Since ;~
rnts ar~ primar$1y a rod-domlnated (S8%) anlmal, EROa are 15 performe~ under ~ar~-~da~t~d condition~ (12-14 hour~). ....
~t~ ar~ an~Jth-tiz-d and placed ~n a heat~ng ~a~ to mnintain norm~l body t-mp-r~tur~
To r-cord E~a~, ~mall agar-A~/AgCl ~loctrodQs ax~
placed on tho aornoa an~ tonquo A r-f-x-nc- ground ~lectrodo 1~ placod undnr ~ho qCAlp. ERO signal~ may b~
Ampl~ d by n approp~late tlf~r-ntial hmpllfi~r and racord t Llght ~tlmulatlon 1- prov~d-d by an approprlat~
~hoto~ti~ul~tor $n eon~unct~on with ~ -ri~ o~ ~eut~al :.;
don~lty fllt-r!~
singl- ~la~h ~10 ~-c ~uratlo~) of wh~t- l~ht 1 u~-d to g norat- lndlvldual ~aa.. Th. umplltude of th b-w~vo~ ~- m ~-ur-d fro~ b~-- lln to p-~k ln th~ ~b~ena- .
of n a-w~e or fxom the trou~h o~ thO a-w~v~ to tho pe~k .
o~ th~ b-wav~. a~W~vo~ ~r~ m-a~ur d form th ba~o l~n~ to 30 tho p-~ o~ th ~-w~v-. ~ho ti~ ~ntorval ~om ~h- on~-t i o~,iy~
o~ th- ~la~h to tho p-aX o~ th~ a- ~nd b-w~vo~ 1~ u~-d ~o~ 'i"",''`'~,','"~'l, ~,` s/~
~ou~ur-m~nt- of l~toncy.
Group d~t~ ar- com~ar-d by m~n~ o~f a two-w~y ~ly~i~ of variAnc-. Co~ ri~on4 i~volving two m an~
35 eqploy Stu~nt~ t-to-t for non-~Alre~ ~t~. D~fforonco~ -` "`.`
b~tween ~ro~ control ~. dr~-txe~tod) ar- r-~ard~ a~
igniflc nt i~ P-v~lu - ar- ~ ~.05, ~. , . ., . ,, ,., - . .~
,~
'''`''~.

. " ~ " ....
.: :- ., ...., ~ ..

Z~)04617 ~ J~

Th~ follow~ng ~Xunp~ ar~ off~r~d ~y way Of lllu~tra~on and no~ by way of limi,tation The mothodology invo~ve~ th~ creatio~ o~ acu~
S rl3tinal lG~h~mla in the eye4 of normal S~rague~Dawley ~lbino) or ~ong-Evan~ ~plgment~) rat-, wblch ~re availa~lo from ~rlan 5pragu--Dawl~3y A~ult r~t~ w~re u~ed, ra~glng ln weight from 17S g to 250 g The~- rat~
were hou~d und r norm~l ovndi~lon~ ~nd f d tandard ~at chow ~at~ wer~ an-~h tl&ed with S0 ~g~kg ~odlum pentob~rbital ~ntrapor~tone~lly (l p ) and the irl~ of th~
eye dllated with ono drop of 10% txopin olution Total retinal i~ch m~- in th -e anlmalff wa~ creat~d by rev-r~ibly occludlng th~ hort po~terlor cill~ry arteries and th~ contral r~tinal rtery Th~ dur-tion of the o~cul~on- variod from fiv~ to 120 ~inut 8 Pr~o~ to the `~
occlu~lon, ba~el~ne ERG~ w-r- recort~d and u~ed ~ an lnd x o~ normal rotin-l function~ Com~l~to r~t1na o~clu~io~ w~ ~o~ermin d by t~e ab~enc~ of ~RG At the ~0 end of tho occlu~ion po~iot, ~ho r-tin~ wa~ llowed to r~porfu--, und c~ngo~ ln norm~l r-~nAl ~trUcture und funct~on ~otermln~d by hl-tologl~l ob~-rv~tion- nd ERG~
Durin~ t~o r-~-rfu-~on p-rlod, ~RG~ w-r- v-lu~t~d a~ on~
to two minuto lnt-rvAl~ ~or th ~irst 30 mlnut~ and th r-~ft~r ~t ton mlnut intorval~ throu~h 120 ~nut~
Ada~tiona G ev~lu-tion~ in aeloetod ~nim w-r~ ~ade at 24 hour~ D~u~ offic~cy w-- b-~-d o~ th ~blllty o~ A
c~pount to ~lnl~180 or ~rovent thQ pathologic chun~os in rotinAl ~tructur- ~nd/or ~unot~on in~ucod by acute r-tin~
30 10chomia ~- g th~ a~geA~anco o~ n~crotic c~ wlthin the ~ -r~tlna or a ~igniflciunt r-duction or lo-~ o~ normal wsve -~orm~ ln th~ ~RG ) `~
Exu~pl- 1 ~llu~t~ato~ Bn la v~v~ bio~o-y which c~n ,, bo em~loyo~ ~or d~t~rminin~ tho f~icacy of compound~ in th~ tr--tm nt of r-tin-l dy~un~tio~
E~ampl-- 2-4, conductod in accordanc- with tho ~ocoduro o~ Ex~m~l~ 1, d~m~n-trat th~t p~etr-~t~ent with r ~

Z0046~7 C~ I chann~l ant~30nl~t~ ca~n pr4te~t r~tinal unction ~la~
~a~ured by ER~ x~covery) ~,rom i~ch~mlc injury. Valu~
aro mean~ ~ ~tandaxd ~rors a~d h~lve boon normal~zed (o-lOOX) to preocclu~ion aontrcll value- At ea~h tlm~ ~ -polnt te~te~, ~lgnif~cant i~p~o~oment in b-wave ~eaov~ry when compared to ~ontrol-treatecl animal~ i~ oxhibltc~
Examplo 5 1~ drawn to the u~e of an exaitatory Amlno acld antagonl~t Ex~m~
~he ~ub~ect ~nventio~ p~ov~des for retinal ~ ~ ~c do~eneration mc~el~ as nv$~enc~ b~ both ~truotu~al a~d functlonAl ch n~o~ A~socl~tod with th~ roti~Al h dy4function and/or degenera~ion 1~ a dr~matic reductlo~ in retlnal p-rfu~lon. Th-~e r~t~ ar- th~ro~or~ qoo~ mo~el~
for 6c~eening co~pound- h~vln~ activitici~ a~ calci~m channol antagonists or ~xcitatory ~mino acid antaqon~ts and th-ir u~- in preventlng or umeliorating r~t~nAl -.;. , ~ogener~t~on. , ;~
Fou~ ~f~ ront ~o~iods o~ retlnal i-chomia in ;~
20 Eong-E~n~ and Spr~guo-Dawloy r~t~ wo~- xumino~. In ..
norm~l 8pra~uo~Dawl-y r~to occlu-ion~ o~ ~iv- minuto4 re~ultod ln th r~pld ~eturn to eontrol lovol o~ both a- ..
an~ b-w~v - of tho E M, whil- ocolu-ion- of two hour~ ?.. -~
r~-ult in th- l~x-v-r-lblo lo-0 o~ rotlnal functton, a~ 2.
25 m~a~u~-d by tho ~. Occlu~lon ~or p-rlo~ b~tw -n f~v~
~lnuto~ to two hour~ ln bot~ on~-~van~ nd Bpragu--D~wloy - rat~ r--ulto~ ln ~ p~rtl~l but p-rm~nont lo~- o~ retln~
funetion, th~t w~ am-nabl- by ~ru~ th-r~py. .
R-p~rfu~ion f~llowlng 30 minut~ o~ ~otal r-tinal .
30 i~ch mi~ r-sult-d in raplt ~-oov ry of th ~-WAV- ~n on~
to two ~lnut ~. ~h- r-covo~y of tho b-wavo wa-con-id-r~bly d~f-ron~. ~h b-wav~ wa- fir~t ob~orv~d ~- . ;x~.
b~tweon ~6 n~ 22 minut-~. From thi~ point th b-wavo ~lowly rocover-d o~er th nex~ 60 to 120 minuto~, but ~}
rnmained ~ignlfic~ntly reduc--d fro~ tho control lev~
By 120 minuto~, th b-wav- h~- rocov~r-d to a~oximat~ly '~
30X of control v~luo-. ~y 24 hours tho m~an b-wav~ w~

~.,, ,.: ~ .. .

..`'~

;~()046~7 ~till only 40X o~ contro~ valuo8. For 8horter poriod~ o~
occl~sion ~c.g. 15 mi~ute~), the a-wave a~ain rapldly recover~d i.n one to two min~tes. ~he in~tial a~p-~Anco ;~
of the b-wa~o al80 occurrsd at 1~ to 22 m~nuto~ o~
reperf~ion, but the magnitude of the ~-wav- recovery at 90 mlnute~ and ~4 hour~ wa~ 61X and 100X of control l~vol~
(a~ compa~od to 26X and ~X, rospectlv 1y, for the 30 ~inute occlu~lon). Sh~- d~ta ind$oato th~t total r4tinal ~ whomla ~or 30 minuto~ r~ults in the partial ~oo~ of - ` ~/`;.
rot~nal unction. ~hl- 104~ pp~r~ to bo p-rman~nt, a~
th- b-w~ r-cov~ry wa- only 40X o~ co~trol valu-s a~ter : ~ ~ "
24 houro of r-~rfu~ion. The rapl~ r-tu~n of tho a-~A~o and ~radual return of th~ b-w~ve indi¢at - th~t tho prlmary lte o~ cut- r-tina lsch~mic ln~u~y 1- th~ lnn~r r~tinal layor.
~t 2 rong-E~an~ rats wero treat~d i.~. with control ~loX
~WE~N 80) or nif~d~lno 30 minuto~ prlor to th- oc~luaion of rotlnal v-~ol~
~blo X ~ho~- the ~ ct of ~if-dlpln l.p. on ~-wave r~covory ~ollowing 30 mlnute~ o~ tot~l r-~inAl i-che~
0 . 05), TABLE
TI~e PRO~
25RRP~U8ION CONT~OL1 ~/k4 3.3 ~/4 10 ~3/~S 33 t-ln~__ ~7) ~n 4),,(~ 5) t~6~ ~ S~
5 ~ 2 13 ~ 3* 20 ~ 6~ 13 ~ 2~ lS ~ 5* ~,,.
19 ~ 4 47 ~ 2~ 60 ~ g~ 39 ~ S~ 41 ~ 6*
2~ 6 66 2 81 ~ 12 8 9 51 ~ . .
30~20 32 ~ ~ 72 t 2*84 ~ 13~ 65 ~ S4 ~ 6~
180 34 ~ S 70 ~ S* al ~ 9~ 67 ~ 9~ 53 ~ 6~ .. ;.. ~ ' Th~ a~llity of th- 3 . 3 ~g/ky do - - to ~ovldb pp~r-ntly botto~ prot ctlon o r-tln-l ~unctlon than th~
10 ~nd 33 ~/kg do~o li~ ly rofl-cts c~rdlov~aular ~ido P~o~t~ of nif~di~in~ n$~icAntly gro4t-r roduct~on~
in h art r~to ~nd blood ~ro--ur- wer~ ob--~v d ~n th~
anl~Alo. ~nc~, th ro~ultlng do~-r-l~tod r~duction in ~ ` ;,:`
c-rdl~o output ~n~ ~-r~h-r-l va~dll~tlon ll~ ly r duca~

03l-~ 6 ~ ~
-:
. .
r~etln-l por.fu~ion in the ischemlc ~ya ~nd reduc~
~u~ctional r~cov~ry ~e.g. ~G'~I) o:~' the ret:lna.

~xam~le 3 ~ -Lon~-E~an~ rats wero treated intra~orito~eally with 5 eithex 10X TWE~N ao 4~ ~ control or . .
~ lmothyl-2~ 3,3~dlphenylproE~yl)-N-me~hyl-a~no]-thyl methyl 1,4-dihydro-2,~-dimethyl~
~-~3-n~tro~henyl~-3,5-pyri~n -dic~rboxyl~t~ hydxochlori 30 minutes prio~ to tho occlu~lon o~ rotlnal vo~sel~
St~tistlc~l compari~ons w~r- m~da an~ the re~ult3 tabulatea at ach time polnt. ~P~0.05 TA~
TIM~ FROM -~
R~PERFU8ION CON5~0~ 0.33 m~/kg 15_ (min2~ 7~ B~5) ,-7.0 ~ 2 13 t 5 19 ~ 3 36 ~ 6 31 ~ 2 52 ~ 5 ~20 35 ~ 2 60 ' 3~
20180 36 ~ 6 64 ~ . `
~x-mp ~ 4 ~ ong ~an- ~at~ wo~- ~roa~od with oith-~ w~t-r ~a~
contsol) or [3R-[l~S~),3~,4~a~-3-(~c-tyloxy)-1,3,~,S-totr~hydro-4- .
(4-methoxyph nyl)~l-(2-~yrrol~dinyl-m thyl)~
(~r~fluoromothyl)-2~ bonzaz-pLn-2 ono, monohydrochlorlt~
30 ~ln~t~- prior to th- oaolu-ion of retin~l v~ol~
StatLcttcal co~Ar~-on- w~rQ mad- at oach tim ~olnt. Seo T-bl- II5. ~ b~O . O~ ) . ;~
T~ III .. ~ ;.. :.
TIM$ FROM
R~P~FU8ION CONTROL 3.3 m~/ko ~ sj ~ /i5~, (mln)_~ ~n 61 ~n~5l ~ ~ 1 ll ~ l ~1 ~ 2 36 ~ 4~
2~ t 2 54 ~ 2b 120 37 1 2 63 ~ 4*
180 42 ' 2 74 ~ 4*
.,,~;,, ''~

~:
2no?~7 ~

Examp~e S
Unllke Ca+~ channelll, w~ich are lo~at~d i~ both ;~
retinal nouron~ and ve~Elel~, ~xcitato~y a~ino aaid rec~ptor are lo~ated only in the retina. ~ence, t~
S ltro chlcX re~ina a-~ay, an a~say inde~ondent of r~tin blood flow, wa~ u~ed to ev~luat~ theq~ exclt~ory ~nino ~eid receptor a~tagonl~t~ Chic~ r~tin~a wer~ isolate~
~rom a ~ay 1~ ~mbryo. I~o~ate~ r-t~nao wor- th~n incubated ~or 40 or 60 ~inutH~ con~rol Rin~r ' 10 uolutlon (5 mM ~lucou- und-r an a~mo~pher~ o 9S% air, 5% :~
C2 ) or in a te~ t Rlnge~ ' ~ uolutlon ~0 mM glu~o-e undor an ~tmospher~ o~ 9SX N2, 5X COa). ~n ~elect~d experiment~
t~e NMDA a~tagon$st, M~ ~01 (10 ~ to 10 ~M), w-~ ~dde~ to rotinas lncubatod ln tho te~t Ring~ solution. At tho 15 ~nd o the ~nou~atlon ~orlod retina~ wero fixod ln 4% ;~
~araforma W~hydo, dohydrat~d in ~thanol and ombetd~d in para~fin. Thlck ~4~) cro~ oction of tho r-tlna w~re then cut, ~tained wlth h~matoxy~in and o~ln, ~d ovaluated by l~ght mlcroocopy to d~t~rmino th~ degr~ of 20 rotln~l d-g~n-ration. ~.`.;..... ~/`.s-.. :
Control rot~na- ~1.. in~b-t~ ln Rin~ r~o with gluco-- under 95% alr) ~howed no ~uma~- or a~t~r~tion in retlnal t~uotur~ ~ollowing lna~b~tlon up to 60 ~inut~
R~tina~ lncubat-d in th- t~-t Ringor~ olution how~d 25 ~lgn~ o~ c-llul~r d-g~n~rat~on ~n th ~angllonlc ~nd lnn~r . ~ -~l-xl~orm l~y r- ~nd ~do~ ln tho lnn r nucl-~r, o~t~r pl~xl~orm and lnn-r pl-xi~orm l~y-r~. ~h- ~dmin~tratlon of 10 ~ M to 10 ~ M MK 801 to ~-tlna~ lncub~t-d ln ~t Rln~ r'~ cau-od a do-- r-lat-d l~p~ov-ment ~n th~o ~tructur~l int gxlty o~ th~ r~tin~, wlth ~11 layor~
pr-~-nt in th- MK 801-t~oatod rotln~ h a co~r-d to nontro~tod r-tln~4. In addltion, th- toma not-d 1 r-tlna~ lncubat-d in th t ~t ~lng~r'~ wa~ roduc-d by th~
a~mi~i~tratlon of MR 801. .
Althou~h the ~or-golng inv~ntlon ha- b~-n do~ri~et ~n ~om d~tall by w-y of lllustr~tlon and oxample ~or pur~o--~ o~ c~arlty o~ un~r~t~ndin~, lt wl~ b~ r~-dily ,,;, ~.",. . .
- ..., ~ .-,. . . ..

''"'."~

2(~0~617 --- 3~

~parent to ~ho~l~ o 02di~ary skill i~ the art in light of ~he teaohings o~' tbi~ in~3ntlon tha~ ce~t~in chango~ and modificatlons ~y be m3do the~.oto without de~arting ~rom the ~pirit or ~cope o the apponde~l clA~

1..,~
.'" ~

Claims

1. A method of treating a subject suffering from ischemia or edema of the retina or optic nerve which comprises administering to said subject a therapeutically effective amount of a calcium channel antagonist selected from the group consisting of dihydropyrimidones and benzazepines.

2. The method of claim 1, wherein said calcium channel antagonist is a dihydropyrimidone.

3. The method of claim 1, wherein said dihydropyrimidone is of the formula:
and pharmaceutically acceptable salts thereof wherein X is oxygen or sulfur; R' is hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R'1 is hydrogen, alkyl, cycloalkyl, aryl, heterocyclo, or halo substituted alkyl, or R' and R'1 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl,

4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl or 1-pyrrolidinyl, 1-piperidinyl, or 1-azeipinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy;
R'2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, , or halo substituted alkyl;
R'3 is hydrogen, alkyl, cycloalkyl, aryl, heterocyclo, , , or halo substituted alkyl;
R'4 is aryl or heterocyclo;
R'5 and R'6 are each independently hydrogen, alkyl, -(CH2)q-aryl or -(CH2)q-cycloalkyl;
Y1 is cycloalkyl, aryl, heterocyclo, hydroxyl, alkoxy, aryl -(CH2)m-O-, mercapto, alkylthio, aryl-(CH2)m-S-, amino, substituted amino, carbamoyl, , carboxyl, alkoxycarbonyl, , or Y2 is cycloalkyl, aryl, heterocyclo, carbamoyl, , carboxyl, alkoxycarbonyl, , aryl-(CH2)m-C- or ;
Y3 is hydroxyl, alkoxy, aryl--(CH2)m-O-, mercapto, alkylthio, aryl-(CH2)m-S-, , , amino or substituted amino;
q is 0, 1, 2 or 3;
m is 0 or an integer of 1 to 6;
n is 0 or an integer of 1 to 5; and p is an integer of 1 to 5.
4. The method of claim 3, wherein said dihydropyrimidone is (R)-1-(aminocarbonyl)-6-(3-chlorophenyl)-1,2,3,6-tetrahydro-4-methyl-2-oxo-5-pyrimidine carboxylic acid, 1-methylethyl ester.

5. The method of claim 1, wherein said calcium channel antagonist is a benzazepine of the formula:
and the pharmaceutically acceptable salts thereof, wherein:
X is -CH2-;
R1 is or -O-Y3;
when X is -CH2-, R2 is , , , , , , , , or ;
when X is -S-, R2 is , , , , , , or ;

R3 and R4 are each independently hydrogen, halogen, alkyl, alkoxy, aryloxy, arylalkoxy, arylalkyl, cyano, hydroxy, alkanoyloxy, , fluoro substituted alkoxy, fluoro substituted alkyl, (cycloalkyl)alkoxy, -NO2, -NY10Y11, -S(O)malkyl, -S(O)maryl, or ;
n or n' are independently 0, 1, 2, or 3;
m is 0, 1 or 2;
Y1 and Y2 are independently hydrogen or alkyl, Y1 is hydrogen and Y2 is alkenyl, alkynyl, aryl, heteroaryl, or cycloalkyl, or Y1 and Y2 together with the carbon atom to which they are attached are cycloalkyl;
Y3 is hydrogen, alkyl, alkanoyl, alkenyl, arylcarbonyl, heteroarylcarbonyl, or ;
Y4 and Y5 are each independently hydrogen, alkyl, aryl or arylalkyl, provided that when both are present they are not both hydrogen, and provided further that when both are attached to the same carbon atom neither of them is hydrogen, Y6 and Y7 are each independently hydrogen, alkyl, cycloalkyl or arylalkyl or Y6 and Y7 together with the nitrogen atom to which they are attached are azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl;
Y8 and Y9 are each independently hydrogen, alkyl, aryl or heteroaryl, or Y8 and Y9 together with the nitrogen atom to which they are attached are pyrrolidinyl, piperidinyl or morpholinyl;
Y10 and Y11 are each independently hydrogen, alkyl, alkanoyl, arylcarbonyl, heteroarylcarbonyl, or ;
Y12 is hydroxy, alkoxy, aryloxy, amino, alkylamino or dialkylamino;
Y13 is alkyl, alkoxy, or aryloxy; and Y14 is hydrogen, hydroxy, alkoxy, aryloxy or arylalokoxy.

6. The method of claim 5, wherein said benezazepine is selected from the group consisting of [3R-[1(S*),3<a,4<a]]-3-(Acetyloxy)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1-(2-pyrrolidinylmethyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-one, monohydrochloride and [3R-(3<a, 4<a)]-3-(Acetyloxy)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1-(2-dimethylaminoethyl-6-(trifluoromethyl) -2H-1-benzazepin-3-one.

7. The method of claim 6, wherein said benzazepine is [3R-[1(S*),3<a,4<a]]-3-(Acetyloxy)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1-(2-pyrrolidinyl-methyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-one, monohydrochloride.

8. A method of treating a subject suffering from ischemia or edema of the retina or optic nerve which comprises administering to said subject a therapeutically effective amount of a benzothiazepine derivative of the formula:
and the pharmaceutically acceptable salts thereof, wherein:
X is -S-;

R1 is or -O-Y3;
when X is -CH2-, R2 is , , , , , , , , or ;

when X is -S-, R2 is , , , , , , or ;

R3 and R4 are each independently hydrogen, halogen, alkyl, alkoxy, aryloxy, arylalkoxy, arylalkyl, cyano hydroxy, alkanoyloxy, , fluoro substituted alkoxy, fluoro substituted alkyl, (cycloalkyl)alkoxy, -NO2, -NY10Y11, -S(O)malkyl, -S(O)maryl, or ;
n or n' are independently 0, 1, 2, or 3;
m is 0, 1 or 2;
Y1 and Y2 are independently hydrogen or alkyl, Y1 is hydrogen and Y2 is alkenyl, alkynyl, aryl, heteroaryl, or cycloalkyl, or Y1 and Y2 together with the carbon atom to which they are attached are cycloalkyl;
Y3 is hydrogen, alkyl, alkanoyl, alkenyl, arylcarbonyl, heteroarylcarbonyl, or ;
Y4 and Y5 are each independently hydrogen, alkyl, aryl or arylalkyl, provided that when both are present they are not both hydrogen, and provided further that when both are attached to the same carbon atom neither of them is hydrogen;
Y6 and Y7 are each independently hydrogen, alkyl, cycloalkyl or arylalkyl or Y6 and Y7 together with the nitrogen atom to which they are attached are azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl;
Y8 and Y9 are each independently hydrogen, alkyl, aryl or heteroaryl, or Y8 and Y9 together with the nitrogen atom to which they are attached are pyrrolidinyl, piperidinyl or morpholinyl;
Y10 and Y11 are each independently hydrogen, alkyl, alkanoyl, arylcarbonyl, heteroarylcarbonyl, or ;
Y12 is hydroxy, alkoxy, aryloxy, amino, alkylamino or dialkylamino;
Y13 is alkyl, alkoxy, or aryloxy; and Y14 is hydrogen, hydroxy, alkoxy, aryloxy or arylalokoxy.

9. The method of claim 1, wherein said compound is administered topically, parenterally or orally.

10. A method of preventing ischemia or edema of the retina or optic nerve which comprises administering to a subject a prophylactically effective amount of a calcium channel antagonist selected from the group consisting of dihydropyrimidones and benzazepines.

11. The method of claim 10, wherein said calcium channel antagonist is a dihydropyrimidone.

12. The method of claim 11, wherein said dihydropyrimidone is is of the formula:
and pharmaceutically acceptable salts thereof wherein X is oxygen or sulfur; R' is hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R'1 is hydrogen, alkyl, cycloalkyl, aryl, heterocyclo, or halo substituted alkyl, or R' and R'1 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylakyl-1-piperazinyl or 1-pyrrolidinyl, 1-piperidinyl, or 1-azeipinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy;
R'2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, , or halo substituted alkyl;
R'3 is hydrogen, alkyl, cycloalkyl, aryl, heterocyclo, , or halo substituted alkyl;
R'4 is aryl or heterocyclo;
R'5 and R'6 are each independently hydrogen, alkyl, -(CH2)q-aryl or -(CH2)q-cycloalkyl;
Y1 is cycloalkyl, aryl, heterocyclo, hydroxyl, alkoxy, aryl -(CH2)m-O-, mercapto, alkylthio, aryl-(CH2)m-S-, amino, substituted amino, carbamoyl, , carboxyl, alkoxycarbonyl, , or Y2 is cycloalkyl, aryl, heterocyclo, carbamoyl, , carboxyl, alkoxycarbonyl, , or ;
Y3 is hydroxyl, alkoxy, aryl-(CH2)m-O-, mercapto, alkylthio, aryl-(CH2)m-S-, , , amino or substituted amino;
q is 0, 1, 2 or 3;
m is 0 or an integer of 1 to 6;
n is 0 or an integer of 1 to 5; and p is an integer of 1 to 5.

13. The method of claim 12, wherein said dihydropyrimidone is (R)-1-(aminocarbonyl)-6-(3-chlorophenyl)-1,2,3,6-tetrahydro-4-methyl-2-oxo-5-pyrimidine carboxylic acid, 1-methylethyl ester.

14. The method of claim 10, wherein said calcium channel antagonist is a benzazepine of the formula:
and the pharmaceutically acceptable salts thereof, wherein:
X is -CH2-;
R1 is or -O-Y3;

when X is -CH2-, R2 is , , , , , , , or ;

when X is -S-, R2 is , , , , , , or ;
R3 and R4 are each independently hydrogen, halogen, alkyl, alkoxy, aryloxy, arylalkoxy, arylalkyl, cyano, hydroxy, alkanoyloxy, , fluoro substituted alkoxy, fluoro substituted alkyl, (cycloalkyl)alkoxy, -NO2, -NY10Y11, -S(O)malkyl, -S(O)maryl, or ;
n or n' are independently 0, 1, 2, or 3;
m is 0, 1 or 2;
Y1 and Y2 are independently hydrogen or alkyl, Y1 is hydrogen and Y2 is alkenyl, alkynyl, aryl, heteroaryl, or cycloalkyl, or Y1 and Y2 together with the carbon atom to which they are attached are cycloalkyl;
Y3 is hydrogen, alkyl, alkanoyl, alkenyl, arylcarbonyl, heteroarylcarbonyl, or ;
Y4 and Y5 are each independently hydrogen, alkyl, aryl or arylalkyl, provided that when both are present they are not both hydrogen, and provided further that when both are attached to the same carbon atom neither of them is hydrogen;
Y6 and Y7 are each independently hydrogen, alkyl, cycloalkyl or arylalkyl or Y6 and Y7 together with the nitrogen atom to which they are attached are azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl;
Y8 and Y9 are each independently hydrogen, alkyl, aryl or heteroaryl, or Y8 and Y9 together with the nitrogen atom to which they are attached are pyrrolidinyl, piperidinyl or morpholinyl;
Y10 and Y11 are each independently hydrogen, alkyl, alkanoyl, arylcarbonyl, heteroarylcarbonyl, or ;
Y12 is hydroxy, alkoxy, aryloxy, amino, alkylamino or dialkylamino;

Y13 is alkyl, alkoxy, or aryloxy; and Y14 is hydrogen, hydroxy, alkoxy, aryloxy or arylalokoxy.

15. The method of claim 14, wherein said benezaepine is selected from the group consisting of [3R-[1(S*),3<a,4<a]]-3-(Acetyloxy)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1-(2-pyrrolidinylmethyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-one, monohydrochloride and [3R-(3<a, 4<a)]-3-(Acetyloxy)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1-(2-dimethylaminoethyl-6-(trifluoromethyl)-2H-1-benzazepin-2-one.

16. A method or preventing ischemia or edema of the retina or optic nerve which comprises administering to a subject a prophylactically effective amount of a benzothiazepine derivative of the formula:
and the pharmaceutically acceptable salts thereof, wherein:
X is -CH2- or -S-;
R1 is or -O-Y3;

when X is -CH2-, R2 is , , , , , , , , or ;
when X is -S-, R2 is , , , , , , or ;

R3 and R4 are each independently hydrogen, halogen, alkyl, alkoxy, aryloxy, arylalkoxy, arylalkyl, cyano, hydroxy, alkanoyloxy, , fluoro substituted alkoxy, fluoro substituted alkyl, (cycloalkyl)alkoxy, -NO2, NY10Y11, -S(O)malkyl, -S(O)maryl, or ;
n or n' are independently 0, 1, 2, or 3;
m is 0, 1 or 2;
Y1 and Y2 are independently hydrogen or alkyl, Y1 is hydrogen and Y2 is alkenyl, alkynyl, aryl, heteroaryl, or cycloalkyl, or Y1 and Y2 together with the carbon atom to which they are attached are cycloalkyl;
Y3 is hydrogen, alkyl, alkanoyl, alkenyl, arylcarbonyl, heteroarylcarbonyl, or ;
Y4 and Y5 are each independently hydrogen, alkyl, aryl or arylalkyl, provided that when both are present they are not both hydrogen, and provided further that when both are attached to the same carbon atom neither of them is hydrogen;
Y6 and Y7 are each independently hydrogen, alkyl, cycloalkyl or arylalkyl or Y6 and Y7 together with the nitrogen atom to which they are attached are azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl;
Y8 and Y9 are each independently hydrogen, alkyl, aryl or heteroaryl, or Y8 and Y9 together with the nitrogen atom to which they are attached are pyrrolidinyl, piperidinyl or morpholinyl;
Y10 and Y11 are each independently hydrogen, alkyl, alkanoyl, arylcarbonyl, heteroarylcarbonyl, or ;
Y12 is hydroxy, alkoxy, aryloxy, amino, alkylamino or dialkylamino;
Y13 is alkyl, alkoxy, or aryloxy; and Y14 is hydrogen, hydroxy, alkoxy, aryloxy or arylalokoxy.