Patent Application: US-27136202-A

Abstract:
a combination therapy comprising a therapeutically - effective amount of an epoxy - free spirolactone - type aldosterone receptor antagonist and a therapeutically - effective amount of an angiotensin ii receptor antagonist is described for treatment of circulatory disorders , including cardiovascular disorders such as hypertension , congestive heart failure , cirrhosis and ascites . preferred angiotensin ii receptor antagonists are those compounds having high potency and bioavailability and which are characterized in having an imidazole or triazole moiety attached to a biphenylmethyl or pyridinyl / phenylmethyl moiety . a preferred epoxy - free spirolactone - type aldosterone receptor antagonist is spironolactone . a preferred combination therapy includes the angiotensin ii receptor antagonist 5 - methyl ]- 2 - pyridinyl ] phenyl - 1h - tetrazole and the aldosterone receptor antagonist spironolactone .

Description:
examples of angiotensin ii ( aii ) antagonists which may be used in the combination therapy are shown in the following categories : a first group of aii antagonists consists of the following compounds : saralasin acetate , candesartan cilexetil , cgp - 63170 , emd - 66397 , kt3 - 671 , lr - b / 081 , valsartan , a - 81282 , bibr - 363 , bibs - 222 , bms - 184698 , candesartan , cv - 11194 , exp - 3174 , kw - 3433 , l - 161177 , l - 162154 , lr - b / 057 , ly - 235656 , pd - 150304 , u - 96849 , u - 97018 , up - 275 - 22 , way - 126227 , wk - 1492 . 2k , ym - 31472 , losartan potassium , e - 4177 , emd - 73495 , eprosartan , hn - 65021 , irbesartan , l - 159282 , me - 3221 , sl - 91 . 0102 , tasosartan , telmisartan , up - 269 - 6 , ym - 358 , cgp - 49870 , ga - 0056 , l - 159689 , l - 162234 , l - 162441 , l - 163007 , pd - 123177 , a - 81988 , bms - 180560 , cgp - 38560a , cgp - 48369 , da - 2079 , de - 3489 , dup - 167 , exp - 063 , exp - 6155 , exp - 6803 , exp - 7711 , exp - 9270 , fk - 739 , hr - 720 , ici - d6888 , ici - d7155 , ici - d8731 , isoteoline , kri - 1177 , l - 158809 , l - 158978 , l - 159874 , lr b087 , ly - 285434 , ly - 302289 , ly - 315995 , rg - 13647 , rwj - 38970 , rwj - 46458 , s - 8307 , s - 8308 , saprisartan , saralasin , sarmesin , wk - 1360 , x - 6803 , zd - 6888 , zd - 7155 , zd - 8731 , bibs39 , ci - 996 , dmp - 811 , dup - 532 , exp - 929 , l - 163017 , ly - 301875 , xh - 148 , xr - 510 , zolasartan and pd - 123319 . a second group of aii antagonists of interest consists of the following compounds : saralasin acetate , candesartan cilexetil , cgp - 63170 , emd - 66397 , kt3 - 671 , lr - b / 081 , valsartan , a - 81282 , bibr - 363 , bibs - 222 , bms - 184698 , candesartan , cv - 11194 , exp - 3174 , kw - 3433 , l - 161177 , l - 162154 , lr - b / 057 , ly - 235656 , pd - 150304 , u - 96849 , u - 97018 , up - 275 - 22 , way - 126227 , wk - 1492 . 2k , ym - 31472 , losartan potassium , e - 4177 , emd - 73495 , eprosartan , hn - 65021 , irbesartan , l - 159282 , me - 3221 , sl - 91 . 0102 , tasosartan , telmisartan , up - 269 - 6 , ym - 358 , cgp - 49870 , ga - 0056 , l - 159689 , l - 162234 , l - 162441 , l - 163007 and pd - 123177 . a family of spirolactone - type compounds of interest for use in the combination therapy is defined by formula a wherein r is lower alkyl of up to 5 carbon atoms , and lower alkyl residues include branched and un - branched groups , preferably methyl , ethyl and n - propyl . methods to make compounds of formula a are described in u . s . pat . no . 4 , 129 , 554 to wiechart et al issued on dec . 12 , 1978 . a second family of spirolactone - type compounds of interest for use in the combination therapy is defined by formula b : r 1 is c 1 - 3 - alkyl or c 1 - 3 acyl and r 2 is hydrogen or c 1 - 3 - alkyl . methods to make the compounds of formula b are decribed in u . s . pat . no . 4 , 789 , 668 to nickisch et al which issued dec . 6 , 19888 . a third family of spirolactone - type compounds of interest for use in the combination therapy is defined by a structure of formula c : methods to make the compounds of formula c are described in u . s . pat . no . 3 , 257 , 390 to patchett which issued jun . 21 , 1966 . of particular interest is the compound spironolactone having the following structure and formal name : spironolactone is sold by g . d . searle & amp ; co ., skokie , ill ., under the trademark “ aldactone ”, in tablet dosage form at doses of 25 mg , 50 mg and 100 mg per tablet . a diuretic agent may be used in the combination of ace inhibitor and aldosterone receptor antagonist . such diuretic agent may be selected from several known classes , such as thiazides and related sulfonamides , potassium - sparing diuretics , loop diuretics and organic mercurial diuretics . angiotensin ii receptor antagonist compounds suitable for use in the combination therapy are described in table ii , below . preferred compounds for use in the combination therapy may be generally characterized structurally as having two portions . a first portion constitutes a mono - aryl - alkyl moiety , or a bi - aryl - alkyl moiety , or a mono - heteroaryl - alkyl moiety , or a bi - heteroaryl - alkyl moiety . a second portion constitutes a heterocyclic moiety or an open chain hetero - atom - containing moiety . typically , the first - portion mono / bi - aryl / heteroaryl - alkyl moiety is attached to the second portion heterocyclic / open - chain moiety through the alkyl group of the mono / bi - aryl / heteroaryl - alkyl moiety to any substitutable position on the heterocyclic / open - chain moiety second portion . suitable first - portion mono / bi - aryl / heteroaryl - alkyl moieties are defined by any of the various moieties listed under formula i : wherein the abbreviated notation used in the moieties of formula i is defined as follows : “ ar ” means a five or six - membered carbocyclic ring system consisting of one ring or two fused rings , with such ring or rings being typically fully unsaturated but which also may be partially or fully saturated . “ phenyl ” radical most typically exemplifies “ ar ”. “ het ” means a monocyclic or bicyclic fused ring system having from five to eleven ring members , and having at least one of such ring members being a hetero atom selected from oxygen , nitrogen and sulfur , and with such ring system containing up to six of such hetero atoms as ring members . “ alk ” means an alkyl radical or alkylene chain , linear or branched , containing from one to about five carbon atoms . typically , “ alk ” means “ methylene ”, i . e ., — ch 2 —. “ l ” designates a single bond or a bivalent linker moiety selected from carbon , oxygen and sulfur . when “ l ” is carbon , such carbon has two hydrido atoms attached thereto . suitable second - portion heterocyclic moieties of the angiotensin ii antagonist compounds , for use in the combination therapy , are defined by any of the various moieties listed under formula iia or iib : wherein each of x 1 through x 6 is selected from — ch ═, — ch 2 —, — n ═, — nh —, o , and s , with the proviso that at least one of x l through x 6 in each of formula iia and formula iib must be a hetero atom . the heterocyclic moiety of formula iia or iib may be attached through a bond from any ring member of the formula iia or iib heterocyclic moiety having a substitutable or a bond - forming position . examples of monocyclic heterocyclic moieties of formula iia include thienyl , furyl , pyranyl , pyrrolyl , imidazolyl , triazolyl , pyrazolyl , pyridyl , pyrazinyl , pyrimidinyl , pyridazinyl , isothiazolyl , isoxazolyl , furazanyl , pyrrolidinyl , pyrrolinyl , furanyl , thiophenyl , isopyrrolyl , 3 - isopyrrolyl , 2 - isoimidazolyl , 1 , 2 , 3 - triazolyl , 1 , 2 , 4 - triazolyl , 1 , 2 - dithiolyl , 1 , 3 - dithiolyl , 1 , 2 , 3 - oxathiolyl , oxazolyl , thiazolyl , 1 , 2 , 3 - oxadiazolyl , 1 , 2 , 4 - oxadiazolyl , 1 , 2 , 5 - oxadiazolyl , 1 , 3 , 4 - oxadiazolyl , 1 , 2 , 3 , 4 - oxatriazolyl , 1 , 2 , 3 , 5 - oxatriazolyl , 1 , 2 , 3 - dioxazolyl , 1 , 2 , 4 - dioxazolyl , 1 , 3 , 2 - dioxazolyl , 1 , 3 , 4 - dioxazolyl , 1 , 2 , 5 - oxathiazolyl , 1 , 3 - oxathiolyl , 1 , 2 - pyranyl , 1 , 4 - pyranyl , 1 , 2 - pyronyl , 1 , 4 - pyronyl , pyridinyl , piperazinyl , s - triazinyl , as - triazinyl , v - triazinyl , 1 , 2 , 4 - oxazinyl , 1 , 3 , 2 - oxazinyl , 1 , 3 , 6 - oxazinyl , 1 , 2 , 6 - oxazinyl , 1 , 4 - oxazinyl , o - isoxazinyl , p - isoxazinyl , 1 , 2 , 5 - oxathiazinyl , 1 , 2 , 6 - oxathiazinyl , 1 , 4 , 2 - oxadiazinyl , 1 , 3 , 5 , 2 - oxadiazinyl , morpholinyl , azepinyl , oxepinyl , thiepinyl and 1 , 2 , 4 - diazepinyl . examples of bicyclic heterocyclic moieties of formula iib include benzo [ b ] thienyl , isobenzofuranyl , chromenyl , indolizinyl , isoindolyl , indolyl , indazolyl , purinyl , auinolizinyl , isoquinolyl , quinolyl , phthalazinyl , naphthyridinyl , quinoxalinyl , quinazolinyl , cinnolinyl , pteridinyl , isochromanyl , chromanyl , thieno [ 2 , 3 - b ] furanyl , 2h - furo [ 3 , 2 - b ] pyranyl , 5h - pyrido [ 2 , 3 - d ][ 1 , 2 ] oxazinyl , 1h - pyrazolo [ 4 , 3 - d ] oxazolyl , 4h - imidazo [ 4 , 5 - d ] thiazolyl , pyrazino [ 2 , 3 - d ] pyridazinyl , imidazo [ 2 , 1 - b ] thiazolyl , cyclopenta [ b ] pyranyl , 4h -[ 1 , 3 ] oxathiolo -[ 5 , 4 - b ] pyrrolyl , thieno [ 2 , 3 - b ] furanyl , imidazo [ 1 , 2 - b ][ 1 , 2 , 4 ] triazinyl and 4h - 1 , 3 - dioxolo [ 4 , 5 - d ] imidazolyl . the angiotensin ii receptor antagonist compounds , as provided by the first - and - second - portion moieties of formula i and ii , are further characterized by an acidic moiety attached to either of said first - and - second - portion moieties . preferably this acidic moiety is attached to the first - portion moiety of formula i and is defined by formula iii : wherein n is a number selected from zero through three , inclusive , and wherein a is an acidic group selected to contain at least one acidic hydrogen atom , and the amide , ester and salt derivatives of said acidic moieties ; wherein u is a spacer group independently selected from one or more of alkyl , cycloalkyl , cycloalkylalkyl , alkenyl , alkynyl , aryl , aralkyl and heteroaryl having one or more ring atoms selected from oxygen , sulfur and nitrogen atoms . the phrase “ acidic group selected to contain at least one acidic hydrogen atom ”, as used to define the — u n a moiety , is intended to embrace chemical groups which , when attached to any substitutable position of the formula i - iia / b moiety , confers acidic character to the compound of formula i - iia / b . “ acidic character ” means proton - donor capability , that is , the capacity of the compound of formula i - iia / b to be a proton donor in the presence of a proton - receiving substance such as water . typically , the acidic group should be selected to have proton - donor capability such that the product compound of formula i - iia / b has a pk a in a range from about one to about twelve . more typically , the formula i - iia / b compound would have a pk a in a range from about two to about seven . an example of an acidic group containing at least one acidic hydrogen atom is carboxyl group (— cooh ). where n is zero and a is — cooh , in the — u n a moiety , such carboxyl group would be attached directly to one of the formula i - iia / b positions . the formula i - iia / b compound may have one — u n a moiety attached at one of the formula i - iia / b positions , or may have a plurality of such — u n a moieties attached at more than one of the formula i - iia / b positions . there are many examples of acidic groups other than carboxyl group , selectable to contain at least one acidic hydrogen atom . such other acidic groups may be collectively referred to as “ bioisosteres of carboxylic acid ” or referred to as “ acidic bioisosteres ”. specific examples of such acidic bioisosteres are described hereinafter . compounds of formula i - iia / b may have one or more acidic protons and , therefore , may have one or more pk a values . it is preferred , however , that at least one of these pk a values of the formula i - iia / b compound as conferred by the — u n a moiety be in a range from about two to about seven . the — u n a moiety may be attached to one of the formula i - iia / b positions through any portion of the — u n a moiety which results in a formula i - iia / b compound being relatively stable and also having a labile or acidic proton to meet the foregoing pk a criteria . for example , where the — u n a acid moiety is tetrazole , the tetrazole is typically attached at the tetrazole ring carbon atom . for any of the moieties embraced by formula i and formula ii , such moieties may be substituted at any substitutable position by one or more radicals selected from hydrido , hydroxy , alkyl , alkenyl , arkynyl , aralkyl , hydroxyalkyl , haloalkyl , halo , oxo , alkoxy , aryloxy , aralkoxy , aralkylthio , alkoxyalkyl , cycloalkyl , cycloalkylalkyl , aryl , aroyl , cycloalkenyl , cyano , cyanoamino , nitro , alkylcarbonyloxy , alkoxycarbonyloxy , alkylcarbonyl , alkoxycarbonyl , aralkoxycarbonyl , carboxyl , mercapto , mercaptocarbonyl , alkylthio , arylthio , alkylthiocarbonyl , alkylsulfinyl , alkylsulfonyl , haloalkylsulfonyl , alkylsulfinyl , aralkylsulfonyl , arylsulfinyl , arylsulfonyl , heteroaryl having one or more ring atoms selected from oxygen , sulfur and nitrogen atoms , and amino and amido radicals of the formula wherein w is oxygen atom or sulfur atom ; wherein each of r 1 through r 5 is independently selected from hydrido , alkyl , cycloalkyl , cycloalkylalkyl , aralkyl , aryl , yr 6 and wherein y is selected from oxygen atom and sulfur atom and r 6 is selected from hydrido , alkyl , cycloalkyl , cycloalkylalkyl , aralkyl and aryl ; wherein each of r 1 , r 2 , r 3 , r 4 , r 5 , r 7 and r 8 is independently selected from hydrido , alkyl , cycloalkyl , cyano , hydroxyalkyl , haloalkyl , cycloalkylalkyl , alkoxyalkyl , alkylcarbonyl , alkoxycarbonyl , carboxyl , alkylsulfinyl , alkylsulfonyl , arylsulfinyl , arylsulfonyl , haloalkylsulfinyl , haloalkylsulfonyl , aralkyl and aryl , and wherein each of r 1 , r 2 , r 3 , r 4 , r 5 , r 7 and r 8 is further independently selected from amino and amido radicals of the formula wherein w is oxygen atom or sulfur atom ; wherein each of r 9 , r 10 , r 11 , r 12 , r 13 and r 14 is independently selected from hydrido , alkyl , cycloalkyl , cyano , hydroxyalkyl , cycloalkylalkyl , alkoxyalkyl , haloalkylsulfinyl , haloalkylsulfonyl , aralkyl and aryl , and wherein each of r 2 and r 3 taken together and each of r 4 and r 5 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical , which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen , nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated ; wherein each of r 2 and r 3 taken together and each of r 7 and r 8 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen , nitrogen and sulfur atoms ; or a tautomer thereof or a pharmaceutically - acceptable salt thereof . the combination therapy of the invention would be useful in treating a variety of circulatory disorders , including cardiovascular disorders , such as hypertension , congestive heart failure , myocardial fibrosis and cardiac hypertrophy . the combination therapy would also be useful with adjunctive therapies . for example , the combination therapy may be used in combination with other drugs , such as a diuretic , to aid in treatment of hypertension . table ii , below , contains description of angiotensin ii antagonist compounds which may be used in the combination therapy . associated with each compound listed in table ii is a published patent document describing the chemical preparation of the angiotensin ii antagonist compound as well as the biological properties of such compound . the content of each of these patent documents is incorporated herein by reference . table ii angiotensin ii antagonists compound # structure source 1 wo # 91 / 17148 pub . 14 nov . 1991 2 wo # 91 / 17148 pub . 14 nov . 1991 3 wo # 91 / 17148 pub . 14 nov . 1991 4 wo # 91 / 17148 pub . 14 nov . 1991 5 wo # 91 / 17148 pub . 14 nov . 1991 6 wo # 91 / 17148 pub . 14 nov . 1991 7 wo # 91 / 17148 pub . 14 nov . 1991 8 wo # 91 / 17148 pub . 14 nov . 1991 9 wo # 91 / 17148 pub . 14 nov . 1991 10 wo # 91 / 17148 pub . 14 nov . 1991 11 wo # 91 / 17148 pub . 14 nov . 1991 12 wo # 91 / 17148 pub . 14 nov . 1991 13 wo # 91 / 17148 pub . 14 nov . 1991 14 wo # 91 / 17148 pub . 14 nov . 1991 15 wo # 91 / 17148 pub . 14 nov . 1991 16 wo # 91 / 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92 / 18092 pub . 29 oct . 1992 267 wo # 92 / 18092 pub . 29 oct . 1992 268 wo # 92 / 18092 pub . 29 oct . 1992 269 wo # 92 / 18092 pub . 29 oct . 1992 270 wo # 92 / 18092 pub . 29 oct . 1992 271 pct / us95 / 02156 filed 8 mar . 1994 272 pct / us94 / 02156 filed 8 mar . 1994 273 pct / us94 / 02156 filed 8 mar . 1994 274 pct / us94 / 02156 filed 8 mar . 1994 275 pct / us94 / 02156 filed 8 mar . 1994 276 pct / us94 / 02156 filed 8 mar . 1994 277 pct / us94 / 02156 filed 8 mar . 1994 278 pct / us94 / 02156 filed 8 mar . 1994 279 pct / us94 / 02156 filed 8 mar . 1994 280 wo # 91 / 17148 pub . 14 nov . 1991 281 ep # 475 , 206 pub . 18 mar . 1992 282 wo # 93 / 18035 pub . 16 sep . 1993 283 wo # 93 / 17628 pub . 16 sep . 1993 284 wo # 93 / 17681 pub . 16 sep . 1993 285 ep # 515 , 533 pub . 19 nov . 1992 286 ep # 535 , 463 pub . 07 apr . 1993 287 ep # 535 , 465 pub . 07 apr . 1993 288 ep # 539 , 713 pub . 05 may 1993 289 ep # 542 , 059 pub . 19 may 1993 290 ep # 05 557 , 843 pub . 01 sep . 1993 291 ep # 563 , 705 pub . 06 oct . 1993 292 ep # 562 , 261 pub . 29 sep . 1993 293 ep # 05 557 , 843 pub . 15 sep . 1993 294 ep # 560 , 163 pub . 15 sep . 1993 295 ep # 564 , 788 pub . 13 oct . 1993 296 ep # 565 , 986 pub . 20 oct . 1993 297 ep # 0 , 569 , 795 pub . 18 nov . 1993 298 ep # 0 , 569 , 794 pub . 18 nov . 1993 299 ep # 0 , 578 , 002 pub . 12 jan . 1994 300 ep # 581 , 003 pub . 02 feb . 1994 301 ep # 392 , 317 pub . 17 oct . 1990 302 ep # 392 , 317 pub . 17 oct . 1990 303 ep # 502 , 314 pub . 09 sep . 1992 304 ep # 468 , 740 pub . 29 jan . 1992 305 ep # 470 , 543 pub . 12 feb . 1992 306 ep # 502 , 314 pub . 09 sep . 1992 307 ep # 529 , 253 pub . 03 mar . 1993 308 ep # 543 , 263 pub . 26 may 1993 309 ep # 552 , 765 pub . 28 jul . 1993 310 ep # 555 , 825 pub . 18 aug . 1993 311 ep # 556 , 789 pub . 25 aug . 1993 312 ep # 560 , 330 pub . 15 sep . 1993 313 ep # 566 , 020 pub . 20 oct . 1993 314 ep # 581 , 166 pub . 02 feb . 1994 315 wo # 94 / 01436 pub . 20 jan . 1994 316 ep # 253 , 310 pub . 20 jan . 1988 317 ep # 324 , 377 pub . 19 jul . 1989 318 u . s pat . no . 5 , 043 , 349 issued 27 aug . 1991 319 wo # 91 / 00281 pub . 10 jan . 1991 320 u . s pat . no . 5 , 015 , 651 pub . 14 may 1991 321 322 wo # 92 / 00977 pub . 23 jan . 1992 323 324 wo # 93 / 04046 pub . 04 mar . 1993 325 wo # 93 / 10106 pub . 27 may 1993 326 u . s pat . no . 5 , 219 , 856 pub . 15 jun . 1993 327 u . s pat . no . 5 , 264 , 325 pub . 09 nov . 1993 328 u . s pat . no . 5 , 264 , 581 pub . 23 nov . 1993 329 ep # 400 , 974 pub . 05 dec . 1990 330 ep # 411 , 766 pub . 06 feb . 1991 331 ep # 412 , 594 pub . 13 feb . 1991 332 ep # 419 , 048 pub . 27 mar . 1991 333 wo # 91 / 12 , 001 pub . 22 aug . 1991 334 wo # 91 / 11 , 999 pub . 22 aug . 1991 335 wo # 91 / 11 , 909 pub . 22 aug . 1991 336 wo # 91 / 12 , 002 pub . 22 aug . 1991 337 u . s pat . no . 5 , 053 , 329 pub . 01 oct . 1991 338 u . s pat . no . 5 , 057 , 522 pub . 15 oct . 1991 339 wo # 91 / 15 , 479 pub . 17 oct . 1991 340 ep # 456 , 510 pub . 13 nov . 1991 341 ep # 467 , 715 pub . 22 jan . 1992 342 u . s pat . no . 5 , 087 , 702 pub . 11 feb . 1992 343 ep # 479 , 479 pub . 08 apr . 1992 344 345 ep # 481 , 614 pub . 22 apr . 1992 346 ep # 490 , 587 pub . 17 jun . 1992 347 u . s pat . no . 5 , 128 , 327 pub . 07 jul . 1992 348 u . s pat . no . 5 , 132 , 216 pub . 21 jul . 1992 349 ep # 497 , 516 pub . 05 aug . 1992 350 ep # 502 , 725 pub . 09 sep . 1992 351 ep # 502 , 575 pub . 09 sep . 1992 352 ep # 503 , 838 pub . 16 sep . 1992 353 ep # 505 , 111 pub . 23 sep . 1992 354 ep # 505 , 098 pub . 23 sep . 1992 355 ep # 507 , 594 pub . 07 oct . 1992 356 ep # 508 , 723 pub . 14 oct . 1992 357 358 ep # 512 , 675 pub . 11 nov . 1992 359 ep # 512 , 676 pub . 11 nov . 1992 360 ep # 512 , 870 pub . 11 nov . 1992 361 ep # 513 , 979 pub . 19 nov . 1992 362 wo # 92 / 20 , 660 pub . 26 nov . 1992 363 wo # 92 , 20 , 661 pub . 26 nov . 1992 364 wo # 92 / 20 , 662 pub . 26 nov . 1992 365 wo # 92 / 20 , 687 pub . 26 nov . 1992 366 ep # 517 , 357 pub . 09 dec . 1992 367 wo # 93 / 01177 pub . 21 jan . 1993 368 u . s pat . no . 5 , 187 , 159 pub . 16 feb . 1993 369 u . s pat . no . 5 , 198 , 438 pub . 30 mar . 1993 370 u . s pat . no . 5 , 202 , 322 pub . 13 apr . 1993 371 ep # 537 , 937 pub . 21 apr . 1993 372 u . s pat . no . 5 , 217 , 882 pub . 08 jun . 1993 373 u . s pat . no . 5 , 214 , 153 pub . 25 may 1993 374 u . s pat . no . 5 , 218 , 125 pub . 08 jun . 1993 375 u . s pat . no . 5 , 236 , 928 pub . 17 aug . 1993 376 u . s pat . no . 5 , 240 , 938 pub . 31 aug . 1993 377 gb # 2 , 264 , 709 pub . 08 sep . 1993 378 gb # 2 , 264 , 710 pub . 08 sep . 1993 379 u . s pat . no . 5 , 256 , 667 pub . 26 oct . 1993 380 u . s pat . no . 5 , 525 , 574 pub . 12 oct . 1993 381 wo # 93 / 23 , 399 pub . 25 nov . 1993 382 u . s pat . no . 5 , 262 , 412 pub . 16 nov . 1993 383 u . s pat . no . 5 , 264 , 447 pub . 23 nov . 1993 384 u . s pat . no . 5 , 266 , 583 pub . 01 sep . 1992 385 u . s pat . no . 5 , 276 , 054 pub . 04 jan . 1994 386 u . s pat . no . 5 , 278 , 068 pub . 11 jan . 1994 387 wo # 94 / 02142 pub . 03 feb . 1994 388 wo # 44 / 02467 pub . 03 feb . 1994 389 ep # 403 , 159 pub . 19 dec . 1990 390 ep # 425 , 211 pub . 02 may 1991 391 ep # 427 , 463 pub . 15 may 1991 392 wo # 92 / 00068 pub . 09 jan . 1992 393 wo # 92 / 02 , 510 pub . 20 feb . 1992 394 wo # 92 / 09278 pub . 11 jun . 1992 395 wo # 92 / 10181 pub . 25 jun . 1992 396 397 398 399 400 401 402 403 wo # 92 / 100097 pub . 25 jun . 1992 404 405 406 407 wo # 92 / 20651 pub . 26 nov . 1992 408 wo # 93 / 03018 pub . 18 feb . 1993 409 wo # 94 / 00120 pub . 06 jan . 1994 410 ep # 459 , 136 pub . 04 dec . 1991 411 ep # 411 , 507 pub . 05 feb . 1991 412 ep # 425 , 921 pub . 08 may 1991 413 ep # 430 , 300 pub . 05 jun . 1991 414 ep # 434 , 038 pub . 26 jun . 1991 415 ep # 442 , 473 pub . 21 aug . 1991 416 ep # 443 , 568 pub . 28 aug . 1991 417 ep # 459 , 136 pub . 04 dec . 1991 418 ep # 483 , 683 pub . 05 may 1992 419 ep # 518 , 033 pub . 16 dec . 1992 420 ep # 520 , 423 pub . 30 dec . 1992 421 ep # 546 , 358 pub . 16 jun . 1993 422 ep # 93 / 00341 pub . 07 jan . 1993 423 ep # 92 / 06081 pub . 16 apr . 1992 424 wo # 93 / 00341 pub . 07 jan . 1993 425 u . s pat . no . 5 , 210 , 204 pub . 11 may 1993 426 ep # 343 , 654 pub . 29 nov . 1989 427 wo # 93 / 13077 pub . 08 jul . 1993 428 wo # 93 / 15734 pub . 19 aug . 1993 429 u . s pat . no . 5 , 246 , 943 pub . 21 sep . 1993 the term “ hydrido ” denotes a single hydrogen atom ( h ). this hydrido group may be attached , for example , to an oxygen atom to form a hydroxyl group ; or , as another example , one hydrido group may be attached to a carbon atom to form a group ; or , as another example , two hydrido atoms may be attached to a carbon atom to form a — ch 2 — group . where the term “ alkyl ” is used , either alone or within other terms such as “ haloalkyl ” and “ hydroxyalkyl ”, the term “ alkyla ” embraces linear or branched radicals having one to about twenty carbon atoms or , preferably , one to about twelve carbon atoms . more preferred alkyl radicals are “ lower alkyl ” radicals having one to about ten carbon atoms . most preferred are lower alkyl radicals having one to about five carbon atoms . the term “ cycloalkyl ” embraces cyclic radicals having three to about ten ring carbon atoms , preferably three to about six carbon atoms , such as cyclopropyl , cyclobutyl , cyclopentyl and cyclohexyl . the term “ haloalkyl ” embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with one or more halo groups , preferably selected from bromo , chloro and fluoro . specifically embraced by the term “ haloalkyl ” are monohaloalkyl , dihaloalkyl and polyhaloalkyl groups . a monohaloalkyl group , for example , may have either a bromo , a chloro , or a fluoro atom within the group . dihaloalkyl and polyhaloalkyl groups may be substituted with two or more of the same halo groups , or may have a combination of different halo groups . a dihaloalkyl group , for example , may have two fluoro atoms , such as difluoromethyl and difluorobutyl groups , or two chloro atoms , such as a dichloromethyl group , or one fluoro atom and one chloro atom , such as a fluoro - chloromethyl group . examples of a polyhaloalkyl are trifluoromethyl , 1 , 1 - difluoroethyl , 2 , 2 , 2 - trifluoroethyl , perfluoroethyl and 2 , 2 , 3 , 3 - tetrafluoropropyl groups . the term “ difluoroalkyl ” embraces alkyl groups having two fluoro atoms substituted on any one or two of the alkyl group carbon atoms . the terms “ alkylol ” and “ hydroxyalkyl ” embrace linear or branched alkyl groups having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl groups . the term “ alkenyl ” embraces linear or branched radicals having two to about twenty carbon atoms , preferably three to about ten carbon atoms , and containing at least one carbon - carbon double bond , which carbon - carbon double bond may have either cis or trans geometry within the alkenyl moiety . the term “ alkynyl ” embraces linear or branched radicals having two to about twenty carbon atoms , preferably two to about ten carbon atoms , and containing at least one carbon - carbon triple bond . the term “ cycloalkenyl ” embraces cyclic radicals having three to about ten ring carbon atoms including one or more double bonds involving adjacent ring carbons . the terms “ alkoxy ” and “ alkoxyalkyl ” embrace linear or branched oxy - containing radicals each having alkyl portions of one to about ten carbon atoms , such as methoxy group . the term “ alkoxyalkyl ” also embraces alkyl radicals having two or more alkoxy groups attached to the alkyl radical , that is , to form monoalkoxyalkyl and dialkoxyalkyl groups . the “ alkoxy ” or “ alkoxyalkyl ” radicals may be further substi - tuted with one or more halo atoms , such as fluoro , chloro or bromo , to provide haloalkoxy or haloalkoxyalkyl groups . the term “ alkylthio ” embraces radicals containing a linear or branched alkyl group , of one to about ten carbon atoms attached to a divalent sulfur atom , such as a methythio group . preferred aryl groups are those consisting of one , two , or three benzene rings . the term “ aryl ” embraces aromatic radicals such as phenyl , naphthyl and biphenyl . the term “ aralky ” embraces aryl - substituted alkyl radicals such as benzyl , diphenylmethyl , triphenylmethyl , phenyl - ethyl , phenylbutyl and diphenylethyl . the terms “ benzyl ” and “ phenylmethyl ” are interchangeable . the terms “ phenalkyl ” and “ phenylalkyl ” are interchangeable . an example of “ phenalkyl ” is “ phenethyl ” which is interchangeable with “ phenylethyl ”. the terms “ alkylaryl ”, “ alkoxyaryl ” and “ haloaryl ” denote , respectively , the substitution of one or more “ alkyl ”, “ alkoxy ” and “ halo ” groups , respectively , substituted on an “ aryl ” nucleus , such as a phenyl moiety . the terms “ aryloxy ” and “ arylthio ” denote radicals respectively , provided by aryl groups having an oxygen or sulfur atom through which the radical is attached to a nucleus , examples of which are phenoxy and phenylthio . the terms “ sulfinyl ” and “ sulfonyl ”, whether used alone or linked to other terms , denotes , respectively , divalent radicals so and so 2 . the term “ aralkoxy ”, alone or within another term , embraces an aryl group attached to an alkoxy group to form , for example , benzyloxy . the term “ acyl ” whether used alone , or within a term such as acyloxy , denotes a radical provided by the residue after removal of hydroxyl from an organic acid , examples of such radical being acetyl and benzoyl . “ lower alkanoyl ” is an example of a more prefered sub - class of acyl . the term “ amido ” denotes a radical consisting of nitrogen atom attached to a carbonyl group , which radical may be further substituted in the manner described herein . the term “ monoalkylaminocarbonyl ” is interchangeable with “ n - alkylamido ”. the term “ dialkylaminocarbonyl ” is interchangeable with “ n , n - dialkylamido ”. the term “ alkenylalkyl ” denotes a radical having a double - bond unsaturation site between two carbons , and which radical may consist of only two carbons or may be further substituted with alkyl groups which may optionally contain additional double - bond unsaturation . the term “ heteroaryl ”, where not otherwised defined before , embraces aromatic ring systems containing one or two hetero atoms selected from oxygen , nitrogen and sulfur in a ring system having five or six ring members , examples of which are thienyl , furanyl , pyridinyl , thiazolyl , pyrimidyl and isoxazolyl . such heteroaryl may be attached as a substituent through a carbon atom of the heteroaryl ring system , or may be attached through a carbon atom of a moiety substituted on a heteroaryl ring - member carbon atom , for example , through the methylene substituent of imidazolemethyl moiety . also , such heteroaryl may be attached through a ring nitrogen atom as long as aromaticity of the heteroaryl moiety is preserved after attachment . for any of the foregoing defined radicals , preferred radicals are those containing from one to about ten carbon atoms . specific examples of alkyl groups are methyl , ethyl , n - propyl , isopropyl , n - butyl , sec - butyl , isobutyl tert - butyl , n - pentyl , isopentyl , methylbutyl , dimethylbutyl and neopentyl . typical alkenyl and alkynyl groups may have one unsaturated bond , such as an allyl group , or may have a plurality of unsaturated bonds , with such plurality of bonds either adjacent , such as allene - type structures , or in conjugation , or separated by several saturated carbons . also included in the combination of the invention are the isomeric forms of the above - described angiotensin ii receptor compounds and the epoxy - free spirolactone - type aldosterone receptor compounds , including diastereoisomers , regioisomers and the pharmaceutically - acceptable salts thereof . the term “ pharmaceutically - acceptable salts ” embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases . the nature of the salt is not critical , provided that it is pharmaceutically - acceptable . suitable pharmaceutically - acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid . examples of such inorganic acids are hydrochloric , hydrobromic , hydroiodic , nitric , carbonic , sulfuric and phosphoric acid . appropriate organic acids may be selected from aliphatic , cycloaliphatic , aromatic , araliphatic , heterocyclic , carboxylic and sulfonic classes of organic acids , example of which are formic , acetic , propionic , succinic , glycolic , gluconic , lactic , malic , tartaric , citric , ascorbic , glucuronic , maleic , fumaric , pyruvic , aspartic , glutamic , benzoic , anthranilic , p - hydroxybenzoic , salicyclic , phenylacetic , mandelic , embonic ( pamoic ), methansulfonic , ethanesulfonic , 2 - hydroxyethanesulfonic , pantothenic , benzenesulfonic , toluenesulfonic , sulfanilic , mesylic , cyclohexylaminosulfonic , stearic , algenic , β - hydroxybutyric , malonic , galactaric and galacturonic acid . suitable pharmaceutically - acceptable base addition salts include metallic salts made from aluminium , calcium , lithium , magnesium , potassium , sodium and zinc or organic salts made from n , n ′- dibenzylethylenediamine , chioroprocaine , choline , diethanolamine , ethylenediamine , meglumine ( n - methylglucamine ) and procaine . all of these salts may be prepared by conventional means from the corresponding compound by reacting , for example , the appropriate acid or base with such compound . human congestive heart failure ( chf ) is a complex condition usually initiated by vascular hypertension or a myocardial infarction ( mi ). in o der to determine the probable effectiveness of a combination therapy for chf , it is important to determine the potency of individual components of the combination therapy . accordingly , in assays “ a ” through “ c ”, the angiotensin ii receptor antagonist profiles were determined for many of the compounds described in table ii , herein . in assays “ d ” and “ e ”, there are described methods for evaluating a combination therapy of the invention , namely , an angiotensin ii receptor antagonist of table ii and an epoxy - free spirolactone - type aldosterone receptor antagonist . the efficacy of the individual drugs , spironolactone and the angiotensin ii receptor blocker , and of these drugs given together at various doses , are evaluated in rodent models of hypertension and chf using surgical alterations to induce either hypertension or an mi . the methods and results of such assays are described below . compounds of the invention were tested for ability to bind to the smooth muscle angiotensin ii receptor using a rat uterine membrane preparation . angiotensin ii ( aii ) was purchased from peninsula labs . 125 i - angiotensin ii ( specific activity of 2200 ci / mmol ) was purchased from du pont - new england nuclear . other chemicals were obtained from sigma chemical co . this assay was carried out according to the method of douglas et al [ endocrinology , 106 , 120 - 124 ( 1980 )]. rat uterine membranes were prepared from fresh tissue . all procedures were carried out at 4 ° c . uteri were stripped of fat and homogenized in phosphate - buffered saline at ph 7 . 4 containing 5 mm edta . the homogenate was centrifuged at 1500 × g for 20 min ., and the supernatant was recentrifuged at 100 , 000 × g for 60 min . the pellet was resuspended in buffer consisting of 2 mm edta and 50 mm tris - hcl ( ph 7 . 5 ) to a final protein concentration of 4 mg / ml . assay tubes were charged with 0 . 25 ml of a solution containing 5 mm mgcl 2 , 2 mm edta , 0 . 5 % bovine serum albumin , 50 mm tris - hcl , ph 7 . 5 and 125 i - aii ( approximately 10 5 cpm ) in the absence or in the presence of unlabelled ligand . the reaction was initiated by the addition of membrane protein and the mixture was incubated at 25 ° c . for 60 min . the incubation was terminated with ice - cold 50 mm tris - hcl ( ph 7 . 5 ) and the mixture was filtered to separate membrane - bound labelled peptide from the free ligand . the incubation tube and filter were washed with ice - cold buffer . filters were assayed for radioactivity in a micromedic gamma counter . nonspecific binding was defined as binding in the presence of 10 μm of unlabelled aii . specific binding was calculated as total binding minus nonspecific binding . the receptor binding affinity of an aii antagonist compound was indicated by the concentration ( ic 50 ) of the tested aii antagonist which gives 50 % displacement of the total specifically bound 125 i - aii from the angiotensin ii at 1 receptor . binding data were analyzed by a nonlinear least - squares curve fitting program . results are reported in table iii . the compounds of the invention were tested for antagonist activity in rabbit aortic rings . male new zealand white rabbits ( 2 - 2 . 5 kg ) were sacrificed using an overdose of pentobarbital and exsanguinated via the carotid arteries . the thoracic aorta was removed , cleaned of adherent fat and connective tissue and then cut into 3 - mm ring segments . the endothelium was removed from the rings by gently sliding a rolled - up piece of filter paper into the vessel lumen . the rings were then mounted in a water - jacketed tissue bath , maintained at 37 ° c ., between moveable and fixed ends of a stainless steel wire with the moveable end attached to an ft03 grass transducer coupled to a model 7d grass polygraph for recording isometric force responses . the bath was filled with 20 ml of oxygenated ( 95 % oxygen / 5 % carbon dioxide ) krebs solution of the following composition ( mm ): 130 nacl , 15 nahco 3 , 15 kcl , 1 . 2 nah 2 po 4 , 1 . 2 mgso 4 , 2 . 5 cacl 2 , and 11 . 4 glucose . the preparations were equilibrated for one hour before approximately one gram of passive tension was placed on the rings . angiotensin ii concentration - response curves were then recorded ( 3 × 10 − 10 to 1 × 10 − 5 m ). each concentration of aii was allowed to elicit its maximal contraction , and then aii was washed out repeatedly for 30 minutes before rechallenging with a higher concentration of aii . aorta rings were exposed to the test antagonist at 10 − 5 m for 5 minutes before challenging with aii . adjacent segments of the same aorta ring were used for all concentration - response curves in the presence or absence of the test antagonist . the effectiveness of the test compound was expressed in terms of pa 2 values and were calculated according to h . o . schild [ br . j . pharmacol . chemother ., 2 , 189 - 206 ( 1947 )]. the pa 2 value is the concentration of the antagonist which increases the ec 50 value for aii by a factor of two . each test antagonist was evaluated in aorta rings from two rabbits . results are reported in table iii . male sprague - dawley rats weighing 225 - 300 grams were anesthetized with methohexital ( 30 mg / kg , i . p .) and catheters were implanted into the femoral artery and vein . the catheters were tunneled subcutaneously to exit dorsally , posterior to the head and between the scapulae . the catheters were filled with heparin ( 1000 units / ml of saline ). the rats were returned to their cage and allowed regular rat chow and water ad libitum . after full recovery from surgery ( 3 - 4 days ), rats were placed in lucite holders and the arterial line was connected to a pressure transducer . arterial pressure was recorded on a gould polygraph ( mmhg ). angiotensin ii was administered as a 30 ng / kg bolus via the venous catheter delivered in a 50 μl volume with a 0 . 2 ml saline flush . the pressor response in mm hg was measured by the difference from pre - injection arterial pressure to the maximum pressure achieved . the aii injection was repeated every 10 minutes until three consecutive injections yielded responses within 4 mmhg of each other . these three responses were then averaged and represented the control response to aii . the test compound was suspended in 0 . 5 % methylcellulose in water and was administered by gavage . the volume administered was 2 ml / kg body weight . the standard dose was 3 mg / kg . angiotensin ii bolus injections were given at 30 , 45 , 60 , 75 , 120 , 150 , and 180 minutes after gavage . the pressor response to aii was measured at each time point . the rats were then returned to their cage for future testing . a minimum of 3 days was allowed between tests . percent inhibition was calculated for each time point following gavage by the following formula : [( control response − response at time point )/ control response ]× 100 . results are shown in table iii . male rats are made hypertensive by placing a silver clip with an aperture of 240 microns on the left renal artery , leaving the contralateral kidney untouched . sham controls undergo the same procedure but without attachment of the clip . one week prior to the surgery , animals to be made hypertensive are divided into separate groups and drug treatment is begun . groups of animals are administered vehicle , aii antagonist alone , spironolactone alone , and combinations of aii antagonist and spironolactone , at various doses , as follow : combination of aii antagonist spironolactone aii antagonist & amp ; spironolactone ( mg / kg / day ) ( mg / kg / day ) ( mg / kg / day ) ( mg / kg / day ) 3 5 3 5 20 3 20 50 3 50 100 3 100 200 3 200 10 5 10 5 20 10 20 50 10 50 100 10 100 200 10 200 30 5 30 5 20 30 20 50 30 50 100 30 100 200 30 200 after 12 to 24 weeks , systolic and diastolic blood pressure , left ventricular end diastolic pressure , left ventricular dp / dt , and heart rate are evaluated . the hearts are removed , weighed , measured and fixed in formalin . collagen content of heart sections are evaluated using computerized image analysis of picrosirius stained sections . it would be expected that rats treated with a combination therapy of aii antagonist and spironolactone components , as compared to rats treated with either component alone , will show improvements in cardiac performance . male rats are anesthetized and the heart is exteriorized following a left sided thoracotomy . the left anterior descending coronary artery is ligated with a suture . the thorax is closed and the animal recovers . sham animals have the suture passed through without ligation . one week prior to the surgery , animals to undergo infarction are divided into separte groups and drug treatment is begun . groups of animals are administered vehicle , aii antagonist alone , spironolactone alone , and combinations of aii antagonist and spironolactone , at various doses , as follow : combination of aii antagonist spironolactone aii antagonist & amp ; spironolactone ( mg / kg / day ) ( mg / kg / day ) ( mg / kg / day ) ( mg / kg / day ) 3 5 3 5 20 3 20 50 3 50 100 3 100 200 3 200 10 5 10 5 20 10 20 50 10 50 100 10 100 200 10 200 30 5 30 5 20 30 20 50 30 50 100 30 100 200 30 200 after six weeks , systolic and diastolic blood pressure , left ventricular end diastolic pressure , left ventricular dp / dt , and heart rate evaluated . the hearts are removed , weighed , measured and fixed in formalin . collagen content of heart sections are evaluated using computerized image analysis of picrosirius stained sections . it would be expected that rats treated with a combination therapy of aii antagonist and spironolactone components , as compared to rats treated with either component alone , will show improvements in cardiac performance . table iii in vivo and in vitro angiotensin ii activity of compounds of the invention test com - pound 1 assay a 3 assay c exam - ic 50 2 assay b dose inhibition duration ple # ( nm ) pa 2 ( mg / kg ) (%) ( min .) 1 nt nt nt nt nt 2 95 7 . 37 / 7 . 59 10 95 60 30 98 90 - 120 3 5 . 4 8 . 70 ± 0 . 2 10 50 & gt ; 180 30 100 200 + 4 nt nt nt nt nt 5 200 7 . 48 / 6 . 91 30 38 20 - 30 6 1300 6 . 55 / 6 . 82 100 90 120 7 84 8 . 01 / 8 . 05 30 90 130 8 17 , 000 nt nt nt nt 9 700 6 . 67 / 6 . 12 30 80 75 100 100 130 10 4 . 9 8 . 19 / 7 . 59 3 86 100 30 100 240 11 160 6 . 45 / 6 . 77 nt nt nt 12 6 . 0 8 . 66 / 8 . 59 nt nt nt 13 17 8 . 70 / 8 . 85 nt nt nt 14 7 . 2 8 . 84 / 8 . 71 nt nt nt 15 16 8 . 31 / 8 . 30 nt nt nt 16 6 . 4 8 . 95 / 9 . 24 nt nt nt 17 4 . 0 8 . 64 / 8 . 40 nt nt nt 18 970 6 . 14 / 6 . 09 nt nt nt 19 12 , 000 5 . 18 / 5 . 35 nt nt nt 20 78 , 000 5 . 89 / 5 . 99 100 10 45 21 87 7 . 71 . 7 . 21 nt nt nt 22 460 6 . 60 / 6 . 46 nt nt nt 23 430 6 . 48 / 7 . 15 nt nt nt 24 10 7 . 56 / 7 . 73 nt nt nt 25 480 6 . 80 / 6 . 73 nt nt nt 26 3 . 2 9 . 83 / 9 . 66 10 50 & gt ; 180 27 180 nt nt nt nt 28 570 5 . 57 / 6 . 00 nt nt nt 29 160 nt nt nt nt 30 22 7 . 73 / 7 . 88 30 50 & gt ; 180 31 14 nt nt nt nt 32 16 7 . 68 / 7 . 29 nt nt nt 33 630 6 . 73 / 6 . 36 nt nt nt 34 640 5 . 34 / 5 . 69 nt nt nt 35 41 7 . 25 / 7 . 47 nt nt nt 36 1400 5 . 92 / 5 . 68 nt nt nt 37 340 6 . 90 / 6 . 85 nt nt nt 38 10 7 . 82 / 8 . 36 nt nt nt 39 10 7 . 88 / 7 . 84 nt nt nt 40 83 7 . 94 / 7 . 61 nt nt nt 41 3700 5 . 68 / 5 . 96 nt nt nt 42 370 6 . 56 / 6 . 26 nt nt nt 43 19 8 . 97 / 8 . 61 nt nt nt 44 16 8 . 23 / 7 . 70 nt nt nt 45 4 . 4 8 . 41 / 8 . 24 nt nt nt 46 110 6 . 80 / 6 . 64 nt nt nt 47 21 7 . 85 / 7 . 58 nt nt nt 48 680 6 . 27 / 6 . 75 nt nt nt 49 120 7 . 06 / 7 . 07 nt nt nt 50 54 7 . 71 / 7 . 89 nt nt nt 51 8 . 7 8 . 39 / 8 . 51 nt nt nt 52 100 8 . 14 / 8 . 12 nt nt nt 53 65 7 . 56 / 7 . 83 nt nt nt 54 3100 6 . 02 nt nt nt 55 80 6 . 56 / 7 . 13 nt nt nt 56 5 . 0 9 . 04 / 8 . 35 nt nt nt 57 2300 6 . 00 nt nt nt 58 140 6 . 45 / 6 . 57 nt nt nt 59 120 7 . 23 / 7 . 59 nt nt nt 60 2200 6 . 40 / 6 . 03 nt nt nt 61 110 7 . 29 / 7 . 70 nt nt nt 62 26 8 . 69 / 8 . 61 nt nt nt 63 61 7 . 77 / 7 . 67 nt nt nt 64 54 7 . 00 / 6 . 77 nt nt nt 65 23 7 . 85 / 7 . 75 nt nt nt 66 12 9 . 34 / 8 . 58 nt nt nt 67 3100 5 . 88 / 5 . 78 nt nt nt 68 8 . 6 8 . 19 / 8 . 65 nt nt nt 69 15 7 . 80 / 8 . 28 nt nt nt 70 44 7 . 71 / 8 . 05 nt nt nt 71 12 , 000 * nt nt nt 72 83 6 . 11 / 6 . 10 nt nt nt 73 790 7 . 65 / 7 . 46 nt nt nt 74 6 . 5 8 . 56 / 8 . 39 nt nt nt 75 570 6 . 00 / 5 . 45 nt nt nt 76 5400 5 . 52 / 5 . 78 nt nt nt 77 15 , 000 5 . 77 nt nt nt 78 101 7 . 0 93 60 - 100 79 4 . 9 9 . 2 100 & gt ; 200 50 & gt ; 180 80 25 8 . 1 nt nt 81 18 8 . 0 40 180 82 7 . 9 8 . 5 20 180 83 3 . 6 8 . 3 15 & gt ; 180 84 16 7 . 1 20 30 85 8 . 7 8 . 9 nt nt 86 9 7 . 8 nt nt 87 91 7 . 8 nt nt 88 50 7 . 7 nt nt 89 18 7 . 9 nt nt 90 5 . 6 9 . 0 nt nt 91 30 8 . 6 40 & gt ; 180 92 35 7 . 9 nt nt 93 480 nt nt nt 94 5 , 800 nt nt nt 95 66 8 . 2 nt nt 96 21 8 . 0 nt nt 97 280 7 . 7 nt nt 98 22 8 . 1 nt nt 99 280 6 . 5 nt nt 100 4 . 4 9 . 4 nt nt 101 36 7 . 8 nt nt 102 43 7 . 7 nt nt 103 12 8 . 0 nt nt 104 15 8 . 0 nt nt 105 290 6 . 6 nt nt 106 48 7 . 7 nt nt 107 180 8 . 3 nt nt 108 720 5 . 3 100 45 90 109 250 7 . 3 30 50 30 110 590 6 . 4 nt nt 111 45 9 . 0 30 87 160 112 2000 5 . 2 nt nt 113 12 8 . 4 10 60 180 114 400 6 . 4 nt 115 11 8 . 2 3 40 & gt ; 240 116 230 6 . 5 nt 117 170 6 . 5 nt 118 37 9 . 21 / 9 . 17 10 70 120 119 16 9 . 21 / 9 . 00 3 20 60 120 25 9 . 05 / 8 . 77 10 80 240 121 46 nt nt 122 46 nt nt 123 50 nt nt 124 40 9 . 42 / 9 . 12 3 45 & gt ; 180 125 40 9 . 25 / 8 . 80 3 35 & gt ; 240 126 240 7 . 20 / 7 . 05 nt 127 12 , 000 4 . 96 nt 128 16 8 . 63 / 8 . 40 nt 129 6 , 700 5 . 30 nt 130 40 8 . 10 / 7 . 94 nt 131 9 . 5 7 . 53 / 8 . 25 132 12 8 . 6 nt 133 10 8 . 7 3 20 180 90 - 120 134 22 9 . 3 3 35 180 135 16 8 . 5 3 35 & gt ; 180 136 nt nt nt 137 220 8 . 3 nt 138 130 8 . 2 nt 139 0 . 270 6 . 3 nt 140 0 . 031 8 . 1 100 160 141 0 . 110 8 . 02 nt nt 142 2 . 000 na nt nt 143 0 . 052 7 . 7 85 75 144 0 . 088 7 . 7 50 125 145 0 . 480 6 . 7 nt nt 146 0 . 072 6 . 4 nt nt 147 5 . 8 5 . 6 3 74 5 - 10 148 0 . 87 5 . 8 3 92 20 - 30 149 1 . 1 6 . 1 3 nt nt 150 14 8 . 03 / 7 . 80 3 25 & gt ; 180 151 17 7 . 76 / 7 . 97 3 15 180 152 150 7 . 46 / 7 . 23 3 10 140 153 13 8 . 30 / 7 . 69 3 25 & gt ; 180 154 97 8 . 19 / 8 . 38 na 155 86 7 . 60 / 7 . 14 na 156 78 8 . 03 / 7 . 66 na 157 530 -/ 6 . 22 na 158 54 8 . 23 / 8 . 14 3 30 & gt ; 180 159 21 7 . 92 / 7 . 56 3 10 150 160 64 7 . 87 / 7 . 71 161 28 na 162 380 6 . 21 / 6 . 55 na 163 420 7 . 42 / 6 . 75 na 164 1700 na 165 410 6 . 90 / 7 . 18 na 166 160 7 . 57 / 7 . 74 na 167 370 7 . 08 / 7 . 11 na 168 420 7 . 69 / 7 . 58 na 169 150 7 . 78 / 7 . 58 3 15 180 170 26 7 . 08 / 7 . 77 3 40 & gt ; 180 171 28 7 . 52 / 7 . 11 3 0 0 172 70 7 . 15 / 7 . 04 na 173 90 7 . 49 / 6 . 92 na 174 180 7 . 29 / 7 . 02 na 175 27 na 3 0 0 176 9 . 8 7 . 69 / 7 . 55 3 10 150 177 26 7 . 41 / 7 . 85 3 15 180 178 88 7 . 54 / 7 . 47 na 179 310 6 . 67 /- na 180 20 7 . 56 / 7 . 15 3 25 180 181 21 7 . 70 / 7 . 12 3 20 180 182 59 na na 183 390 na na 184 1100 6 . 78 /- na 185 6 . 5 8 . 82 / 8 . 53 3 50 & gt ; 180 186 38 8 . 13 / 7 . 40 3 25 18 187 770 7 . 46 / 6 . 95 na 188 140 7 . 72 / 7 . 09 na 189 29 8 . 64 / 8 . 23 na 190 10 7 . 87 / 7 . 89 3 10 180 191 81 7 . 75 / 7 . 76 3 10 180 192 140 na 193 11 9 . 27 / 8 . 87 3 10 180 194 47 7 . 64 / 7 . 35 na 195 34 8 . 44 / 8 . 03 na 196 31 7 . 68 / 8 . 26 na 197 14 8 . 03 / 8 . 60 na 198 7 . 6 8 . 76 / 8 . 64 3 35 & gt ; 180 199 10 8 . 79 / 8 . 85 3 60 & gt ; 180 200 20 8 . 42 / 8 . 77 3 45 & gt ; 180 201 17 8 . 78 / 8 . 63 3 10 180 202 12 8 . 79 / 8 . 64 3 65 & gt ; 180 203 9 . 2 8 . 43 / 8 . 36 3 50 & gt ; 180 204 16 9 . 17 / 8 . 86 3 75 & gt ; 180 205 20 9 . 14 / 9 . 15 3 40 & gt ; 180 206 5 . 4 8 . 75 / 8 . 89 3 30 & gt ; 180 207 99 9 . 04 / 8 . 60 na 208 22 9 . 19 / 8 . 69 3 50 & gt ; 180 209 5 . 0 9 . 41 / 9 . 16 3 25 & gt ; 180 210 3 . 6 8 . 36 / 8 . 44 3 15 180 211 18 8 . 74 / 8 . 67 3 35 & gt ; 180 212 23 8 . 85 / 8 . 25 3 15 180 213 51 na na 214 65 na na 215 45 na na 216 5 . 4 8 . 80 / 9 . 04 3 50 & gt ; 180 217 9 . 4 na 3 65 & gt ; 180 218 9 . 0 na na 219 14 na na 220 7 . 0 na 3 75 120 221 4 . 8 na 3 25 & gt ; 180 222 5 . 0 na na 223 14 7 . 45 / 7 . 87 3 20 & gt ; 180 224 91 na na 225 160 na na 226 93 na na 227 89 7 . 55 / 7 . 67 na 228 4 . 5 9 . 17 / 8 . 25 3 80 & gt ; 180 229 19 nt 3 40 & gt ; 180 230 2 . 6 8 . 23 / 8 . 69 3 25 & gt ; 180 231 3 . 6 nt 3 75 & gt ; 180 232 4 . 4 8 . 59 / 8 . 89 3 70 & gt ; 180 233 84 8 . 51 / 8 . 78 nt 234 5 . 0 8 . 49 / 9 . 00 3 20 — 235 34 7 . 14 / 7 . 07 nt 236 4 . 9 nc 3 70 & gt ; 180 237 3 . 6 nt nt 238 1 . 7 nt 3 15 & gt ; 180 239 6 . 8 7 . 88 / 8 . 01 3 20 & gt ; 180 240 120 na na 241 6 . 9 8 . 57 / 8 . 24 3 40 & gt ; 180 242 110 7 . 11 / 6 . 60 na 243 250 na na 244 150 7 . 17 / 7 . 17 na 245 98 6 . 64 / 7 . 04 na 246 72 7 . 46 / 7 . 59 na 247 9 . 4 8 . 26 / 8 . 41 3 20 180 248 20 7 . 68 / 7 . 50 3 10 — 249 4 . 4 na 3 20 & gt ; 180 250 43 na 3 0 — 251 25 na na 252 13 na na 253 2 . 6 na na 254 72 na na 255 12 7 . 61 / 7 . 46 3 20 & gt ; 180 256 4 . 1 8 . 43 / 7 . 78 3 30 & gt ; 180 257 160 6 . 63 / 6 . 68 na 258 350 6 . 84 / 6 . 84 na 259 54 na na 260 220 na na 261 18 na na 262 530 -/ 6 . 22 na 263 57 na na 264 11 na na 265 110 na na 266 290 na na 267 25 na 3 25 & gt ; 180 268 520 na 3 0 — 269 9 . 7 na na 270 21 na na 271 14 nc 3 20 % — 272 97 nc 3 70 % & gt ; 180 min . 273 9 . 8 8 . 53 / 8 . 61 3 25 % & gt ; 180 min . 274 13 9 . 06 / 8 . 85 3 35 % & gt ; 180 min . 275 6 . 3 9 . 07 /- 3 40 % & gt ; 180 min . 276 33 8 . 71 / 8 . 64 3 & lt ; 20 % 277 190 -/ 6 . 54 nt 278 30 8 . 49 / 8 . 51 3 50 % & gt ; 180 min . 279 270 8 . 06 / 8 . 25 nt 280 480 6 . 41 / 6 . 35 nt nt nt # # 139 -# 149 which were given intraduodenally . administration of the angiotensin ii receptor antagonist and the aldosterone receptor antagonist may take place sequentially in separate formulations , or may be accomplished by simultaneous administration in a single formulation or separate formulations . administration may be accomplished by oral route , or by intravenous , intramuscular or subcutaneous injections . the formulation may be in the form of a bolus , or in the form of aqueous or non - aqueous isotonic sterile injection solutions or suspensions . these solutions and suspensions may be prepared from sterile powders or granules having one or more pharmaceutically - acceptable carriers or diluents , or a binder such as gelatin or hydroxypropyl - methyl cellulose , together with one or more of a lubricant , preservative , surface - active or dispersing agent . for oral administration , the pharmaceutical composition may be in the form of , for example , a tablet , capsule , suspension or liquid . the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient . examples of such dosage units are tablets or capsules . these may with advantage contain an amount of each active ingredient from about 1 to 250 mg , preferably from about 25 to 150 mg . a suitable daily dose for a mammal may vary widely depending on the condition of the patient and other factors . however , a dose of from about 0 . 01 to 30 mg / kg body weight , particularly from about 1 to 15 mg / kg body weight , may be appropriate . the active ingredients may also be administered by injection as a composition wherein , for example , saline , dextrose or water may be used as a suitable carrier . a suitable daily dose of each active component is from about 0 . 01 to 15 mg / kg body weight injected per day in multiple doses depending on the disease being treated . a preferred daily dose would be from about 1 to 10 mg / kg body weight . compounds indicated for prophylactic therapy will preferably be administered in a daily dose generally in a range from about 0 . 1 mg to about 15 mg per kilogram of body weight per day . a more preferred dosage will be a range from about 1 mg to about 15 mg per kilogram of body weight . most preferred is a dosage in a range from about 1 to about 10 mg per kilogram of body weight per day . a suitable dose can be administered , in multiple sub - doses per day . these sub - doses may be administered in unit dosage forms . typically , a dose or sub - dose may contain from about 1 mg to about 100 mg of active compound per unit dosage form . a more preferred dosage will contain from about 2 mg to about 50 mg of active compound per unit dosage form . most preferred is a dosage form containing from about 3 mg to about 25 mg of active compound per unit dose . in combination therapy , the aldosterone receptor antagonist may be present in an amount in a range from about 5 mg to about 400 mg , and the aii antagonist may be present in an amount in a range from about 1 mg to about 800 mg , which represents aldosterone antagonist - to - aii antagonist ratios ranging from about 400 : 1 to about 1 : 160 . in a preferred combination therapy , the aldosterone receptor antagonist may be present in an amount in a range from about 10 mg to about 200 mg , and the aii antagonist may be present in an amount in a range from about 5 mg to about 600 mg , which represents aldosterone antagonist - to - aii antagonist ratios ranging from about 40 : 1 to about 1 : 60 . in a more preferred combination therapy , the aldosterone receptor antagonist may be present in an amount in a range from about 20 mg to about 100 mg , and the aii antagonist may be present in an amount in a range from about 10 mg to about 400 mg , which represents aldosterone antagonist - to - aii antagonist ratios ranging from about 10 : 1 to about 1 : 20 . the dosage regimen for treating a disease condition with the combination therapy of this invention is selected in accordance with a variety of factors , including the type , age , weight , sex and medical condition of the patient , the severity of the disease , the route of administration , and the particular compound employed , and thus may vary widely . for therapeutic purposes , the active components of this combination therapy invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration . if administered per os , the components may be admixed with lactose , sucrose , starch powder , cellulose esters of alkanoic acids , cellulose alkyl esters , talc , stearic acid , magnesium stearate , magnesium oxide , sodium and calcium salts of phosphoric and sulfuric acids , gelatin , acacia gum , sodium alginate , polyvinylpyrrolidone , and / or polyvinyl alcohol , and then tableted or encapsulated for convenient administration . such capsules or tablets may contain a controlled - release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose . formulations for parenteral administration may be in the form of aqueous or non - aqueous isotonic sterile injection solutions or suspensions . these solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration . the components may be dissolved in water , polyethylene glycol , propylene glycol , ethanol , corn oil , cottonseed oil , peanut oil , sesame oil , benzyl alcohol , sodium chloride , and / or various buffers . other adjuvants and modes of administration are well and widely known in the pharmaceutical art . although this invention has been described with respect to specific embodiments , the details of these embodiments are not to be construed as limitations .