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CA2079344A1 - Substituted pyrimidines, pyrimidinones and pyridopyrimidines - Google Patents

Substituted pyrimidines, pyrimidinones and pyridopyrimidines

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Publication number
CA2079344A1
CA2079344A1 CA002079344A CA2079344A CA2079344A1 CA 2079344 A1 CA2079344 A1 CA 2079344A1 CA 002079344 A CA002079344 A CA 002079344A CA 2079344 A CA2079344 A CA 2079344A CA 2079344 A1 CA2079344 A1 CA 2079344A1
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Prior art keywords
alkyl
heteroaryl
aryl
cycloalkyl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
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CA002079344A
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French (fr)
Inventor
Eric E. Allen
William J. Greenlee
Malcolm Maccoss
Arthur A. Patchett
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Merck and Co Inc
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Individual
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P9/12—Antihypertensives
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    • C07—ORGANIC CHEMISTRY
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

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Abstract

Substituted pyrimidines, pyrimidinones and pyridopyrimidines of formula (I) are as angiotensin II antagonists useful in the treatment of hypertension, ocular hypertension and certain CNS
ailments; in the said formula, K is -N(R8a)-C(=M) or -N=C(R8b) where M is O or NR22.

Description

Wo91/15209 PCT/US91/01951 TITL~ OF TH~ INVENTIONSUBSTITUTED PYRIMIDINES, PYRIMIDINONES AND PYRID9-PYRIMIDINES ~

SUMMAR~ OF ~H~ INVENTI~N
The is a continuation-in-part of copending Application S. N. 50l,580, filed March 30, l990.
This invention rslates to novel substituted pyrimidine, pyrimidinone and pyridopyrimidine compounds and derivatives thereof which are useful as angiotensin II antagonists in the treatment of elevated blood pressure and congestive heart failure. The compounds of the invention are also useful-as ocular antihypertensives.
- , . ...
-... . . - ..
. . . , ~ .. . ..... .. . . ... .. . .. .
~. .. ~ - . . . . . :
. - - ' ~ , :

. .
, .

wos1/15209 PcT/us9l/ols
2~ ?~ 2 -The compounds of this invention also have central nervous system (CNS) activity. They are useful in the treatment of cognitive dysfunctions including Alzheimer's disease, amnesia and senile dementia. These compounds also have anxiolytic and antidepressant properties and are therefore, useful in the relief of symptoms of anxiety and tension and in the treatment of patients with depressèd or dysphoric mental states.

BACKG~0UND OF~EE_l~y~NTION
Renin-angiotensin system (RAS) plays a central role in the regulation of normal blood pressure and seems to be critically in~olved in hypertension development and maintenance as well as congestive heart failure. Angiotensin II (A II), an octapeptide hormone is produced mainly in the blood during the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the endothelium of blood vessels of lung, kidney, and many other organs, and is the end product of the RAS-A II is a powerful arterial vasoconstrictOr that-exerts its action by interacting with ~pecific receptors present on cell membranes. One-of the possible modes of controlling the RAS is angiotensin II receptor antagonism. Several peptide analogs of A II are known to inhibit the effect of this hormone by competitively blocking the receptors, but their experimental and clinical applications have been ~ -limited by partial agonist activity and lack of oral absorption [M. Antonaccio. Clin. Exp. ~ypertens. A4, 27-46 (198Z); D. ~. P. Streeten and G. H. ~nderson, wosl/l5209 PCT/US91/01951 ~; t, ~ $ ~,, !~
- 3 - ~ -Jr. - Handbook of Hypertension, Clinical Pharmacology of Antihvpertensive Drug~, ed. A. E. -Doyle, Vol. 5, pp. 246-271, Elsevier Science --Publisher, Amsterdam, The Netherlands, 1984].
Recently, several non-peptide compounds have been described as A II antagonists. Illustrative of such compounds are those disclosed in U.S. Patents
4,207,324; 4,340,598; 4,576,958; and 4,582,847; in European Patent Applications 028,834; 245,637;
253,310; 291,969; 323,841; and 324,377; and in articles by A.T. Chiu, et al. tEur. J._Pharm Exp.
Therap, 157, 13-21 (1988)] and by P.C. Wong, et al.
~J. Pharm. ~a~ Therap, 247, 1-7(1988)]. All of the U.S. Patents, European Patent Applications 028,834 and 253,310 and the two articles disclose substituted imidazole compounds which are generally bonded through a lower alkyl bridge to a substituted phenyl. European Patent Application 245,637 discloses derivatives of 4,5,6,7-tetrahydro-2E-imidazo[4,5-c]-pyridine-6-carboxylic acid and analogs thereof as antihypertensive agents. ' DETAILED D~SCRIPTION OF T~ INVENTION .
This invention relates to novel substituted pyrimidine, pyrimidinone and pyridopyrimidine compounds and derivatives thereof which are useful as angiotensin II antagonists, as antihypertensives, in ~
the treatment of congestive heart failure and in the . .
treatment of elevated intraocular pressure. The compounds of t~is in~ention have the general formula ,j~- j . ` ., : '.' . ,'. ~ . ., .'. ~ : !, ' . , .'~ . ' ' :''' ' , , ' ~ " `.' ' : , WO91/15209 PCT/US91/~1951 .~
2 ~J.~.'~

N ~
R6- E~K

R3 b - ~R3 R2 b~R1 R2 a ~. .

(I) wherein: ~
K is -N(R8a)-C(=M) or -N=C(R8b)-wherein M is 0 or : .
NR22 . ::

Thus, the compounds of formula I can also be e~pressed as compounds having the following formulae (Ia), (Ib), and ((Ic) if R7 and R8a are joined) -~

.

- . . .

.
-~, .

.;, .
!

WO 91/15209 PCr/US91/01951 ~y~

N~N,Ra a N~N
R6 _ E~M R6 _ E~ 8 b ~ ~ `

R3 b~ -R3a ~3b~3 _R3a X . ` .
R2b~R1 ~,R

~R26 ( Ia) NlN~~ Ib) R6 E~M : '-CH2 ., R3b$l--R3-R2 b~R1 R :

( Ic) ~` , .
.,........................................................... ~ ~

~ .
.

WO 91/15209 PCr/US91/01951 J~ 6 -wherein:

Rl i s ( a ) -Co2R4, ( b ) - So3R5, ( c ) -NHS02 ( C l-C4-polyf luoroalkyl ) ( d ) -PO ( oR5 ) 2 ~
( e ) - So2-NH-R9, (f ) -CoNHoR5, OH O
(g) -C--P-oR5, R9 oR5 (h) -CN, (i) -S02N~-heteroaryl, (j~ -C~I2S02NH-heteroaryl, (k) -So2NH-Co-R23, (1) -C~I2S02NH-CO-R23, (m) -CONEI-S02R23, (n) -CHzCON~I-S02R23, ( o ) -N~IS02N~CO-R23, (p) -NEICON~S02-R23, .~, . .

, ,' ' ' ' , . ''' , ` :' ", , ` ,' , ' ::
5~0~ PCr/US91/0195 N-N
) ~N,N ~
Rl 1 .

N--N
( r ) ~ CH2 ~N~N
Rl1 ~
N--N
( s ) - CON~ N
H R~

t ) - CONHN~ O2 CF3 , , N--N
( u) N CF3 H

N~N
( v) ~

.
: ~ .

PCT/US91/019~1 2~'?'~ 8 wherein heteroaryl is an unsubstituted, monosub- ~ ~ :
stituted or disubstituted five or six membered aromatic ring comprising ~rom l to 3 heteroatoms selected from the group consisting of 0, N or S and .
wherein the substituents are members selec~ed from the group consisting of -OH, -SH, -Cl-C4-alkyl, -Cl-C4-alkoxy, -CF3, Cl, Br, F, I, -N02, -C02H, -C02-Cl-C4-alkyl, -NH2, NH(Cl-C4-alkyl) and -N(Cl-c4-alkYl)2;

R2a and R2b are each independently (a) ~, (b) Cl ,Br, I or F, (c) N02, .
(d~ NE2, :
(e) Cl-C4-alkylamino, (f) di-(Cl-C4-alkyl)amino (g) So2NHR9, (h) CF3, (i) Cl-C4-alkyl, or (j) Cl-C4-alkoxy;

R3a is (a) E, (b) Cl, 2r, I, F
(c) Cl-C6-alkyl, (d) Cl-C6-alkoxy, (e) Cl-C6-alkoxy-Cl-C4-alkyl; : .
' , .

.
. .

WO91/15209 PCTiUS91/01g51 _ 9 _ .

R3b i S
(a) H
(b) Cl, Br, I, F
(C) N02, (d) Cl-C6-alkyl, ~e) C2-C6-alkanoyloxy, (f) C3-C6-cycloalkyl, :
(g) Cl-C6-alkoxy, (h) -MHSo2R4, (i) hydroxy-Cl-C4-alkyl, ~',' (j) aryl-Cl-C4-alkyl, (k) Cl-C4-alkylthio, (1) Cl-C4-alkylsulfinyl, ''-~
(m) Cl-C4-alkylsulfonyl, (n~ NH2, (o.) Cl-C4-alkylamino, (p) Cl-C4-dialkylamino, (q~ CF3, (r) -So2-NHR9, (s) aryl or (t) furyl;

wherein aryl is phenyl or naphthyl unsubstituted or ~: substituted with one or two substituents selected from the group con~isting of Cl, Br, I, F, Cl-C4-alkyl, Cl-C4-alkoxy, NO2, CF~, Cl-C4-alkylthio, 0~ NH2~ -NH(Cl-C4-alkYl). -N(Cl-C4-alkyl)2~ -CO2H, Cl-C4 polyfluoroalkyl, C3-C6-polyfluorocvcloalkyl~
-CO2-Cl-C4-alkyl or -; Nl It `

H :
~' ~

~:

WO91/15209 PCT/US91/019~1 2~

R4 is H, Cl-C6-alkyl, benzyl or phenyl;

R5 is H, -CH-o-C-R4;

E is a single bond, -NRl3(CH2)S-, -S~O)x~CH2)s-where x is 0 to 2 and s is 0 to 5, -C~(OH)-, -O-, -CO-; ~

R6 iS
(a) Cl-C6-alkyl, C2-C5-alkenyl or C2-C5-alkynyl -each of which can be substituted with a substituent selected from the group -.
consisting of aryl, C3-C7-cycloalkyl, Cl, - :
Br, I, F, -0~, CF3, CC13. -NX2, -NH(Cl-c4-alkYl). -N(cl-c4-alkyl)2, -N~I-S02R4, -CooR4, -S02NHR9, Cl-C4-alkoxy, ' .
Cl-C4-alkyl-S. -CF2CF3;

(b) C3-C5-cycloalkyl;
(c) polyfluoro-Cl-C4-alkyl;
.
R7 is (a) hydrogen, (b) aryl, (c) heteroaryl, ~' (d) Cl, Br, I, F, ::
(e) -C02H, ~ : .
(f) -C02R4, (g) NX2, (h) -NH(Cl-C4-alkyl), (i) -N~Cl-C4-alkyl)2, ( j ) -So2NR9R10, ,~
(k) -N~IS02-51-C4-alkyl, ( 1 ) -S ( O )x-Cl-C4-alkyl, ~ .
.

W091/15209 pcT/ussl/ol9s (m) -OH, (n) -SH, (o) -S(O)x-aryl, , .:
(p) ~Cl-C4-alkyl or -O(Cl-C4-alkyl) or -S(Cl-C4-alkyl) each of which can be substituted with aryl, heteroaryl, :
-OH, -NH2, -CF3, G3-C5-cycloalkyl, -NH(Cl-c4-alkYl)~ -N(cl-c4-alkyl) -C02H, -Co2R4, Cl, ~r, I, or F, (q) C3-C5-cycloalkyl or (r) -CF3;

R8a is (a) aryl, (b) heteroaryl, (c) Cl-C4-alkyl either unsubstituted or substituted with aryl, heteroaryl, -OH, -NH2, -NH(Cl-C4-alkyl), N(Cl-C4-alkyl)2, -C02H, -Co2R4 Cl, Br, I, or F, or (d) Cl-C4-alkylaryl either unsubstituted or substituted with Co2R4;
or R7 and R8a when alkyl groups on adjacent atoms may be joined together with the atoms to which they are bound to form a pyridine ring which may~be unsubstituted or.substituted with R26 or R27 or R26 ~
and R27 wherein R26 is ~ ~.
-.-(a) R7 - (b) -NHCO(C~-C5-alkyl), ~c) :-NHCO(C3-C6-cycloalkyl), (d) .~-NHCO(aryl), .-(e) -NHCO(heteroaryl),--.
(f) -N(Cl-C~-alkyl)CO~Cl-C5-alkyl~

.

.. ~ . . .. .

wosl/ls2o9 PC~r/ussl/o1s ~_, Z ,~

(g) -N(Cl-C5-alkyl)CO(C3-C6-cyclo-alkyl), (h) -N~Cl-C5-alkyl)CO(aryl), (i) -N(Cl-C5-alkyl)CO(heteroaryl).

and R27 is Cl-C4-alkyl, Cl, Br, F, I, -CF3, aryl or heteroaryl;

R8b is (a) -OH, (b) -NH2, (c) -N~(Cl-C4-alkyl), (d) -N(Cl-C4-alkYl)2~

(e~ -MHC02-Cl-C4-alkyl, (f) -NHCO-Cl-C4-alkyl, ( g ) -N~S02-Cl-C4-alkyl, (h) -NHS02-aryl, ;

(i) -MHS02(Cl-C4-polyfluoroalkyl), (j) -C0zH, (k) -Co2R4, (1) Cl, Br, I, F, (m) -CONHS02-aryl, ~ ~ .

(n) -CONHS02-heteroaryl, (o) -CONHS02-Cl-C4-alkyl, (p) -CONHS02(Cl-C4-polyfluoroalkyl), (q) -C~20~

(r) -CH20CoR4, (s) -0-Cl-C4-alkyl-, unsubstituted or substituted with Co2R4, (t) -S(0)x-aryl unsubstituted or ---substituted with C02R4, ~u) -S(0)~-Cl-C4-alkyl unsubstituted or l~:

substituted:with C02R4, I
(v) ---S02NHR25, -. ~) -CN,. . . i-'~' WO91/15209 pcT/vss (x) tetrazol-5-yl;
R9 is H, Cl-C5-alkyl, phenyl or benzyl;
R10 iS H, Cl-C4-alkyl;
Rll is H, Cl-C6-alkyl, C2-C~-alkenyl, Cl-C4-alkoxy alkyl, or -CH2-C6H4R20;
R12 is -CN, -N02, -Co2R4, or -CF3;
R13 is H, C2-C4-alkanoyl, Cl-C6-alkyl, allyl, C3-C6-cycloalkyl, phenyl or benzyl;
R14 is H, Cl-C8-alkyl, Cl-C8-perfluoroalkyl, C3-C6-cycloalkyl, phenyl or benzyl;
R15 is ~, Cl-C6 alkyl;
R16 is H, Cl-C6-alkyl, C3-C6-cycloalkyl, phenyl or -~
benzyl;
Rl7 iS -NR9R10, -OR10, -NHCONH2, -NHCSNH2, - N~SO2~CH3 or - N~02~ ;

R18 and R19 are independently Cl-C4-alkyl or taken together are ~~CH2)q~ where q-is 2 or 3;
20 is H, -NO2, -NH2, -O~ or -OcH3;
R21 is (a) -CO-aryl, ~-(b) -CO-Cl-C4-alkyl, (c) -COCF3, (d) -CO-heteroary', (e) heteroaryl; .
R22 is the same as R8a or -H;
,, - , - . .
', .: .

. .

W091/1520~ PCT/VSs~/01951 R23 is (a) aryl, (b) heteroaryl, (c) C3-C7-cycloalkyl, (d) Cl-C6-alkyl unsubstituted or substituted with a substituent selected from the group consisting of aryl, heteroaryl, -0~, S~, -C1-C4-alkyl, -O(Cl-C4-alkyl), -S ( Cl-C4-alkyl ), -CF3, Cl, Br, F, or I, -N2 . -C02H, -C02-Cl-C4-alkyl, -NH2 -NH(Cl-C4-a~kYl). -N(Cl-C4-alkyl)2, -P3~2, or -po(oH>(o-cl-c4-alkyl);
R25 is (a) H, (b) Cl-C4-alkYl;

X is (a) a carbon-carbon single bond, (b) -CO-, (c) --O--, (d) -S , ~e) -N-, :~

(f) -CON-, RlS
(g) -NCO-, R15 ' - ~ ~, (h) -OCH2-, ( i ) -C~I20-(j) SC~2-, ~ .,, .. " ~ ' (k) -C~2S-, --( 1 ) -NHC ( R9 ) ( Rl ) -, .

WO91/l5209 (m) -NR9So2-, (n) -So2NR9-, (o~ -C(R9)(RlO)N~-, (p) -C~=CH-, (q) -CF=CF-, (r) -CH=CF-, (s) -CF=CH-, (t) -C~2CH2-' (U ) -CF2CF2-, (v) ~ / C~2 `C~
,C\ ¦ or ¦ / CH2 C~2 / CH
oR14 (w) -CEI-, ocoR16 . ,::
(x) -CH-, i, .
~ (y) -C-, or R180 oR19 (z) --C--;

~ ~ Z is 0, NR13 or S; or, : : :
a pharmaceutically acceptable salt thereoP.
The terms "alkyl", "alkenyl", ~alkynyl" and the like include both the straight chain and branched chain species of these generic terms wherein the number of car~on ~toms in the species permit. Unless otherwise noted, the specific names for these generic terms shall mean the straight chain species. For example, the term "butyl" shall mean the normal butyl ;;substituent, a-butYl.
~ ~ .

U'O 91/1~209 PCT/I~S91 /01 9' 1 .~:~, '? .~ ~

One embodiment of the novel compounds is that of formula Ib wherein K is -N=C(R8b) In a class of this embodiment, N-N
Rl is -COOH; ~ " -NH-SO2CF3; -Co2R4; ~ ~-H

-S02N~- heteroaryl or CH2S02N~- heteroaryl wherein the heteroaryl is an unsubstituted, :
monosubstituted or disubstituted 5- or
6-membered aromatic ring 1 to 3 heteroatoms selected from O, N and S and wherein the substituents are members selected from the group consisting of OH, S~, Cl-C4-alkyl, Cl-C4-alkoxy, CF3. Cl, Br, F, I, NO2, C2~, C2-Cl-C4-alkYl' NH2, NH(Cl-C4-alkyl) and N(Cl-C4-alkyl)2;
-SozNHCoR23;-CH2SO2N~COR23; -CoNHS02R23;
-CH2CoNEsS02R23; -N~So2NECoR23; or -MEsCOMHSo2R23; : -R2a and R2b are H, F, Cl, CF3, Cl-C4-alkyl Cl-C4-alkoxy;
~3a is Es~ F or Cl; :
R3b is H, F, Cl, CF3, Cl-C4-alkyl, Cl-C4-alkoxy, ~:
-COOC~3, -COOC2Hs, -S02-CE3, MH2, :.
-N(Cl-c4-alkYl)2 or -NH-so2cEs3;
.
E is a single bond, -O- or -S-;
.... .. .~ .. .. ~ . . . . . . ... .. .

: .

-::

wo 91/15209 PCl`/US91/01~1 Z'~, ~i ~ .J ''_ ~

R6 is (a) Cl~C5-alkyl, C2-C5-alkenyl or C2-C5-alkynyl each of which can be substituted with a substituent selected from the group consisting of, CF3, CF2CF3, -0-CH3, -OC2H5, -S-CH3, -S-C2H5, phenyl and C3-C5-cyclo-alkyl;
~b) C3-Cs-cycloalkyl; and (c) polyfluoro-Cl-C4-alkyl;

X is a C-C single bond.

In a more preferred class of this embodiment are those compounds wherein:

E i~ a sin~le bond;
R2a R2b R3a and R3b are each H; and X is a single bond.
~ .
Exemplifying this embodiment are the following compounds of the Formula II shown in Table ::

, .:
.- R7 I
~: N~N
~, ~
~R8 b WO 91/15209 pcl/ussl/olss n,~

Table 1 Compd.
No. Rl R6 R7 R8b __~__ _ II-l tetrazol-5-yl Bu Me -COOMe II-2 tetrazol-5-yl Bu Me -COOEt II-3 tetrazol-5-yl Bu Me -COOH
II-4 tetrazol-5-yl Bu Me -CHO
II-5 tetrazol-5-yl Bu Me -CH20H
II-6 tetrazol-5-yl Bu Me -NHS02CF
II-7 tetrazol-5-yl Bu Me -NHso2cF2cF3 II-8 tetrazol-5-yl Bu Me -NHS02Ph II-9 tetrazol-5-yl Bu Me -CONHS02Ph ~ :
II 10 tetrazol-5-yl Bu Me -S02NHCOCYPr II-ll tetrazol-5-yl Bu Me -SOzNHSO2CF3 II-lZ tetrazol-5-yl Pr Me -COOMe II-13 tetrazol-5-yl Pr Me -COOEt II-14 tetrazol-5-yl - Pr Me -COOH :
II-15 tetrazol-5-yl Pr Me -CHO
II-16 tetrazol-5-yl Pr Me -C~20H
II-17 tetrazol-5-yl Pr Me -NHS02CF3 II-18 tetrazol-5-yl Pr Me NHS02CF2CF
II-l9 tetrazol-5-yl Pr Me -NHS02Ph :
II-20 tetrazol-5-yl Pr Me -CONHS02Ph .
II-21 tetrazol-5-yl Pr Me -S02NHCOCYPr II-22 tetrazol-5-yl Pr Me -S02NHSO CF3 II-23 -NHS02CF3 Bu Me -COOMe II-24 -NHS02CF3 . Bu Me -COOEt .. -. .II-25 -NHS02CF3 Bu Me -COOH
II-26 -NHSO~CF3 Bu Me -CHO
:' ' . . .

'':,"',-"'''',.''''',"``,,'''' . . '"`

W O 91/15209 2r~,$ ~ PCT/US91/01951 -- 19 -- : .

Compd.
No. Rl R6 R7 R8b _ I
!~ ~
II-27 -NHS02CF3 Bu Me -CH20H
II-28 -NHS02CF3 Bu Me -NHS02CF3 II-29 -NHS02CF3 Bu Me -NHS02CF2CF3 II-30 -NHS02CF3 Bu Me -NHS02Ph II-31 -NHS02CF3 Bu Me -CONHS02Ph II-32 -NHS02CF3 Bu Me -S02NHCOCYPr II-33 -NHS02CF3 Bu Me -S02NHS02CF3 II-34 -NHS02CF3 Pr Me -COOMe II-35 -NHS02CF3 Pr Me -COOEt II-36 -NHS02CF3 Pr Me -COOH
II-37 -NHS02CF3 Pr Me -CHO
II-38 -NHS02CF3 Pr Me -CH20H
II-39 -NHS02CF3 Pr Me NHS02CF3 II-40 -NHS02CF3 Pr Me -NHS02CF2CF3 II-41 -NNS02CF3 Pr Me -NHS02Ph II-42 -NHS02CF3 Pr Me ~CONHS02Ph II-43 -NHS02CF3 Pr Me S02NHCOCYPr II-44 -NHS02CF3 Pr Me -S02NHS02CF3 II-45 -S02NHCOCYPr Bu Me -COOMe II-46 -S02NHCOCYPr Bu Me -COOEt `~
47 -S02NHCOCYPr Bu Me -COOH
II-48 :-S02NHCOCYPr: Bu Me --CHO
:II-49 -S02NHCOCYPr Bu. Me -CH20H
II-50 -S02NHCOCYPr -Bu Me -NHS02CF3 -II-51 -S02NHCOCgPr Bu. Me: -NHS02CF2CF3 .

II-52` -S02NHC~CYPr Bu - Me -NHS02Ph ~ .
II-53 -S02NHCOCYPr Bu Me -CONHS02Ph II-54 -S02NHCQCYPr Bu - Me -S02NHCOCYPr -.
.

~:

W O 91/15209 P~T/US9~/01951 .~ , 2 ~ 20 -Compd~ - .
No. Rl R6 R7 R8b ::. -:

II-55 -S02NHCOCYPr Bu Me S02NHS02CF3 II-56 -S02NHCOCYPr Pr Me -COOMe : .
II-57 -S02NHCOCYPr Pr Me -COOEt II-58 -S02NHCOCYPr Pr Me -COOH
II-59 -S02NHCOCYPr Pr Me -CHO
II-60 -S02NHCOCYPr Pr Me -CH20H
II-6l -S02NHCOCYPr Pr Me -NHS02CF3 II-6Z -S02NHCOCYPr Pr Me -NHS02CF2CF3 -~
II-63 -S02NHCOCYPr Pr Me -NHS02Ph II-64 -S02NHCOCYPr Pr Me -CONHS02Ph II-65 -S02NHCOCYPr Pr Me -S02NHCOCYPr II-66 -S02NHCOCYPr Pr Me -S02NHS02CF3 II-67 tetrazol-5-yl' Pr -CF2CF3 -COOMe II-68 tetrazol-5-yl Pr -CF2CF3 -COOEt II-6g tetrazol-5-yl Pr -CF2CF3 -COOH
II-70 tetrazol-5-yl Pr -CF2CF3 -C~O
II-71 tetrazol-5-yl Pr -CF2CF3 -CH20H
II-72 tetrazol-5-yl Pr -CF2CF3 -NHS02CF3 ~:~
II-73 tetrazol-5-yl Pr -CF2CF3 HS02CF2CF3 ~
II-74 tetrazol-5-yl Pr -CF2CF3 -NHS02Ph : :
II-75 tetrazol-5-yl Pr -CF2CF3 -CONHS02Ph II-76 tetrazol-5-yl Pr -CF2CF3 -S02NHCOCYPr II-77 tetrazol-5-yl Pr -CF2CF3 -S02NHS02CF3 :
II-78 -NHS02CF3 Pr -CF2CF3 -COOMe II-79 : -NHS02CF3 Pr -CF2CF3 - -COOEt -~
II-80 -NHS02Cr3 Pr -CF2CF3 -COOH~
II-81 - -:NHS02CF3 Pr -CF2CF3 -CHO .' II-82: -NNS02CF3 --Pr . -CF2CF3 -CH20H -:
; ~
'~ ; ' : . ~ ' . :

WO 91/15209 PCr/US91/01951 ~.,, ~., Compd.
No~ Rl R6 R7 RBb II-33 -NHS02CF3 Pr-CF2CF3 NHS02CF3 II-84 -NHS02CF3 Pr-CF2CF3 -NHS02CF2CF3 II-85 -NHS02CF3 Pr-CF2CF3 -NHS02Ph :~
II-86 -NHS02CF3 Pr-CF2CF3 -CONHS02Ph II-87 -NHS02CF3 Pr-CF2CF3 -S02NHCOCYPr II-88 -NHS02CF3 Pr-CF2CF3 -S02NHS02CF3 II-89 -S02NHCOCYPr Pr -CF2CF3 -COOMe II-90 -S02NHCOCYPr Pr -CF2CF3 -COOEt II-91 -S02NHCOCYPr Pr -CF2CF3 -COOH
II-92 -S02NHCOCYPr Pr -CF2CF3 -CHO
II-93 -S02NHCOCYPr Pr -CF2CF3 -CH20l~
II-94 -S02NHCOCYPr Pr -CF2CF3 -NHS02CF3 II-95 -S02NHCOCYPr Pr -CF2CF3 -NHS02CF2CF3 II-96 -S02NHCOCYPr Pr -CF2CF3 -NHso2ph II-97 -S02NHCOCYPr Pr -CF2CF3 -CONHS02Ph II-g8 -S02NHCOCYPr Pr -CF2CF3 -S02NHCOCYPr II-99 -S02NHCOCYPr Pr -CF2CF3 -S02NHS02CF3 II-100 -S02NHCOPh Pr Me -COOMe II-101 -S02NHCOPh Pr-CF2CF3 -COOMe II-102 -S02NHCO- Pr Me -COOMe.
.` (CH2)5NH2 -' II-103 -S02NHCO- Pr-CF2CF3 -COOMe (~H2)5NH2 . j ' - .
II-104 -S02NHCOPh Pr..... Me -NHSO CF3 -II-105 -S02NHCOPh Pr . -CF2CF3 -SO NHCOCYPr II-106 -S02NHC~ Pr- Me - - -NHS02CF3 (CHZ)5NHz II-107 -S02NHCO- Pr -C ~ F3 -S02NHCOCYPr (CH2)5N~2 ,:
j- .

2 ~ J ~?~
- 2~ -In another embodiment of the novel compounds is that of formula Ia (M=O) wherein K is -N(R8a)-CO-.

In a class of this embodiment N--N
Il ~ ` , . ~
Rl is -COOE; ~ ~N ; -NH-SO2CF3; Co2R4;

H ~ -.

-S02NH- heteroaryl or C~2S02NH- heteroaryl wherein the heteroaryl is an unsubstituted, :
monosubstituted or disubstituted 5- or 6-membered aromatic ring comprising contain l to 3 heteroatoms selected from O, N and S and wherein .
the substituents are members selected from the group consisting of O~, SH, Cl-C4-alkyl, Cl-C4-alkoxy, CF3, Cl, Br, F, I, N02, CO2~ 9 C02-Cl-C4-alkyl, NH2, NH(Cl-C4-alkyl) and N(Cl-C4-alkyl~2; -So2NHCoR23;-CH2So2N~coR23;
-CoN~So2R23; -CH2CoN~So2R23; -N~So2N~CoR23; and -N~CoNHSo2R23;
R2a and R2b are H, F, Cl, CF3, Cl-C4-alky Cl-C4-alkoxy; .
R3a is H, F or Cl; --R3b is Hi F, Cl. CF3. cl-C4-alkyl. Cl-C4-alk~i`
.-COOCH3, -COOC2H5.--S02-CH3, NH2, N(Cl-C4-alkyl)2 or -NH-SO2CH3;

. . .

,~ ' .

W091/15209 PCT/US91~01951 E is a single bond, -O- or -S-;
R6 is (a) Cl-C5-alkyl, C2-C5-alkenyl or C2-C5-alkynyl each of which can be substituted with a substituent selected from the group consisting of Cl, CF3, CF2CF3, CCl3, -O-C~3~ -C2x5~ -S-CH3, -S-C2Hs, phenyl and C3-C5-cycloalkyl;
(b> C3-C5-cycloalkyl;
(c) polyfluoro-Cl-C4-alkyl;

R7 and R8a are as defined above or together with the atoms to which they are bonded may be joined to form a pyridine ring which can be subætituted with R26 and R27; and X is a C-C single bond.

In a more preferred clas~ of this embodiment are those compounds wherein:

E is a single bond;
R2a R2b, R3a and R3b are each H; and X is a single bond.
., Exemplifying this embodiment are the following compounds- of the Formula III shown in Table 2: :~
.
.. . .

- ' ` -~' ~
.

,~, .
2~

~1~ R~ a R ~ O
~ Rl : :

III
Tabl e 2 Compd.
No. ~ R6 R7 R8a : :

III-l tetrazol-5-yl Bu Me H
III-Z tetrazol-5-yl Pr Me 2-CF3-phenyl III-3 tetrazol-5-yl Pr . Me 2-Cl-phenyl III-4 tetrazol-5-yl Pr Me 2,6-diCl-phenyl III-5 tetrazol-5-yl Pr -CF2CF3 2-CF3-phenyl :
III-6 tetrazol-5-yl Pr -CF2CF3 2-Cl-phenyl III-7 tetrazol-5-yl Pr Me 2-COOH-phenyl III-8 tetrazol-5-yl Pr Me F2CF3 III-9 -NHS02CF3 . Bu Me H :
III-IO -NHSO2CF3 Pr Me 2-CF3-phenyl :
III-ll -NHSO2CF3 Pr Me 2-Cl-phenyl III-12 -NHSO2CF3 Pr Me 2~6-diCl-phenyl III-13 -NHSO2CF3 Pr CF2CF3 2-CF3-phenyl III-14 -NHSO2CF3 Pr -CF2CF3 2-Cl-phenyl : :
III-15 -NHSO2CF3 Pr Me ~ ~ 2-COOH-phenyl --: '. , ' W O 91/15t09 PCT/US91/01951 2 ` ~

Compd.
No~ Rl R6 R7 R~b III-16 -NHSO2CF3 Pr Me CF2CF3 III-17 -S02NHCOCYPr Pr Me 2-CF3-phenyl III-18 -S02NHCOCYPr Pr Me 2-Cl-phenyl III-l9 -S02NHCOCYPr Pr Me 2,6-diCl-phenyl III-20 -S02NHCOCYPr Pr -CF2CF3 2-CF3-phenyl III-21 -S02NHCOCYPr Pr -CF2CF3 2-Cl-phenyl III-22 -S02NHCO~YPr Pr Me 2-COOH-phenyl III-23 -SQ2NHCOCYpr Pr Me -CF2CF3 III-24 -S02N~COPh Pr Me 2-CF3-phenyl III-25 -S02NHCOPh Pr Me 2-Cl-phenyl III-26 -S02NHCOPh Pr Me 2,6-diCi-phenyl III-27 -SO2NHCOPh Pr -CF2CF3 2-CF3-phenyl III-28 -S02NHCOPh Pr -CF2CF3 2-Cl-phenyl III-29 -SO2NHCOPh Pr Me -C~2CF3 III-30 -SO2NHCOPh Pr Me 2-COOH-phenyl III-31 -S02NHCO- Pr Me 2-CF3~phenyl (CH2)5NH2 : :"
III-32 -S02NHCO- Pr CF2CF3 2-Cl-phenyl (CH2)5NH2 : :

Also exemplifying this embodiment are the following compounds of the Formula IV shown in Table ~ -3- :
-..
..... .. ~ . . . . , -.. . .
:.. , . .~ - :

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

2 .~ J',~ ~~
: ' .

9 ~ 27 :~

R6 ~ O

IV
Table Compd.
No. Rl R6 RZ6 R27 ~:
. _ IV-l tetrazol-5-yl Bu H 7-Me ;
IV-2 tetrazol-5-yl Bu H 7-iPr ::
IV-3 tetrazol-5-yl Pr H 7-N(Pen)COPh .
IV-4 tetrazol-5-yl Pr H 7-N(Pen)CO(4-Cl-Ph) IV-5 tetrazol-5-yl Pr H 7-N(Pr)C02-iBu IV-6 tetrazol-5-yl Pr H 7-N(Bn)COBu IV-7 tetrazol-5-yl Bu 8-Cl 7-S02Me :
IV-8 tetrazol-5-yl Bu . H . . 8-Cl IV-9 -NHS02CF3 Bu H 7-Me IV-iO -NHS02CF3 Bu H 7-iPr :
IV-ll -NHS02CF3 Pr H 7-N(Pen)COPh IV-12 -N~S02CF3 Pr H 7-N(Pen)COt4-Cl-FhJ
IV-13 -NHS02CF3 Pr H 7-N(Pr)C02-iBu :
IV-14 -NHS02CF3 Pr H 7-N(Bn)COBu :
~? IV-15 -NHS02CF3 Bu 8-Cl 7-S02Me .
IV-16 -NHS02CF3 Bu H 8-Cl :~
IV-l7 -S02NHCOCYPr Bu H 7-Me '.

- ' W O 91/15209 PCT/US91/019~1 Compd.
No. Rl R6 R26 R27 -IV-18 ~S02NHCOCYPr Bu H 7-iPr IV-l9 -S02NHCOCYPr Pr H 7-N(Pen)COPh IV-20 -S02NHCOCYPr Pr H 7-N[Pe~1)CO~4-Cl-Ph) IV-21 -S02NHCOCYPr Yr H 7-N~Pr)C02-iBu IV-22 -S02NHCOCYPr Pr H 7-N(Bn~COBu IV-23 -S02NHCOCYPr Bu 8-Cl 7-S02Me IV-24 -S02NHCOCYPr Bu H 8-Cl IV-25 -S02NHCOPh Bu H 7-Me ~
IV-26 -S02NHCOPh Bu H 7_ipr :
IV-27 -S02NHCOPh Pr H 7-N(Pen)COPh - .
IV-28 -S02NHCOPh Pr H 7-N(Pen)CO(4-Cl-Ph) IV-29 -S02NHCOPh Pr H 7-N(Pr~C02-iBu :.
IV-30 -S02NHCOPh Pr H 7-N(Bn)COBu IV-31 -S02NHCOPh Bu 8-Cl 7-S02Me IV-32 -S02NHCOPh Bu H 8-Cl :
IV-33 -S02NHCO- Bu H 7-iPr (CH2 )5NH2 IV-34 -S02NHCO- Bu 8-Cl 7-S02Me . :
(CH2)5NH2 IV-35 -S02NHCO- Bu H 8-Cl (CH2 )5NH2 IV-36 -S02NHCO- Pr H 7-N(Pen)CO(4-Cl-Ph) (CH2)sNH2 IV-37 -S02NHCO- Pr . . ~ 7-N(Pr)C02-iBu (CH2)5NH2 IV-38 -S02NHCO- Pr Me ; . 2-CF3-phenyl (CH2)5NH2 IV-39 -S02NHCO- Pr -CF2CF3 2-Cl-phenyl ( CH2 )5NH2 :
'' ' ' ~. .

WO 91/15209 PCr/US91/01951 ., ~ ?~ 28 -In another embodiment of the novel compounds of this invention is that of formula Ia (M is NR22) wherein K is -N(R8a)-C(=NR22)-In a class of this embodiment:

N-N
~N~N; : :
Rl iS --COOH; H -NH-SO2CF3; Co2R4;
.

-S02NH-heteroaryl or -CH2SO2NH-heteroaryl wherein the ~
heteroaryl is an unsubstituted, monosubstituted or disubstituted 5-or 6-membered aromatic ring comprising 1 to 3 heteroatoms selected from O, N and S and wherein the substituents are members selected from the group consisting of OH, SH, Cl-C4-alkyl, Cl-C4-alkoxy, CE3, Cl,Br, F, I, NO2,CO2H, CO2-Cl-C4-alkyl, NH2, MH(Cl-C4-alkyl) and N(Cl-C4-alkyl)2; .
-So2N~CoR23; -CH2So2NHCoR23; -CoNHS02R23; --CH2Co~S02R23; -N~So2NXCoR23; a~d - N~CoNHso2R23;

R2a and R2b are H, F, Cl, CF3, Cl-C4-alkyl Cl-C4-alkoxy;
R3a is - H, F or Cl;
R3b is H, F, Cl, CF3, Cl C4-alkyl- C5-C6-cycloalkyl, -COOCH3, -COOC2H5, -S02CH3;
NH2, -N(Cl-C4-alkyl)2 or -NH-SO2CH3;
E is -a single bond, -O- or -S-;
,. - :~ , .
. . . ~ . . .
:: .

: -- -!

. , .. . .. . .. . . .. .. ~ . ~

WO91/15209 PCT/US91/019~1 2 ~` ' J/~'~'~'~

R6 is (a) Cl-C5-alkYl- C2-Cs-alkenyl or C2-C5-alkynyl each of which can be substituted with a substituent selected from the group consisting of Cl, CF3, CCl3, -O-CH3, -OC2Hs, -S~CH3, -S-C2Hs, phenyl, and C3-C5-cycloalkyl;
(b~ C3-C5-cycloalkyl;
(c) perfluoro-Cl-C4-alkyl;
R7 and R8a are as defined above or together with the atoms to which they are bonded may be joined to form a pyridine ring which may be substitùted with R26 and R27; and X is a C-C single bond.

In a more preferred class of this embodiment are those compounds wherein.
E is a single bond;
R2a R2b, R3a and R3b are each ~; and X is a single bond.
Exemplifying this embodiment are the :
following compounds of the Formula V shown in Table 4:
- ~-R7 .:
N ~ ,R~
R6 J~NR2 2 .

'? .~
V ~ d"

~ . : ' ~, WO 91/15209 pcr/us91/ol95 , ,'J?..~

Tabl e 4 Compd.
No. Rl R6 R7 R8a R22 ... .
V-l tetrazol-5-yl Bu Me - H -CF3-phenyl V-2 tetrazol-5-yl Pr Me 2-CF3-phenyl Me .
V-3 tetrazol-5-yl Pr Me 2-Cl-phenyl Me V-4 tetrazol-5-yl Pr Me 2,6-diCl-phenyl Me ;
V-5 tetrazol-5-yl Pr -CF2CF3 2-CF3-phenyl Me V-6 tetrazol-5-yl Pr -CF2CF3 2-Cl-phenyl Me V-7 tetrazol-5-yl Pr Me 2-COOH-phenyl Me V-8 tetrazol-5-yl Pr Me -CF2CF3 2-pyridyl V-9 -NHSO2CF3 Bu Me H 2-CF3-phenyl ~
V-10 -NHS02CP3 Pr Me 2-CF3-phenyl Me ..
V-ll -NIIS02CF3 Pr Me 2-Cl-phenyl Me V-12 -NHS02CF3 Pr Me 2,6-diCl-phenyl Me V 13 -NHS02CF3 Pr -CF2CF3 2-CF3-phenyl Me V-14 -NHS02CF3 Pr -CP2CF3 2-Cl-phenyl Me V-15 -NHSO2CF3 Pr Me 2-COOH-phenyl Me .~:. :
V-16 -NHS02CF3 Pr Me -CF2CF3 Z-pyridyl V-17 -S02NHCOCYPr . Pr Me 2-CF3-phenyl Me V-18 -SOzNHCOcYPr Pr Me 2-Cl-phenyl Me V-l9 -SOzN~COcYpr Pr Me 2,6-diCl-phenyl MeV-20 -S02NHCOCYPr Pr CF2CF3 2-CF3-phenyl Me V-21 -S02NHCOCYPr Pr -CF2CF3 2-Cl-phenyl Me :V-22 -SO2NHCOCYpr Pr Me 2-COOH-phenylMe V-23 -S02NHCOCYPr Pr Me -CF~CF3 2-pvr V-24~ -SO2NHCOPh Pr Me 2-CF3-phenyl M~ l V-25 -SO2NHCOPI. Pr I Me 2-Cl-phenyl Me .
V-26 -S02NHCOPh Pr Me 2,6-diCl-phenyl Me V-27 -S02NHCOPh Pr -CF2CF32-CF3-phenyl Me .
.,.

~ ' Compd .
No. Rl R6 R7 R8a R22 V-28 -S02NHCOPh Pr -CF2CF3 2-Cl-phenyl Me V-29 ~S02NHCOPh Pr Me -CF2CF3 Me V-30 -S02NHCOPh Pr Me 2-COOH-phenyl Me V-31 -S02NHCO- Pr Me 2-CF3-phenyl Me ~:
t CH2 ) 5NH2 V-32 -S02NHCO- Pr -CF2CF3 2-Cl-phenyl Me (CH2)5NH2 Also exemplifying this embodiment are the following compounds of the Formula VI shown in Table 8 ~2~
g ~ ~27 N~N 6 R6 ~ NRa2 ~) VI
Table 5 Compd.
No. Rl R6 R22 R26 ~ R27 . .
: . - , .

: ,., ,_ ............................. ...
VI-l tetrazol-5-yl Bu CYpr H . . 7-Me -;
VI-2 tetrazol-5-yl Bu cypr H 7-iPr .
Vl-3 tetrazol-5-yl Pr Me H 7-N(Pen)COPh ~
': :

W O 9l/15209 PCT/US91/Ot951 - 32 - ..
;~ b ~ ~
Co~pd.
No. Rl R6 R22 R26 R27 VI-4 tetrazol-5-yl Pr Me H 7-N(Pen3C3-(4-Cl-Ph) VI-5 tetrazol-5-yl Pr Me H 7-N(Pr)C02-iBu VI-6 tetr2zol-5-yl Pr Me H 7-N(Bn)COBu .:
VI-7 tetrazol-5-yl Bu cypr 8-C1 7-S02Me VI-8 tetrazol-5-yl Bu CYpr H 8-Cl VI-9 -NHS02CF3 Bucypr H 7-Me VI-10 -NHS02CF3 Bucypr H 7-ipr :~
VI-ll -NHS02CF3 Pr Me H 7-N(Pen)COPh ~.
VI-12 -NHS02CF3 Pr Me H 7-N(Pen)CO-(4-Cl-Ph) .
VI-13 -NHS02CF3 Pr Me H 7-N(Pr)C02-iBu VI-14 -NHS02CF3 Pr Me H 7-N(Bn~COBu VI-15 -NHS02CF3 Bucypr 8-C1 7-S02Me VI-16 -NHS02CF3 Bucypr H 8-Cl VI-17 -S02NHCOCYPr Bucypr H 7-Me VI-18 -S02NHCOCYPr Bucypr H 7-iPr VI-l9 -S02NHCOCYPr . Pr Me H 7-N(Pen)COPh VI-20 -S02NHCOCYPr Pr Me H 7-N(Pen)CO-~ .~,1 (4-Cl-Ph) VI-21 -S02N~COC~Pr Pr Me H 7-N(Pr)C02-iBu VI-22 -S02NHCOCYPr Pr Me H 7-N(Bn)COBu VI-23 -S02NHCOCYPr Bucypr 8-C1 7-S02Me VI-24 -S02NHCOCYPr Bucypr H 8-Cl VI-25 -S02NHCOPh Bucypr H 7-Me VI-26--S02NHCOPL -- -- Bu - cypr -H- - 7-iPr VI-27 -S02NHCOPh Pr Me H 7-N(Pen)COPh Vl-28 -S02NHCOPh ` Pr Me H ~ -N(Pen)CO-(4-Cl-Ph) :.

W O 91~15209 PCT/US91/01951 -- 33 ~

Comp~.
No. Rl R6 R22 R26 R27 VI-29 -S02NHCOPh Pr Me ~ 7~N(Pr)C02-iBu VI-30 -S02NHCOPh Pr Me H 7-N(Bn)COBu V1-31 -S02NHCOPh Bucypr 8-C1 7-S02Me VI-32 -S02NHCOPh Bucypr H 8-Cl VI-33 -S02NHCO- Bucypr H 7-i2r ~-(CH2)5NH2 VI-34 -S02NHCO- Bucypr 8-C1 7-S02Me (CH2)sNH~ : -VI-35 -S02NHCO- Bucypr H 8-Cl (CH2)sN~2 VI-36 -S02N~CO- Pr Me H 7-N(Pen)CO-(CH2)5NH2 (4-Cl-Ph) VI-37 -S02NHCO- Pr Me H 7-N(Pr)C02-1Bu (CH2 )5NH2 VI 38 -S02NHCO- Prcypr H 7-iPr ( CH2 )5NH2 VI-~9 -S02NHCO- Prcypr H 7-S02Me (CH2)5NH2 Several methods for preparing the compounds of this invention are illustrated in the ensuing Schèmes. .
'' ' ' ' `

- Abbrçviations Used in Schemes ~
.. . ...
Reagen~ ? -- - , NBS-- . - N-bromosuccinimide AIBN Azo(bis)isobutyronitrile DDQ ~ - ~ Dichlorodicyanoqi~inone Ac~O acetic a~hydride TE~ triethylamine -2~ ?~ ~

DMAP 4-dimethylaminopyridine PPh3 triphenylphosphine TFA trifluroacetic acid : :
TMS-Cl trimethylsilyl chloride - :.
Im imidazole AcSK potassium thioacetate p-TsOH p-toluenesulfonic acid Solvents~
DMF dimethylformamide ~.
HOAc (AcOH) acetic acid ' EtOAc (EtAc) ethyl acetate Heæ hexane THF tetrahydrofuran DMSO dimethylsulfoxide MeOH methanol iPrOH isopropanol Others:
rt room temperature T8DMS t-butyldimethylsilyl OTf OS02CF~
OTs OS02-(~-methyl)phenyl OMs OSo2cH3 Ph phenyl FAB-MS (FABMS) Fast atom bombardment mass spectroscopy NOE . Nuclear Overhauser Effect SiO~ silica gel tri~yl triphenylmethyl ' . Pyrimidinones substituted in the 2,4,5, : and 6 positions may be prepared as shown in Scheme l. '' The dianion of ethyl hydrogen malonate is made usin~
two equivalents of butyllithium in THF at - 780C. It ~' is then quenched with an acyl chloride then acidified ~ ' ' giving the necessary'~-ketoester as shown. l The~
-ketoéstër'is`'then`alkylated with the appropriate ~ : . .
:
~ .
. ~ .

WO91/15209 PcT/uss1/019s1 2; ;~ ~

sidechain using sodium hydride in DMSO (or other suitable base in a suitable solvent) to give intermediate l- Intermediate 1 may then be treated with an appropriate R7-amidine, guanidine, O-alkyl or aryl isoureat or S-alkyl or aryl isothiourea, to ~ive the 2,5,6-trisubstituted pyrimidin-4(3H)-one 2 2 Pyrimidin-4(3H)-one 2 itself may be an A-II antagonist but may also be used as an intermediate for the preparation of 2,3,5,6-tetrasubstituted pyrimidin-4(3H)-ones as indicated in Scheme 2. Intermediate 2 may be deprotonated in DME with sodium hydride (or other suitable solvent and base) and alkylated with an R8a ele~trophile to afford the pyrimidin-4(3H)one 3.3 Scheme 3 illustrates an alternative preparation of pyrimidinone 3. An R7 nitrile can be converted to an imidate then to an amidine with an R8a amine. This can then be condensed with ~-ketoester l to give 3. Similar procedures also exist for the preparation of isoureas, isothiuronium salts, and guanidines.4 Other methods are also available for the introduction of substituents at the 2-position of the pyrimidine.5 - Scheme 4 shows how pyrimidlnone 2 can be converted to 4-chloropyrimidine 4, which is a useful intermediate for the preparation of other 4-substituted pyrimidines. One could also envision using triflic anhydride and a suitably hindered amine base to give the corresponding pyrimidine triflate that could be used~in a similar fashion to the 4-chloropyrimidine.
. -. , .
. "

WO9ltlS209 PCT/US91/01951 2~ 36 -Scheme 5 shows how nucleophilic displacement would be achieved using an R8b nucleophile which could be an amine, alcohol, thiol, or carbon nucleophile with or without a Ni2~ or PdO
catalyst, to give the 2,4,5,6-tetrasubstituted pyrimidine 5.7 Scheme 6 provides a route to the useful intermediate ~-ketonitrile 6. Cyanoacetic acid can be condensed with an R6 acyl chloride to give the a-unsubstituted R6 ~-ketonitrile.8 This can then be a alkylated using Na~ in DMS0 (or other suitable base and solvent) and the appropriate sidechain: :
electrophile to afford 6.
Scheme 7 shows how the ~-ketonitrile 6 can be condensed with an amidine or isourea to give 4-aminopyrimidine 7. The 4-aminopyrimidines such as 7 can be converted to pyrimidin-4(3H)-ones simply by .~
diazotizing them with nitrous acid.9 .
Scheme 8 shows an alternative pyrimidinone synthesis via an intermediate isoxazole.10 The ~-ketonitrile 6 can be converted to the 5-aminoisoxazole 8 upon treatment with hydroxyl- .
amine. Acylation with an R7 acyl halide gives intermediate isoxazole 9~which upon~xeduction and : .heating~-gives:pyrimidinone 2. . ::
: .Pyridopyrimidinones such as 10 can be ~ -o~tained by condensing variouæly substituted 2-aminopyridines with ~-ketoesters 1 as shown in;
Scheme 9.11 ~ ' Scheme lO.illustrates-a preparation of a 4-carboxy or 4-carboalkoxy pyrimidine. Ethyl hydrogen malonate can be doubly deprotonated using ~wo : ~;

, . : - . . i - 37 - , equivalents of butyllithium. The dianion can then be used as a nucleophile on which to add the electrophile sidechain to give ethyl ester 11. The ester can then be deprotonated and be added to diethyl oxalate to give the diethyl oxalacetate derivative-12.12 Condensation of this material with an R7 amidine or isourea would give the 6-carbo-ethoxypyrimidin-4(3H)-one 13.13 Conversion of this material to the 4-chloro (or 4-trifluoromethane- sulfonato) derivative followed by nucleophilic displacement by an R6-E: ' nucleophile such as an amine, alkoxide, or thiol, would give the 2,5,6-trisubstituted-4-carboethoxy- ~
pyrimidine 14. Hydrolysis of the ester would give the '-corresponding 4-carboxypyrimidine.
Conversion of the 4-carboxypyrimidine to the 4-acetyl derivative followed by peracid oxidation and hydrolysis would give pyrimidinone 15 as illustrated in Scheme 11. Scheme 12 shows how the 2,3,5,6-tetrasubstituted pyrimidin-4(3H)-one 16 could be prepared from pyrimidinone 15. Scheme 13 shows how the 2,4,5,6-tetrasubstituted pyrimidine 17 can be prepared from intermediate 15 with the R8b ~ucleophile as described above.l4 .Alternatively, one could use triflic anhydride and hindered-amine base in place of POC13.
- Scheme 14 illustrates how the pyrimidine ,~
ring system can be built onto what would become the 5-sidechain. Conversion of the bromide 18 to a-Grignard reagent,`organo-zinc reagent, organo-lithium , ,,reagent, or o.her-related or~ano-metal reagent , ~ollowed by.addition of diethyl oxalate would give the pyruvate derivative l9. -Addition of metho~y- or ~^
ethoxymethylenetriphenyl-phosphorane or related .

.: . . . . . : . . ..

WO91~152~9 PC~/US91/01951 2~ 38 -reagent would give the ethyl ~-ethoxyacrylate derivative 20. Condensation of this material with an R7-amidine or isourea would provide pyrimidinone 21 .
Conversion of the 4-hydroxy function to the methoxy followed by addition of a Grignard reagent or alkyllithium and oxidation with dichlorodicyanoquinone would afford the 2,5,6-trisubstituted~4-methoxy-pyrimidin-4(3H)-one 23. Conversion of the methoxy back to a hydroxy then provides pyrimidinone 2.
Scheme 15 describes the preparation of ..
4-methoxy-5-bromopyrimidines 25 that may either be converted into nucleophiles and added to the electrophilic sidechain as shown in Scheme 16 or used as electrophiles as illustrated in Scheme 17.
Condensation of ~-etho~yacrylate with R7-amidine or isourea would provide pyrimidinone 24. Conversion of this material to the 4-methoxy-5-bromopyrimidine 25 is straight forward as.shown. .
: In Scheme 16 the 5-bromopyrimidine i~
converted to a Grignard, organolithium, or related reagent then added to the electrophilic sidechain (a . -catalyst or stoichiometric reagent such as CuCN may be added to enhance nucleophilicity or selecti~ity if .~ necessary) to give-pyrimidine 22 which may be used as illustrated previously.
~ Scheme 17 provides a route to the same -intermediate 22 by conversion of the bromide l8 to the organo-metal reagent followed by addition .to the :
: ,.eIectrophilic 5-bromopyrimidine 25.
S.cheme-2l:illust-rates one specific method used to prepare...two of-the more-preferred compounds in T~ le l...Scheme 22:..illustrates another-specific :
method used to prepare a:~preferred compound in Table 3.
: ~ .
-: .
:
~ , ' . z~ ;"/l IDENTIFI~ATION OF REFERENCES CITED IN SCHEMES

W. Wierenga, ~.I Skulnick, ~g~_~yn_ (1982) 61 5.
D.J. Brown, The Pyrimidines, (1962), J. Wiley &
Sons, pp. 48-51.
3 S. Hirokami, T. Takahashi, K. Kurosawa, M.
Nagata, J. Org. Chem. (1985) 50 166.
T. Takahashi, S. Hirokami, M. Nagata, T.
Yamazaki, J. Chem. ~oc.. P~rkin Tr~ns. I (1988) 2653.
4 S.S. Ahmad, S.I. Haidea, I. Fatima, Svn Çomm.
(1987) 17 1861.
G.D. Daves Jr., F. Baiocchi, R.K. Robins, C.C.
Cheng, J. Org. Chem. (1961) 26 2756.
6 J.R. Marshall, J. Walker, J. Chem. Soc. (1951) 1004. `.. :`
7 T. Sakamoto, H. Yoshizawa, H. Yamanaka, Chem.
Phar~ ull. (1984) 32 2005.
8 J.C. Krauss, T.L. Cupps, D.S. Wise, L.B.
Townsend, Syn~hesis (1983) 308.
9 D.J. Brown, The Pyrimidines, (1962), J. Wiley Sons, p. 333. -~
G. Shaw, G. Sugowdz, J. Chem. ~oc. (1954) 665.
Y. Honma, Y. Sekine, T. ~ashiyama, M. Takeda, Y. `~
Ono, K. Tsuzurahara, Chem. Pharm. Bull. ~1982) 30 ~
4314. -11 M. Shur, S.S. Israelstam, J. Org. Chem. (1968) 3015.
F. Fulop, I. Hermec ~ Z. Mes~aros, G. Dombi. G.
Bernath, J. ~et._Chem. ~1979) 16 457.
P.L. Ferrarini~ C. Mori, O. Livi, G. Biagi, A.M.
~arini, J. ~et. Chem. (1983) 20 1053.
H. Antaki, V. Petrow, J. Chem. Soc. (1951) 551. --: :,.', .

: ~ .. ~; .. .
.

12 M.W. Goldberg, F. Hunziker, J.R. Billeter, H.R.
Rosenberg, Helv. Chim. Acta. (1947) 30 200.
13 W.K. Hagmann, F.Z. Basha, M. Hashimoto, R.B. -Frye, S. Kojo, S.M. Hecht, J. Org. Chem. (1981) 46 1413.
T.A. Riley, W.J. Xennen, N.K. Dalley, B.E.
Wilson, R.K. Robins, S.B. Larson, J. Het. Chem.
(1987) 24 955.
Y. Muraoka, T. Takita, K. Maeda, H. Umezawa, J. ~:
Antibio~ics (1970) 23 253.
M. Otsuka, S. Kobayashi, M. Ohno, Y. Umezawa, H.
Morishima, H. Umezawa, Chem. Pharm. Bull. (1985) :
~3 515.
G.D. ~avies, Jr., R. Baiocchi, R.K. Robins, C.C.
Cheng, J. ~Fg~ Chem.. (1961) 26 2755.
14 E. Ochiai, H. Yamanaka, Chem. Pharm. Bull. (1955) 3 173.

'; ' ' .
- ', .

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

: ~ ` ~ ; , - , I

..
~ ~ ~"" , , ~

Wo 91/1520~ PCr/USsl/01951 ~ r~

S C~EME 1 ~COOEt BuLi O O
COOH R6COCl R6~OEt NaH, DMSO O
LGR ~ OEt R7--(/

CH2 ~ ::- .
R3b~R3a R ~}R3"

RZ b~

N~N-H
R6 /~
CH2 --- LG=Cl, I, Br, - :
R3b_~}R3a OTf, OTS, OM~;

X : .. :

R2 b~
R2a ` , .' ' . .

P~/US91/019~1 S CEIEMl~; 2 :.

R7 R7 R8 a N~N- H N~N~
R6 /~ R6 ~ , CH2 NaH, D~ CH2 R3b~R3a R~ L" R3b~} _3_ ~,Rl 1 P'~
R2 b~J R2 b~

~ ~ -.

~ .

WO 91/15209 PCr/US91/01951 :

_ 4 3 ~ s ~L

R7-CN 1 )HC1, M~OH 7 R
2 ) R8 a NH /R~ a H ;
; .,. ~
., _~ R7 NJ~N_ ~8 a R~OEt R6 /~

R3b~R3a 1 3 . .
R2a R2a ...

,~

-~: .' '~' :~ :

I '' -WO 91/15209 PCr/US91/019~1 :
.

S C~EME 4 N-- NH N ~
R ~O R6 ~1 CH2 POC13 C~I2 R3 b~R3 a r e f 1 ux R3 b~R3 a J~R1 ~ ,R1 R2b~ R2b~
R2a R2a - . '.

- , . ,:

WO 91/1~209 PCl/US91/019~1 N-- ~ N ~ ~
R6 J~c1 R6 ~ ';
CHz CH2 R3b~}R3~ R3~ R3b~

~2 ~R

E~ a R2 a . . .

, ~
!
- : ., 1 .'' PCr/USgl/01951 f~ ?.~7 ?~ - 46 ~CN 2 BULi o COOH R6COCl R6~N

NaH, DMSO
.. ... .
LG R,jJ~C

R3b~3--R3a R3b ~R3a ~ ' R2b~Rl R2b~R1 '-' R2a R2a ,.. . .. .. .

WO 91~15209 PCr/lJS91/019~1 ~
.

- 47 ~ ?;~

S CH~ME 7 O
R6 ~,C 1 )CH2N2 R7 :

CH2 R7 N~ N -~
R3b~R3a -- 2) HN NH2, R6 R2a R3b~R3~i ~ ,R
R2b~ , . ' " .
R .
,: -, " , .
: . ''' ;" . ' ~ .;~ '.

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

:: ~ : '~
: ' ., ~ ~ '' ""

PCrJUS9 1/0195 1 -- 4~3 --2~ ?~ ~
S CHEMEQ

O N--O
f N R~
(CH,)r . (C~2), ~N-OH
Rlb~X R~ ~b_~-R~' R7 b_~

R7 - COCl N--O O ~ Pd - C
---- - o~ R thon h~t:
(C~)r _~R
R~' :

N~{
~ .
Cl ~)r X ':
R~r~ R' . .

I -. .

. ". .. ., ,: ., , .. ' , , : ' : ' `':

WO 91~15209 PCT/US91/0195 1 - 4g - :

~26 ,~R2 7 O O :, ' .
R6 /~OEt R2 6 ~O

R3b~R3~ HzN~ R3b~--R3a ~ ~

X X :

,, ., R2 a R2 a ; .
1 0 . ,`:
'.,`.`' s~

.
..

,~

WO ~1/15209 PCI/US91/019~1 . W~

Z' ~ 5 0 ,~, ... .

Et OOC ~
COOH 2 BULi Et OOC
then CH2 R3 b~R3a R3b~l?3a X 1 ,, X RZ

R2 ~
then H30+
t hen heat Base O
t henEt OOC~l COOEt EtO~/ R3b~_R3a ~r~

2 b~
1?2a .~ .

WO91/15209 ~,~ "~, ~ P~/US91/01951 ; `~ ,.. ~:, ' SCHEME 10 (Cont ' d) ~ ~ ''',.:
CH2 1 )POC13, h2at ~COOEt 1 3 R3b~R

R2~R R' R
~ ''' ' ~

., .:

' ' ' ~

~ ~ .:. , ~ . ,' .

PCI/US91~019~1 ~$CooEt 2) ~3Li ~EJ~O
lH2 3 ) RCO3H :lH2 R3b--~$}R3~ 4~ NaOH R3b-~_R3~

R2b~ _~Rl :
R2~ . ' ~E=-S-) ~: .

: : .
' : .. .

WO 91/15209 P~/US91/01951 f~r.~!~,'q ~

S t;HEME 12 R7 R7 ~8a N~ NH N ~ N
R E~ E~O
CH2 NaH, DMF CH2 R3b--~?3a R~-LG R3b ~

R2 b~ R2 b~ ~ :
RZa R2a ?~, .', ', ': '' , . " . ,. .. , - ; . .' ' ~ :' '. , , .'' ' . - . ' WO 91/1~209 P~US91/01951 R7 R7 :

R ~E ~o `E--~R8 b CH2 1 ) Pocl3 CH2 ~ -~
2): R8b ,~
R3 b~ R3a R3b~3--R3a R2b~R' R2b~Rl ..

R2a R2a '~:.::

~, , ', ' ~: :
~.
: ',., ..
: . :` ' WO 91~15209 PCJ/US91/01951 :

'~ .

' , ' Sc EME 14 ~r M

~;_ Et O ~OEt ~OEt X R3 b~ R3n R2~ R2 b_~
18 EtO O R2~ J~ .
N NH
OEt ~

_~_R3~ R7R3b--~; R

- RZ' X

_ ,, .
~, :
. .

:.
. . . . ., .. ... . . , . . ., .. ... , . _ .. .. ... . . . .. ...... . ..... . . , . . . . ~ . . ... . . ..
. . . .. .. . . .

Pcr/US9l/0195 SC~IEME 14 ~Cont ' d 2 1 )POC13 or ~$ 1 )R6-M
Tf OTf OMe CH2 2 ) DDQ
2)M~ONa R3b~R3a R2 b~R1 .

R2a :

N~ N~NH

R6/~OM~ NaI/AcOH R )~O
CH2 .. ~ CH2 R3b~ R30 R3b~R3a ~ R1 ~R -R2 b~ R2 b ~ , , ' . .
R a R2a 23 2 !: ~
.

: ~ .

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

:
Wo 91/15209 Pcr/U~9l/01951 2~

SCHE.ME 15 EtO HN/J NH N/ NH

~o , COOEt 2 R
1 )POC13 or TfOTf N N
I I

2)M~ONa ~OM~
3 ) NBS Br : :: Ac OH

: ' : ~

WO 91/15209 P(~/U.S91/D1951 2~

N~ 1 ) M ~
N ' N
~OMe 2 ~ C UC N~ ,~ -:
~r t hen ~r LG
2 5 CH2 R3b_~R3a R3b~R3a X
~Rl X R2 b~J
R2 b~ R2a 2 :
:~?2 a 2 " ' wo 91/15209 pcr/us91/ol95 N~N
Br ~O~b CH2 1 ) M CH2 R3b~}R3a 2)c talyst+ R3b_~R3a ~R2~ 13r ~R~

: ~ , ~ ~;:' ','' ~ '' . ~ .

Wo91~15209 PCT/US91/0l951 . .
Where condensations of N-C-N group (amidines, isoureas, isothiuronium salts, etc.) with the C-C-C
group (generally the ~-keto esters) fail because of initial addition of N-C-N group to the ester rather than the keto group, the ~-keto esters may be converted to ~-acetoxy, ~-ethoxy~ ~-enol phosphate, ~-enol triflate, or similar ~-leaving group ~,~-unsaturated esters. [E. Piers, et al, Tet.L~., 25, 3155 (1984); M. Alderdice, ~1, Org.
Syn. 62, 14 (1984)] Such a reaction is illustrated in Scheme 18. The N-C-N group may then be condensed with the C-C-C group to give the expected pyrimidinone or pyridopyrimidine.
.

'~. ' WO 91/15209 P(-r/US91tOt951 ( Et ) 2P~

R~OEt NaH, THF
R3b~R3a ( I;tO32POCl R3b_~R3a X X
{~Rl R2 b ~ 26 R2a R2a N ~ NH

- R6 ~o 173~3b~}R3~

HN~NH2 X 1 2 R ~R

R2a :
, . . . :
- . .....

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

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

PCT/US91~01951 2.. ~

Scheme 19 provides a route for the preparation of acyl sulfonamides 27. The carboxylic acid can be activated by conversion to the acid chloride by various methods including treatment with refluxing thionyl chloride or preferably with oxalyl chloride and a catalytic amount of DMF at low temperature.15 Activation by conversion to the acyl imidazole can be achieved upon treatment of acid 26 with carbonyldiimidazole. N,N-Diphenylcarbamoyl anhydride intermediates may be prepared as activated carbonyls.16 Treatment of the activated carbonyls with alkali metal salts of alkyl or aryl sulfonamides or with the sulfonamide and DBU will give the expected acyl sulfonamide 27.17 Scheme 20 provides a route to the isomeric acyl sulfonamides 33. The commercially available bromobenzenesulfonyl chloride 28 may be converted to the corresponding sulfonamide upon treatment with ammonia or ammonium carbonate. Protection with the triphenylmethyl group gives sulfonamide 29.
Palladium catalyzed cross-coupling gives the biaryl 3Q 18 Treatment of this material with N-bromosuccinimide and catalytic AIBN in refluxing CC14 will give the alkylatin~ agent 31. The bromide 31 may now be used as the alkylating agent shown in previous scheme~ to give intermediate 32.
Deprotection and acylation will give the acyl sulfonamide 33.
.
A.W. Burgstahler, LØ Weigel, C.G. Shaefer, Synth~is (1976~ 767.
16 F.J. Brown, et al, European Patent Application # EP 199~43 -K.L. Shepard, W. ~alczenko, J. Het. Chem. (1979) 16 321~;~
17 J.T. Drummond, G. Johnson, Tet. Lett. (1988) 29 16~3.
18 T.R. Bailey, Tet. ~ett. (1986) 27 4407.
I.P. Beletskaya, I. Qr~a~ometallic Chem. (1983) 250 551.

-......
~ . . .
'.. .. .

WO 91/15:209 PCr/US91/01951 .
~r ~ n,~,~ A

S C~EME 19 N~(R N~?
R_ E--~K R- E--~K
CHz CH2 R3b~_R30 R3 b~--R3 ~ 1) ?Cnrboxyl oot~votlon ~
X X
~COOH 2) ~9OZN~ ~CON~ o2R23 R2b~ ' ~ b~- R2b_~ :
R2~ R20 .:
, :: :
: :

*:~ a. SOC12, reflux .: : ~ b. ~(COC1)2, DMF, -~0C
c. N (N,N- Diphenylcarban~I) p~ridinium chl~rido/
agueous. NaOH :~
: d. : carbonyl diimidazole ** :base can be NaEj KH, DBU

WO 91/15209 P~T/US91/0195 2~ ?;'~ 64-.

~3r ~3r ~SO2Cl 1 ) NH3 or ,~S02NHCPh3 ( NH4)2CO3 2 ) Ph3CCl '~ .:
M3 ~*

Snl~3 ~/SOzNHCPh3 N~S, AI13N cat.
Pd ~ ~J CCl4 r~f lux ~3r ~ 7 ~sozNHcPh~ 2 ~SO2NHCPh3 31 I~J

, . j, . . .

' "

-:

wo 91/15209 PCr/USsl/01951 SCHEME 20 (Cont. ) R6_E 1~,K
1 ) AcOH/HzO
2) R23 cocl CH2 ~), ,": , ,, I So2N~CORZ3 ~/

.

: -~ - ;

. .,, ~

- ~--s ~ ~,~ ~ ., . i: r,, ~, ! ~ , ~

PC~/US91/01951 2~,~ 66 -;~, ~ ... . --SC~EME 21 ~ -~COOEt 2 eq. ~3uLi. THF O
COOH t hen ~
\~ COCl \/` OOEt then H30~ - :

NaH, DMF
~3r ~COOEt ~
DMF, beat M~ ' N~N 1 ) POCl3, heat 2) CuCN : .

3) H2O2, NaO~ M;OH : .
4) An~erlystR -15, M30~ heat .

, .

WO 91/15209 PC~/US91/01951 SC~IEMI: 21 (CONT':~) Tr Tr N~ `NN--N N--N
N~N NpN

`13 TEIF, ~Ph3P)2PdCl~(cat. ), reFlux, 4 h N~N
--~CO0~3 AcO~ H20 35 NaOE~ ~30H, 36 N I
N - N

Tr ME~

~ ~R

35 R=t~ .
U

..... ,.. :.:'. ' ' ... .
~ ' .

: :

! :

:
. .

SC~IEME 22 ~ ".
Et H2 N~NJ N~N ~ ~
~ PPA, hea t ~\~ ~ ~ -34 ~ ~ :~
~ , .

Tr Me N~,~N N~N N~ `N
~Zn~, ~COO~b ~ ~ ~q ".
W~
THF, (Ph~,P)2PdCl2(cat- ),,N ~:J
ref lux. 4 h N
N--N , ' ~b , NlN , . .

AcOH, H20 \[~
3 7,1~
N `H ::
~'' ,,." ': .

':. ' ;

W091/15209 ~ ~ ~ PCT/US91/019~1 The compounds of this invention form salts with various inorganic and organic acids and bases which are also within the scope of the invention.
Such salts include ammonium salts, alkai metal salts like sodium and potassium salts, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases; e.g., dicyclohexylamine salts, N-methyl-~-glucamine, salts with amino acids like arginine, lysine, and the like. Also, salts with organic and inorganic acids may be prepared; e.g., HCl, ~Br, H2S04, H3P04, methanesulfonic, toluensulfonic, maleic, fumaric, camphorsulfonic.
The non-toxic, physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product.
The salts can be formed by conventional means~such as by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed i~ ~acuo or by freeze-drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.
- Antiotensin II-(AII) is a powerful arterial vasoconstrictor,-and it exerts its action by -interacting with specific receptors present on cell membranes. The compounds describediin-the present invention act as competitive antagonists of AIISat~
the receptors. In order to identify AII antagonists and determine their efficacy in vitro, the following two ligand-receptor ~ ding assays were established.

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wosl/l~2o9 PCTtUS91/01951 2 r; ~ 70 Receptor binding assay using rabbit aortae membrane preparation:
Three frozen rabbit aortae (obtained from Pel-Freeze Biologicals) were suspended in SmM -Tris-0.25M Sucrose, pE 7.4 buffer (50 ml), ~ , ' homogenized, and then centifuged. The mixture was filtered through a cheesecloth and the supernatant was centrifuged for 30 minutes at 20,000 rpm at 4C.
The pellet thus obtained was resuspended in 30 ml of 50mM Tris-5 mM MgC12 buffer containing 0.2% Bovine Serum Albumin and 0.2 mg/ml Bacitracin, and the suspension was used for lO0 assay tubes. Samples tested for screening were done in duplicate. To the membrane preparation (0.25 mI) there was added l25I-SarlIle8-angiotensin II [ovtained from New England Nuclear] (lO ~l; 20,000 cpm) with or without the test sample, and the mixture was incubated at 37~C for 90 minutes. The mixture was then diluted -with ice-cold 50mM Tris-0.9% NaCl, p~ 7.4 (4 ml) and filtered through a glass fiber filter (GF/B Whatman 2.4",diameter). The filter was soaked in seintillation cocktail (lO ml) and counted for radioactivity using Packard 2660 Tricarb liquid scintillation counter. The inhibitory concentration (IC50) of potential AII antagonist, which gives 50%
displacement of the total specifically bound : ' l25I-SarlIle8-angiotensin II, was presented as a measure of the efficacy of such compounds as'`AII ,, antagonists. - - ~ '-' ' " . '' . . .

WO9]/15~0~ ~,~'~,~!'1 ~ PCTtVS91/019~1 Receptor assav usin~ BQvine adrenal cortex preparation Bovine adrenal cortex was selected as the source of AII receptor. Weighed tissue (O.l g is needed for iO0 assay tubes) was suspended in Tris.HCl (50mM), p~ 7.7 buffer and homogenized. The homogenate was centrifuged at 20,000 rpm for 15 minutes. Supernatant was discarded and pellets resuspended in buffer CNa2~P04 (lOmM)-NaCl (120mM)-disodium EDTA (5mM) containing phenylmethane sulfonyl fluoride (PMSF~(O.lmM)~. (For screening of compounds generally duplicates of tubes are used).
To the membrane preparation (0.5 ml) there was added 3~-angiotensin II (50 mM) (lO ~l), with or without the test sample, and the mixture wa incubated:at 37C for l hour. The mi~ture was then diluted with Tris buffer (4 ml) and filtered through a glass fiber filter (GF/B Whatman 2.4" diameter). The filter was soaked-in scintillation cocktail (lO ml) and counted for radioactivity using Packard 2660 Tricarb liquid scintillation counter. The inhibitory concentration (IC50) of potential AII antagonist, which gives 50%
displacement o~ the total specifically bound ~' 3H-angiotensin II, was presented as a measure of the efficacy of such compoundæ as AII antagonists.
The,potential antihypertensive:-effects of the compounds described in the present invention may -~
be evaluated using the methodology described belo~: ~

Male Charles,~iver Sprague-Dawley-rats.(300-375 gm) ' , were anesthetized with methohexital (Brevital; 50 ~
mg/kg i.p.). The trachea was cànnulated--with PE 205 tubing. A stainless steel-pithing rod (l.5 mm thick, '~

WO 91J15209 PcI/l)S91/0195i 2 ;~

150 mm long~ was inserted into the orbit of the right eye and down the spinal column. The rats were immediately placed on a Harvard Rodent Ventilator (rate - 60 strokes per minute, volumn - 1.1 cc per 100 ~rams body weight). The right carotid artery was ligated, both left and right vagal nerves were cut, the left carotid artery was cannulated with PE 50 tubing for drug administration, and body temperature was maintained at 37C by a thermostatically controlled heating pad which received unput from a rectal temperature probe. Atropine ( lmg/kg i.v.) was then administered and 15 minutes later propranolol (1 mg/kg i.v.). Thirty minutes later angiotensin II or other agonists were administered intravenously at 30-minute intervals and the Increase in the diastolic blood pressure was recorded before and after drug or vehicle administration.
Using the methodolo~y described above, representative compounds of the invention were -evaluated and were found to exhibit an activity of at least IC50 ~ 50~M, thereby demonstrating and confirming the utility of the compounds of the invention as effective AII antagonists. -Thus, the compounds of the invention are useful in treating hypertension. They are also of value in the management of acute and chronic : -congestive heart failure, in the treatment of secondary hyperaldosteronism, primary and secondar-;
pulmonary hypertension, renal failure such as diabetic neph_opathy, glomerulonephritis, -sclerederma, and the-like,irenal vascular -hypertens~ ; left ventricular-dysfunction, diabetic retinopathy, and in the management of vascular W091/15209 2 ~ ~n ~ ~ pcT/ussl/olss disorders such as migraine or Raynaud's disease. The application of the compounds of this invention for these and similar disorders ~ill be apparent to those skilled in the art.
The compounds of this invention are also useful to treat elevated intraocular pressure and can be administered to patients in need of such treatment with typical pharmaceutical formulations such as tablets, capsules. injectables and the like as well as topical ocular formulations in the form of solutions, ointments, inserts, gels, and the like.
Pharmaceutical formulations prepared to treat intraocular pressure would typically contain about 0.1% to 15% by weight, preferably-0.5% to 2% by weight, of a compound of this invention.
In the management of hypertension and the -~
clinical conditions noted above the compounds of this invention may be utilizcd in compositions such as tablets, capsule3 or eli~irs for oral administration, suppositories for rectal administration, ~terile solutions or suspensions for parenteral or intramusoular administration, and the like. The compounds of this invention can be administered to patients (animals and human3 in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. -Although the dose will vary from patient to patient, depending upon the nature .-and severity of disease, the patient~s-.weight,--special diets then being followed by a patient,~
concurrent medication and other:factors,-which-:those skilled in the art will recognize the dosage range will generally be about l to lO00 mg. per~ ~ ient per day which can be administered in single or multiple ;
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WO 91 / 15209 PCI /US9 1 ~01 951 2~

doses. Perferably, the dosage ran~e will be about 2.5 to 250 mg. per patient per day; more preferably about 2.5 to 75 mg. per patient per day. ;~
The compounds of this invention can also be administered in combination with other antihyper-tensives such as diuretic~, angiotensin convertin~
enzyme inhibitors, clacium channel blockers or ~-blockers. For example, the compounds of this invention can be given in combination with such compounds as amiloride, atenolol, bendroflu-methiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates-and cryptenamine :
tannates, deserpidine, diazoxide, guanethidene sulfate, hydralazine hydrochloride, hydrochloro- : .
thiazide, metolazone, metoprolol tartate, methy-clothiazide, methyldopa, methyldopate hydrochloride, ;
minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, ~a~olfi~ se~p~ntiD~, rescinnamine, reserpine, sodium nitroprusside, spironolactone, timolol maleate, thrichlormethiazide, trimethophan camsylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, amino-phylline, cyclothiazide, ethacrynic acid, furosemide, merethoxylline procaine, sodium ethacrynate, .:
captopril,-delapril hydrochloride,-enalapril, enalaprilat, fosinopril sodium, lisinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zofenopril calcium~ diflusinal~ diltiazem.
felodipine,1 nicardipine,:nifedipine, niludipine,. ~:
nimodipine, nisoldipine, nitrendipine, and the-Iike, aæ well as admixtures and combinations thereof.- .
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' WO9l/15209 PCT/US91/01~51 2~ ? ~?, ~, ~

Typically, the individual daily dosages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly.
To illustrate these combinations, one of the angiotensin II antagonist of this invention effective clinically in the 2.5-250 milligrams per day range can be ef~ectively combined at levels at :
the 0.5-250 milligrams per day range with the following compounds at the indicated per day dose range: hydrochlorothiazide ~15-200 mg) chloro-thiazide (125-2000 mg), ethacrynic acid (15-200 mg), amiloride (5-20 mg), furosemide (5-80 mg), propranolol (20-480 mg), timolol maleate (5-60 mg), methyldopa (65-2000 mg), felodipine (5-60 mg), nifedipine 5-60 mg), and nitrendipine (5-60 mg). In addition, triple drug combinations of hydrochloro-thiazide (15-200 mg) plus amiloride (5-20 mg) plus angiotensin II antagonist of this invention (3-200 mg) or hydrochlorothiazide (15-200 mg) plus timolol maleate (5-60) plus an angiotensin II antagonist of this invention (0.5-250 mg) or hydrochlorothiazide (15-200 mg) and nifedipine (5-60 mg) plus an angïotensin II antago~ist of this invention (0.5-250 mg) are effective combinations to control bllod pressure in hypertensive patients.- Naturally, these :
dose ranges can be adjusted on a unit basis as -- - -necessary to permit divided daily.dosage~and, as~
noted above, the dose will vary depending on the-: , nature~and sevêrity of the,disease, weight of ;~ -patiènt, special diéts and other fàctors.
~ .

WO91/1520~ PCTtUS91/01951 Typically, these combinations can be formulated into pharmaceutical compo~itions as discussed below.
About l to lO0 mg. of compounds or mixture of compounds o~ Formula I or a physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, ". -~' preservative, stabi~izer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical '~
practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained. ' Illustrative of the adjuvants which can be -incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient sich as microcrystalline cellulose; a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of ~integreen or cherry. When the dosage ' unitform is a capsule, it may contain, in addition to materials of~the above type, a Iiquid carrier such as fatty oil. 'Various other materials may be present as coatings or to otherwise-modify the physical form of the dosage unit; For instance', tablets may be coated with shellac, sugar or both. A syrup or elixir m~-:
contain the~active compound,'''sucrose as a sweétëning agent, methyl and~propyl'-parabens'as preservatives, a dye and a flavoring such as cherry or orànge flavor.

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Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic faffy vehicle like ethyl oleate or the - -like. Buffers, preservatives, antioxidants and the like can be incorporated as reguired.
The following examples illustrate the preparation of the compounds of formula (I> and their incorporation into pharmaceutical compositions and as such are not to be considered as limiting the invention set forth in the claimæ appended hereto.
All lH-NMR spectra were recorded on a Varian XL-300 Fourier transform spectrometer or on a Bruker 250 MHz spectrometer. Chemical shifts are reported as (parts per million) downfield from tetramethylsilane. Mass spectra were obtained from the Merck and Co. mass spectral facility in Rahway, N.J. Analytical TLC was conducted on E. Merck precoated silica plates (0.25 mm in glass, Kieselgel 60 F254~ with W
visualization. All chromatography was conducted on -E. Merck silica gel. All reactions were carried out under an atmosphere of dry nitrogen under standard conditions for those skilled in the art.-. --. .

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The useful central nervous system ~CNS) - -activities of the compounds of this invention are ~ ~-demonstrated and exemplified by the ensuing assays.

CQGNITIVE FuN~TIoN ASSAY

The efficacy of these compounds to enhance cognitive function can be demonstrated in a rat passive avoidance assay in which cholinomimetics such as physostigmine and nootropic agents are known to be active. In this assay, rats are trained to inhibit their natural tendency to enter dark areas. The test apparatus used consists of two chambers, one of which is brightly illuminated and the other is dark. Rats are placed in the illuminated chamber and the elapsed time it takes for them to enter the darkened chamber .
is recorded. On entering the dark chamber, they receive a brief electric shock to the feet. The test animals are pretreated with 0.2 mg/kg of the muscarinic antagonist scopolamine which disrupts learning or are treated with scopolamine and the compound which is to be-tested for possible reversal o~ the scopolamine effect. Twenty-four~hours later, the rats are retu-rned to-the illuminated chamber.
Upon-return to the illuminated chamber, normal young rats who have been subjected to this training and who have been treated only with control vehicle take -longer to re-enter the dark chamber than test animals who have been exposed to the apparatus but who have not received a shock. Rats treated with scopolamine be~ore training do not Rhow this hesitation when tested 24 hours later. Efficaciou ~ est compounds can ~ ~ .

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overcome the disruptive effect on learning which scopolamine produces. Typically, compounds of this invention should be efficacious in this passive avoidance assay in the dose range of from about 0.1 mg/kg to about 100 mg/kg. .

ANXIOLYTI~ ASS~Y

The anxiolytic activity of the invention compounds can be demonstrated in a conditioned emotional response (CER) assay. Diazepam is a clinically useful anxiolytic which is active in this assay. In the CER protocol, male Sprague-Dawley rats ' (250-350 g) are trained to press a lever on a variable int:erval (VI) 60 second schedule for food reinforcement in a .' standard operant chamber over weekly (five days per week) training sessions. All animals then receive daily 20 minute conditioning sessions, each session partitioned into alternating 5 minute light (L) and 2 minute dark (D) periods in a ~ixed LlDlL2DZL3 sequence. During both periods (L or D), pressing a lever delivers food pellets on a VI 60 second schedule: in the dark (D), lever presses also elicit mild footshock (0.8 mA, O.5 sec) o~ an independent shock presentation schedule of VI 20 seconds. Lever pressing is suppressed,during,the dark periods reflecting the formation of a conditioned emotional response (CER)., ,-,, , ,- , i- , ~ -, Drug-.testing,;in this paradigm is carried out under e~tinction conditions. During"extinction, animals,learn;that:responding for-food in the dark is no longer punished by,shock. Thereforel response - , -rates gradually increase in the dark periods and ~- .

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Wo91/15209 PCT/US91/01951 '-~d ~ .; Y. .t - 80 - ' animals treated with an anxiolytic drug show a more rapid increase in response rate than vehicle treated ' animals. Compounds of this invention should be '' efficacious in this test procedure in the range of ':' from about O.l mg/kg to about lOO mg/kg.
DEPRESSION ASSAY
.~.
The antidepressant activity of the compounds of this invention can be demonstrated in a tail suspension test using'mice. A clinically useful antidepressant which serves as a positive control in this assay is desipramine. The method is based on the observations that a mouse suspended by the tail shows alternate periods of agitation and immo~ility and that antidepressants modify the balance between these two forms of behavior in favor of agitation.
Periods of immobility in a 5 minute test period are recorded using a keypad linked to a microcomputer which allows the experimenter to assign to each animal an identity code and to measure latency, duration and frequency of immobile periods.
Compounds of this invention should be efficacious in ' this test procedure in the range of from abou~ O.l mg/kg to about lOO m~/kg.~

~ SCHIZOPHRENIA ASSAY
. . - - ................................................... ~ : .
The anti'dopaminergic activitv of the :- compounds of.Xhis invention can b'e demonstrated in an apomorphine-induced~sterotypy model:.- A'clinically useful antip'sychotic d'rug that is;used' ~ po'sitive ~ -control-in this asæay is haloperidol."' The assay method is based upon the obser~ation that stimulation , ~ . .
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WO91/15209 ~ PCT/US91/01951 of the dopaminergic system in rats produces stereo-typed motor behavior. There is a strong correlation between the effectiveness of classical neuroleptic drugs to block apomorphine-induced stereotypy and to prevent schizophrenic symptoms. Stereotyped behavior induced by apomorphine, with and without pretreatment with test compounds, is recorded using a keypad linked to a microcomputer. Compounds of the inven-tion should be efficacious in this assay in the range of from about O.l mg/kg to about lO0 mg/kg.
In the treatment of the clinical conditions noted above, the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or snspen-sions for parenteral or intramuscular administration, and the like. The compounds of this invention can be `
administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. Although the dose will vary from patient to patient depending upon the nature and severity of disease, the patient's ` -weight, special diets then being followed by a patient,-concurrent medication, and other factors which those skilled in the art will recognize, the dosage range will generally be about 5 to 6000 mg.
per patient per day which can be administered in single or multiple doses. Perferably, the dosage range will be about lO to 4000 mg. per patient per day; more pr~ferably about 20 to 2000 mg. per patient per day.
In order to obtain ma~imal enhancement of cognitive function, the compounds of this invention .... - .. - - . - -.. - .,;. - . . , - . .. - j.. - ., . , .. , - .. , .. . - .. . ... . . . .

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WO91/15209 PCr/US91/01951 2~t5~ 82 -may be combined with other cognition-enhancing -~
agents. These include acetylcholinesterase inhibitors such as heptylphysostigmine and tetrahydroacridine ~THA; tacrine~, muscarinic agonists such as oxotremorine, inhibitors of angiotensin-converting enzyme such as octylramipril, captopril, ceranapril, enalapril, lisinopril, fosinopril and zofenopril, centrally-acting calcium channel blockers and as nimodipine, and nootropic agents such as piracetam.
In order to achieve optimal anxiolytic activity, the compounds of this invention may be combined with other anxiolytic agents such as alprazolam, lorazepam, diazepam, and busipirone.
In order to achieve optimal antidepressant activity, combinations of the compounds o~ this invention with other antidepressants are of use.
These include tricyclic antidepressants such as nortriptyline, amitryptyline and trazodone, and monoamine oxidase inhibitors such as tranylcypromine.
In order to obtain maximal antipsychotic activity, the compounds of this invention may be combined with other antipsychotic agents such as promethazine, fluphenazine and haloperidol.
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Wog~ 209 PCT/US9 1/01951 PREPARATION OF INTERMEDIATES

2-t-~UTOXYCARBQNYL-4'-METHYLBIPHENYL
To a solution of p-bromotoluene (30g) in dry ether (150 ml) at -78C,. a solution of t-BuLi in pentane (1.7M) (210 ml) was added slowly over a period of 1.5 hr using a dropping funnel. The bath was then removed and the mixture was stirred at room temperature for an additional 2 hours. The content of the flask was then added slowly (using a cannula) at room temperature to a premixed solution of ZnC12 in ether (lM, 180 ml) and dry THF (360 ml). The mixture was stirred for 2 hr at.that temperature and then the slurry was added (using a cannula) to a solution of 2-t-butoxycarbonyl iodobenzene (35.6 g) and NiCl~(Ph3P)2 (2.1 g) in dry THF (360 ml). The mixture, after stirring at room temperature overnight (18 hr), was poured slowly under stirring into -ice-cold 0.5N HCl (1500 ml). The organic layer was separated, and the aqueous phase was extracted with ether (3 X 300 ml). The combined organic layer was washed with water, brine and then dried over MgS04. -Removal of the solvent gave the crude product as an oil (32 g). The materi-al was purified on a . silica-gel flash column using ethyl acetate-hexane 12) to give the titled compound as an oll (24 g, 76%). lH NMR..(CDC13): ~ 1.24 (s,9H) 2.42 (s,3H), 7.2-7.8 (m,8H-); FAB-~S: m/e 269(M+H~
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WO91/15209 PCT/US91/0l951 ~r ~
~,~, ~.., 4-BROMOMETHYL-2'-t-BUTOXYCARBONYL-BIPHENYL
To a solution of 2-t-butoxycarbonyl-h'-methylbiphenyl (25.3 g, 95 mmol) in CC14 (200 ml) were added freshly opened N-bromosuccinimide (17.6 g, 0.099 mole) and dibenzoyl peroxide ~2.28 g, 0.0094 moles). The mixture was refluxed for 4 hours, cooled to room temperature and filtered. The filtrate was washed with sat. NaHS03 (lx50 ml), sat. NaHC03 (lx50 ml), water (lx50 ml), sat. NaCl (lx50 ml) and dried over MgS04. The solution was filtered and concentrated in vacuo. The residue was dissolved in 100 ml of hot hexane. Crystallization gradually took place as the solution cooled. The flask was finally cooled to -20C and the precipitate recovered by filtration. The solid was washed with ice cold hexanes and dried in vacuo to give 27 g (88%~ of a white solid. l~_NMR (CDC13):1.23 (s, 9H), 4.53 (s, 2H), 7.2-7.5 (m, 7H), 7.68 (d, lH).

2-CYAN0-4'-MET~YLBIPHENYL
To a solution of p-bromotoluene (30 g) in dry ether (150 ml) at -78C, a solution of t-BuLi in pentane (1.7 M) (210 ml) was added slowly o~er a period of 1.5 hr-,-using a dropping funnel~. The bath was -then removed and the mixture was stirred at room temperature for an additional 2 hr. The contents of the flask was then added slowly (using a cannula) at room temperature to a.premi~ed solution ^f ZnC12 i~
ether (lM) (180 ml) and dry THF (3~0 ml). The mixture was s~irred for 2h at that temperature and then the slurry was added (using a cannula) to a solution of 2-bromobenzonitrile (21.3 g) and i~.

W091/1~209 PCT/US91/01951 '' 2 ~..

NiCl2(Ph3P)2 (2.l g) in dry THF (300 ml). The mixture, after stirring at room temperature overnight (18h), was poured slowly under stirring into ice-cold lN HCl (1500 ml). The organic layer was separated, and the agueous phase was extracted with ether (3 X
300 ml). The combined organic layer was washed with water, brine and then dried over MgS04. Removal of the solvent gave the crude product as a semisolid mass (34 g). The material was purified on a ~' silica-gel flash column using ethyl acetate-hexane (l:12) to give the desired nitrile as a low-melting , ':' solid (28 g, 88%). lH NMR (CDGl3): 2.42 (s, 3H), ~' 7.2-7.8 (m, 8H); FAB-MS: m/e 194 (M++l). :

TRIM~I~YLSTANNYL A~IDE : ~:
To a concentrated solution of NaN3 (1.2 kg, '', 18.5 moles) in water (3 L), a solution of ,~, trimethyltin chloride (600 g, 3 moles) in dioxane ~
(400 ml) was added in three portions under vigorous ;-~,' stirring. A precipitate formed instantaneously. The mixture, after stirring overnight at room temperature, was filtered. The residue was washed with water and dried under suction and then in vacuo ~, over P205. Yield 541 g (88a/o)~ mp-l20-l22C. ~ -5- r 2-(4'-M~T~YLBIP~ENYL~lTETRAZOLE
To a solution of 2-cyano 4'-methylbiphenyl '-(390 g, 2.02 moles) in toluene ~2.3 L) was added- '~
trimethyltin azide (525 g, 2.55 moles) at,r.t. The mixture was refl,uxed for-24,h.,cooled to r.t., .; filtered, washed with,t,oluene and sucked-dry -in~a funnel. The-precipitate was resuspended in toluene -~
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(3.5 L) and THF (250 mL) was added. Anhydrous HCl '~
was bubbled in at a moderate rate at r.t. to give a clear solution (45 min). Addition of HCl gas was continued for another 20 min. with stirring whereupon a white precipitate formed. The reaction mixture was stirred over night. The solid product was filtered, '~
washed with toluene followed with ether and then dried under vacuum. This produced 250 g (53% yield of the tetrazole. m.p. 152-154C; l~-NMR (CDCl3):2.40 ;~
(s, 3H), 7.19 (dd, lH), 7.55 (m, 2H), 8.25 (dd, lH).

N-TRIpHEN~LMET~yL-5-~2-(4l-METE~LBIp~ENyL)] ~ETRAZOLE
To a cloudy solution of 5-~2-(4~-methylbi-phenyl)]tetrazole (250 g (1.06 mole) in CH2C12 (4 L) was added triphenylmethylchloride (310 g l.ll mole) ~ ' :
at r.t. The reaction mixtur~e was stirred and ' triethylamine (190 mL, 138 g, 1.36 mole) was added -portionwise. After addition, the mixture was stirred at reflux for 90 min. The solution was cooled to r~.t.~, washed with water (2xl~L) and dried over MgS04, `fi~ltered;;th~rough a silica gel plug and concentrated on the~rotovap;to a~solid. This was cry~tallized '' from toluene`to-~give the~product as an off-white ' ' :
solid~(425 g,~84%),~m.p. 166-168 C; lE- ~ (CDC13):
2.~28~<s,~3~ 6.9-7.05 (m, lOH), 7.2-7.5 (m, 12H), YL~ET~YL-5-t2-<4'-BROMOMETHYLBIPHENYi)~
T~TRAZOLE
;To~a~-solution~of~:N-triphenylmethyl-5-'-' , ' 2 ~ 4'-methylbipheny'1)3~tetrazole (425-g, O.89-moles) in~14~4.0:~L)'~werè~added~N-br'omsuccinimide (159 g, WO91/15209 2~'J ~S~ PC~/US91tO1951 0.89 mole) and dibenzoyl peroxide (22 g, 0.089 moles). The mixture was refluxed for 2 hours, cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give a thick oil. The addition of ether (2.0 L) to this oil resulted in a clear solution. Crystallization, followed by filtration, gave a white solid (367 g, 74%). m.p.
137-139.5C; lH-NMiR (CDC13): 4.38 (s, 2H), 6.9~8.0 (m, 23H).

A two liter, three neck, round bottom flask ~-; -equipped with a mechanical stirrer was charged with 50 g ethyl hydrogen malonate, 875 mL dry THF, and a few milligrams of l,10-phenanthroline as indi:cator, under dry nitrogen. The stirred mixture was cooled to -78OC. To this was added 308 mL 2.5 M
n-butyllithium in hexanes over 30 minutes until a brown color persisted several minutes. The mixture was warmed to 0C for -30 minutes then was cooled to -78C again. To this was added 22.5 mL valeroyl chloride in Z5 mL TXF over 15 minutes. The mixture was then warmed to room temperature, stirred 15 minutes, and acidified with ~150 mL 5% ~Cl. The mixture was extracted 3 times with ether. The combined organic material was washed twice with -saturated NaHC03 solution and twice with brine, dried over Na2SO4, stripped of solvent in-vacuo. and distilled at-~15 Torr with the title compound:-- ;distilling a~ 80-83C. -The title compound-was~
isolated as a--clear oil, 21.4 g, 66% yield. Rf 0;30 i ~ % EtOAc/hexane,- visualized by W and~-ninhydrin .. .. . - ..
., : ., ' : ' WO 91/1~209 PCr/US91/01951 2~ ?.~ ~

stain; lH-NMR ~250 MHz, CDC13): ~ 4.19 (q, 2H), 3.44 (s, 2H), 2.54 (3 line m, 2~), 1.59 (m, 2~), 1.30 (m, 2H), 1.28 (t, 3H), 0.90 (t, 3H).

To a mechanically stirred solution of 14.3 g MgS04-dried cyanoacetic acid and ~100 mg l,10-phenanthroline in 500 mL T~F at -780C was added 60 mL 2.5 M n-butyllithium in hexanes (~one half of the total). The indicator color persisted at this point. The solution was warmed to -5 to +5C after which the indicator color disappeared. Another 55 mL
2.5 M n-butyllithium in hexanes was added until the indicator color again persisted. The mixture was cooled to -78C then 10.0 mL valeroyl chloride in 10 mL THF was added over 3 minutes. After 10 minutes the now yellow solution was allowed to warm to room temperature and stir for 1 hour. The mixture was poured into a solution of 50 mL concentrated HCl in 300 mL water. The mixture was extracted 3 times with ether. The combined organic material was washed twice with saturated NaHC03 solution then once with brine. The washes were back extracted with ether and the back extracts were washed with brine. The back extracts were combined with the other organic material and then were dried over MgS04. The organic material was stripped of solvent in vacuo then was distilled at ~l Torr with the title compound distilling at-87-91C. The title compound was isolated.;as a.clear oil,.6.32 g,--60% yield.:-To-this : material there was added 1% by~weight BHT to prevent polymerization. The material was also kept ^
refrigerated at 0C under nitrogen. Rf 0.18 in 20%
~ ` .

. ~.
. ^ - .
j:

WO91/15209 ~ '~` PCT/US91/01951 .
.

EtOAc/hexane, visualized by ninhydrin stain, lH-NMR .
(300 MHz, CDCl3): ~ 3.46 (s, 2H), 2.62 (3 line m, 2H), 1.61 (m, 2H), 1.35 (m, 2H), 0.92 (t, J=7.3Hz, 3H); 13C-NMR (75.4 M~Iz, CDCl3): ~ 197.6, 113.8, 41.9, 31.9, 25.3, 22.0, 13.7. -;

ETHYL 2-[(2'-(N-TRIPHENYLMETHYL-TETRAZOL-5-YL)~IPHEN-4-YL~METHYLl-3-OXOHEPTANOATE .:
To a solution of 370 mg ethyl 3-oxoheptan- -~
oate in lO mL DMSO was added 86 mg 60% Na~ in oil.
After two minutes 600 mg N-triphenylmethyl-5-[2-(41-bromomethylbiphenyl)]tetrazole was added all at once .
to the solution. After 20 minutes the solution was .. ~:
poured into brine and extracted 3 time~ with ether.
The organic material was dried over MgSO4, stripped .
of solvent in vacuo, and MPLC'd in 10% EtOAc/hexane. .
The title compound was isolated as a white foam. Rf 0.30 in 20% EtOAc/hexane, visualized by W and ammonium molybdate/ceric sulfate stain; dialkylated material was observed at Rf 0.21; l~-NMR (300 MHz, .
CDCl3): ~ 8.l9 (4 line m, lH), 7.57 (ll line m, 2H), :
7.4Q (4 line m, lH), 7.19 (m, 4~), 4.17 (4 line m, `.:
2H), 3.79 (3 line m,. lH), 3.19 (d, J=8.3 Ez, 2~), - 2.66-2.32 (m, 2H),- 1.54 (m, 2H), 1.28 (m, 2H), 1.24 (3 line m, 3H),-0.88 (3 line m, 3H). Spectrum recorded after detritylation in MeO~/HCl. .. ~

Z-[(2'-(N-TRIPHENYLMETHYL-ThTRAZOL-5-YL~BIPHEN-4-YL)M~THYLl-3-OXO~EPTANENITRILF
. To a solytion of 225 mg 3-oxoheptanenitrile in lO mL DMSO was added 144.-mg 60% NaH in oil. After two minutes 500 ~g~:N-triphenylmethyl-5 ~2-(4'-: ;:

.

WO 91/15209 PCI/US9i/019~1 2 ~ ~ ~ 7 bromomethylbiphenyl)]tetrazole was added all at once to the solution. After ~0 minutes the solution was poured into brine and extracted 3 times with ether.
The organic material was dried over MgS04, stripped of solvent in vacuQ, and MPLC~d in 15% EtOAc/hexane.
The title compound was isolated as a white foam, 125 mg, 23% yield. Rf 0.23 in 20% EtOAc/hexane, visualized by W and ammonium molybdate/ceric sulfate stain; lH-NMR (300 MHz, CDCl3): ~ 7.93 (m, lH), 7.47 (10 line m, 2H), 7.40-7.20 (m, lOH), 7.04 (m, 4H), 6.90 (m, 6E), 3.44 (X of ABX, lH), 3.03 (AB of ABX, JAB=13.8 Hz, JAX=8.6 Hz, J~X=5 3 Hz, ~v=43.5 ~z, 2H), 2.59 (sym. 12 line m, 2H), 1.55 (m, 2H), 1.28 (m, 2H), 0.88 (t, J=7.3 Hz, 3H).

~ B~pLE 1 Ethvl 2-r(2'-(N-triphenylme~thvl-tetrazol-5-y~ hen-4-vl)methyl]-3-(trifluoromethanesulfonato)-2~Z)-heptenoate The title compound is prepared by dissolving 1.0 equivalent of ethyl 2-[2'~(N-triphenyl-methyl-tetrazol-5-yl)biphen-4-yl)methyl]-3-oxoheptan-oate in.THF so that the solution is ~0.1-0.3 M. To this is added 1.3 equivalents of sodium hydride.
After 10 minutes a room temperature, 1.2 equivalents of trifluoromethanesulfonic anhydride is added. When the reaction is complete the mixture is neutralized with ~saturated NaHC03 solution-and extracted with ether. The combined organic matërial:is-dried over -` MgS04, strip~ed of solvent in vacuo,- and MPLC~d to --give .the title compound.

WO91/15209 P~ S91/01~51 ~` ., -- 91 -- , _AMPLE~2 6-Butvl-2-methvl-5- r ( 2'-(N-triphenvlmethvl-tet~azol-5-vl)biphen-4-vl~methvllpyrimidin-4(3H~-one The title compound may be prepared by dissolving 1-5 equivalents of acetamidine hydrochloride and an equal mole-equivalent of sodium methoxide or sodium acetate in DMF. To this mixture is added 1.0 equivalent of ethyl 2-C(2'-(N-triphenyl-methyl-tetrazol-5-yl)biphen-4-yl)methyl]-3-~trifluoromethanesulfonato)-2(Z)-heptenoate. Enough DMF is used so the the solution is ~0.1-1.0 M in the heptenoate compound. The mixture is either stired at RT or is heated to reflux, until complete. The mixture is poured into brine and extracted with ether. The combined organic material is dried over MgSO4, stripped of solvent in vacuo, and MPLC'd to give the title compound.

6-Butyl-2-methvl-5-r(2'-(tetrazol-5-yl~iphen-4-yl)-methyllpyrimidin-4-(3H~-one The title compound may be prepared by dissolving 6-butyl-2-methyl-5-[(21-(N-triphenylmethyl-tetrazol-5-yl)biphen-4-yl)methyl]pyrimidin-4(3~)-one in methanol and adding excess co~centrated ~Cl and stirring for 10-30 minutes. An indicator quantity of phenolphthalein is added followed by 10% NaO~ .
solution until pink. Excess acetic acid~is added .~n~!
the -mixture is-extracted three times with e~her.
The combined organic material is dried-over.MgSO4, -,stripped of solvent in vacuo, and MPLC'd to give the title compound.
'': -WO91/15209 PcT/ussl/ol951 2~ 7~ 92 -6-Butyl-2-methyl-5-r(2'-(tetrazol-5-yl)~iphen-4-yl) methvl~4-trifluoromethan~sulfonatopyrimidine To a solution of 1.0 equivalents of 6-butyl~2-methyl-5-[(2'-(tetrazol-5-yl)biphen-4-yl~
methyl]pyrimidine-4(3H)-one and 5.0 equivalents of 2,4,6-collidine in methylene chloride at 0C is added 2.4 equivalents of trifluoromethanesulfonic anhydride. When the reaction is complete, the mixture is washed twice with saturated CuS04 solution, dried over MgS04, and stripped of ~olvent in vacuo.

EXA~PL~ 5 6-Butyl-4-cya~o-2-methyl-~-[(2'-(tetr~zol-5-yl)biph~n-4-vl)methvllpvr mi~in~
A solution of CuCN and 6-Butyl-2-methyl-5-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]-4-trifluoromet hanesulfonatopyrimidi~e in pyridine is heated to give the title compound with standard brine workup.

6-Butyl 4-carboxv-2-~.ç~hyl-5- r (2'-(tetrazol-5-yl)bi- -~hen-4-yl)methvllpyrimidine -- ~--- ~~ Heating 6-Butyl-4-cyano 2-methyl-5-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrimidine with several equivalents of sodium hydroxide and excess hydrogen peroxide-in methanol provides the corresponding primary-amide after~workup. --Treatment of this mater~al.~with concentrated~HCl with warming -~following by an-neutralization and extractive workup gives th ~title compound. ~ ~~

.

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

WO~1/15209 Pcr/us9l/ol9 ~ 3~

6-Butvl-4-methoxvcarbonyl-2-methyl-5-r(2'(tetrazol-5-yl)biphen-4-vl)methyllpyrimidin Step A: Ethyl 2-[(4-iodophenyl)methyl]-3-oxohep-tanoate To a solution of 3.77 g (43.8 ~mol) ethyl 3-oxoheptanoate in 200 mL DMS0 was added 1.75 g ~43.8 mmol) 65% NaH in oil. After 10 minutes, 6.5 g (21.9 mmol) a-bromo-4-iodotoluene was added. The mixture was allowed to stir for 2 hours. It was then poured into an ice/brine mixture and extracted 3 times with ~-ether. The combined organic material was washed with -brine, dried over MgS04, stripped of solvent in vacuo, then Still flash chromatographed in 40alO
CH2C12/hexane to give 2.46 g of the title compound, 29% yield. Rf 0.23 in 40% CH2C12/hexane, visualized by UV and ninhydrin stain;
l~-NMR (300 M~z, CDC13): ~ 7.58 (m,ZH), 6.93 (m, 2H), 4.14 ~m,2~), 3.72 (3 line m, lH), 3.09 (m, 2H), 2.44 (12 line m, 2H), 1.50 (m, 2H), 1.22 (m, 2H), 1.21 (3 line m, 3H), 0.86 (3 line m, 3H).
, Step B: 6-Butyl-2-methyl-5-[(4-iodophenyl)methyl]
. pvrimidine-4(3H)-one A solution of 2.46 g (6.33 mmol) ethyl 2-[(4-iodophenyl)methyl]-3-oxoheptanoate, 6.0 g (63.3 .
mmol) acetamidine hydrochloride, 5.2 g (63.3 mmol~ .
sodium acetate. and 84-mg (0.381 mmol) 2~6-di-tert-butyl-4-methylphenol in.30 mL-DMF was heated to 153C
for 12 hours.~-.The cooled reaction mixture wa~ poured '~ ' ~, . ~:
.
: .
.:
' WO 9 l / 1 5209 PCI /US9 l /o 1 95 1 .6 ~ L 94 _ into brine and extracted 3 times with ether. The combined organic material was washed with brine, dried over MgS04, stripped of solvent in vacuo, then was medium pressure chromatographed on silica gel using 1/65/34 AcOH/EtOAc/hexane to give 485 mg of the title compound, 20% yield. Unreacted ethyl 2-[(4-iodophenyl)methyl]-3-oxoheptanoate was recycled. Rf 0.25 in 1/65/34 AcOH/EtOAc/hexane, visualized by W
and ninhydrin stain;
lH-NMR (300 MHz, CDC13~: ~ 7.56 (m, 2H), 6.98 (m, 2H), 3.83 (s, 2H), 2.54 (3 line m, 2H), 2.38 (s, 3H), 1.52 (m, 2H), 1.43 (m, 2H), 0.89 (3 line m, 3H).

Step C: 6-Butyl-4-cyano-2-methyl-5-[(4-iodophenyl) methvl~pyrimidine A solution of 485 mg (1.27 mmol) 6-butyl-2-methyl-5-~(4-iodophenyl)methyl]pyrimidine-4~3H)-one in 7 mL POC13 was refluxed for 60 minutes. After cooling to room temperature, excess POC13 was stripped off in vacuo~ The crude product was partitioned between CH2C12 and a mixture of brine and NaHC03. The organic layer was removed and the aqueous layer was extracted three more times with - CH2Cl~. The combined~organic material was dried over MgS04, stripped of solvent in vacuQ, then was medium pressure chromatographed on silica gel using 10%
EtOAc/hexane to give 380 mg of 6-butyl-4-chloro-2-methyl-5-[(4-iodophenyl)methyl3pvrimidine, 75%-yiel~
. - :a . To a solution of 380 mg (O.947 mmol) -~6-butyl-4-chl~ro-2-methyl-5-[(4-iodophenyl)methyl]-pyrimidine in 10-mL acetone were~added 0.119 mL 57%
HI <0.900 mmol) a~d 8Sl mg (5.68 mmol) NaI. The .. . .
~'.

Wo91/15209 ~ ~ PCT/US9l/019~1 mixture was warmed to 40C for 2.5 hours. As the reaction proceeds, NaCl can be seen precipitating out of solution. The mixture was diluted with brine and --saturated NaHC03 solution. The mixture was extracted 3 times with ether. The combined organic material was dried over MgS04 and decolorized with activated charcoal, was stripped of solvent in vacuo, then was medium pres~ure chromatographed on silica gel using
10% EtOAc/hexane to give 440 mg of 6-butyl-4-iodo-2-methyl-5-[(4-iodophenyl)methyl]pyrimidine, 94% yield.
A mixture of 800 mg (8.94 mmol) CuCN and 10 mL pyridine was heated to llO~C until all of the CuCN
went into solution ( 7 minutes~. To this mixture was added a solution of 440 mg (0.894 mmol) 6-butyl-4-iodo-2-methyl-5-[(4-iodophenyl)methyl]pyrimidi:ne in 3 mL pyridine. After 5 minutes, the reacton mixture was cooled to room temperature, diluted with CH2C12, filtered through powdered cellulose flock, stripped of solvent ~a vacuo, and was medium pressure -chromatographed on silica gel using 13% EtOAc/hexane to give 306 mg of the title compound, 87% yield. Rf . .
0.29 in 15% EtOAc/hexane, visualized by W and ammonium molybdate/ceric sulfate stain;
lH-NMR (300 M~z, CDC13): ~ 7.63 (m, 2H), 6.84 (m, ~ -2H), 4.16 (s, 2E), 2.73 (s, 3K), 2.68 (3 line m, 2H), 1.53 (m, 2E), 1.31 (m, 2H), 0.87 (3 line m, 3H).
.. - . : .:
; , .. . . . .
: :

~

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W091/15209 PCr/US9l/Ol9~l ~fff` f'`'~
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Step D: 6-Butyl-4-methoxycarbonyl-2-methyl-5-r ~ 4-iodophenvl)methvll pyr imi d ine To a solution of 306 mg 6-butyl-4-cyano-2-methyl-5-[(4-iodophenyl)methyl]pyrimidine in 6 mL
methanol was added O.885 mL (~7.81 mmol) 30~/0 X202 and 0.937 mL f~2.34 mmol) 2.5 N NaOH. The mixture was allowed to stir for 1 hour at room temperature. To the mixture was added ~l mL HOAc. Solvent was removed in va~uo. The crude material (409 mg) was dissolved in ~20 mL methanol. To this wa~ added 4.0 g Amberlyst-15~. The mixture was heated to 60 for 18 hours. After cooling to room temperature, ~5 mL
pyridine was added. After stirring for 1 hour, the mixture was filtered through powdered cellulose floc~, stripped of solvent in vacuo, stripped from toluene to remove remaining pyridine, then was medium pressure chromatographed on silica gel using 25%
EtOActhexane to give 152 mg of the title compound, 46% yield. Rf 0.21 in 30% EtOAc/hexane, visualized -by UV and ammonium molybdate/ceric sulfate stain;
lH-NMR (300 MHz, CDC13); f~ 7.58 (m, 2HO, 6.81 (m, 2H), 4.12 (s, 2~), 3.87 (s, 3H), 2.75 (s, 3H), 2.67 (3 line m, 2H), 1.53 (m, 2~), 1.31 (m, 2~), 0.86 (3 line m, 3X).

Step E: 6-Butyl-4-methoxycarbonyl-2-methyl-5-[(2'-tetraæol-5-yl)biphen-4-yl)methyl]-pvrimidine _ To -25C solution f2f 278 mg (0.717 mmol~
5~phenyl-2-triphenylmethyltetrazole in 4 mL THF was added dropwise a solution of 1.7 M tert-butyllithium in pentane until a faint ~ d color persisted (drying , .

.' ' :' -O 91~15209 PCr/US~1/019r !--~, ~ ~9 ~

- 97 - ....

process). Then 0.420 mL (0.717 mmol) of the 1.7 M
tert-butyllithium in pentane was added. After 2 minutes the solution was blood red. After 25 minutes, the organolithium salt was precipitating from the THF. At this time, 0.358 mL (0.358 mmol) 1.0 M ZnC12 in ether was added. The color changed from blood red to medium yellow and the precipitate went back into solution. The mixutre was warmed to room temperature. To the solution was added 13 mg (O.018 mmol) (Ph3P)2PdC12 followed by 152 mg (0.358 -mmol) 6-butyl-4-methoxycarbonyl-2-methyl-5-~(4- ~r .
iodophenyl)methyl]pyrimidine. The mixture was refluxed for 3.25 hours then cooled to room temperature, diluted with water and brine, and was extracted 3 times with ether. The combined o~ganic material was dried over MgSO4, stripped of solvent in vacuo, then was medium pressure chromatographed on silican gel using 30% EtOAc/hexane to give 146 mg of the trityl protected title compound, 60% yield. Rf 0.18 in 30% EtOAc/hexane, visualized by W and ~, ammonium molybdate/ceric sulfate stain.
A solution of 146 mg of the trityl protected title compound in 4/1/1 AcOHlE2O/CH2C12 was ~tirred for 6 hours at room temperature.- The mixture was diiuted with brine and extracted 3 times with CH2C12. The-combined organic material was dried over MgSO4, stripped of solvent ~B Yacuo, stripped from toluene, then was Still flash chromatographed in 1/13/86 NH40H/MeOHtCH2C12 to give 9Z mg of the title compound, 97/O yield. Rf 0.18 in 1/50/49 AcOH/EtOAc/
hexane; Rf 0.2Z in 1/13/86 NH4OH/MeOH/CH2C12, visualized by W ; a: ~ :
, :.

WO91/15209 PCT/US91/0l9~l , 2.

lH-NMR (300 MHz, CDC13): ~ 8.10 (m, lH), 7.57 (m, 2H), 7.37 (m, lH), 7.04 (m, 4E), 4.24 (s, 2H), 3.79 ~s, 3H), 2.67 (3 line m, 2H), 2.53 (s, 3H), 1.58 (m, 2H), 1.34 (m, 2H), 0.88 (3 line m, 3H); MS (FAB) m/e 443 (M~l).

~ XAMPLE 8 6-Butyl-4-carboxy-2-methyl-5-[~2~ etrazol-~-yl)-biphen-4-vl~methyllpvrimidine To a solution of 68.4 mg (0.155 mmol) 6-butyl-4-methoxycarbonyl-2-methyl-5-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrimidine in 5 mL methanol was added ~0.300 mL 10% NaOH. After stirring at room ~ :
temperature for 2.5 hours, the mixture was acidified with ~0.500 mL HOAc. Volatiles were removed ~n vacuo. --The crude material was redissolved in methanol along with a couple of drops of TFA, then was HPLC'd using the following conditions: Rainin Dynamax~ C-18 column, 25 ~ 2.14 cm w/Guard Column; gradient of acetonitrile in water 5 to 100% over 40 minutes at 5 mL/minute; gradient held at 82% for 7 minutes. A .-yield of 66.1 mg (100%) of the title compound was obtained. Rf 0.14 in 1/30/69 N~40~/MeOH/CH2C12, visualized by- W ; ~~-H-MMR (300 MHz, CDC13): ~~9.7-8.8 (v br s, 2H), 7.97 (m,- lH), 7.52 (m, 2H), 7.37 (m, lH), 7.00 (br s, 4H), 4.51 (br s, 2H), 2.86 (3 line m, 2H), 2.75 (br s, 3E), 1.-62 (m, 2H), 1.36 (m, 2H), 0.88 (3 line m. 3H~:
MS(FAB) m/e 429 (M+l).

: . . - . . ~ . .:

WO91/1~209 ~ ~J~!~ ~ PCT/USgl/01 _ 99 _ 6-Butvl-6-methyl-3-r(2'-(tetrazol-S-yl)biphen-4-yl)-methyl~-4H-pyrido[l.2-alpvrimidine-4-one Step A: 2-Butyl-3-[(4-iodophenyl)methyl]-6-methyl-4H-pvridorl.2-a~pyrimidin-4-one A mixture of 1.59 g (4.09 mmol) ethyl 2-[(4-iodophenyl)methyl]-3-oxoheptanoate, 487 mg (4.50 mmol~ 2-amino-5-methylpyridine, and 3 g PPA was heated to 160~C for 1 hour. The mixture was cooled -to room temperature then NH40H was added with cooling. When all of the PPA had reacted, the mixture was extracted e times with ether. The cominbed organic material was dried over MgS04, stripped of solvent in vaCuo, then Still flash chromatographed in 10/S0/40 EtOAc/CH2C12/hexane to give 177 mg of the title compound, 10% yield. Rf 0.21 in 10/50/40 EtOAc/C~2C12/hexane, visualized by UV;
lH-NMR (300 MHz, CDCl3): ~ 8.80 (s, lH), 7.55 (m, 2H), 7.51 (s, 2H), 7.02 (m, 2H), 4.05 (s, 2H), 2.72 (3 line m, 2H), 2.40 (s, 3H), 1.61 (m, 2H), 1.39 (m, 2H), 0.91 (3 line m, 3H).

Step B: 2-Butyl-6-methyl-3-~(2'-(tetrazol-5-yl)-biphen-4-yl)methyl3-4H-pyridotl,2-a]- -pyrimidin-4-one ~ -To -25C solution of 318 mg (0.819 mmol) r`_ , phenyl-2-triphenylmethyltetra~Ie in S mL THF was added dropwiso a solution of 1.7 M .~Q_~-butyllithium -in pentane until:a faint red color.persisted (drying :' .

process). Then 0.482 mL (0.819 mmol) of the 1.7 M
tert-butyllithium in pentane was added. After 2 minutes the solution was blood red. After 30 minutes, the organolithium salt was precipitating -from the THF. At this time, 0.410 mL (0.410 mmol) 1.0 M ZnC12 in ether was added. The color changed from blood red to medium yellow and the precipitate went back into solution. The mixture was warmed to room temperature. To the solution was added 14 mg (0.020 mmol) (Ph3P)2PhC12 ~ollowed by 177 mg (0.410 mmol) 2-butyl-3-[(4-iodophenyl)methyl]-6-methyl-4H-pyrimidin-4-one. The mixture was refluxed for 4 hours then was cooled to room temperature, diluted with water and brine, and was extracted 3 times with ether. The combined organic material was dried over MgS04, stripped of solvent ~ vacuo, then was medium pressure chromatographed on silica gel using 40%
EtOAc/hexane to give 159.4 mg of the trityl protected title compound, 56% yield. Rf 0.18 in 40%
EtOAc/hexane, visualized by W and ammonium molybdate/
ceric sulfate stain.
To a solution of 159.4 mg of the trityl protected title compound in 5 mL methanol was added 10 drops concentrated HCl. After 30 minutes, an indicaor ~uantity of phenolphthalein was added and the mixture was basified with 10% NaOH then reacidified with HOAc. Ether was added and the mixture was dried over M~SO4~ stripped of solven in vacuo,:then was:Still flash chromato~raphed--in l/12/87 NH40H/MeOH/CH2C12:to give 95.7--mg-of the -title compound as.its ammonium~salt, 89% yield. Rf 0.22 in 1/13/86 N~40H/MeOX/CH2C12, visualized by W YQ~

.
. . ..

:: ' - ; ' ' i . ' ~ :. ; ; . i WO 91/15209 PCI/US9l/01951 "~

1H-NMR (300 MHZ~ CDC13): ~ 8.78 (s, lT~, 8.13 (m, lH), 7.53 (m, 4H), 7.37 (m, lH), 7 .17 (m, 2H), 7 . 06 (m, 2H), ~6.1-5.0 (v br s, 4H~, 4.06 (s, 2H), 2.75 (3 ....
line m, 2H), 2.39 (s, 3H), 1.67 (m, 2H), 1.41 (m, ~. :
2H), 0.92 (3 line m, 3H); MS (FAB) m/3 451 (M+l).

EXAMPLE 10 : ::
Typical Pharmaceutical Compositions Containing a ÇQmPOUnd of the Invention . .

A: Dry Filled Capsules Containing 50 mg of Active .:
Ingredient Per Capsule : ::
Ing~edient. Amount per capsule (mg) ;.:.
6-butyl-4-carboxy-2- 50 methyl-5-[(2'-(tetraæol-5-yl)biphen-4-yl)methyl]-pyrimidine ' . ' .
Lactose 149 Magnesium stearate Capsule ~size No. 1) 200 . .

The 6-butyl-4-carboxy-2-methyl-5-[(2'- .~.
(tetrazol-5-yl)biphen-4-yl)methyl]pyrimidine can be reduced to a No; 60-powder and the lactose and magnesium stearate can then be passed through a No. 60 blotting:cloth onto the powder. The combine~
ingredients can-then be mixed.for about 10 minutes and filled-:into aANo. l dry gelatin.:capsule.: :

.. . . .. .. ..

: .

. i ~ .

I' . ' ., ' ' '' '' :' ` ',' ' ' . '' I ''`,. . ' ' ' ' ' ' '. " :' : ' ' . ' WO91/15209 PCl/US91/01951 ?~

B: Tablet A typical tablet would contain 6-butyl-4-carboxy-2-methyl-5-[(2'-(tetrazo]-5-yl)biphen-4-yl)-meth~l]pyrimidine (25 mg), pregelatinized starch USP
(82 mg), microcrystaline cellulose ~82 mg) and magnesium stearate (1 mg).
. .
C: Combinat_Qn Tablet A typical combination tablet would contain, for example, 6-butyl-4-carboxy-2-methyl-5-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrimidine a diuretic such as hydrochlorothiazide and consist of hydrochlorothiazide (50 mg) pregelatinized stareh USP
(82 mg), microcrystalline cellulose (82 mg) and magnesium stearate ~1 mg).

D: S~pposi~ry Typical suppository formulations for rectal administration can contain 6-butyl-4-carboxy-2-methyl-S-[(2'- (tetrazol-5-yl)biphen-4-yl)methyl]pyrimidine (0.08-1.0 mg), disodium calcium edetate (0.25-0.5 mg), and polyethylene glycol (775-1600 mg). Other suppository ~ormulations can be made by substituting, for example, butylated hydroxytoluene (0.34-0.08 mg) for the disodium calcium edetate and a hydrogenated vegetable oil (675-1400 mg) such as Suppocire L, Wecobee FS, Wecobee M, Witepsols, and-the-likej for the polyethylene glycol. Further, these suppository ~-formulations can also include another active .

~ .
, ~

.. . I . . , , .. . ~ .. .... . . -WO91/15209 P~T/US91/01951 ingredient such as another antihypertensive and/or a diuretic and/or an angiotensin converting enzyme and/or a calcium channel blocker in pharmaceutically effective amounts as described, for example, in C
above.

E: Injection A typical injectible formulation would contain 6-butyl-4-carboxy-2-methyl-5-~(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrimidine, sodium phosphate dibasic anhydrous (11.4 mg) benzylalcohol (O.Ol ml) and water for injection (l.0 ml). Such an injectible formulation can also include a pharmaceutically effective amount of another active ingredient such as another antihypertensive and/or a diuretic and/or an angiotensin converting enzyme inhibitor and/or a calcium channel blocker.

' ' ' ~ . . ' '~.~ . ; ' .; ' . ' '

Claims

WHAT IS CLAIMED IS:

1. A method of treating cognitive dysfunctions, anxiety, depression and schizaphrenia which comprises administring to a patient in need of such treatment a therapeutically effective amount of a compound having the formula:

(I) wherein:
K is -N(R8a)-C(=M) or -N=C(R8b)-wherein M is O or NR22;

R1 is (a) -CO2R4, (b) -SO3R5, (c) -NHSO2CF3, (d) -PO(OR5)2, (e) -SO2-NH-R9, (f) -CONHOR5, (g) , (h) -CN, (i) -SO2NH-heteroaryl, (j) -CH2SO2NH-heteroaryl, (k) -SO2NH-CO-R23, (l) -CH2SO2NH-CO-R23, (m) -CONH-SO2R23, (n) -CH2CONH-SO2R23, (o) -NHSO2NHCO-R23, (p) -NHCONHSO2-R23, (q) , (r) , (s) (t) -CONHNHSO2CF3 , (u) (v) (w) wherein heteroaryl is an unsubstituted, monosub-stituted or disubstituted five or six membered aromatic ring comprising from 1 to 3 heteroatoms selected from the group consisting of O, N and S and wherein the substituents are members selected from the group consisting of -OH, -SH, -C1-C4-alkyl, -C1-C4-alkoxy, -CF3, Cl, Br, F, I, -NO2, -CO2H, CO2-C1-C4-alkyl, -NH2, NH(C1-C4-alkyl) and -N(C1-C4-alkyl)2;

R2a and R2b are each independently (a) H, (b) halogen, (c) NO2, (d) NH2, (e) C1-C4-alkylamino, (f) di-(C1-C4-alkyl)amino (g) SO2NHR9, (h) CF3, (i) C1-C4-alkyl, or (j) C1-C4-alkoxy;

R3a is (a) H, (b) Cl, Br, I, F, (c) C1-C6-alkyl, (d) C1-C6-alkoxy, (e) C1-C6-alkoxy-C1-C4-alkyl;

R3b is (a) H, (b) halo (Cl, Br, I, F) (c) NO2, (d) C1-C6-alkyl, (e) C2-C6-alkanoyloxy, (f) C3-C6-cycloalkyl, (g) C1-C6-alkoxy, (h) -NHSO2R4, (i) hydroxy-C1-C4-alkyl, (j) aryl-C1-C4-alkyl, (k) C1-C4-alkylthio, (l) C1-C4-alkylsulfinyl, (m) C1-C4-alkylsulfonyl, (n) NH2, (o) C1-C4-alkylamino, (p) C1-C4-dialkylamino, (q) CF3, (r) -SO2-NHR9, (s) aryl or (t) furyl;

wherein aryl is phenyl or naphthyl unsubstituted or substituted with one or two substituents selected from the group consisting of Cl, Br, I, F, C1-C4-alkyl, C1-C4-alkoxy, NO2, CF3, C1-C4-alkylthio, OH, NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -CO2H, C1-C4-polyfluoroalkyl, C3-C6-polyfluorocycloalkyl, -CO2-C1-C4-alkyl or R4 is H, C1-C6-alkyl, benzyl or phenyl;
R5 is H, ;
E is a single bond, -NR13(CH2)s-, -S(O)x(CH2)s-where x is 0 to 2 and s is 0 to 5, -CH(OH)-, -O-, CO-;
R6 is (a) C1-C6-alkyl, C2-C5-alkenyl or C2-C5-alkynyl each of which can be optionally substituted with a substituent selected from the group consisting of aryl as defined above, C3-C7-cycloalkyl, Cl, Br, I, F, -OH, CF3, CCl3, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -HN-SO2R4, -COOR4, -SO2NHR9, C1-C4-alkoxy,C1-C4-alkyl-S,and -CF2CF3;
(b) C3-C5-cycloalkyl;
(c) -polyfluoro-C1-C4-alkyl;

R7 is (a) hydrogen, (b) aryl, (c) heteroaryl, (d) Cl, Br, I, F, (e) -CO2H, (f) -CO2R4, (g) -NH2, (h) -NH(C1-C4-alkyl), (i) -N(C1-C4-alkyl)2, (j) -SO2NR9N10, (k) -NHSO2-C1-C4-alkyl, (l) -S(O)x-C1-C4-alkyl, (m) -OH, (n) -SH, (o) -S(O)x-aryl, (p) -C1-C4-alkyl or -O(C1-C4-alkyl) or -S(C1-C4-alkyl) each of which can be substituted with aryl, heteroaryl, -OH, -NH2,-CF3, C3-C5-cycloalkyl.
-NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -CO2H, -CO2R4 or Cl, Br, I, F, (g) C3-C5-cycloalkyl, or (r) -CF3;

R8a is (a) aryl, (b) heteroaryl, (c) C1-C4-alkyl unsubstituted or substituted with aryl, heteroaryl, -OH, -NH2, -NH(C1-C4-alkyl), N(C1-C4-alkyl)2, -CO2H, -CO2R4 or Cl, Br, I, or F, (d) C1-C4-alkylaryl unsubstituted or substituted with CO2R4;
or R7 and R8a when alkyls on adjacent atoms may be joined together with the atoms to which they are bound to form a pyridine ring which may be substituted with R26 and/or R27 wherein R26 is (a) R7 (b) -NHCO(C1-C5-alkyl) (c) -NHCO(C3-C6-cycloalkyl), (d) -NHCO(aryl), (e) -NHCO(heteroaryl), (f) -N(C1-C5-alkyl)CO(C1-C5-alkyl), (g) -N(C1-C5-alkyl)CO(C3-C6-cycloalkyl), (h) -N(C1-C5-alkyl)CO(aryl), (i) -N(C1-C5-alkyl)CO(heteroaryl), and R27 is C1-C4-alkyl, Cl, Br, F, I, -CF3, aryl or heteroaryl;
R8b is (a) -OH, (b) -NH2, (c) -NH(C1-C4-alkyl), (d) -N(C1-C4-alkyl)2, (e) -NHCO2-C1-C4-alkyl, (f) -NHCO-C1-C4-alkyl, (g) -NHSO2-C1-C4-alkyl, (h) -NHSO2-aryl, (i) -NHSO2(C1-C4-polyfluoroalkyl), (j) -CO2H, (k) -CO2R4, (1) Cl, Br, I, F, (m) -CONHSO2-aryl, (n) -CONHSO2-heteroaryl, (o) -CONHSO2-C1-C4-alkyl, (p) -CONHSO2(C1-C4-polyfluoroalkyl), (q) -CH2OH, (r) -CH2OCOR4, (s) -O-C1-C4-alkyl unsubstituted or substituted with CO2R4, (t) -S(O)x-aryl unsubstituted or substituted with CO2R4, (u) -S(O)x-C1-C4-alkyl unsubstituted or substituted with CO2R4.
(v) -SO2NHR25, (w) -CN, (x) tetrazol-5-yl;
R9 is H, C1-C5-alkyl, phenyl or benzyl;
R10 is H, C1-C4-alkyl;
R11 is H, C1-C6-alkyl, C2-C4-alkenyl, C1-C4-alkoxy alkyl, or -CH2-C6H4R20;
R12 is -CN, -NO2, -CO2R4, or -CF3;
R13 is H, C2-C4-alkanoyl, C1-C6-alkyl, allyl, C3-C6-cycloalkyl, phenyl or benzyl;
R14 is H, C1-C8-alkyl, C1-C8-perfluoroalkyl, C3-C6-cycloalkyl, phenyl or benzyl;
R15 is H, C1-C6-alkyl;
R16 is H, C1-C6-alkyl, C3-C6-cycloalkyl, phenyl or benzyl;

R17 is -NR9R10, -OR10, -NHCONH2, NHCSNH2, or ;

R18 and R19 are independently C1-C4-alkyl or taken together are -(CH2)q- where q is 2 or 3;
R20 is H, -NO2, -NH2, -OH or -OCH3;
R21 is (a) -CO-aryl, (b) -CO-C1-C4-alkyl, (c) -COCF3, (d) -CO-heteroaryl, or (e) heteroaryl;
R22 is the same as R8a or -H;
R23 is (a) aryl, (b) heteroaryl, (c) C3-C7-cycloalkyl, (d) C1-C6-alkyl unsubstituted or substituted with a substituent selected from the group consisting or aryl. heteroaryl, -OH, -SH, -C1-C4-alkyl, -O(C1-C4-alkyl), -S(C1-C4-alkyl), -CF3, Cl, Br, F, I, -NO2, -CO2H, -CO2-C1-C4-alkyl, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2.
-PO3H2, or -PO(OH)(O-C1-C4-alkyl):
R25 is (a) H, (b) C1-C4-alkyl;

X is (a) a carbon-carbon single bond, (b) -CO-, (c) -O-, (d) -S-, (e) , (f) , (g) , (h) -OCH2-, (i) -CH2O-(j) -SCH2-, (k) -CH2S-, (l) -NHC(R9)(R10)-, (m) -NR9SO2-, (n) -SO2NR9-, (o) -C(R9)(R10)NH-, (p) -CH=CH-, (q) -CF=CF-, (r) -CH=CF-, (s) -CF=CH-, (t) -CH2CH2-, (u) -CF2CF2-, (v) or (w) , (x) , (y) or (z) ;

Z is O, NR13 or S; or a pharmaceutically acceptable salt thereof.

2. The compound of Claim 1 wherein K is -N=C(R8b) of structure 3. The method of Claim 2 wherein:

R1 is -COOH; ; -NH-SO2CF3; -CO2R4;

-SO2NH- heteroaryl or CH2SO2NH- heteroaryl wherein the heteroaryl is an unsubstituted, monosubstituted or disubstituted 5- or 6-membered aromatic ring conprising 1 to 3 heteroatoms selected from O, N and S and wherein the substituents are members selected from the group consisting of OH, SH, C1-C4-alkyl, C1-C4-alkoxy, CF3, Cl, Br, F, I, NO2, CO2H, CO2-C1-C4-alkyl, NH2, NH(C1-C4-alkyl) and N(C1-C4-alkyl)2; -SO2NHCOR23;-CH2SO2NHCOR23;
-CONHSO2R23; -CH2CONHSO2R23; -NHSO2NHCOR23; and -NHCONHSO2R23;
R2a and R2b are H, F, Cl, CF3, C1-C4-alkyl or C1-C4-alkoxy;
R3a is H, F or Cl;
R3b is H, F, Cl, CF3, C1-C4-alkyl. C1-C4-alkoxy, -COOCH3, -COOC2H5, -SO2-CH3, NH2, -N(C1-C4-alkyl)2 or -NH-SO2CH3;

E is a single bond, -O- or -S-:
R6 is (a) C1-C5-alkyl, C2-C5-alkenyl or C2-C5-alkynyl each of which can be substituted with a substituent selected from the group consisting of CF3, CF2CF3, -O-CH3, -OC2H5, -S-CH3, -S-C2H5, phenyl and C3-C5-cycloalkyl;
(b) C3-C5-cycloalkyl;
(c) polyfluoro-C1-C4-alkyl; and X is a C-C single bond.

4. The method of Claim 3 wherein:

E is a single bond;
R2a, R2b, R3a and R3b are each H; and X is a single bond.

5. The compound of Claim 4 which is a member of the group of compounds of Formula II and described in Table I:

II

6. The compound of Claim 1 wherein K is -N(R8a)-CO- of structure 7. The compound of Claim 6 wherein R1 is -COOH; ; -NH-SO2CF3; CO2R4;

-SO2NH- heteroaryl or CH2SO2NH- heteroaryl wherein the heteroaryl is an unsubstituted, monosubstituted or disubstituted 5- or 6-membered aromatic ring comprising 1 to 3 heteroatoms selected from O, N and S and wherein the substituents are members selected from the group consisting of OH, SH, C1-C4-alkyl,C1-C4-alkoxy, CF3, Cl, Br, F, I, NO2, CO2H, CO2-C1-C4-alkyl, NH2, NH(C1-C4-alkyl) and N(C1-C4-alkyl)2;
-SO2NHCOR23;-CH2SONHCOR23; -CONHSO2R23;
-CH2CONHSO2R23; -NHSO2NHCOR23; and -NHCONHSO2R23;
R2a and R2b are H, F, Cl, CF3, C1-C4-alkyl or C1-C4-alkoxy;
R3a is H, F or Cl;
R3b is H, F, Cl, CF3, C1-C4-alkyl, C1-C4-alkoxy, -COOCH3, -COOC2H5, -SO2-CH3, NH2, -N(C1-C4-alkyl)2 or -NH-SO2CH3;

E is a single bond, -O- or -S-;
R6 is (a) C1-C5-alkyl, C2-C5-alkenyl or C2-C5-alkynyl each of which can be substituted with a substituent selected from the group consisting of Cl, CF3, CF2CF3, CCl3, -O-CH3, -OC2R5, -S-CH3, -S-C2H5, phenyl and C3-C5-cycloalkyl;
(b) C3-C5-cycloalkyl;
(c) polyfluoro-C1-C4-alkyl;
R7 and R8a are as defined above or together with the atoms to which they are bonded may be joined to form a pyridine ring which may be substituted with R26 and/or R27;

X is a C-C single bond.

8. The compound of Claim 7 wherein:
E is a single bond;
R2a R2b R3a and R3b are each H; and X is a single bond, 9. The compound of Claim 8 which is a member of the group of Formula III and described in Table 2:

III

10. The compound of Claim 8 whichis a member of the group of compound of Formula IV and described in Table 3:

IV

11. The compound of Claim 1 wherein K is -N(R8a)-C(=NR22)- of structure 12. The compound of Claim 11 wherein:

R1 is -COOH; ; -NH-SO2CF3; CO2R4;

-SO2NH-heteroaryl or -CH2SO2NH-heteroaryl wherein the heteroaryl is an unsubstituted, monosubstituted or disubstituted 5-or 6-membered aromatic ring comprising 1 to 3 heteroatoms selected from O, N and S and wherein the substituents are members selected from the group consisting of OH, SH, C1-C4-alkyl, C1-C4-alkoxy, CF3, Cl,Br, F, I, NO2,CO2H, CO2-C1-C4-alkyl, NH2, NH(C1-C4-alkyl) and N(C1-C4-alkyl)2;
-SO2NHCOR23; -CH2SO2NHCOR23; -CoNHSO2R23;
-CH2CONHSO2R23; -NHSO2NHCOR23; and - NHCONHSO2R23;

R2a and R2b are H, F, Cl, CF3, C1-C4-alkyl or C1-C4-alkoxy;
R3a is H, F or Cl;
R3b is H, F, Cl, CF3, C1-C4-alkyl, C5-C6-cycloalkyl, -COOCH3, -COOC2H5, -SO2CH3;
NH2, -N(C1-C4-alkyl)2 or -NH-SO2CH3;
E is a single bond, -O- or -S-;

R6 is (a) C1-C5-alkyl, C2-C5-alkenyl or C2-C5-alkynyl each of which can be substituted with a substituent selected from the group consisting of Cl, CF3, CCl3, -O-CH3, -OC2H5, -S-CH3, -S-C2H5, phenyl, and C3-C5-cycloalkyl;
(b) C3-C5-cycloalkyl; or (c) polyfluoro-C1-C4-alkyl;
R7 and R8a are as defined above or together with the atoms to which they are bonded may be joined to form a pyridine ring which may be optionally substituted with R26 and R27; and X is a C-C single bond.

13. The compound of Claim 12 wherein:
E is a single bond;
R2a, R2b, R3a and R3b are each H; and X is a single bond.

14. The compound of Claim 13 which is a member of the group consisting of compounds of Formula V and described in Table 4:

V

15. The compound of Claim 13 which is a member selected from the group consisting of compounds of Formula VI and described in Table 5:

VI

'r 16. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of Claim 1.

17. The composition of Claim 14 which includes another antihypertensive agent selected from an angiotension converting anzyme inhibitor, a calcium channel blocker, or a .beta.-blocker selected from the group consisting of:
amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamide tannates, deserpidine, diazoxide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serepentina, rescinnamine, reserpine, sodium nitroprusside, spironolactone, timolol maleate, trichlormethiazide, trimethophan camsylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, furosemide, merethoxylline procaine, sodium ethacrynate, captopril, delapril hydrochloride, enalapril, enalaprilat, fosinopril sodium, lisinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zofenopril calcium, diflusinal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nimodipine, nisoldipine, nitrendipine, as well as admistures and combinations thereof.

18. A method of treating hypertension which comprises administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of Claim 1.

19. An ophthalmological formulation for the treatment of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a compound of Claim 1.

20. A method of treating ocular hypertension comprising administering to a patient in need of such treatment an effective ocular antihypertensive amount of a compound of Claim 1.

21. A method of treating cognitive dysfunction, anxiety, or depression comprising administering to a patient in need of such treatment an effective therapeutic amount of a compound of
Claim 1.
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