Substituted 1-(2H)-isoquinolinones.

SUMMARY OF THE INVENTION

0001This invention relates to novel compounds of structural formula I which are angiotensin II antagonists useful in the treatment of hypertension, congestive heart failure, and elevated intraocular pressure.

0002It also relates to processes for preparing the novel compounds; pharmaceutical formulations comprising one or more of the compounds as active ingredient; and, a method of treatment of hypertension, congestive heart failure, and elevated intraocular pressure.

0003The 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 depressed or dysphoric mental states.

0004In addition, these compounds exhibit antidopaminergic properties and are thus useful to treat disorders that involve dopamine dysfunction such as schizophrenia. The compounds of this invention are especially useful in the treatment of these conditions in patients who are also hypertensive or have a congestive heart failure condition.

BACKGROUND OF THE INVENTION

0005Renin-angiotensin system (RAS) plays a central role in the regulation of normal blood pressure and seems to be critically involved in hypertension development and maintenance as well as congestive heart failure. Angiotensin II (AII), 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. AII is a powerful arterial vasoconstricter that exerts its action by interacting with specific 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 the partial agonist activity and lack of oral absorption [M. Antonaccio. <u>Clin. Exp. Hypertens.</u> A4, 27-46 (1982); D. H. P. Streeten and G. H. Anderson, Jr. - <u>Handbook of Hypertension</u>, <u>Clinical Pharmacology of Antihypertensive Drugs</u>, ed. A. E. Doyle, Vol. 5, pp. 246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984].

0006Recently, 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; 4,582,847; and 4,880,804; in European Patent Applications 028,834; 245,637; 253,310; and 291,969; and in articles by A.T. Chiu, <u>et al</u>. [<u>Eur. J. Pharm. Exp. Therap</u>, <u>157</u>, 13-21 (1988)] and by P.C. Wong, <u>et</u><u>al</u>. [<u>J. Pharm.</u><u>Exp. Therap</u>, <u>247</u>, 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-2H-imidazo[4,5-<u>c</u>]-pyridine-6-carboxylic acid and analogs thereof as antihypertensive agents.

0007None of the compounds disclosed in the above identified U.S. Patents, European Applications and articles have the heterobicyclic structure of the compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

0008This invention relates to substituted 1-(2H)-isoquinolinones of the formula I shown below which are angiotensin II antagonists and are useful in the treatment of hypertension, congestive heart failure, and elevated intraocular pressure. <chemistry id="chem0001" num="0001"><img file="EP0502575A1_D0001.tif" /></chemistry> wherein: <dl id="dl0001"><dt>R¹ is</dt><dd><ul id="ul0001" list-style="none"><li>(a) -CO₂R⁴,</li><li>(b) -SO₃R⁵,</li><li>(c) -NHSO₂R²²,</li><li>(d) -PO(OR⁵)₂,</li><li>(e) -SO₂-NH-R²²,</li><li>(f) <chemistry id="chem0002" num="0002"><img file="EP0502575A1_D0002.tif" /></chemistry></li><li>(g) <chemistry id="chem0003" num="0003"><img file="EP0502575A1_D0003.tif" /></chemistry></li><li>(h) -SO₂NH-CO-R²²,</li><li>(i) -CH₂SO₂NH-CO-R²²,</li><li>(j) -CONH-SO₂R²²,</li><li>(k) -CH₂CONH-SO₂R²²,</li><li>(l) -NHSO₂NHCO-R²²,</li><li>(m) -NHCONHSO₂-R²²,</li><li>(n) <chemistry id="chem0004" num="0004"><img file="EP0502575A1_D0004.tif" /></chemistry></li><li>(o) <chemistry id="chem0005" num="0005"><img file="EP0502575A1_D0005.tif" /></chemistry></li><li>(p) <chemistry id="chem0006" num="0006"><img file="EP0502575A1_D0006.tif" /></chemistry></li><li>(q) <chemistry id="chem0007" num="0007"><img file="EP0502575A1_D0007.tif" /></chemistry></li><li>(r) <chemistry id="chem0008" num="0008"><img file="EP0502575A1_D0008.tif" /></chemistry></li><li>(s) <chemistry id="chem0009" num="0009"><img file="EP0502575A1_D0009.tif" /></chemistry></li><li>(t) -CONHNHSO₂CF₃ ,</li><li>(u) -SO₂NH-CN,</li><li>(v) <chemistry id="chem0010" num="0010"><img file="EP0502575A1_D0010.tif" /></chemistry></li><li>(w) <chemistry id="chem0011" num="0011"><img file="EP0502575A1_D0011.tif" /></chemistry></li><li>(x) -PO(OR⁵)(OR⁴),</li><li>(y) -SO₂NHCONR⁴R²², or</li><li>(z) -CH₂SO₂NHR²²;</li></ul> wherein heteroaryl is an unsubstituted, monosubstituted or disubstituted five or six membered aromatic ring which contains from 1 to 3 heteroatoms selected from the group consisting of O, N or 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;</dd><dt>R^2a and R^2b are</dt><dd>each independently <ul id="ul0002" list-style="none"><li>(a) H,</li><li>(b) Cl, Br, I, or F,</li><li>(c) NO₂,</li><li>(d) NH₂,</li><li>(e) C₁-C₄-alkylamino,</li><li>(f) di(C₁-C₄-alkyl)amino,</li><li>(g) SO₂NHR⁹,</li><li>(h) CF₃,</li><li>(i) C₁-C₆-alkyl,</li><li>(j) C₁-C₆-alkoxy,</li><li>(k) C₁-C₆-alkyl-S-,</li><li>(l) C₂-C₆-alkenyl,</li><li>(m) C₂-C₆-alkynyl;</li><li>(n) aryl,</li><li>(o) aryl(C₁-C₄-alkyl), or</li><li>(p) C₃-C₇-cycloalkyl;</li></ul></dd><dt>R^3a is</dt><dd><ul id="ul0003" list-style="none"><li>(a) H,</li><li>(b) Cl, Br, I, or F,</li><li>(c) C₁-C₆-alkyl,</li><li>(d) C₁-C₆-alkoxy, or</li><li>(e) C₁-C₆-alkoxyalkyl;</li></ul></dd><dt>R^3b is</dt><dd><ul id="ul0004" list-style="none"><li>(a) H,</li><li>(b) Cl, Br, I, or F,</li><li>(c) NO₂,</li><li>(d) C₁-C₆-alkyl,</li><li>(e) C₁-C₆-acyloxy,</li><li>(f) C₃-C₇-cycloalkyl,</li><li>(g) C₁-C₆-alkoxy,</li><li>(h) -NHSO₂R⁴,</li><li>(i) hydroxy(C₁-C₄-alkyl),</li><li>(j) aryl(C₁-C₄-alkyl),</li><li>(k) C₁-C₄-alkylthio,</li><li>(l) C₁-C₄-alkyl sulfinyl,</li><li>(m) C₁-C₄-alkyl sulfonyl,</li><li>(n) NH₂,</li><li>(o) C₁-C₄-alkylamino,</li><li>(p) di(C₁-C₄-alkyl)amino,</li><li>(q) fluoro-C₁-C₄-alkyl-,</li><li>(r) -SO₂-NHR⁹,</li><li>(s) aryl,</li><li>(t) furyl,</li><li>(u) CF₃,</li><li>(v) C₂-C₆-alkenyl, or</li><li>(w) C₂-C₆-alkynyl;</li></ul> wherein aryl is phenyl or naphthyl, or a substituted phenyl or naphthyl with one or two substituents selected from the group consisting of Cl, Br, I, F, N(R⁴)₂, CO₂R⁴, C₁-C₄-alkyl, C₁-C₄-alkoxy, NO₂, CF₃, C₁-C₄-alkylthio, OH, or SO_x(C₁-C₄-alkyl);</dd><dt>R⁴ is</dt><dd>H, aryl, C₁-C₆ alkyl, or substituted C₁-C₆ alkyl in which substituent is aryl or heteroaryl;</dd><dt>R^4a is</dt><dd>aryl, C₁-C₆-alkyl or a substituted C₁-C₆-alkyl with an aryl substituent;</dd><dt>R⁵ is</dt><dd>H, <chemistry id="chem0012" num="0012"><img file="EP0502575A1_D0012.tif" /></chemistry> provided that when R⁴ is H, R⁵ is not H;</dd><dt>E is</dt><dd>a single bond, -NR¹³(CH₂)_s-, -S(O)x(CH₂)_s- where s is 0 to 5, or CO-;</dd><dt>R⁶ is</dt><dd><ul id="ul0005" list-style="none"><li>(a) aryl, or a substituted aryl with 1 or 2 substituents selected from the group consisting of Cl, Br, I, F, -0-C₁-C₄-alkyl, C₁-C₄-alkyl, -NO₂, -CF₃, -SO₂NR⁹R¹⁰, -S-C₁-C₄-alkyl, -OH, -NH₂, C₃-C₇-cycloalkyl, or C₃-C₁₀-alkenyl,</li><li>(b) C₁-C₆-alkyl, C₂-C₅-alkenyl or C₂-C₅-alkynyl, or a substituted C₁-C₆-alkyl, a substituted C₂-C₅-alkenyl or a substitued C₂-C₅-alkynyl, in which the substituent is selected from the group consisting of aryl, C₃-C₇-cycloalkyl, Cl, Br, I, F, CF₃, CF₂CF₃, -NH₂, -NH(C₁-C₄-alkyl), -OR⁴ -N(C₁-C₄-alkyl)₂, -NH-SO₂R⁴, -COOR⁴, or -SO₂NHR⁹,</li><li>(c) an unsubstituted, monosubstituted or disubstituted heteroaromatic 5 or 6 membered cyclic ring which contains one to three members selected from the group consisting of N, O, S, and wherein the substituents are members selected from the group consisting of -OH, -SH, C₁-C₄-alkyl, C₁-C₄-alkoxy, -CF₃, Cl, Br, I, F, or NO₂</li><li>(d) C₃-C₇-cycloalkyl,</li><li>(e) perfluoro-C₁-C₄-alkyl, or</li><li>(f) H;</li></ul></dd><dt>R^7a, R^7b, R^8a and R^8b are</dt><dd>independently <ul id="ul0006" list-style="none"><li>(a) H,</li><li>(b) C₁-C₈-alkyl or a substituted C₁-C₈-alkyl with a substituent selected from the group consisting of -OH, -guanidino, C₁-C₄-alkoxy, -N(R⁴)₂, COOR⁴, -CON(R⁴)₂, -O-COR⁴, -aryl, -heteroaryl, -S(O)_x-R²², -tetrazol-5-yl, -CONHSO₂R²², -SO₂NH-heteroaryl, -SO₂NHCOR²², -PO(OR⁴)₂, -PO(OR⁴)R⁹, -SO₂NH-CN, -NR¹⁰COOR²², -(CH₂)₁₋₄R⁴, -CO-R⁴, -CO-heteroaryl, -NR⁴CONR⁴R²², -NR⁴COR²², <chemistry id="chem0013" num="0013"><img file="EP0502575A1_D0013.tif" /></chemistry></li><li>(c) -C₃-C₇-cycloalkyl,</li><li>(d) aryl-C₁-C₆alkyl in which the aryl group is unsubstituted, mono or disubstituted with V or W,</li><li>(e) aryl or substituted aryl in which the substituents are V or W,</li><li>(f) Cl, Br, I, or F,</li><li>(g) -OR^22a,</li><li>(h) -C₁-C₄-perfluoroalkyl,</li><li>(i) -S(O)_x-R²²,</li><li>(j) -COOR⁴,</li><li>(k) -SO₃H,</li><li>(l) -NR⁴R²²,</li><li>(m) -NR^22aCOR²²,</li><li>(n) -NR^22aCOOR²²,</li><li>(o) -SO₂NR⁴R⁹,</li><li>(p) -NO₂,</li><li>(q) -N(R^22a)SO₂R²²,</li><li>(r) -NR^22aCONR⁴R²²,</li><li>(s) <chemistry id="chem0014" num="0014"><img file="EP0502575A1_D0014.tif" /></chemistry></li><li>(t) -NHSO₂R²²,</li><li>(u) -SO₂NH-heteroaryl,</li><li>(v) -SO₂NHCOR²²,</li><li>(w) -CONHSO₂R²²,</li><li>(z) -PO(OR⁴)₂,</li><li>(y) -PO(OR⁴)R⁴,</li><li>(z) -tetrazol-5-yl,</li><li>(aa) -CONH(tetrazol-5-yl),</li><li>(bb) -COR^22a,</li><li>(cc) -SO₂NHCN</li><li>(dd) -NR^22aSO₂NR⁴R²²,</li><li>(ee) -NR^22aSO₂OR²²</li><li>(ff) -CONR⁴R²²,</li><li>(gg) <chemistry id="chem0015" num="0015"><img file="EP0502575A1_D0015.tif" /></chemistry> where n=0 or 1,</li><li>(hh) <chemistry id="chem0016" num="0016"><img file="EP0502575A1_D0016.tif" /></chemistry></li><li>(ii) <chemistry id="chem0017" num="0017"><img file="EP0502575A1_D0017.tif" /></chemistry></li><li>(jj) <chemistry id="chem0018" num="0018"><img file="EP0502575A1_D0018.tif" /></chemistry></li><li>(kk) <chemistry id="chem0019" num="0019"><img file="EP0502575A1_D0019.tif" /></chemistry></li><li>(ll) heteroaryl as defined hereinabove, or</li><li>(mm)</li></ul><chemistry id="chem0020" num="0020"><img file="EP0502575A1_D0020.tif" /></chemistry></dd><dt>V and W are</dt><dd>independently: <ul id="ul0007" list-style="none"><li>(a) hydrogen,</li><li>(b) C₁-C₅-alkoxy,</li><li>(c) C₁-C₅-alkyl,</li><li>(d) hydroxy,</li><li>(e) C₁-C₅-alkyl-S(O)_x-,</li><li>(f) CN,</li><li>(g) NO₂,</li><li>(h) N(R⁴)₂,</li><li>(i) CON(R⁴)₂,</li><li>(j) CO₂R⁴,</li><li>(k) COR⁴,</li><li>(l) CF₃,</li><li>(m) Cl, Br, I, or F,</li><li>(n) hydroxy-C₁-C₅-alkyl,</li><li>(o) C₁-C₅-alkylthio,</li><li>(p) -SO₂NR⁹R¹⁰,</li><li>(q) C₃-C₇-cycloalkyl, or</li><li>(r) C₂-C₁₀-alkenyl;</li></ul></dd><dt>R⁹ is</dt><dd>H, C₁-C₅-alkyl, aryl or arylmethyl;</dd><dt>R¹⁰ is</dt><dd>H, C₁-C₄-alkyl;</dd><dt>R¹¹ is</dt><dd>H, C₁-C₆-alkyl, C₁-C₄-alkenyl, C₁-C₄-alkoxy alkyl, or <chemistry id="chem0021" num="0021"><img file="EP0502575A1_D0021.tif" /></chemistry></dd><dt>R¹² is</dt><dd>-CN, -NO₂, -CF₃ or -CO₂R⁴;</dd><dt>R¹³ is</dt><dd>H, (C₁-C₄-alkyl)CO-, C₁-C₆-alkyl, allyl, C₃-C₆-cycloalkyl, aryl or arylmethyl;</dd><dt>R¹⁴ is</dt><dd>H, C₁-C₈-alkyl, C₁-C₈-perfluoroalkyl, C₃-C₆-cycloalkyl, aryl or arylmethyl;</dd><dt>R¹⁵ is</dt><dd>H, C₁-C₆-alkyl;</dd><dt>R¹⁶ is</dt><dd>H, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, aryl or arylmethyl;</dd><dt>R¹⁷ is</dt><dd>-NR⁹R¹⁰, -OR¹⁰, -NHCONH₂, -NHCSNH₂, <chemistry id="chem0022" num="0022"><img file="EP0502575A1_D0022.tif" /></chemistry></dd><dt>R¹⁸ and R¹⁹ are</dt><dd>independently C₁-C₄-alkyl or taken together are -(CH₂)_q- where q is 2 or 3;</dd><dt>R²⁰ is</dt><dd>H, -NO₂, -NH₂, -OH or -OCH₃;</dd><dt>R²¹ is</dt><dd><ul id="ul0008" list-style="none"><li>(a) H,</li><li>(b) Cl, F, Br or I,</li><li>(c) aryl,</li><li>(d) heteroaryl, or</li><li>(e) C₁-C₄-alkyl or a substituted C₁-C₄-alkyl with a substituent selected from the group consisting of aryl, heteroaryl, -OH, -NH₂, -NH(C₁-C₄-alkyl), -N(C₁-C₄-alkyl)₂, -CO₂R^4a, Cl, Br, F, I, or -CF₃;</li></ul></dd><dt>R²² is</dt><dd><ul id="ul0009" list-style="none"><li>(a) aryl,</li><li>(b) heteroaryl,</li><li>(c) C₃-C₇-cycloalkyl,</li><li>(d) C₁-C₆-alkyl or a substituted C₁-C₆-alkyl with one or two substituents selected from the group consisting of 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, -PO(OH)(O-C₁-C₄-alkyl), -PO(OR⁴)R⁹, morpholinyl, -SO_xR⁴ piperazinyl-4-COR²² or C₁-C₄alkylpiperazinyl, or</li><li>(e) perfluoro-C₁-C₄-alkyl;</li></ul></dd><dt>R^22a is</dt><dd><ul id="ul0010" list-style="none"><li>(a) hydrogen,</li><li>(b) aryl,</li><li>(c) heteroaryl,</li><li>(d) C₃-C₇-cycloalkyl,</li><li>(e) C₁-C₆-alkyl or a substituted C₁-C₆-alkyl with a substituent selected from the group consisting of 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, -PO(OH)(O-C₁-C₄-alkyl), -PO(OR⁴)R⁹, morpholinyl, -SO_xR⁴, piperazinyl-4-COR²², or C₁-C₄alkylpiperazinyl,</li><li>(f) perfluoro-C₁-C₄-alkyl, or</li><li>(g) CH₂CH₂(C₂-C₄-alkenyl);</li></ul></dd><dt>X is</dt><dd><ul id="ul0011" list-style="none"><li>(a) a carbon-carbon single bond,</li><li>(b) -CO-,</li><li>(c) -O-,</li><li>(d) -S-,</li><li>(e) <chemistry id="chem0023" num="0023"><img file="EP0502575A1_D0023.tif" /></chemistry></li><li>(f) <chemistry id="chem0024" num="0024"><img file="EP0502575A1_D0024.tif" /></chemistry></li><li>(g) <chemistry id="chem0025" num="0025"><img file="EP0502575A1_D0025.tif" /></chemistry></li><li>(h) -OCH₂-,</li><li>(i) -CH₂O-</li><li>(j) -SCH₂-,</li><li>(k) -CH₂S-,</li><li>(l) -NHC(R⁹)(R¹⁰),</li><li>(m) -NR⁹SO₂-,</li><li>(n) -SO₂NR⁹-,</li><li>(o) -C(R⁹)(R¹⁰)NH-,</li><li>(p) -CH=CH-,</li><li>(q) -CF=CF-,</li><li>(r) -CH=CF-,</li><li>(s) -CF=CH-,</li><li>(t) -CH₂CH₂-,</li><li>(u) -CF₂CF₂-,</li><li>(v) <chemistry id="chem0026" num="0026"><img file="EP0502575A1_D0026.tif" /></chemistry></li><li>(w) <chemistry id="chem0027" num="0027"><img file="EP0502575A1_D0027.tif" /></chemistry></li><li>(x) <chemistry id="chem0028" num="0028"><img file="EP0502575A1_D0028.tif" /></chemistry></li><li>(y) <chemistry id="chem0029" num="0029"><img file="EP0502575A1_D0029.tif" /></chemistry> or</li><li>(z)</li></ul><chemistry id="chem0030" num="0030"><img file="EP0502575A1_D0030.tif" /></chemistry></dd><dt>r is</dt><dd>1 or 2,</dd><dt>x is</dt><dd>0 to 2, and the pharmaceutically acceptable salts thereof.</dd></dl>

0009The terms "alkyl," "alkenyl," "alkynyl," and the like include both the straight chain and branched chain species of these generic terms wherein the number of carbon atoms 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 means the normal butyl substituent, <u>n</u>-butyl.

0010One embodiment of this invention is represented by the compounds of the formula (I) wherein: <dl id="dl0002"><dt>R¹ is</dt><dd><ul id="ul0012" list-style="none"><li>(a) -CO₂R⁴,</li><li>(b) <chemistry id="chem0031" num="0031"><img file="EP0502575A1_D0031.tif" /></chemistry></li><li>(c) -NH-SO₂R²²;</li><li>(d) -SO₂NH-heteroaryl,</li><li>(e) -CH₂SO₂NH-heteroaryl,</li><li>(f) -SO₂NH-CO-R²²,</li><li>(g) -CH₂SO₂NH-CO-R²²,</li><li>(h) -CONH-SO₂R²²,</li><li>(i) -CH₂CONH-SO₂R²²,</li><li>(j) -NHSO₂NHCO-R²²,</li><li>(k) -NHCONHSO₂-R²², or</li><li>(l) -SO₂NHCN;</li></ul></dd><dt>R^2a is</dt><dd>H;</dd><dt>R^2b is</dt><dd>H, F, Cl, CF₃, NO₂, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, or aryl;</dd><dt>R^3a is</dt><dd>H;</dd><dt>R^3b is</dt><dd>H, F, Cl, CF₃, NO₂, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₅-C₆-cycloalkyl, -COOCH₃, -COOC₂H₅, -SO₂-CH₃, NH₂, -N(C₁-C₄-alkyl)₂ or -NH-SO₂CH₃;</dd><dt>E is</dt><dd>a single bond, -O- or -S-;</dd><dt>R⁶ is</dt><dd><ul id="ul0013" list-style="none"><li>(a) C₁-C₅ alkyl or a substituted C₁-C₅ alkyl with a substituent selected from the group consisting of C₃-C₅-cycloalkyl, Cl, CF₃, CCl₃, -O-CH₃, -OC₂H₅, -S-CH₃, -S-C₂H₅, phenyl, or F;</li><li>(b) C₂-C₅-alkenyl or C₂-C₅-alkynyl; or,</li><li>(c) C₃-C₅-cycloalkyl;</li></ul></dd><dt>R^7a, R^7b, R^8a and R^8b are</dt><dd>independently <ul id="ul0014" list-style="none"><li>(a) H,</li><li>(b) C₁-C₈-alkyl or a substituted C₁-C₈-alkyl with a COOR, OCOR^4a, OH, aryl, -(CH₂)₁₋₄R⁴, -CO-R⁴, -CO-heteroaryl, <chemistry id="chem0032" num="0032"><img file="EP0502575A1_D0032.tif" /></chemistry> substituent,</li><li>(c) OR^22a,</li><li>(d) -NO₂,</li><li>(e) <chemistry id="chem0033" num="0033"><img file="EP0502575A1_D0033.tif" /></chemistry></li><li>(f) -CONR⁴R²²,</li><li>(g) <chemistry id="chem0034" num="0034"><img file="EP0502575A1_D0034.tif" /></chemistry></li><li>(h) -NR⁴R²²,</li><li>(i) Cl, F, or Br,</li><li>(j) -CF₃,</li><li>(k) -CO₂R⁴,</li><li>(l) -CO-aryl,</li><li>(m) -S(O)_x-R²²,</li><li>(n) -SO₂-NR⁴R⁹,</li><li>(o) -N(R^22a)SO₂R²²,</li><li>(p) aryl,</li><li>(q) heteroaryl,</li><li>(r) -N(R^22a)CONR⁴R²²,</li><li>(s) -N(R^22a)SO₂N(R⁴)R²²,</li><li>(t) -N(R^22a)SO₂OR²²,</li><li>(u) <chemistry id="chem0035" num="0035"><img file="EP0502575A1_D0035.tif" /></chemistry></li><li>(v) <chemistry id="chem0036" num="0036"><img file="EP0502575A1_D0036.tif" /></chemistry></li><li>(w) <chemistry id="chem0037" num="0037"><img file="EP0502575A1_D0037.tif" /></chemistry> or</li><li>(x)</li></ul><chemistry id="chem0038" num="0038"><img file="EP0502575A1_D0038.tif" /></chemistry></dd><dt>R²¹ is</dt><dd>H, F, or Cl;</dd><dt>X is</dt><dd>a single bond;</dd><dt>r is</dt><dd>one.</dd></dl>

0011A class of this embodiment is represented by the compound of the formula (I) <dl id="dl0003"><dt>R¹ is</dt><dd><ul id="ul0015" list-style="none"><li>(a) -CO₂R⁴,</li><li>(b) <chemistry id="chem0039" num="0039"><img file="EP0502575A1_D0039.tif" /></chemistry></li><li>(c) -NH-SO₂-R²²,</li><li>(d) -SO₂NH-heteroaryl,</li><li>(e) -SO₂NH-CO-R²²,</li><li>(f) -CONH-SO₂R²², or</li><li>(e) -SO₂NHCN;</li></ul></dd><dt>E is</dt><dd>a single bond;</dd><dt>R^2b and R^3b</dt><dd>independently are H, -C₁-C₄-alkyl, -C₂-C₄-alkenyl, -C₂-C₄-alkynyl, -Cl, -F, NO₂, or CF₃;</dd><dt>R⁶ is</dt><dd>-C₁-C₄-alkyl, -cyclopropyl, -CH₂CH₂CH₂CF₃, CH₂CH₂CF₃, -C₂-C₅-alkenyl, -CH₂OCH₃ or -cyclopropyl;</dd><dt>R^7a, R^7b, R^8a and R^8b are</dt><dd>each independently H, -C₁-C₄-alkyl, -NO₂, -NR⁴R²², -OCH₃, -N(R^22a)COOR²², -Cl, -CH₂COOR^4a, -S(O)_x-R²², alkyl, N(R^22a)CON(R⁴)R²², CH₂OCO(C₁-C₄-alkyl), N(R^22a)COR²², -F, -CH₂Ph, -CONR⁴R²², CO₂R⁴, aryl, heteroaryl, -C₁-C₄-alkyl-heteroaryl as defined hereinabove, <chemistry id="chem0040" num="0040"><img file="EP0502575A1_D0040.tif" /></chemistry>    Illustrating this class are the compounds of the following structural formula (II) <chemistry id="chem0041" num="0041"><img file="EP0502575A1_D0041.tif" /></chemistry> wherein:</dd><dt>R¹ is</dt><dd><ul id="ul0016" list-style="none"><li>(a) -CO₂R⁴,</li><li>(b) <chemistry id="chem0042" num="0042"><img file="EP0502575A1_D0042.tif" /></chemistry></li><li>(c) -SO₂NHCOR²²,</li><li>(d) -CONHSO₂R²²,</li><li>(e) -NHSO₂R²², or</li><li>(f) -SO₂NHCN;</li></ul></dd><dt>R^2a and R^2b are</dt><dd>independently hydrogen or C₁-C₄alkyl;</dd><dt>R⁶ is</dt><dd><ul id="ul0017" list-style="none"><li>(a) -C₁-C₄alkyl,</li><li>(b) -CH₂CH₂CH₂CF₃,</li><li>(c) -CH₂CH₂CF₃,</li><li>(d) -CH₂OCH₃, or</li><li>(e) cyclopropyl;</li></ul></dd><dt>R^7a is</dt><dd><ul id="ul0018" list-style="none"><li>(a) hydrogen,</li><li>(b) C₁-C₄alkyl,</li><li>(c) -NR⁴R²²,</li><li>(d) -NR^22aCONR⁴R²²,</li><li>(e) -NR^22aCOR²², or</li><li>(f) -NR^22aCO₂R²²;</li><li>(g) aryl as defined hereinabove,</li><li>(h) heteroaryl as defined hereinabove,</li><li>(i) <chemistry id="chem0043" num="0043"><img file="EP0502575A1_D0043.tif" /></chemistry></li><li>(j) <chemistry id="chem0044" num="0044"><img file="EP0502575A1_D0044.tif" /></chemistry></li><li>(k) <chemistry id="chem0045" num="0045"><img file="EP0502575A1_D0045.tif" /></chemistry></li><li>(l) <chemistry id="chem0046" num="0046"><img file="EP0502575A1_D0046.tif" /></chemistry></li><li>(m) <chemistry id="chem0047" num="0047"><img file="EP0502575A1_D0047.tif" /></chemistry> or</li><li>(n) <chemistry id="chem0048" num="0048"><img file="EP0502575A1_D0048.tif" /></chemistry></li></ul></dd><dt>R^7b is</dt><dd><ul id="ul0019" list-style="none"><li>(a) hydrogen</li><li>(b) C₁-C₄alkyl,</li><li>(c) F, or</li><li>(d) CO₂R⁴;</li></ul></dd><dt>R^8a is</dt><dd><ul id="ul0020" list-style="none"><li>(a) hydrogen,</li><li>(b) C₁-C₄alkyl,</li><li>(c) F;</li></ul></dd><dt>R^8b is</dt><dd><ul id="ul0021" list-style="none"><li>(a) hydrogen,</li><li>(b) C₁-C₄alkyl,</li><li>(c) -CO₂R⁴;</li></ul></dd><dt>R²¹ is</dt><dd>hydrogen or F.</dd></dl>

0012Exemplifying this class are the following compounds having the structure III: <chemistry id="chem0049" num="0049"><img file="EP0502575A1_D0049.tif" /></chemistry><tables id="tabl0001" num="0001"><img file="EP0502575A1_D0050.tif" /></tables><tables id="tabl0002" num="0002"><img file="EP0502575A1_D0051.tif" /></tables><tables id="tabl0003" num="0003"><img file="EP0502575A1_D0052.tif" /></tables><tables id="tabl0004" num="0004"><img file="EP0502575A1_D0053.tif" /></tables><tables id="tabl0005" num="0005"><img file="EP0502575A1_D0054.tif" /></tables><tables id="tabl0006" num="0006"><img file="EP0502575A1_D0055.tif" /></tables><tables id="tabl0007" num="0007"><img file="EP0502575A1_D0056.tif" /></tables><tables id="tabl0008" num="0008"><img file="EP0502575A1_D0057.tif" /></tables>

0013Further exemplifying this class are the following compounds having the structure IV: <chemistry id="chem0050" num="0050"><img file="EP0502575A1_D0058.tif" /></chemistry><tables id="tabl0009" num="0009"><table frame="all"><tgroup cols="8" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="19.68mm" /><colspec colnum="2" colname="col2" colwidth="19.68mm" /><colspec colnum="3" colname="col3" colwidth="19.68mm" /><colspec colnum="4" colname="col4" colwidth="19.68mm" /><colspec colnum="5" colname="col5" colwidth="19.68mm" /><colspec colnum="6" colname="col6" colwidth="19.68mm" /><colspec colnum="7" colname="col7" colwidth="19.68mm" /><colspec colnum="8" colname="col8" colwidth="19.68mm" /><thead valign="top"><row><entry namest="col1" nameend="col1" align="left">R¹</entry><entry namest="col2" nameend="col2" align="center">R^2a</entry><entry namest="col3" nameend="col3" align="center">R^2a</entry><entry namest="col4" nameend="col4" align="left">ER⁶</entry><entry namest="col5" nameend="col5" align="center">R²¹</entry><entry namest="col6" nameend="col6" align="center">R^8a</entry><entry namest="col7" nameend="col7" align="left">R^8b</entry><entry namest="col8" nameend="col8" align="left">R^7a</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">COOH</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Bu</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">H</entry></row><row><entry namest="col1" nameend="col1" align="left">TET</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">H</entry></row><row><entry namest="col1" nameend="col1" align="left">TET</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">Me</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">H</entry></row><row><entry namest="col1" nameend="col1" align="left">TET</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">F</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">H</entry></row><row><entry namest="col1" nameend="col1" align="left">TET</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">N(n-Pn)Bz</entry></row><row><entry namest="col1" nameend="col1" align="left">TET</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">Me</entry></row><row><entry namest="col1" nameend="col1" align="left">TET</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">c-Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">H</entry></row><row><entry namest="col1" nameend="col1" align="left">TET</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">N(n-Bu)CO₂-n-Bu</entry></row><row><entry namest="col1" nameend="col1" align="left">TET</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">N(n-Bu)COPh-4-F</entry></row><row><entry namest="col1" nameend="col1" align="left">SO₂NHCOPh-4-F</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Et</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">i-Pr</entry><entry namest="col8" nameend="col8" align="left">H</entry></row><row><entry namest="col1" nameend="col1" align="left">SO₂NHCOPh</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">N(Me)CONHiPr</entry></row><row><entry namest="col1" nameend="col1" align="left">SO₂NHCOPh</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">F</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">N(Me)CON(Me)iPr</entry></row><row><entry namest="col1" nameend="col1" align="left">TET</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Bu</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">COOH</entry><entry namest="col8" nameend="col8" align="left">H</entry></row><row><entry namest="col1" nameend="col1" align="left">TET</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Et</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">N(n-Pn)COPh-4-CF₃</entry></row><row><entry namest="col1" nameend="col1" align="left">SO₂NHCOPh</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">N(n-Pn)COPh</entry></row><row><entry namest="col1" nameend="col1" align="left">SO₂NHCOcPr</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">N(n-Pn)COPh</entry></row><row><entry namest="col1" nameend="col1" align="left">SO₂NHCOCH₂NH₂</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">N(n-Pn)CO-4-Cl</entry></row><row><entry namest="col1" nameend="col1" align="left">SO₂NHCOPn</entry><entry namest="col2" nameend="col2" align="left">Pr</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">NHCONHEt</entry></row><row><entry namest="col1" nameend="col1" align="left">SO₂NHCOPn</entry><entry namest="col2" nameend="col2" align="left">Pr</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Bu</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">NHCONHEt</entry></row><row><entry namest="col1" nameend="col1" align="left">SO₂NHCOBu</entry><entry namest="col2" nameend="col2" align="left">Pr</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Bu</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">NHCONHEt</entry></row><row><entry namest="col1" nameend="col1" align="left">SO₂NHCO(CH₂)₃OMe</entry><entry namest="col2" nameend="col2" align="left">Pr</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">NHCONHEt</entry></row><row><entry namest="col1" nameend="col1" align="left">SO₂NHCOPn</entry><entry namest="col2" nameend="col2" align="left">Pr</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Bu</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">2-Pyridyl</entry></row><row><entry namest="col1" nameend="col1" align="left">SO₂NHCOPn</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">Pr</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">NHCONHEt</entry></row><row><entry namest="col1" nameend="col1" align="left">SO₂NHCOPn</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">Pr</entry><entry namest="col4" nameend="col4" align="left">Bu</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">NHCONHEt</entry></row><row><entry namest="col1" nameend="col1" align="left">SO₂NHCOBu</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">Pr</entry><entry namest="col4" nameend="col4" align="left">Bu</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">NHCONHEt</entry></row><row><entry namest="col1" nameend="col1" align="left">SO₂NHCO(CH₂)₃OMe</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">Pr</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">NHCONHEt</entry></row><row><entry namest="col1" nameend="col1" align="left">SO₂NHCOPn</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">Pr</entry><entry namest="col4" nameend="col4" align="left">Bu</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">2-Pyridyl</entry></row><row><entry namest="col1" nameend="col1" align="left">TET</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">Pr</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">N(CH₂-2-Pyr)Bz</entry></row><row><entry namest="col1" nameend="col1" align="left">TET</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">N(CH₂-2-Pyr)CO-2-Pyr</entry></row><row><entry namest="col1" nameend="col1" align="left">TET</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">N(Bn)CO-2-Pyr</entry></row><row><entry namest="col1" nameend="col1" align="left">TET</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">N(Bn)CO₂Et</entry></row><row><entry namest="col1" nameend="col1" align="left">TET</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">N(Pn)CO-4-Pyr</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">TET</entry><entry namest="col2" nameend="col2" align="left">H</entry><entry namest="col3" nameend="col3" align="left">H</entry><entry namest="col4" nameend="col4" align="left">Pr</entry><entry namest="col5" nameend="col5" align="left">H</entry><entry namest="col6" nameend="col6" align="left">H</entry><entry namest="col7" nameend="col7" align="left">H</entry><entry namest="col8" nameend="col8" align="left">NHCON(CH₃)iPr</entry></row></tbody></tgroup></table></tables>

0014The compounds of Formula (I) can be synthesized using the reactions and techniques described below. The reaction are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effective. It is understood by those skilled in the art of organic synthesis that the functionality present on the heterocycle and other parts of the structure should be consistent with the chemical transformations proposed. Depending upon the reactions and techniques employed, this may involve changing the order of the synthetic steps, the use of required protecting groups followed by deprotection, and, depending upon the particular pyrimidinone fused heterocycle being formed, the use of different strategies may be employed regarding the cyclization steps and the particular starting materials utilized. <tables id="tabl0010" num="0010"><img file="EP0502575A1_D0059.tif" /></tables><tables id="tabl0011" num="0011"><img file="EP0502575A1_D0060.tif" /></tables>

0015Compounds of Formula (I) may be prepared via intermediate <u>4</u> by alkylation of the anion of 1(2H) isoquinolinone <u>2</u> with alkylating agent <u>3</u> (<u>Scheme 1</u>). Alternatively, the isoquinolinone may be converted to a silyl imine and then regioselectively alkylated on nitrogen by treatment with the alkylating agent in the presence of fluoride ion. Deprotection of the R¹ protecting group of intermediate product <u>4</u> will give rise to compounds of Formula I. Alternatively, if R¹ is nitrile and a tetrazole is desired, trimethyltin azide will convert the intermediate <u>4</u> to <u>1</u> where R¹ is tetrazole.

SCHEME 1

0016<chemistry id="chem0051" num="0051"><img file="EP0502575A1_D0061.tif" /></chemistry> Q = halogen, -O-tosyl or -O-mesyl <ul id="ul0022" list-style="none"><li>a. NaH, DMF</li><li>b. (i) (CH₃)₃Si)₂NH or (CH₃)₃SiCl/Et₃N (ii) <u>3</u>, F⁻</li></ul>    Isoquinolinones <u>2</u> and 2,3-disubstituted isoquinolinones <u>4</u> may be prepared from isocoumarins <u>6</u> (<u>Scheme 2</u>). There are many synthetic approaches available to isocoumarins. [Compendium of Heterocyclic Chemistry] Treatment of an isocoumarin with ammonia will give rise to the isoquinolinones <u>2</u>. Treatment of the isocoumarin with an alkyl amine <u>7</u> will give rise to the 2-substituted isoquinolinone <u>4</u>. Both <u>2</u> and <u>4</u> may then be transformed into compounds of Formula I as shown in Scheme 1.

SCHEME 2

0017<chemistry id="chem0052" num="0052"><img file="EP0502575A1_D0062.tif" /></chemistry>

0018One of the most useful methods of preparing 1(2H)-isoquinolinones is from homophthalic anhydrides <u>8</u> (<u>Scheme 3</u>). [R.B. Tirodkar, R.N. Usgaonkar. <u>Indian J. Chemistry</u>, 1060, 1972] Acylation of <u>8</u> under basic conditions with anhydrides gives rise to intermediate 4-acylisochroman-1,3-diones <u>9</u>. In a similar fashion the diacid <u>10</u> may also be converted to <u>9</u>. Treatment of <u>9</u> with ammonia will give rise to 1(2H)-isoquinolinones <u>2</u>. Alternatively, acid treatment results in decarboxylation and formation of an isocoumarin <u>6</u>. Both <u>2</u> and <u>6</u> may in turn be converted to compounds of Formula I by following <u>Schemes 1</u> and <u>2</u> respectively.

SCHEME 3

0019<chemistry id="chem0053" num="0053"><img file="EP0502575A1_D0063.tif" /></chemistry><ul id="ul0023" list-style="none"><li>a. (R⁶CO)₂O, py</li><li>b. H₂SO₄, 95°C.</li></ul>

0020There are several other direct routes to 1(2H)-isoquinolinones <u>2</u> shown in <u>Scheme 4</u>. Treatment of <u>11</u> with an alkyl metal enolate and irradiation will give rise directly to a 1(2H)-isoquinolinone <u>2</u>. [R. Beugelmans, M. Bois-Coussy. <u>Synthesis</u>. 729, 1981] Similarly, o-iodo benzamides <u>12</u> may be alkylated with copper acetylides in pyridine to give intermediate acetylide <u>13</u>. These may be cyclized to <u>2</u> under palladium catalysis in the presence of sodium hydride in THF to give <u>2</u>. [A. Nagarajam, T.R. Balasubramanian. <u>Ind. J. Chem</u>. 67, 1989] 2-Substituted indanones <u>14</u> may be rearranged to intermediate 2-alkyl-N-hydroxy-1(2H)-isoquinolinones <u>15</u> by treatment with an alkyl nitrite in the presence of acid. Reduction of <u>15</u> with, for example, iodine and red phosphorous will give 2. [E.J. Moriconi, F.J. Creegan. <u>J. Org. Chem.</u> 31, 2090, 1966] 2-N-Methyl benzamides <u>16</u> may be converted to the intermediate dilithio species with n-butyl lithium. Addition of an alkyl nitrile followed by acid gives rise to <u>2</u>. [G.S. Poindexter. <u>J. Org. Chem</u>. 3787, 1982] The 1-(2H)-isoquinolinones may be converted to compounds of formula I by following the chemistry described in <u>Scheme 1</u>.

SCHEME 4

0021<chemistry id="chem0054" num="0054"><img file="EP0502575A1_D0064.tif" /></chemistry><ul id="ul0024" list-style="none"><li>a. (i) nBuNO₂, H₂SO₄ (ii) MeOH, Δ</li><li>b. I₂, P</li><li>c. <chemistry id="chem0055" num="0055"><img file="EP0502575A1_D0065.tif" /></chemistry> hv</li><li>d. (i) BuLi, (ii) R⁶CN, (iii) H⁺</li><li>e. Cu-C≡C -R⁶, pyridine</li><li>f. PdCl₂, CH₃CN, NaH, THF.</li></ul>

0022Two alternative routes directly to 2,3-disubstituted isoquinolinones <u>5</u> may be available as shown in <u>Scheme 5</u>. Irradiation of N-vinyl benzamides <u>18</u> in methanol followed by oxidation by treatment with iodine will give rise to 2,3-disubstituted isoquinolinones <u>5</u>. [A. Couture, P. Grandclaudin. <u>Synthesis</u>, 576, 1985] Alternatively, 2-methyl benzamides <u>19</u> may be dilithiated with n-butyl lithium and treated with an amide <u>20</u> to give the 2,3-disubstituted isoquinolinone <u>5</u>. Compound <u>5</u> may then be converted to (I) as shown in <u>Scheme 2</u>.

SCHEME 5

0023<chemistry id="chem0056" num="0056"><img file="EP0502575A1_D0066.tif" /></chemistry><ul id="ul0025" list-style="none"><li>a. hv, argon, CH₃OH, I₂</li><li>b. (i) BuLi, (ii) R⁶CON(CH₃)₂.</li></ul>

0024The benzyl halides (<u>3</u>) including the more preferred alkylating agents (<u>21a</u> and <u>21b</u>, <u>Scheme 6</u>) can be prepared as described in European Patent Applications 253,310 and 291,969 and the references cited therein. However, a preferred method to prepare the biphenyl precursors <u>22a</u>, <u>22b</u> and <u>22b</u>, using Ni(O) or Pd(O) catalyzed cross-coupling reaction [E. Negishi, T. Takahashi, and A. O. King, <u>Org. Synthesis</u>, <u>66</u>, 67 (1987)], is outlined in <u>Scheme 6</u>. As shown in <u>Scheme 6</u>, treatment of 4-bromotoluene (<u>23</u>) with t-BuLi, followed by the addition of a solution of ZnCl₂, produces the organo-zinc compound (<u>24</u>). Compound (<u>24</u>) is then coupled with <u>25a</u> or <u>25b</u> in the presence of Ni(PPh₃)₂Cl₂ catalyst to produce the desired biphenyl compound <u>22a</u> or <u>22b</u> (PPh₃=triphenylphosphine). Similarily, 1-iodo-2-nitro-benzene (<u>25c</u>) is coupled with organo-zinc compound <u>24</u> in the presence of Pd(PPh₃)₄ catalyst [prepared by treating Cl₂Pd(PPh₃)₂ with (i-Bu)₂AlH (2 equiv.)] to give the biphenyl compound <u>22c</u>. These precursors, <u>22a</u>, <u>22b</u> and <u>22c</u>, are then transformed into halomethylbiphenyl derivatives <u>21a</u>, <u>21b</u> and <u>21c</u>, respectively, according to procedures described in European Parent Applications 253,310 and 291,969.

SCHEME 6

0025<chemistry id="chem0057" num="0057"><img file="EP0502575A1_D0067.tif" /></chemistry>

0026When there is additional substitution on the second phenyl ring (R^2a, R^2b = hydrogen) the preferred method to prepare the biphenyl precursors <u>22d</u> and <u>22e</u>, using the Pd(O) catalyzed cross-coupling reaction [J. K. Stille, <u>Angew. Chem. Int. Ed. Engl</u>., <u>25</u>, 508 (1986)], is outlined in reaction Scheme 7. As shown in <u>Scheme 7</u>, p-tolyltrimethyltin (<u>26</u>) is coupled with <u>25d</u> or <u>25e</u> in refluxing toluene in the presence of 5 mole % of Pd(PPh₃)₄ to produce the desired biphenyl compounds <u>22d</u> and <u>22e</u>. Table I illustrates the synthetic utility of this protocol. Compounds 22d (R² = NO₂) and 22e (R² = NO₂) could be converted to their respective chlorides by catalytic hydrogenation, diazotization and treatment with copper (I) chloride. The biphenyl fluorides which could not be obtained by direct coupling to a fluoro arylbromide were prepared from <u>22d</u> (R² = NO₂) and <u>22e</u> (R² = NO₂) via reduction, formation of the diazonium tetrafluoroborate salt and thermal decomposition. These precursors <u>22d</u> (R² = NO₂ or F or Cl) and <u>22e</u> (R² = NO₂ or F or Cl) are then transformed into the halomethyl biphenyl derivatives <u>21d</u> and <u>21e</u>, respectively according to the procedures described in European Patent Applications 253,310 and 292,969. <tables id="tabl0012" num="0012"><img file="EP0502575A1_D0068.tif" /></tables>

REACTION SCHEME 7

0027<chemistry id="chem0058" num="0058"><img file="EP0502575A1_D0069.tif" /></chemistry>

0028Compounds of formula I where R¹ is -CONHSO₂R²² (where R²² = alkyl, aryl or heteroaryl) may be prepared from the corresponding carboxylic acid derivatives (<u>27</u>) as outlined in <u>Scheme 8</u>. The carboxylic acid (<u>27</u>), obtained as described in <u>Scheme 2</u>, can be converted into the corresponding acid chloride by treatment with refluxing thionyl chloride or preferably with oxalyl chloride and a catalytic amount of dimethylformamide at low temperature [A.W. Burgstahler, L.O. Weigel, and C.G. Shaefer-<u>Synthesis</u>, 767, (1976)]. The acid chloride then can be treated with the alkali metal salt of R²²SO₂NH₂ to form the desired acylsulfonamide (<u>28</u>). Alternatively, these acylsulfonamides may be prepared from the carboxylic acids using N,N-diphenylcarbamoyl anhydride intermediates [F.J. Brown <u>et</u><u>al</u>, European Patent Application, EP 199543; K.L. Shepard and W. Halczenko- <u>J. Het. Chem.</u>, <u>16</u>, 321 (1979)]. Preferably the carboxylic acids can be converted into acyl-imidazole intermediates, which then can be treated with an appropriate aryl or alkylsulfonamide and diazabicycloundecane (DBU) to give the desired acylsulfonamide <u>28</u> [J.T. Drummond and G. Johnson, <u>Tetrahedron. Lett.</u>, <u>28</u>, 1653 (1988)].

SCHEME 8

0029<chemistry id="chem0059" num="0059"><img file="EP0502575A1_D0070.tif" /></chemistry>

*

Alternative Methods

:

0030<ul id="ul0026" list-style="none"><li>a) <ul id="ul0027" list-style="none"><li>(i) SOCl₂, reflux</li><li>(ii) R²²SO₂NH⁻M⁺ (where M is Na or Li)</li></ul></li><li>b) <ul id="ul0028" list-style="none"><li>(i) (COCl)₂-DMF, -20°C</li><li>(ii) R²²SO₂NH⁻M⁺</li></ul></li><li>c) <ul id="ul0029" list-style="none"><li>(i) N(N,N-Diphenylcarbamoyl)pyridinium chloride/aq. NaOH</li><li>(ii) R²²SO₂NH⁻M⁺.</li></ul></li></ul>

0031Compounds of formula I where R¹ is SO₂NHCOR²² or SO₂NHCN may be prepared as outlined in <u>Scheme 9</u>. The nitro compound, for example <u>22c</u> (prepared as described in <u>Scheme 6</u>), can be reduced to the corresponding amino compound and converted into aromatic diazoniun chloride salt, which then can be reacted with sulfur-dioxide in the presence of a copper (II) salt to form the corresponding arylsulfonyl chloride <u>29</u> [H. Meerwein, G. Dittmar, R. Gollner, K. Hafner, F. Mensch and O. Steifort, <u>Chem. Ber.</u>, <u>90</u>, 841 (1957); A.J. Prinsen and H. Cerfontain, Recueil, <u>84</u>, 24 (1965); E.E. Gilbert, <u>Synthesis</u>, 3 (1969) and references cited therein]. The sulfonyl chloride can be reacted with ammonia in aqueous solution or in an inert organic solvent [F.H. Bergheim and W. Baker, <u>J. Amer.</u><u>Chem. Soc.</u>, 66, (1944), 1459], or with dry powdered ammonium carbonate, [E.H. Huntress and J.S. Autenrieth, <u>J. Amer. Chem. Soc.</u>, 63 (1941), 3446; E.H. Huntress and F.H. Carten, <u>J. Amer.</u><u>Chem. Soc.</u>, 62, (1940), 511] to form the sulfonamide <u>30</u>. The sulfonamide must then be protected preferably with the triphenylmethyl group by reaction with triphenylmethylchloride and triethylamine to give <u>31</u>. The benzyl bromide <u>32</u> may be prepared from the sulfonamide <u>31</u> as outlined in <u>Scheme 6</u>, and then can be reacted with an alkali metal salt of an appropriate heterocyclic compound to form the key sulfonamide <u>33</u>. The sulfonamide <u>33</u> may then be acylated under appropriate conditions to give <u>34</u>. N-Cyanosulfonamides of structure <u>34a</u> may be prepared by alkylation of the sodium salt of <u>33</u> with cyanogen bromide. The sulfonamide <u>33</u> may be also prepared from the aromatic sulfonyl chloride <u>36</u> by treatment with ammonia. Compound <u>36</u> may be prepared from the aryl amine <u>35</u> as outlined in <u>Scheme 10</u>.

SCHEME 9

0032<chemistry id="chem0060" num="0060"><img file="EP0502575A1_D0071.tif" /></chemistry><ul id="ul0030" list-style="none"><li>a. <ul id="ul0031" list-style="none"><li>(i) H₂/Pd-C,</li><li>(ii) NaNO₂-HCl,</li><li>(iii) SO₂, AcOH, CuCl₂</li></ul></li><li>b. NH₃ or (NH₄)₂CO₃</li><li>c. (C₆H₅)₃CCl, Et₃N, CH₂Cl₂, 25°C</li><li>d. N-Bromosuccinimide</li><li>e. R²²COCl or R²²CO-Im or other acylating agents.</li></ul>

0033The compounds bearing R¹ as -SO₂NHR^y (where R^y is heteroaryl or R⁹) may be prepared by reacting the aromatic sulfonyl chloride <u>36</u> with appropriate heteroaryl amines as outlined in <u>Scheme 10</u> to give <u>37</u>. The sulfonyl chloride <u>36</u> may be prepared using similar chemistry to that outlined above. The sulfonyl chloride <u>36</u> may be the preferred intermediate for the synthesis of this class of compounds. The aromatic sulfonyl chlorides may also be prepared by reacting the sodium salt of aromatic sulfonic acids with PCl₅ or POCl₃ [C.M. Suter, <u>The</u><u>Organic Chemistry of Sulfur, John Wiley &amp; Sons</u>, 459, (1944)]. The aromatic sulfonic acid precursors may be prepared by chlorosulfonation of the aromatic ring with chlorosulfonic acid [E.H. Huntress and F.H. Carten, <u>J. Amer. Chem. Soc.</u>, <u>62</u>, 511 (1940)].

SCHEME 10

0034<chemistry id="chem0061" num="0061"><img file="EP0502575A1_D0072.tif" /></chemistry>

0035The biaryl sulfonamides <u>38</u> and <u>39</u> (described in <u>Scheme 9</u> as <u>31</u>) can be prepared alternatively using palladium(O) catalyzed cross-coupling reactions of appropriate aryl-organotin precursors [J.K. Stille, <u>Pure Appl. Chem.</u>, <u>57</u>, 1771 (1985); T.R. Baiely, <u>Tetrahedron Lett.</u>, <u>27</u>, 4407 (1986); D.A. Widdowson and Y.Z. Zhang, <u>Tetrahedron</u>, <u>42</u>, 2111 (1986)], as outlined in <u>Scheme 11</u>. The organotin compound <u>40</u> [S.M. Moerlein, J. Organometallic Chem., <u>319</u>, 29 (1987)], obtained from the aromatic precursor <u>41</u>, may be coupled with aryl sulfonamide <u>42</u> and <u>43</u> using Pd(PPh₃)₄ or (PPh₃)₂PdCl₂ as catalysts to give biaryl sulfonamide <u>38</u> and <u>39</u>. Similarly, the benzyl bromide <u>44</u> may be alternatively prepared from the appropriate organotin precursor <u>45</u> using the Pd(O) catalyzed cross-coupling reaction as outlined in <u>Scheme 12</u>.

SCHEME 11

0036<chemistry id="chem0062" num="0062"><img file="EP0502575A1_D0073.tif" /></chemistry><ul id="ul0032" list-style="none"><li>a. <ul id="ul0033" list-style="none"><li>(i) t-BuLi/ether, -78°C</li><li>(ii) Me₃SnCl</li></ul></li><li>b. <ul id="ul0034" list-style="none"><li>(i) NaNO₂/HCl</li><li>(ii) SO₂, CuCl₂</li></ul></li><li>c. Pd(PPh₃)₄, toluene, reflux or (PPh₃)₂PdCl₂, DMF, 90°C.</li></ul>

SCHEME 12

0037<chemistry id="chem0063" num="0063"><img file="EP0502575A1_D0074.tif" /></chemistry><ul id="ul0035" list-style="none"><li>a. t-BuMe₂Si-Cl/imidazole, DMF</li><li>b. t-BuLi, -78°C, Me₃SnCl</li><li>c tetrabutylammonium fluoride</li><li>d. CBr₄/Ph₃P.</li></ul>

0038The compounds bearing R¹= -CH₂SO₂NHCOR²² and -CH₂SO₂NHR²² may be prepared as outlined in <u>Scheme 13</u>. The key precursor aryl-methanesulfonyl chloride <u>46</u> may be prepared either from the reaction of arylmethylmagnesium chloride <u>47</u>, obtained from the corresponding benzyl chloride <u>48</u> and magnesium, or by oxidation of the aryl-methylthioacetate <u>49</u> (prepared from the benzyl bromide <u>50</u> with chlorine in presence of trace amount of water) [Bagnay and Dransch, <u>Chem. Ber.</u>, <u>93</u>, 784 (1960)]. Alternatively, the aryl-methylthioacetate <u>49</u> can be oxidized with sulfuryl chloride in presence of acetic anhydride to form arylmethylsulfinyl chloride [S. Thea and G. Cevasco, <u>Tet.</u><u>Lett.</u>, <u>28</u>, 5193 (1987)], which can be further oxidized with appropriate oxidizing agents to give the sulfonyl chloride <u>46</u>. The compounds <u>51</u> and <u>52</u> can be obtained by reacting the sulfonyl chloride <u>46</u> with appropriate amines.

SCHEME 13

0039<chemistry id="chem0064" num="0064"><img file="EP0502575A1_D0075.tif" /></chemistry><ul id="ul0036" list-style="none"><li>a. <ul id="ul0037" list-style="none"><li>(i) EtOCOCl/Et₃N, THF, 0°C</li><li>(ii) NaBH₄</li><li>(iii) CCl₄ or CBr₄/PPh₃</li></ul></li><li>b. AcSK</li><li>c. SO₂Cl₂</li><li>d. Cl₂, AcOH, H₂O or, <ul id="ul0038" list-style="none"><li>(i) SO₂Cl₂</li><li>(ii) oxidation</li></ul></li><li>e. R^yNH₂ or, <ul id="ul0039" list-style="none"><li>(i) NH₃</li><li>(ii) acylation.</li></ul></li></ul>

0040Compounds where R¹= -NHSO₂NHR²² may be prepared by the reaction of appropriate primary amines with the sulfamide <u>53</u> [S.D. McDermott and W.J. Spillane, <u>Synthesis</u>, 192 (1983)], as described in <u>Scheme 14</u>. The compound <u>53</u> may be obtained from the corresponding N-t-butylsulfamide <u>54</u> after treatment with anhydrous trifluoroacetic acid [J.D. Catt and W.L. Matier, <u>J. Org. Chem.</u>, <u>39</u>, 566 (1974)]. The N-t-butylsulfamide <u>54</u> may be prepared by the reaction of the aromatic amine <u>55</u> (prepared as in <u>Scheme 10</u>) with t-butylsulfamoyl chloride [W.L. Matier, W.T. Comer and D. Deitchman, <u>J. Med. Chem.</u>, <u>15</u>, 538 (1972)].

SCHEME 14

0041<chemistry id="chem0065" num="0065"><img file="EP0502575A1_D0076.tif" /></chemistry>

0042Further functionalization of compounds of Formula 1 where R^7a, R^7b, R^8a or R^8b is nitro is available through the following route (Scheme 15). The nitro group of <u>56</u> may be reduced to the amine <u>57</u> by reduction with hydrogen over palladium on carbon. The amine may then be acylated with acid chlorides to give amides under basic conditions. The acylation of the amine with chloroformates is best carried out in the presence of sodium hydride to form the anilinium anion. This anion reacts quickly with chloroformates to give the carbamates <u>58</u>. The carbamate may be isolated and then deprotonated with lithium hexamethyldisilazide and alkylated to give the N,N-dialkylated carbamates <u>59</u>. Alternatively this process may be carried out in one pot by first preforming the anilinium anion, acylating it and then deprotonating <u>in</u><u>situ</u> and alkylating with R⁴ iodide group to give <u>59</u>. The amine <u>57</u> reacts slowly with isocyanates to give ureas <u>60</u>. Trisubstituted ureas <u>61</u> may be prepared from the benzyl carbamate <u>58</u> (R²²= benzyl) by treatment with the magnesium salt of a secondary amine. The trisubstituted ureas may be N-alkylated by deprotonation with lithium hexamethyldisilazide and alkylation with an R⁴ iodide to give <u>62</u>. The amine may be further derivatized or converted to other groups by means of chemical procedures well known to those skilled in the art. Alternative R^22a groups may be converted from intermediates prepared using the above protocol. The methods of carrying out these conversions are well known to those skilled in the art.

0043Related amides may be prepared by acylation of compound <u>57</u> to give the primary amide <u>63</u> which may then be deprotected to give a compound of structure 1, or alternatively alkylated under basic conditions (NaOH, K₂CO₃, phase transfer catalyst) to give a trisubstituted amide of structure <u>64</u>.

SCHEME 15

0044<chemistry id="chem0066" num="0066"><img file="EP0502575A1_D0077.tif" /></chemistry><chemistry id="chem0067" num="0067"><img file="EP0502575A1_D0078.tif" /></chemistry><ul id="ul0040" list-style="none"><li>a. H₂, 10% Pd/C, EtAc; b. NaH, ClCO₂R²², DMF;</li><li>c. LiN(TMS)₂, R^22aI;</li><li>d. MeMgBr, R⁴NHR²², THF, reflux;</li><li>e. LiN(TMS)₂, R^22aI, DMF; f. R²²NCO, CH₂Cl₂</li></ul>

0045Compounds wherein R¹ = PO(OR⁵)₂ or PO(R⁹)(OR⁵) may be prepared as indicated in <u>Scheme 16</u>. Coupling of compound <u>26</u> with a dibromoaryl will give compound <u>60</u>. The aryl bromide <u>60</u> may be converted to an aryl phosphonic acid ester <u>61</u> or phosphinate <u>62</u>. These may in turn be brominated under free radical conditions and then attached to the requisite isoquinolinone ring as shown in <u>Scheme 1</u>.

SCHEME 16

0046<chemistry id="chem0068" num="0068"><img file="EP0502575A1_D0079.tif" /></chemistry>

0047It will be appreciated by those skilled in the art that functional group transformations can be conducted on aryl and heterocyclic rings to afford desired analogs. For example, esters may be converted to amides by heating them with amines and an amide nitrogen if present in the heterocycle may be alkylated using bases such as sodium hydride in DMF with the appropriate alkyl halide. Functional group protection throughout these syntheses will be chosen to be compatible with subsequent reaction conditions. Ultimately such protecting groups will be removed to generate the desired optimally active compounds of Formula I. For example, R¹ as carboxyl is often protected as its t-butyl ester which in the last step is removed by treatment with trifluoroacetic acid. Aqueous acetic acid at room temperature overnight is a preferred method to remove a trityl protecting group to liberate an R¹ tetrazole group.

0048The 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, alkali 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-D-glucamine, salts with amino acids like arginine, lysine, and the like. Also, salts with organic and inorganic acids may be prepared; e.g., HCl, HBr, H₂SO₄, H₃PO₄, methane-sulfonic, toluene-sulfonic, 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.

0049The 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 <u>in</u><u>vacuo</u> or by freeze-drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.

0050Angiotensin II (AII) is a powerful arterial vasoconstrictor, and it exerts its action by interacting with specific receptors present on cell membranes. The compounds described in the present invention act as competitive antagonists of AII at the receptors. In order to identify AII antagonists and determine their efficacy <u>in vitro</u>, the following two ligand-receptor binding assays were established.

Receptor binding assay using rabbit aortae membrane preparation:

0051Three frozen rabbit aortae (obtained from Pel-Freeze Biologicals) were suspended in 5mM Tris-0.25M Sucrose, pH 7.4 buffer (50 ml) homogenized, and then centrifuged. The mixture was filtered through a cheesecloth and the supernatant was centrifuged for 30 minutes at 20,000 rpm at 4°C. The pellet thus obtained was resuspended in 30 ml of 50mM Tris-5 mM MgCl₂ buffer containing 0.2% Bovine Serum Albumin and 0.2 mg/ml Bacitration and the suspension was used for 100 assay tubes. Samples tested for screening were done in duplicate. To the membrane preparation (0.25 ml) there was added ¹²⁵I-Sar¹Ile⁸-angiotensin II [obtained from New England Nuclear] (10µl; 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, pH 7.4 (4ml) and filtered through a glass fiber filter (GF/B Whatman 2.4" diameter). The filter was soaked in scintillation cocktail (10 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 ¹²⁵I-Sar¹Ile⁸-angiotensin II was presented as a measure of the efficacy of such compounds as AII antagonists.

Receptor assay using Bovine adrenal cortex preparation

0052Bovine adrenal cortex was selected as the source of AII receptor. Weighed tissue (0.1 g is needed for 100 assay tubes) was suspended in Tris.HCl (50mM), pH 7.7 buffer and homogenized. The homogenate was centrifuged at 20,000 rpm for 15 minutes. Supernatant was discarded and pellets resuspended in buffer [Na₂HPO₄ (10mM)-NaCl (120mM)-disodium EDTA (5mM) containing phenylmethane sulfonyl fluoride (PMSF)(0.1mM)]. (For screening of compounds, generally duplicates of tubes are used). To the membrane preparation (0.5 ml) there was added 3H-angiotensin II (50mM) (10µl) with or without the test sample and the mixture was incubated at 37°C for 1 hour. The mixture was then diluted with Tris buffer (4ml) and filtered through a glass fiber filter (GF/B Whatman 2.4" diameter). The filter was soaked in scintillation cocktail (10ml) 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 ³H-angiotensin II was presented as a measure of the efficacy of such compounds as AII antagonists.

Receptor assay using rat brain membrane preparation

0053Membranes from rat brain (thalamus, hypothamus and midbrain) were prepared by homogenization in 50 mM Tris HCl (pH 7.4), and centrifuged at 50,000 x g. The resulting pellets were washed twice in 100 mM NaCl, 5 mM Na₂·EDTA, 10 mM Na₂HPO₄ (pH 7.4) and 0.1 mM PMSF by resuspension and centrifugation. For binding assays, the pellets were resuspended in 160 volumes of binding assay buffer (100 mM NaCl, 10 mM Na₂HPO₄, 5 mM Na₂·EDTA, pH 7.4, 0.1 mM PMSF, 0.2 mg/ml soybean trypsin inhibitor, 0.018 mg/ml o-phenanthroline, 77 mg/ml dithiothreitol and 0.14 mg/ml bacitracin. For ¹²⁵I.Ile⁸-angiotensin II binding assays, 10 µl of solvent (for total binding), Sar¹,Ile⁸-angiotensin II (1 µM) (for nonspecific binding) or test compounds (for displacement) and 10 µl of [¹²⁵I]Sar¹,Ile⁸-angiotensin II (23-46 pM) were added to duplicate tubes. The receptor membrane preparation (500 µl) was added to each tube to initiate the binding reaction. The reaction mixtures were incubated at 37°C for 90 minutes. The reaction was then terminated by filtration under reduced pressure through glass-fiber GF/B filters and washed immediately 4 times with 4 ml of 5 mM ice-cold Tris HCl (pH 7.6) containing 0.15 M NaCl. The radioactivity trapped on the filters was counted using a gamma counter.

0054Using the methodology described above, representative compounds of this invention were evaluated and were found to exhibit an activity of at least IC₅₀&lt;50 µM, thereby demonstrating and confirming the utility of the compounds of the invention as effective A II antagonists.

0055The antihypertensive effects of the compounds described in the present invention may be evaluated using the methodology described below: Male Charles River Sprague-Dawley rats (300-375 gm) were anesthetized with methohexital (Brevital; 50 mg/kg i.p.) and the trachea was cannulated with PE 205 tubing. A stainless steel pithing rod (1.5 mm thick, 150 mm long) was inserted into the orbit of the right eye and down th spinal column. The rats were immediately placed on a Harvard Rodent Ventilator (rate - 60 strokes per minute, volumn - 1.1 cc per 100 grams body weight). The right carotid artery was ligated, both left and right vagal nerves were cut, and the left carotid artery was cannulated with PE 50 tubing for drug administration, and body temperature was maintained at 37°C by a thermostatically controlled heating pad which received input from a rectal temperature probe. Atropine (1 mg/kg i.v.) was then administered, and 15 minutes later propranolol (1 mg/kg i.v.). Thirty minutes later antagonists of the Formula I were administered intravenously or orally. Angiotensin II was then typically given at 5, 10, 15, 30, 45 and 60 minute intervals and every half hour thereafter for as long as the test compound showed activity. The change in the mean arterial blood pressure was recorded for each angiotensin II challenge and the percent inhibition of the angiotensin II response was calculated.

0056The compounds of the invention are useful in treating hypertension. They are also of value in the management of acute and chronic congestive heart failure. These compounds may also be expected to be useful in the treatment of secondary hyperaldosteronism, primary and secondary pulmonary hyperaldosteronism, primary and secondary pulmonary hypertension, renal failure such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, end stage renal disease, renal transplant therapy, and the like, renal vascular hypertension, left ventricular dysfunction, diabetic retinopathy and in the management of vascular disorders such as migraine, Raynaud's disease, luminal hyperclasia, and to minimize the atherosclerotic process. The application of the compounds of this invention for these and similar disorders will be apparent to those skilled in the art.

0057The compounds of this invention are also useful to treat elevated intraocular pressure and to enhance retinal blood flow 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.

0058In the management of hypertension and 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 suspensions 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 1 to 1000 mg. per patient per day which can be administered in single or multiple doses. Perferably, the dosage range will be about 2.5 to 250 mg. per patient per day; more preferably about 5 to 150 mg. per patient per day.

0059The compounds of this invention can also be administered in combination with other antihypertensives and/or diuretics and/or angiotensin converting enzyme inhibitors and/or calcium channel blockers. For example, the compounds of this invention can be given in combination with such compounds as amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, <u>rauwolfia</u><u>serpentina</u>, 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, and the like, as well as admixtures and combinations thereof.

0060The useful central nervous system (CNS) activities of the compounds of this invention are demonstrated and exemplified by the ensuing assays.

COGNITIVE FUNCTION ASSAY

0061The 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 of the scopolamine effect. Twenty-four hours later, the rats are returned 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 before training do not show this hesitation when tested 24 hours later. Efficacious test compounds can 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.

ANXIOLYTIC ASSAY

0062The 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 interval (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 fixed L1D1L2D2L3 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, 0.5 sec) on 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).

0063Drug testing in this paradigm is carried out under extinction conditions. During extinction, animals learn that responding for food in the dark is no longer punished by shock. Therefore, response rates gradually increase in the dark periods and 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 0.1 mg/kg to about 100 mg/kg.

DEPRESSION ASSAY

0064The 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 immobility 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 about 0.1 mg/kg to about 100 mg/kg.

SCHIZOPHRENIA ASSAY

0065The antidopaminergic activity of the compounds of this invention can be demonstrated in an apomorphine-induced sterotypy model. A clinically useful antipsychotic drug that is used as a positive control in this assay is haloperidol. The assay method is based upon the observation that stimulation 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 invention should be efficacious in this assay in the range of from about 0.1 mg/kg to about 100 mg/kg.

0066In 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 suspensions 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 10 to 4000 mg. per patient per day; more preferably about 20 to 2000 mg. per patient per day.

0067In order to obtain maximal enhancement of cognitive function, the compounds of this invention 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.

0068In 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.

0069In order to achieve optimal antidepressant activity, combinations of the compounds of 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.

0070In order to obtain maximal antipsychotic activity, the compounds of this invention may be combined with other antipsychotic agents such as promethazine, fluphenazine and haloperidol.

0071Typically, 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.

0072To illustrate these combinations, one of the angiotensin II antagonists of this invention effective clinically in the 2.5-250 milligrams per day range can be effectively 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) chlorothiazide (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 hydrochlorothiazide (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 angiotensin II antagonist of this invention (0.5-250 mg) are effective combinations to control blood 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 severity of the disease, weight of patient, special diets and other factors.

0073Typically, these combinations can be formulated into pharmaceutical compositions as discussed below.

0074About 1 to 100 mg. of compound or mixture of compounds of Formula I or a physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, 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.

0075Illustrative 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 such 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 wintergreen or cherry. When the unit dosage unitform is a capsule, it may contain, in addition to materials of the above type, a liquid 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 may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

0076Sterile 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 occuring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can be incorporated as required.

0077The following examples further illustrate the preparation of the compounds of Formula I and their incorporation into pharmaceutical compositions and, as such, are not to be considered or construed as limiting the invention recited in the appended claims.

EXAMPLE 1

3-Butyl-2-[(2'-(tetrazole-5-yl)biphen-4-yl)methyl]-1(2H)-isoquinolinone

(a)

3-n-Butyl-1(2H)-isoquinolinone

0078To a solution of 4 g (24 mmol) of homophthalic anhydride in 12 ml of dry pyridine in a 250 L 3 neck flask fitted with a reflux condenser and addition funnel at 0°C was added 5.4 g (45 mmol) of valeryl chloride in 16 ml of dry chloroform over 45 minutes. The reaction mixture was stirred for a further 1 hour and then was treated with 100 ml of conc. ammonium hydroxide dropwise. The mixture was refluxed for 2 hours and then allowed to stand overnight at room temperature. The two phases were separated and the organic phase was washed with water (1 x 20 ml). The organic phase was dried over MgSO₄, filtered and concentrated <u>in</u><u>vacuo</u>. The residue was recrystallized from hot MeOH/water to give a pale purple solid. ¹H-NMR (CDCl₃): 0.96 (t, 3H, J=7.2Hz), 1.45 (m, 2H), 1.73 (m, 2H), 2.64 (3 line m, 2H, J=7.8Hz), 6.32 (s, 1H), 7.37-7.67 (m, 3H), 8.37 (d, 1H, J=7.8Hz). FABMS: 202 (M⁺+1).

(b)

3-Butyl-2-[(2'-(N-triphenylmethyl-tetrazole-5-yl)biphen-4-yl)methyl]-1(2H)-isoquinolinone

0079To a suspension of 32.8 mg (1.09 mmol) of sodium hydride in 1.5 ml of dry DMF at 0°C was added 0.2 g (0.99 mmol) of 3-n-butyl-1(2H)-isoquinolinone as a solid. The solid dissolved with evolution of H₂ gas. After 1 hour 0.6 g (1.09 mmol) of N-triphenylmethyl-5-[2-(4'-bromomethylbiphenyl)]tetrazole was added dissolved in 2 ml of DMF. The reaction mixture was stirred overnight. The solution was diluted with 50 ml of EtOAc, washed with water (3 x 10 ml) and brine (1 x 10 ml), dried over MgSO₄ and concentrated <u>in</u><u>vacuo</u>. The product was purified by flash chromatography over silica eluting with 20% EtOAc/hexanes to give a thick oil. ¹H-NMR (CDCl₃): 0.87 (t, 3H, J=7.3Hz), 1.28 (m, 2H), 2.46 (t, 2H), J=7.7Hz), 5.30 (bs, 2H), 6.89 (m, 8H), 7.03 (d, 2H, J=7.8Hz), 7.17-7.31 (m, 10H), 7.42 (m, 4H), 7.61 (t, 1H, J=7.6Hz), 7.85 (dd, 1H, J=1.8, 7.6Hz), 8.40 (dd, 1H, J=0.7, 8.1Hz).

(c)

General Procedure for the Deprotection of the Tetrazole

0080The triphenyl methyl group was removed by dissolving, for example, 3-Butyl-2-[(2'-(N-triphenylmethyl-tetrazole-5-yl)biphen-4-yl)methyl]-1(2H)-isoquinolinone (0.33 g) in MeOH (5 ml) in the presence of several drops (3-5) of concentrated hydrochloride acid. After 2 hours at room temperature a few crystals of phenophthalien were added and the reaction mixture made basic by addition of 5N NaOH solution. The reaction mixture was reacidified by addition of acetic acid and then concentrated <u>in</u><u>vacuo</u>. The residue was dissolved in 20 ml of EtOAc and washed with water (3 x 5 ml) and brine (1 x 5 ml) and dried over MgSO₄. The mixture was filtered and concentrated <u>in</u><u>vacuo</u> and the residue was purified by flash chromatography over silica gel eluting with the solvent indicated below.

3-Butyl-2-[(2'-(tetrazole-5-yl)biphen-4-yl)methyl]-1(2H)-isoquinolinone

0081Purified by elution with 50% EtOAc/hexanes 1% acetic acid. ¹H-NMR (CDCl₃): 0.91 (t, 3H, J=7.4Hz), 1.39 (m, 2H), 1.62 (m, 2H), 2.60 (3 line m, 7.4Hz), 5.33 (bs, 2H), 6.44 (s, 1H), 7.02 (ABq, 4H, J=8.0Hz), 7.35 (m, 2H), 7.36 (m, 2H), 7.54 (t, 1H, J=7.7Hz), 7.61 (t, 1H, J=7.0Hz), 7.97 (bm, 1H), 8.17 (d, 1H, J=8.0Hz). FABMS=436 (M⁺+1).

EXAMPLE 2

7-(N-Methyl-N-isobutyloxycarbonyl)amino-3-propyl-2-[(2'-(tetrazole-5-yl)biphen-4-yl)methyl]-1(2H)-isoquinolinone

(a)

7-Nitro-3-propyl-1(2H)-isoquinolinone

0082To a mixture of 50 ml of butyric anhydride and 10 ml of pyridine in a dry flask was added 10 g (0.45 mol) of 4-nitrohomophthalic anhydride (prepared as in <u>J. Organic Chemistry</u>, 533, 1945). A thick red suspension formed which prevented efficient stirring. 50 ml of ether was added to facilitate stirring. After 3 hours the reaction mixture was filtered and the precipitate was washed with ether. The residue was dried under vacuum to give 15.3 g of a red solid. The solid was suspended in 250 ml of ammonium hydroxide and heated to 80°C for 3 hours. Further 20 ml portions of ammonium hydroxide were added at 45 minute intervals. The mixture was cooled to room temperature and filtered. The residue was recrystallized from hot ethanol to give yellow crystals. ¹H-NMR (CDCl₃): 1.04 (t, 3H, J=7.4Hz), 1.79 (m, 2H), 2.62 (3 line m, 2H, J=7.6Hz), 6.37 (s, 1H), 7.57 (d, 1H, J=8.8Hz), 8.39 (dd, 1H, J=2.4, 8.8Hz), 9.20 (d, 1H, J=2.1Hz).

(b)

7-Nitro-3-propyl-2-[(2'-(N-triphenylmethyl-tetrazole-5-yl)biphen-4-yl)methyl]-1(2H)-isoquinolinone

0083To a suspension of 0.377 g (0.0157 mol) of sodium hydride in 20 ml of dry DMF at 0°C was added 3.32 g (0.0143 mol) of 7-nitro-3-propyl-1(2H)-isoquinolinone as a solid. Some hydrogen evolution occured with formation of a deep red suspension. Addition of a further 10 ml of DMF failed to give complete solvation. After 30 minutes at room temperature the reaction mixture was cooled to 0°C and 8.74 g (0.0157 mol) of N-triphenylmethyl-5-[2-(4'-bromomethylbiphenyl)]tetrazole dissolved in 40 ml of dry DMF was added. The reaction mixture was stirred overnight at room temperature and poured into 300 ml of water. The suspension was filtered and the solid residue dissolved in 200 ml of CH₂Cl₂. The solution was washed with brine (2 x 20 ml) and dried over MgSO₄, filtered and concentrated <u>in</u><u>vacuo</u>. The residue was purified by flash chromatography over silica gel eluting with 50% EtOAc/hexanes to give a foam. This material was contaminated with a regioisomer to the extent of 10%. ¹H-NMR (CDCl₃): 0.83 (t, 3H), 1.62 (m, 2H), 2.50 (t, 2H), 5.31 (bs, 2H), 6.39 (s, 1H), 6.89 (m, 8H), 7.05 (d, 2H), 7.17-7.31 (m, 10H), 7.41 (m, 2H), 7.55 (d, 1H), 7.87 (d, 1H), 7.38 (dd, 1H), 9.25 (d, 1H).

(c)

7-Amino-3-propyl-2-[(2'-(N-triphenylmethyl-tetrazole-5-yl)biphen-4-yl)methyl]-1(2H)-isoquinolinone

0084A solution of 1.45 g (2.04 mmol) of 7-Nitro-3-propyl-2-[(2'-(N-triphenylmethyl-tetrazole-5-yl)biphen-4-yl)methyl]-1(2H)-isoquinolinone dissolved in 50 ml of EtOAc was hydrogenated at atmospheric pressure over 0.2 g of 10% Pd/C overnight. The reaction mixture was filtered through celite and the filtrate was concentrated <u>in</u><u>vacuo</u>. The residue was purified by flash chromatography over silica gel eluting with 50% EtOAc/hexanes to give the pure amine as a foam. ¹H-NMR (CDCl₃): 0.87 (t, 3H, J=7.36Hz), 1.56 (m, 2H), 2.39 (3 line m, 2H, J=7.7Hz), 5.29 (bs, 2H), 6.24 (s, 1H), 6.91 (d, 4H, J=7.9Hz), 7.03 (m, 2H), 7.19-7.22 (m, 10H), 7.42 (m, 2H), 7.63 (d, 1H, J=2.4Hz), 7.85 (dd, 1H, J=1.7, 7.4Hz).

(d)

General Procedure for Preparation of Carbamates

0085To a suspension of 1.1 eq. of 80% NaH suspended in a volume of dry DMF that would make a 0.1 M solution was added at 0°C under N₂ a solution of 1.0 eq. of 7-amino-3-propyl-2-[(2'-(N-triphenylmethyl-tetrazole-5-yl)biphen-4-yl)methyl]-1(2H)-isoquinolinone dissolved in a minimal amount of DMF. After 30 minutes the chloroformate (ClCOOR²²) of choice was added neat. The reaction mixture was stirred for 30 minutes. To this mixture was added 1.2 eq of a 1M solution of lithium hexamethyldisilazide in THF. After 30 minutes at 0°C the alkylating agent (R^22a) was added neat and the reaction mixture was stirred overnight allowing the temperature to increase to room temperature. The reaction mixture was diluted with EtOAc (10 times the volume of DMF used) and brine. The solution was dried over MgSO₄, filtered and concentrated <u>in</u><u>vacuo</u>. The residue was purified using the techniques described below for the specific examples.

7-(N-Methyl-N-isobutyloxycarbonyl)amino-3-propyl-2-[(2'-(N-triphenylmethyl-tetrazole-5-yl)biphen-4-yl)-methyl]-1(2H)-isoquinolinone

0086Purified by HPLC over a Lobar B silica gel column eluting with 30% EtOAc/hexanes to give a single product as a foam. ¹H-NMR (CDCl₃): 0.83-0.91 (m, 9H), 0.58 (m, 2H), 0.89 (m, 1H), 2.44 (3 line m, 2H, J=7.4Hz), 3.37 (s, 3H), 3.90 (d, 2H, J=6.6Hz), 5.29 (bs, 2H), 6.32 (s, 1H), 7.89 (m, 4H), 7.03 (d, 2H, J=8.2Hz), 7.19-7.31 (m, 10H), 7.42 (m, 3H), 7.61 (bm, 1H), 7.86 (dd, 1H, J-1.95, 7.3Hz), 8.20 (d, 1H, J=2.2Hz).

(e)

7-(N-Methyl-N-isobutyloxycarbonyl)amino-3-propyl-2-[(2'-(tetrazole-5-yl)biphen-4-yl)methyl]-1(2H)-isoquinolinone

0087Utilizing the General Procedure for the Deprotection of Tetrazole from Example 1(c), the above title compound was prepared from the compound from Example 2(d) and the purified by flash chromatography over silica gel eluting with 50% EtOAc/hexanes 1% acetic acid. ¹H-NMR (CDCl₃): 0.86 (d, 6H, J=6.02 Hz), 0.90 (t, 3H, J=7.04 Hz), 1.67 (m, 2H), 1.87 (m, 1H), 2.57 (3 line m, 2H, J=7.7 Hz), 3.32 (s, 3H), 3.38 (d, 2H, J=6.2Hz), 5.33 (bs, 2H); 6.42 (s, 1H); 7.02 (m, 4H); 7.15 (d, 1H, J=7 Hz); 7.22 (d, 1H, J=7 Hz), 7.35 (d, 1H, J=7.9 Hz); 7.43 (d, 1H, J=8.8 Hz); 7.45-7.67 (m, 2H); 8.03 (bs, 1H).

(f)

7-(N-Benzyl-N-isobutyloxycarbonyl)-amino-3-propyl-2-[(2'-(tetrazol-5-yl)biphen-4-yl)-methyl]-1(2H)-isoquinolinone

0088Prepared as described in the general procedure outlined in 2(d). Purified by flash chromatography over silica gel eluting with 40% EtOAc/hexanes. ¹H-NMR (CDCl₃): 0.80 (d, 6H, J=6.9 Hz), 0.87 (t, 3H, J=7.6 Hz), 1.57 (m, 2H), 1.83 (m, 1H), 2.42 (3 line m, 2H, J=7.6 Hz), 3.91 (d, 3H, J=6.6 Hz), 7.16-7.49 (m, 19H), 7.87 (dd, 1H, J=1.5, 7.4 Hz), 8.24 (s, 1H).

(g)

7-(N-Benzyl-N-isobutyloxycarbonyl)-amino-3-propyl-2-[(2'-(tetrazol-5-yl)biphen-4-yl)-methyl]-1(2H)-isoquinolinone

0089Utilizing the general procedure outlined in 1(c), the product of 2(f) was deprotected to give the title compound as a foam. ¹H-NMR (CDCl₃): 0.79 (d, 6H, J=6.7 Hz), 0.97 (t, 3H, J=7.0 Hz), 4.90 (s, 2H), 5.28 (s, 2H), 6.38 (s, 1H), 6.97 (m, 4H), 7.12-7.24 (m, 6H), 7.32-7.48 (m, 3H), 7.52 (t, 1H, J=7.7 Hz), 7.85 (bs, 1H), 8.07 (s, 1H).

FORMULATION EXAMPLES

Typical Pharmaceutical Compositions Containing a Compound of the Invention

A:

Dry Filled Capsules Containing 50 mg of Active Ingredient Per Capsule

0090<tables id="tabl0013" num="0013"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col1" align="left">Ingredient</entry><entry namest="col2" nameend="col2" align="center">Amount per capsule (mg)</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">Compound 1</entry><entry namest="col2" nameend="col2" align="right">50</entry></row><row><entry namest="col1" nameend="col1" align="left">Lactose</entry><entry namest="col2" nameend="col2" align="right">149</entry></row><row><entry namest="col1" nameend="col1" align="left">Magnesium stearate</entry><entry namest="col2" nameend="col2" align="right">1</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Capsule (size No. 1)</entry><entry namest="col2" nameend="col2" align="right"><maths id="math0001" num=""><math display="inline"><mrow><mover accent="true"><mrow><mtext>200</mtext></mrow><mo>¯</mo></mover></mrow></math><img file="EP0502575A1_D0080.tif" /></maths></entry></row></tbody></tgroup></table></tables>

0091Compound 1 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 combined ingredients can then be mixed for about 10 minutes and filled into a No. 1 dry gelatin capsule.

B:

Tablet

0092A typical tablet would contain Compound 1 (25 mg), pregelatinized starch USP (82 mg), microcrystaline cellulose (82 mg) and magnesium stearate (1 mg).

C:

Combination Tablet

0093A typical combination tablet would contain, for example, a diuretic such as hydrochlorothiazide and consist of Compound 1 (7.5 mg), hydrochlorothiazide (50 mg) pregelatinized starch USP (82 mg), microcrystalline cellulose (82 mg) and magnesium stearate (1 mg).

D:

Suppository

0094Typical suppository formulations for rectal administration can contain Compound 1 (1-25 mg), butylated hydroxyanisole (0.08-1.0 mg), disodium calcium edetate (0.25-0.5 mg), and polyethylene glycol (775-1600 mg). Other suppository formulations can be made by substituting, for example, butylated hydroxytoluene (0.04-0.08 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 like, for the polyethylene glycol. Further, these suppository formulations can also include another active 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

0095A typical injectable formulation would contain Compound 1 (5.42 mg), sodium phosphate dibasic anhydrous (11.4 mg) benzyl alcohol (0.01 ml) and water for injection (1.0 ml). Such an injectable 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.