Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to compounds which are endothelin antagonists, processes for making such compounds, synthetic intermediates employed in these processes and methods and compositions for antagonizing endothelin.
• ET Endothelin
• Big ET precursor peptide big endothelin
• ECE endothelin converting enzyme
• Endothelin has been shown to constrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility in vitro, stimulate mitogenesis in vascular smooth muscle cells in vitro, contract non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus in vitro, increase airway resistance in vivo, induce formation of gastric ulcers, stimulate release of atrial natriuretic factor in vitro and in vivo, increase plasma levels of vasopressin, aldosterone and catecholamines, inhibit release of renin in vitro and stimulate release of gonadotropins in vitro.
• vasoconstriction is caused by binding of endothelin to its receptors on vascular smooth muscle (Nature 332 411 (1988), FEBS Letters 231 440 (1988) and Biochem. Biophys. Res. Commun. ______ 868 (1988)).
• An agent which suppresses endothelin production or an agent which binds to endothelin or which inhibits the binding of endothelin to an endothelin receptor will produce beneficial effects in a variety of therapeutic areas.
• an anti-endothelin antibody has been shown, upon intrarenal infusion, to ameliorate the adverse effects of renal ischemia on renal vascular resistance and glomerular filtration rate (Kon, et al., J. Clin.
• an anti-endothelin antibody attenuated the nephrotoxic effects of intravenously administered cyclosporin (Kon, et al., Kidney Int. 3_7 1487 (1990)) and attenuated infarct size in a coronary artery Clozel et al. (Nature 365: 759-761 (1993)) report that Ro 46-2005, a nonpeptide ET-A/B antagonist, prevents post-ischaemic renal vasoconstriction in rats, prevents the decrease in cerebral blood flow due to subarachnoid hemorrhage (SAH) in rats, and decreases MAP in sodium-depleted squirrel monkeys when dosed orally.
• SAH subarachnoid hemorrhage
• the compounds claimed in the current invention differ from those previously described and are unique in that they bind potently and selectively to the ET ⁇ subtype, blocking the actions of the endothelins on these receptors. As such, they may find utility in the treatment of diseases that are mediated by the ET ⁇ receptor.
• R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is (a) -C(0)2-G wherein G is hydrogen or a carboxy protecting group,
• Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyi, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyaikyl, heterocyclic, (heterocyclic)alkyl and ( R aa )( R bb) N - R cc" wherein R aa is ar
• R3 is R4-C(0)-R ⁇ - or R ⁇ -S(0)2-R7- wherein R5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R2o)- R 8- or " R ⁇ a" N ( R 2 ⁇ )" R 8' wherein R 8 and R 8a are independently selected from the group consisting of alkylene and alkenylene; and R20 is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl or cycloalkylalkyi or (v) -O-R9- or -Rg a -0-R 9 - wherein Rg and R 9a are independently selected from alkylene;
• R7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R2i)-R ⁇ cr or -R 10a -N(R2i)-R ⁇ o- wherein R10 and R 10a are independently selected from the group consisting of alkylene and alkenylene and R21 is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl; wherein R4 and R 6 are
• R-n and R12 are independently selected from the group consisting of loweralkyl, cyano, alkoxy, halo, haloalkyi and phenyl and R-13, R-
• a preferred embodiment of the invention is a compound of formula (II)
• a more preferred embodiment of the invention is a compound of formula (i) or (II) wherein R3 is R4-C(0)-Rs- wherein R4 is as defined above and R5 is alkylene or R3 is R6-S(0)2-R7- wherein R7 is alkylene and Re is defined as above.
• An even more preferred embodiment of the invention is a compound of formula (I) or (II) wherein R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is -C(0)-NHS(0) 2 R 16 wherein R 16 is loweralkyl, haloalkyi or aryl, R1 and R2 are independently selected from (i) loweralkyl, (ii) cycloalkyl, (iii) substituted and unsubstituted aryl, and (iv) substituted or unsubstituted heterocyclic, and R3 is R4-C(0)-Rs- wherein R4 is as defined above and R5 is alkylene or R3 is R ⁇ -S(0)2-R7- wherein R7 is alkylene and Re is defined as above.
• a yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0) 2 R ⁇ 6 wherein R 16 is loweralkyl, haloalkyi or aryl, R1 is (i) alkoxyalkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, (v) furanyl or (vi) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4- propoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4- pentafluoroethylphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-
• R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0) 2 R 16 wherein R 16 is loweralkyl, haloalkyi or aryl, R1 is (i) alkoxyalkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, (v) furanyl or (vi) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4- propoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4- pentafluoroethylphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro- 4-e
• a still more preferred embodiment of the invention is a compound of formula (I) or (II) wherein R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0) 2 R 16 wherein R 16 is loweralkyl or haloalkyi, Ri is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4- ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 3-fluoro-4-methoxyphenyl, 3- fluoro-4-ethoxyphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3- methoxy-4-propoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4- methoxymethoxyphenyl, 4-(2-methoxyethoxy)phenyl,
• R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group
• Ri is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-ethoxyphenyl, 4- propoxyphenyl, 4-isopropoxyphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4- propoxyphenyl, 3-methoxy-4-propoxyphenyl, 4-methoxymethoxyphenyl, 4-(2- methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropoxyethoxy)phenyl, 4- hydroxyphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substitu
• R- ⁇ and R12 are independently selected from loweralkyl, and R13,
• R14, and R 5 are independently selected from the group consisting of hydrogen, loweralkyl, hydroxy, amino, alkoxy, aryl, heterocyclic, halo, carboxy, nitro, aikylsulfonyl, arylsulfo ⁇ yl, thioalkoxy, thioaryloxy, or cyano and R5 is alkylene.
• a most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Ri is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-ethoxyphenyl, 4- propoxyphenyl, 4-isopropoxyphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4- propoxyphenyl, 3-methoxy-4-propoxyphenyl, 4methoxymethoxyphenyl, 4-(2- methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropoxyethoxy)phenyl, 4- hydroxyphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodiox
• R- ⁇ and R 2 are independently selected from the group consisting of lower alkyl, alkoxy and halo
• R13, R14, and R15 are independently selected from the group consisting of hydrogen, loweralkyl, hydroxy, amino, alkoxy, aryl, heterocyclic, halo, carboxy, nitro, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy, or cyano
• R5 is alkylene.
• R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, R-
• Rn and R12 are independently selected from the group consisting of methyl, ethyl, and isopropyl
• R13, R14, and R15 are independently selected from the group consisting of hydrogen, loweralkyl, hydroxy, amino, alkoxy, aryl, heterocyclic, halo, carboxy, nitro, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy, or cyano
• R5 is alkylene.
• Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Ri is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2- fluorophenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-ethoxyphenyl, 4- propoxyphenyl, 4-isopropoxyphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4- propoxyphenyl, 3-methoxy-4-propoxyphenyl, 4-methoxymethoxyphenyl, 4-(2- methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropoxyethoxy)phenyl, 4- hydroxyphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodiox
• R- ⁇ and R12 are independently selected from the group consisting of methyl, ethyl, and isopropyl
• R13, R14, and R15 are independently selected from the group consisting of hydrogen, loweralkyl, hydroxy, amino, alkoxy, aryl, heterocyclic, halo, carboxy, nitro, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy, or cyano
• R5 is methylene.
• the present invention also relates to processes for preparing the compounds of formula (I) and (II) and to the synthetic intermediates employed in these processes.
• the present invention also relates to a method of antagonizing endothelin in a mammal (preferably a human) in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or (II).
• the invention further relates to endothelin antagonizing compositions comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of formula (I) or (II).
• the compounds of the invention comprise two or more asymmetrically substituted carbon atoms.
• racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention are included in the present invention.
• the terms "S" and "R” configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.
• carboxy protecting group refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out.
• Carboxy protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis” pp. 152-186 (1981 ), which is hereby incorporated herein by reference.
• a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo , for example by enzymatic hydrolysis, to release the biologically active parent.
• carboxy protecting groups are Ci to Cs alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyi; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cyclopentyl and the like; cycloalkylalkyi and substituted derivatives thereof such as cyclohexylmethyl, cyclopentylmethyl and the like; aryialkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5- indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl, cyclopentyl and the like); cycloalkylalkyi and
• N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981 )), which is hereby incorporated by reference.
• N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4- chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyioxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzy
• N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t- butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl
• alkanoyl refers to an alkyl group as defined herein appended to the parent molecular moiety through a carbonyl (-C(O)-) group.
• alkanoyl examples include acetyl, propionyl and the like.
• alkanoylamino refers to an alkanoyl group as previously defined appended to an amino group. Examples alkanoylamino include acetamido, propionamido and the like.
• alkanoylaminoalkyl refers to R43-NH-R44- wherein
• R43 is an alkanoyl group and R44 is an alkylene group.
• alkanoyloxyalkyl refers to R30-O-R31- wherein R30 is an alkanoyl group and R31 is an alkylene group. Examples of alkanoyloxyalkyl include acetoxymethyl, acetoxyethyi and the like.
• alkenyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond.
• Alkenyl groups include, for example, vinyl
• alkenylene denotes a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond.
• alkenyloxy refers to an alkenyl group, as previously defined, connected to the parent molecular moiety through an oxygen (-0-) linkage.
• alkenyloxy examples include allyloxy, butenyloxy and the like.
• alkoxy refers to R42O- wherein R42 is a loweralkyl group, as defined herein.
• alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-butoxy, tert-butoxy, and the like.
• alkoxyalkoxy refers to RsrjO-RsiO- wherein R ⁇ o ss loweralkyl as defined above and Rs ⁇ is alkylene.
• Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
• alkoxyalkoxyalkoxy refers to R82O-R83O-R84O- wherein R ⁇ 2 is loweralkyl as defined above and Rs3 and R ⁇ 4 are alkylene.
• alkoxyalkoxyalkoxy groups include methoxyethoxymethoxy, ethoxymethoxymethoxy, t-butoxymethoxymethoxy and the like.
• (alkoxyalkyl)sulfonyl refers to R85-0-R86-S(0)2-, wherein R85 is loweralkyl and R86 is alkylene.
• alkoxyalkoxyalkyl refers to an alkoxyalkoxy group as previously defined appended to an alkyl radical.
• Representative examples of alkoxyalkoxyalkyl groups include methoxyethoxyethyl, methoxymethoxymethyl, and the like.
• alkoxyalkyl refers to an alkoxy group as previously defined appended to an alkyl radical as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.
• alkoxycarbonyl refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.
• alkoxycarbonylalkenyl refers to an alkoxycarbonyl group as previously defined appended to an alkenyl radical.
• alkoxycarbonylalkenyl include methoxycarbonylethenyl, ethoxycarbonylethenyl and the like.
• alkoxycarbonylalkyl refers to R34-C(0)-R35- wherein
• R34 is an alkoxy group and R35 is an alkylene group.
• alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl and the like.
• alkoxycarbonylaminoalkyl refers to alkoxycarbonylaminoalkyl
• alkoxycarbonylaminoalkyl examples include methoxycarbonylaminoethyl and the like.
• alkoxycarbonyloxyalkyl refers to R36-C(0)-0-R37- wherein R36 is an alkoxy group and R37 is an alkylene group.
• alkoxycarbonyloxyalkyl examples include (ethoxycarbonyloxy)methyl and the like.
• (alkoxycarbonyl)thioalkoxy refers to an alkoxycarbonyl group as previously defined appended to a thioalkoxy radical.
• Examples of (alkoxycarbonyl)thioalkoxy include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like.
• alkyl and “loweralkyl” as used herein refer to straight or branched chain alkyl radicals containing from 1 to 15 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1- methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
• alkylamino refers to R5-1 NH- wherein R51 is a loweralkyl group, for example, ethylamino, butylamino, and the like.
• (alkylamino)alkoxy refers R52NH-R53-O- wherein
• R52 is loweralkyl and R53 is alkylene.
• alkylaminocarbonyl refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl
• alkylaminocarbonyl examples include methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl and the like.
• alkylaminocarbonylalkenyl refers to an alkenyl radical to which is appended an alkylaminocarbonyl group.
• alkylaminocarbonylalkyl refers to a loweralkyl radical to which is appended an alkylaminocarbonyl group.
• alkylaminocarbonylaminoalkyl refers to
• alkylene denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 15 carbon atoms by the removal of two hydrogen atoms, for example -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, - CH 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 - and the like.
• alkylsulfonyl refers to an alkyl group appended to the parent molecular moiety through a sulfonyl group -S(0)2-.
• alkylsulfonyl include methylsulfonyl, ethylsulfonyl, isopropylsulfonyl and the like.
• (alkylsulfonyl)amino refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino (-S(0)2-NH-) group.
• Examples of (alkylsulfonyl)amino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the like.
• (alkylsulfonyl)alkoxy refers to an alkylsulfonyl group as previously defined appended to the parent molecular moiety through a alkoxy group.
• alkylsulfonyl)alkoxy include methylsu.fonylmethoxy, ethylsulfonylethoxy, isopropylsulfonylisopropoxy and the like.
• (alkylthio)alkoxy refers to R54-S-R55-O-, wherein R54 is loweralkyl and R55 is alkylene.
• alkynyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond.
• alkynyl include -C ⁇ C-H, H-C ⁇ C- CH 2 -, H-C ⁇ C-CH(CH 3 )-, CH3-C ⁇ C-CH2-, and the like.
• aminocarbonyl refers to H2N-C(0)- .
• aminocarbonylalkenyl refers to an alkenyl radical to which is appended an aminocarbonyl (NH 2 C(0)-) group.
• aminocarbonylalkoxy refers to H2N-C(0)- appended to an alkoxy group as previously defined. Examples of aminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxy and the like.
• aminocarbonylalkyl refers to a loweralkyl radical to which is appended an aminocarbonyl (NH 2 C(0)-) group.
• aroyloxyalkyl refers to R32-C(0)-0-R33- wherein R32 is an aryl group and R33 is an alkylene group.
• aroyloxyalkyl include benzoyloxymethyl. benzoyloxyethyl and the like.
• aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
• Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo, haloalkyi, haloalkoxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxyalkoxyalkoxy, (cycloalkyl)alkoxy, cycloalkoxy, (alkylamino)alkoxy, (alkylthio)alkoxy, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, (dialkylamino)alkyl, (dialkylamino)alkoxy, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aryloxy, mercapto, cyano, nitro, carboxaldehyde, carboxy, carb
• arylalkenyl refers to an alkenyl radical to which is appended an aryl group, for example, phenylethenyl and the like.
• arylalkoxy refers to R45O- wherein R45 is an arylalkyl group, for example, benzyloxy, and the like.
• arylalkoxyalkyl refers to a loweralkyl radical to which is appended an arylalkoxy group, for example, benzyloxymethyl and the like.
• arylalkyl refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
• aryloxy refers to R46O- wherein R46 is an aryl group, for example, phenoxy, and the like.
• arylalkylcarbonyloxy refers to a R 62 C(0)0- wherein
• R 62 is an arylalkyl group.
• arylalkylcarbonyloxyalkyl refers to a loweralkyl radical to which is appended an arylalkylcarbonyloxy group.
• aryloxyalkyl refers to an aryloxy group as previously defined appended to an alkyl radical. Examples of aryloxyalkyl include phenoxymethyl, 2- phenoxyethyl and the like.
• carboxydehyde refers to a formaldehyde radical
• carboxyamide refers to NH2-C(0)-.
• carboxy refers to a carboxylic acid radical, -C(0)OH.
• carboxyalkenyl refers to a carboxy group as previously defined appended to an alkenyl radical as previously defined. Examples of carboxyalkenyl include 2-carboxyethenyl, 3-carboxy-1 -propenyl and the like.
• carboxyalkoxy refers to a carboxy group as previously defined appended to an alkoxy radical as previously defined. Examples of carboxyalkoxy include carboxymethoxy, carboxyethoxy and the like.
• cyanoalkoxy refers to an alkoxy radical as previously defined to which is appended a cyano (-CN) group. Examples of cyanoalkoxy include 3-cyanopropoxy, 4-cyanobutoxy and the like.
• cycloalkanoyloxy refers to R6o-C(0)-0- wherein R60 is a cycloalkyl group.
• cycloalkanoyloxyalkyl refers to a loweralkyl radical to which is appended a cycloalkanoyloxy group.
• cycloalkyl refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like.
• Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyi, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
• cycloalkyloxy herein refers R61 -0- wherein R61 is a cycloalkyl group. Examples of cycloalkyloxy include cyclohexyloxy and the like.
• (cycloalkyl)alkoxy herein R63-R64-0- wherein R63 is a cycloalkyl as defined above and is appended to the parent molecular moiety through an alkoxy radical wherein R64 is an alkylene group. Examples of (cycloalkyl)alkoxy include (cyclopropyl)ethoxy and the like.
• cycloalkylalkyi refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
• dialkylamino refers to (R56)( R 57)N- wherein R56 and R57 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like.
• dialkylaminoalkyl refers to a loweralkyl radical to which is appended a dialkylamino group.
• dialkylaminoalkoxy refers to an alkoxy radical to which is appended a dialkylamino group.
• dialkylaminocarbonyl refers to a dialkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (-C(O)-) linkage.
• dialkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl and the like.
• dialkylaminocarbonylalkenyl refers to an alkenyl radical to which is appended a dialkylaminocarbonyl group.
• dialkylaminocarbonylalkyl refers to R58-C(0)-Rs9- wherein R58 is a dialkylamino group and R59 is an alkylene group.
• halo or halogen as used herein refers to I, Br, Cl or F.
• haloalkenyl refers to an alkenyl radical to which is appended at least one halogen substituent.
• haloalkoxy refers to an alkoxy radical as defined above, bearing at least one halogen substituent, for example, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, 2,2,3,3,3-pentafluoropropoxy and the like.
• haloalkoxyalkyl refers to a loweralkyl radical to which is appended a haloalkoxy group.
• haloalkyi refers to a lower alkyl radical, as defined above, to which is appended at least one halogen substituent, for example, chloromethyl, fluoroethyl, trifluoromethyl or pentafluoroethyl and the like.
• heterocyclic ring or “heterocyclic” or “heterocycle” as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non- adjacent positions.
• the 5-membered ring has 0-2 double bonds and the 6- and 7- membered rings have 0-3 double bonds.
• heterocyclic or “heterocycle” also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cycloalkane ring or another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like).
• Heterocyclics include: aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl
• Heterocyclics also include compounds of the formula where X* is
• Y * is -C(O)- or [-C(R") 2 -] V where R" is hydrogen or C-
• Heterocyclics also include bicyclic rings such as quinuclidinyl and the like.
• nitrogen containing heterocycles can be N-protected.
• (heterocyclic)alkoxy refers to a heterocyclic group as defined above appended to an alkoxy radical as defined above.
• Examples of (heterocyclic)alkoxy include 4-pyridylmethoxy, 2-pyridylmethoxy and the like.
• (heterocyclic)alkyl refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.
• Examples of (heterocyclic)alkyl include 2-pyridylmethyl and the like.
• heterocyclic(amino) refers to R77.NH- wherein R77 is an aromatic heterocyclic group as defined above which is appended to an amino group.
• the aromatic heterocycle is substituted with substituents R75 and R76 which are both bonded to the atoms of the aromatic heterocycle which are directly adjacent to the nitrogen.
• heterocyclic(amino) examples include 2,4-diethyipyridine-3-amino, 2,4-diethylthiophene-3-amino, 2,4-diethylpyridine-2-amino, and the like.
• heterocycliccarbonyloxyalkyl refers to R47-C(0)-0-R48- wherein R47 is a heterocyclic group and R48 is an alkylene group.
• hydroxy refers to -OH.
• hydroxyaikenyl refers to an alkenyl radical to which is appended a hydroxy group.
• hydroxyalkoxy refers to an alkoxy radical as previously defined to which is appended a hydroxy (-OH) group.
• hydroxyalkoxy include 3-hydroxypropoxy, 4-hydroxybutoxy and the like.
• hydroxyalkyl refers to a loweralkyl radical to which is appended a hydroxy group.
• mercapto refers to -SH.
• methylenedioxy and ethylenedioxy refer to one or two carbon chains respectively attached to the parent molecular moiety through two oxygen atoms. In the case of methylenedioxy, a fused 5 membered ring is formed. In the case of ethylenedioxy, a fused 6 membered ring is formed. Methylenedioxy substituted on a phenyl ring results in the formation of a benzodioxolyl
• substantially pure as used herein means 90% or more of the specified compound.
• tetrazolyl refers to a radical of the formula
• tetrazolylalkoxy refers to a tetrazolyl radical as defined above appended to an alkoxy group as defined above.
• examples of tetrazolylalkoxy include tetrazolylmethoxy, tetrazolylethoxy and the like.
• thioalkoxy refers to R70S- wherein R70 is loweralkyl.
• examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like.
• thioalkoxyalkoxy refers to R71 S-R72O- wherein R71 is loweralkyl as defined above and R72 is alkylene.
• Representative examples of thioalkoxyalkoxy groups include CH 3 SCH 2 0-, CH3CH2SCH 2 0-, t-BuSCH 2 0- and the like.
• thioalkoxyalkoxyalkyi refers to a thioalkoxyalkoxy group appended to an alkyl radical.
• Representative examples of thioalkoxyalkoxyalkyi groups include CH 3 SCH 2 CH 2 OCH 2 CH 2 -, CH 3 SCH 2 OCH 2 -, and the like.
• R and R2 are cis and R and Ri are trans and the case where R2 and R are trans and R and Ri are cis.
• cis,cis refers to the orientation of substituents (Ri and R2) relative to the central substituent R as shown
• Representative compounds of the invention include:
• Preferred compounds of the invention are selected from the group consisting of: rra/7SJrans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -((2,6- diethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; frans,frans-2-(4-Propoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -((2,6- diethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; fra ⁇ s,fra ⁇ s-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -((2,6- diethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; fra ⁇ sJ
• Scheme I illustrates the general procedure for preparing the compounds of the invention when m is 0 and W is -CO2H.
• a ⁇ -ketoester 1 where E is loweralkyl or a carboxy protecting group, is reacted with a nitro vinyl compound 2, in the presence of a base (for example, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sodium ethoxide or sodium hydride and the like) in an inert solvent such as toluene, benzene, tetrahydrofuran or ethanol and the like.
• DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
• the condensation product 3 is reduced (for example, by hydrogenation using a Raney nickel or platinum catalyst).
• the resulting amine cyclizes to give the dihydro pyrrole 4.
• Reduction of 4 for example, sodium cyanoborohydride or catalytic hydrogenation and the like
• THF solvent or the like gives the pyrrolidine compound 5 as a mixture of cis-cis, trans,trans and cis,trans products.
• Chromatographic separation removes the cis-cis isomer leaving a mixture of the trans rans and cis,trans isomers which is further elaborated.
• the cis-cis isomer can be epimerized (for example, using sodium ethoxide in ethanol or DBU in toluene) to give the trans,trans isomer and then carried on as described below.
• the pyrrolidine nitrogen is (1 ) acylated or sulfonylated with R3-X (R3 is R4-C(0)- or R6-S(0)2- and X is a leaving group such as a halide (Cl is preferred) or X taken together with R4-C(0)- or R ⁇ -S(0)2- forms an activated ester including esters or anhydrides derived from formic acid, acetic acid and the like, alkoxycarbonyl halides, N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole, N-hydroxy-5- norbornene-2,3-dicarboxamide, 2,4,5-trichlorophenol and the like) or (2) alkylated with R3-X where X is a leaving group (for example, X is a halide (for example, Br or I) or X is a leaving group such as a sulfonate (for example, mesylate, tosylate, triflate and
• Vlll(a) an aromatic, heteroaromatic, or ⁇ - quarternary methyl ketone is deprotonated (e.g., with sodium hydride or lithium diisopropylamide) and treated with a reagent capable of transferring a carboalkoxy group (e.g., diethyl carbonate, methyl chloroformate, or di-tert-butyldicarbonate).
• a carboalkoxy group e.g., diethyl carbonate, methyl chloroformate, or di-tert-butyldicarbonate.
• a carboxylic acid may be activated (e.g., with carbonyldiimidazole or oxalyl chloride) and treated with an acetate equivalent (e.g., ethyl lithioacetate, magnesium methylmalonate, or Meldrum's acid followed by thermal alcoholysis).
• an acetate equivalent e.g., ethyl lithioacetate, magnesium methylmalonate, or Meldrum's acid followed by thermal alcoholysis.
• a preferred embodiment is shown in Schemes II and III.
• a benzoyl acetate such as 26. or 4-(2-methoxyethoxy)benzoyl acetate is reacted with a nitro vinyl benzodioxolyl compound 27 using 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base in toluene to give compound 28.
• DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
• Catalytic hydrogenation using Raney nickel leads to reduction of the nitro group to an amine and subsequent cyclization to give the dihydropyrrole 29.
• the double bond is reduced with sodium cyanoborohydride to give the pyrrolidine compound 3_d as a mixture of cis-cis, trans, trans and cis rans isomers. Chromatography separates the cis-cis isomer, leaving a mixture of the trans rans and cis,trans is
• Scheme III illustrates the further elaboration of the trans,trans isomer.
• the mixture (31) of trans,trans and cis rans pyrrolidines described in Scheme IV is reacted with Br-CH2C(0)NHR4 in acetonitrile in the presence of ethyldiisopropylamine to give the alkylated pyrrolidine compound 3 , still as a mixture of trans,trans and cis,trans isomers.
• Sodium hydroxide in ethanol-water hydrolyzes the ethyl ester of the trans,trans compound but leaves the ethyl ester of the cis.trans compound untouched, thus allowing separation of the trans,trans carboxylic acid 33 from the cis,trans ester 34.
• Scheme IV illustrates the preparation of compounds where W is other than carboxylic acid.
• Compound 55 which can be prepared by the procedures described in Scheme I, is converted (for example, using peptide coupling condition, e.g. N- methylmorpholine, EDCI and HOBt, in the presence of ammonia or other amide forming reactions) to give carboxamide 5_6.
• the carboxamide is dehydrated (for example, using phosphorus oxychloride in pyridine) to give nitrile 57.
• Nitrile 57 under standard tetrazole-forming conditions (sodium azide and triethylamine hydrochloride or trimethylsilylazide and tin oxide) is reacted to give tetrazole 58.
• nitrile 57 is reacted with hydroxylamine hydrochloride in the presence of a base (for example, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH) in a solvent such as DMF, DMSO, or dimethylacetamide to give amidoxime 5_9.
• a base for example, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH
• a solvent such as DMF, DMSO, or dimethylacetamide
• the amidoxime f> ⁇ is allowed to react with a methyl or ethyl chloroformate in a conventional organic solvent (such as, chloroform, methylene chloride, dioxane, THF, acetonitrile or pyridine) in the presence of a base (for example, triethylamine, pyridine, potassium carbonate and sodium carbonate) to give an O-acyl compound.
• a base for example, triethylamine, pyridine, potassium carbonate and sodium carbonate
• Heating of the O-acyl amidoxime in an inert solvent such as benzene, toluene, xylene, dioxane, THF, dichloroethane, or chloroform and the like results in cyclization to compound 60.
• Scheme V illustrates a method for synthesizing pyrrolidines by an azomethine ylide type [3+2]-cycloaddition to an acrylate.
• General structures such as compound 70 are known to add to unsaturated esters such as 71 to provide pyrrolidines such as compound ⁇ (O. Tsuge, S. Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983), O. Tsuge, S. Kanemasa, T. Yamada, K. Matsuda, J. Org. Chem. 52 2523-30 (1987), and S. Kanemasa, K. Skamoto, O. Tsuge, Bull. Chem. Soc. Jpn.
• Silylimine 73 is reacted with acrylate 74 in the presence of trimethylsilyl triflate and tetrabutylammonium fluoride to give the desired pyrrolidine Z5 as a mixture of isomers.
• This method can be modified to provide the N-acetamido derivatives directly by reacting 73 and 74 with the appropriate bromoacetamide (for example, dibutyl bromoacetamide) in the presence of tetrabutylammonium iodide and cesium fluoride to give compound 7_6.
• bromoacetamide for example, dibutyl bromoacetamide
• Scheme VI illustrates a method for producing an enantiomerically pure pyrrolidine 80, which can be further elaborated on the pyrrolidine nitrogen.
• Intermediate racemic pyrrolidine ester 7_Z (for example, prepared by the procedure described in Scheme V) is Boc-nitrogen protected (for example, by treatment with B0C2O) and then the ester is hydrolyzed (for example, using sodium or lithium hydroxide in ethanol and water) to give t-butyl carbamoyl pyrrolidine carboxylic acid 78.
• the carboxylic acid is converted to its (+)- ⁇ -methylbenzylamine salt, which can be recrystallized (for example from ethyl acetate and hexane or chloroform and hexane) to afford the diastereomerically pure salt.
• This diastereomerically pure salt can be neutralized (for example, with sodium carbonate or citric acid) to afford enantiomerically pure carboxylic acid 79.
• the pyrrolidine nitrogen can be deprotected (for example, using trifluoroacetic acid) and the ester reformed by the use of ethanolic hydrochloric acid to give salt 80.
• ethanolic HCI to cleave the protecting group and form the ester in one step.
• the pyrrolidine nitrogen can be further elaborated (for example, by treatment with the 2,6- diethylbenzamide of bromoacetic acid in acetonitrile in the presence of diisopropylethylamine) to give optically active compound 81-
• optically active compound 81- The use of (-)- ⁇ - methylbenzylamine will give the opposite enantiomer.
• Other optically active amines may also be employed.
• Nitro vinyl compound (88) is reacted with ⁇ -keto ester 89 in the presence of a base such as sodium ethoxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as THF, toluene, DMF, acetonitrile, ethyl acetate, isopropyl acetate or methylene chloride and the like at a temperature of from about 0° C to about 100° C for a period of time from about 15 minutes to overnight to give compound 90.
• a base such as sodium ethoxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like
• an inert solvent such as THF, toluene, DMF, acetonitrile, ethyl
• Reduction of the nitro group followed by cyclization was effected for example by catalytic hydrogenation with a hydrogen pressure of from about atmospheric pressure to 300 p.s.i. over from about 1 hour to about 1 day of compound 90 in an inert solvent such as THF, ethyl acetate, toluene, ethanol, isopropanol, DMF or acetonitrile and the like, using a hydrogenation catalyst such as Raney nickel, palladium on carbon, a platinum catalyst, such as platinum oxide, platinum on carbon or platinum on alumina and the like, or a rhodium catalyst, such as rhodium on carbon or rhodium on alumina and the like, and the like affords intermediate nitrone 91 a or a mixture of nitrone 91 a and imine 91 b.
• a hydrogenation catalyst such as Raney nickel, palladium on carbon
• a platinum catalyst such as platinum oxide, platinum on carbon or platinum on alumina and the like
• reaction mixture comprising the nitrone or nitrone/imine mixture is treated with an acid such as trifluoroacetic acid or acetic acid or sulfuric acid or phosphoric acid or methanesulfonic acid and the like, and the hydrogenation is continued to give pyrrolidine compound £2 as the cis.cis-isomer.
• an acid such as trifluoroacetic acid or acetic acid or sulfuric acid or phosphoric acid or methanesulfonic acid and the like
• Epimerization at C-3 is effected by treatment of compound 92 with a base such as sodium ethoxide, potassium t- butoxide, lithium t-butoxide or potassium t-amyloxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as ethanol, ethyl acetate, isopropyl acetate, THF, toluene or DMF and the like at a temperature of from about -20° C to about 120° C to give the trans.trans compound 93.
• a base such as sodium ethoxide, potassium t- butoxide, lithium t-butoxide or potassium t-amyloxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like
• the substantially pure (i.e., at least 95% of the desired isomer) optically active (+)-isomer of compound __3 is obtained by treatment of a mixture of the (+)-isomer and the (-)-isomer of 93 with S- (+)-mandelic acid, D-tartaric acid or D-dibenzoyl tartaric acid or the like in a solvent such as acetonitrile, ethyl acetate, isopropyl acetate, ethanol or isopropanol and the like.
• the (+)-isomer of 9_3 selectively crystallizes as the salt, leaving the (-)-isomer of 93 in solution.
• the substantially pure (i.e., at least 95% of the desired isomer) optically active (-)-isomer of compound __3 can be selectively crystallized by reaction of a mixture of the (+)-isomer and the (-)-isomer of 93 with L-tartaric acid, L- dibenzoyl tartaric acid or L-pyroglutamic acid and the like, leaving the desired (+)- isomer of compound 9J3 in solution.
• Compound __3 (racemic or optically active) is reacted with X-R3 (where X is a leaving group (for example, a halide or a sulfonate) and R3 is as previously defined) using a base such as diisopropylethylamine, triethylamine, sodium bicarbonate or potassium carbonate and the like in an inert solvent such as acetonitrile, THF, toluene, DMF or ethanol and the like at a temperature of from about 0° C to about 100° C to give the intermediate ester 94-
• the ester can be isolated or converted in situ to the carboxylic acid (95) using hydrolysis conditions such as a base such as sodium hydroxide or lithium hydroxide or potassium hydroxide and the like in a solvent such as ethanol-water or THF-ethanol and the like.
• W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2,
• Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyi, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyi, cycloalkyl, cycloalkylalkyi, ami ⁇ ocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic, (heterocyclic)alkyl and (R aa )(R bb )N-R cc - wherein R a
• W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group
• Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyi, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyi, cycloalkyl, cycloalkylalkyi, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic,
• R aa is aryl or arylalkyl
• R bb is hydrogen or alkanoyl
• R cc is alkylene, with the proviso that one or both of R 1 and R 2 is other than hydrogen; or a salt thereof.
• Preferred intermediates include compounds of formula (III), (IV) and (V) wherein m is zero or 1 ;
• W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
• Particularly preferred intermediates are compounds of formula (III), (IV) and (V) wherein m is 0; W is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) alkoxyalkylalkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, (v) furanyl or (vi) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4- trifluoromethylphenyl, 4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 2-fluoro-4-ethoxyphenyl, 4-(2- methoxyethoxy)phenyl, 4-(2-ethoxyethoxy)phenyl, 4-(2-isopropoxyethoxy)phenyl
• Boc for tert- butyloxycarbonyl
• Cbz for benzyloxycarbonyl
• DBU for 1 ,8-diazabicyclo[5.4.0]undec- 7-ene
• EDCI for 1 -(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride
• EtOAc for ethyl acetate
• EtOH for ethanol
• HOBt for 1 -hydroxybenzotriazole
• E.3N for triethylamine
• TFA trifluoroacetic acid
• THF for tetrahydrofuran.
• Example 1A Ethyl 2-(4-methoxybenzoyl)-4-nitromethyl-3-(1 ,3-benzodioxole-5-yl)butyrate
• ethyl (4-methoxybenzoyl)acetate 23.0 g, 0.104 mol
• 5-(2-nitrovinyl)-1 ,3- benzodioxole (17.0 g, 0.088 mol) dissolved in 180 mL of toluene and heated to 80 °C was added 1 ,8-diazabicyclo[5,4,0] undec-7-ene (DBU, 0.65 g) with stirring.
• DBU 1,8-diazabicyclo[5,4,0] undec-7-ene
• Example 1 B Ethyl 2-(4-methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-4.5-dihydro-3H-pyrrole-3- carboxylate
• the compound resulting from Example 1A (21 g) in 500 mL of ethanol was hydrogenated under 4 atmospheres of hydrogen pressure using a Raney nickel 2800 catalyst (51 g).
• the Raney nickel was washed with ethanol three times before use.
• the catalyst was removed by filtration, and the solution was concentrated under reduced pressure.
• the residue obtained was chromatographed on silica gel eluting with 8.5% ethyl acetate in methylene chloride to give 12.34 g of the desired product.
• Example 1 E tra ⁇ s.fra ⁇ s-2- ( 4-Methoxyphenyl)-4- ⁇ .3-benzodioxol-5-yl)-1 -((2.4.6- trimethy ⁇ phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
• the mixture of 64% trans rans- and 34% c/sJratis-pyrrolidines (the mixture resulting from Example 1 C) (5.72 g, 15.50 mmol), ethyldiisopropylamine (4.20 g,
• Example 4 trans.frans-2-(4-MethoxyphenyO-4-(1 .3-benzodioxol-5-yl)-1 -((2.6- diethyl)phenylaminocarbonylmethy ⁇ -pyrrolidine-3-carboxylic acid
• the title compound was prepared by the procedures described in Example 1.
• Example 6 fransJ/'a ⁇ s-2-(3-Fluoro-4-methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 -((2.6- diethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
• the title compound was prepared by the procedures described in Example 1.
• Example 7 frat7SJrat7s-2-(3-Fluoro-4-ethoxyphenyl)-4-(1 .3-benzodioxol-5-vn-1 -((2.6- diethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
• the title compound was prepared by the procedures described in Example 1.
• Example 1 fra ⁇ sJra ⁇ s-2-(4-methoxyphenv ⁇ -4-(1 .3-benzodioxol-5-v ⁇ -1 -((2.6- dimethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
• Example 12 f/-ansJrat?s-2-(4-propoxypheny ⁇ -4-(7-methoxy-1 .3-benzodioxol-5-yl)-1 -((2.6- diethyl)phenylaminocarbonylmethy ⁇ -pyrrolidine-3-carboxylic acid
• Example 13 trans. frans-2-(3-methoxy-4-propoxyphenyl)-4-(7-methoxy-1 .3-benzodioxol-5-y ⁇ -1 -
• Example 15A 5-(2-Nitrovinyl)-1 ,3-benzodioxole To piperonal (15.55 kg, 103.5 mol) under mechanical stirring and under nitrogen was added ammonium acetate (13.4 kg, 173.8 mol), acetic acid (45.2 kg), and nitromethane (18.4 kg, 301.4 mol) sequentially. The mixture was warmed to 70 °C. After about 30 minutes, the yellow product began to crystallize. The reaction temperature was raised to B0 °C and stirred for about 10 hours until minimal piperonal remains. The somewhat thick reaction mixture was cooled to 10 °C and filtered. The precipitate was washed with acetic acid (2 x 8 kg) and then water (2 x 90 kg).
• Example 15B Ethyl (4-methoxybenzoyl)acetate To potassium t-amylate (25 wt %, 50.8 kg, 99.26 mol) in toluene (15.2 kg) cooled to 5 °C under mechanical stirring and under nitrogen was added a mixture of 4-methoxyacetophenone (6.755 kg, 44.98 mol) and diethyl carbonate (6.40 kg, 54.18 mol) in toluene over 1 hour maintaining the temperature below 10 °C.
• the reaction mixture was heated to 60 °C for 8 hours until no 4-methoxyacetophenone was detected by HPLC.
• the mixture was cooled to 20 °C and quenched by adding to a mixture of acetic acid (8 kg) and water (90 kg) over 30 minutes while maintaining the temperature at ⁇ 20 °C.
• the layers were separated, and the organic layer was washed with 5% sodium bicarbonate solution (41 kg) and concentrated to 14.65 kg. The temperature is maintained below 50 °C during the distillation.
• the yellow product concentrate was assayed by HPLC against an external standard and the yield was found to be 9.40 kg (94%).
• Example 15C Ethyl 2-(4-methoxybenzoyl)-4-nitromethyl-3-(1 ,3-benzodioxole-5-yl)butyrate To the compound resulting from Example 15A (7.5 kg, 37.9 mol) suspended in THF (56 kg) with mechanical stirring under nitrogen was added the compound resulting from Example 15B (8.4 kg, 37.9 mol). The mixture was cooled to 17 °C, sodium ethoxide (6.4 g, 0.095 mol) was added, and the reaction was stirred for 30 minutes. After about 15 minutes, the nitrostyrene was completely dissolved.
• Example 15D Ethyl c/s.c/s-2-(4-methoxyphenyl)-4-(1 .3-benzodioxol-5-y ⁇ -pyrrolidine-3-carboxylate
• Raney nickel (20.0 g)
• THF 20 mL
• the crude compound resulting from Example 15C 40.82 g, 0.0482 mol
• acetic acid 2.75 mL, 0.0482 mol
• Example 15D The solution of the compound resulting from Example 15D (38.1 g, 0.103 mol) was chased with ethanol (200 mL) to a final volume of 100 mL and sodium ethoxide (3.40 g, 0.050 mol) was added. The mixture was heated to 75 °C. When HPLC shows ⁇ 3% of the cis,cis isomer remaining, the mixture was cooled to room temperature. The product was assayed by HPLC against an external standard and found to contain 34.4 g (90% yield) of the title compound. The crude compound solution was concentrated and the residue taken up in isopropyl acetate (400 mL). The organic layer was washed with water (2 x 150 mL) and then extracted with 0.25 M.
• Example 15F Ethyl f 3 4S
• the racemic amino ester from Example 1 (32.9 g) was dissolved in 50 mL of acetonitrile.
• (S)-(+)-Mandelic acid (2.06 g, 0.0136 mmol) was added and allowed to dissolve. The mixture was seeded with the product and allowed to stir at room temperature for 16 hours. The reaction mixture was cooled to 0 °C and stirred for 5 hours. The product was filtered and dried in a vacuum oven with a nitrogen purge for 1 day at 50 °C.
• Example 15G The compound of Example 15G (450 mg) was dissolved in 10 mL of isopropanol. A slight excess of saturated HCI in ethanol was added, and the resultant solution was stirred for 10 min. The solvents were removed in vacuo, and the excess HCI was chased with isopropanol. The residue was taken up in ether and filtered, leaving 448 mg of the title compound as a white solid. MS (DCI/NH3) m/e
• Example 17 fra ⁇ s.rrat7s-2-(4-methoxypheny ⁇ -4-(1 .3-benzodioxol-5-yl)-1 -((4-bromo-2.6- diethyl)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
• the racemic amino ester from Example 3 (8.00 g) was combined with 4.45 g of di-tert-butyldicarbonate in 100 mL of THF; 10 mL of triethylamine was added, and the resultant solution was stirred at ambient temperature for 3 hrs. The solvents were removed in vacuo; the residue was taken up in EtOAc and washed sequentially with aqueous 1 N H3PO4, bicarb, and brine. The crude product was dissolved in 30 mL of ethanol; 12 mL of 2.5 N NaOH solution was added, the mixture was stirred overnight at ambient temperature, then warmed to 50 °C for 2 hrs. The solvents were removed in vacuo; the residue was partitioned between water and ether.
• the aqueous extract was acidified with aqueous 1 N H3PO4 and extracted twice with EtOAc. The organic extracts were washed with brine and dried over Na2S04 to give 9.2 g of trans,trans- 2-(4-propoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -tert-butoxycarbonyl-pyrrolidine-3- carboxylic acid.
• This material was dissolved in 30 mL of EtOAc, and 1.3 mL of (R)- (+)- ⁇ -methylbenzylamine was added. The solution was stirred for 10 min; the solvents were removed in vacuo, 50 mL of ether were added, and the resultant solution was seeded.
• Example 20B Ethyl [2R3R4Sl2-(4-PropoxyphenylV4-(1 .3-benzodioxol-5-vh-pyrrolidine-3- carboxylate
• the compound of Example 20A was dissolved in ethanol and cooled in an ice bath. Gaseous HCI was bubbled through the solution until saturated; the resultant solution was warmed to ambient temperature and allowed to stir overnight under a blanket of nitrogen. The solvents were removed in vacuo; the residue was taken up in bicarb and extracted with EtOAc. The organic layer was decanted, then washed with brine and dried over Na2S ⁇ 4.
• Example 21 frat7SJrat7s-2-(4-methoxyphenv ⁇ -4-(1 .3-benzodioxol-5-yl')-1 -((2.6- diisopropyOphenylaminocarbonylmethv ⁇ -pyrrolidine-3-carboxylic acid
• Example 25A 2,4,6-trimethylaniline
• Potassium ethylmalonate (3.68 g) was combined with 2.29 g of magnesium chloride in 12 mL of DMF; the reaction mixture was heated at 60 °C for 4 hrs. The resultant mixture was cooled to ambient temperature. Simultaneously, 3-methoxy-2- nitrobenzoic acid (3.4 g) was dissolved in 12 mL of DMF; 3.06 g of 1 ,1- carbonyldiimidazole was added (gas evolves), and the resultant solution (after stirring at ambient temperature for 4 hrs) was added to the malonate mixture. The resultant slurry was stirred at ambient temperature for 14 hrs.
• Example 27A The compound of Example 27A (3.2 g) was dissolved in 50 mL of concentrated sulfuric acid and stirred at ambient temperature for 48 hrs. The reaction mixture was poured onto 300 mL of ice and extracted twice with EtOAc. The organic extracts were washed sequentially with water, bicarb, and brine, and were concentrated in vacuo. The crude product was heated neat at 160 °C for 3 hrs. The resultant dark brown residue was extracted with EtOAc. The organic extracts were concentrated. The crude product was dissolved in 15 mL of ethanol; sodium borohydride (450 mg) was added, and the resultant solution was stirred at ambient temperature for for 2 hrs.
• sodium borohydride 450 mg
• Example 27B The compound of Example 27B (310 mg) was dissolved in 10 mL of THF; 1.5 mL of H3P04 was added, followed by 50 mg of 10% palladium-on-charcoal. The resultant mixture was purged with nitrogen, then placed under a balloon of hydrogen, and stirred overnight. Bicarb was added carefully, and the mixture was filtered through a pad of Celite. The filtrate was extracted with EtOAc; the organic extracts were washed with bicarb and brine, and were concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 1 :1 ether/hexanes, to give 102 mg (43% yield) of the title compound as a colorless oil.
• Example 27D frat7s.fra ⁇ s-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -(N-(2-ethyl-6- methoxy)phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
• Example 28 fra ⁇ sJ ans-2-(4-/so-Propoxyphenvn-4-(1 .3-benzodioxol-5-vn-1-(2.6- diethylphenylaminocarbonylmethy ⁇ -pyrrolidine-3-carboxylic acid
• the title compound was prepared by the procedures described in Example 1.
• Example 29 fr ⁇ /7S.frans-2-(2-Fluoro-4-Propoxyph ⁇ nyl)-4-(1 .3-bBnzodioxol-5-yl)-1 -(2.6- diethvlphenvlaminocarbonvlmethv ⁇ -pvrrolidine-3-carboxvlic acid
• the title compound was prepared by the procedures described in Example 1.
• the title compound was prepared by the procedures described in Example 1.
• Methyl 4-hydroxybenzoate was reacted with 1 -bromo-2-methoxyethane, and potassium carbonate in dimethylformamide.
• the resultant ester was hydrolyzed to the acid with NaOH in alcohol. This acid was reacted with carbonyl diimidazole in
• Example 858 transJrat7S-2-( ' 4-Methoxv ⁇ phenvl-4-n .3-benzodioxol-5-vn-1 -(( ⁇ /-2.6- diethylphenvhaminocarbonv ⁇ amino-pyrrolidine3-carboxylic acid
• Example 859 [2R.3S.4S]-2[4-( ' 2-methoxyethoxy ⁇ phenyll-4-(1 .3-benzodioxol-5-vn-1 -(2.6- diethvlphenvlaminocarbonvlmethvh-pvrrolidine-3-carboxylic acid
• Example 859A Ethyl [2R.3S.4S1-2f4- ⁇ / 2-methoxv8thoxv.phenvll-4-(1.3-benzodioxol-5-yl)- pvrrolidine-
• the resolved salt was washed with aqueous HCI to remove the resolving agent, then heated with HCI in ethanol at 70 degrees C for 18 hours to produce ethyl [2R,3S,4S]-2[4-(2-methoxyethoxy)]-4-(1 ,3-benzodioxol-5-yl)- pyrrolidine-3-carboxylate, which was purified by chromatography on silica gel, eluting with ethyl acetate.
• Example 860 trans, traw -2-(4-(2-Ethoxyethoxy))-4-( 1 ,3-benzodioxol-5-yl)- 1 -(2,6- diethylphenylaminocarbonylmethyl)-pyrrolidine-3 -carboxylic acid
• Example 863 trans. frans-2f .4-butoxyphenvl)]-4-(1 .3-benzodioxol-5-vn-1 -(2.6- diethylphenylaminocarbonylmethvh-pyrrolidine-3-carboxylic acid
• Example 865 trans. frat75-2[(3-DropoxyDhenv ⁇ ]-4-(1.3-benzodioxol-5-v ⁇ -1 J2.6- diethylphenylaminocarbonylmethy ⁇ -pyrrolidine-3-carboxylic acid
• the mixture was heated to reflux under N 2 for 5 min, then cooled to ambient temperature.
• the Grignard reagent was transferred via syringe to a 50 mL 3-necked flask under N 2 .
• a balloon of C0 2 was opened over the reaction, and the red color quickly faded to yellow.
• the reaction was concentrated in vacuo. The residue was taken up in
• Example 868B trans. fAang-2[(2-methyl-4-propoxvphsnyl ⁇ ]-4-(1 .3-benzodioxol-5-yl)-1 -(2.6- diethylphenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
• Binding Assay fie Receptor
• Porcine cerebellum was homogenized in 25 volumes (w/v) of 10 mM Hepes
• Membranes prepared from cells were diluted -100 fold in Buffer B (20 mM Tris, 100 mM NaCI, 10 mM MgCI 2 , pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 ⁇ g/mL Pepstatin A, 0.025% bacitracin, and 3 mM EDTA) to a final concentration of 0.2 mg/mL of protein.
• Buffer B 20 mM Tris, 100 mM NaCI, 10 mM MgCI 2 , pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 ⁇ g/mL Pepstatin A, 0.025% bacitracin, and 3 mM EDTA.
• membranes (0.02 mg) were incubated with 0.1 nM of [ 125 l]ET-3 in Buffer B (final volume: 0.2 mL) in the presence of increasing concentrations of unlabeled ET-3 or a test compound for 4 hours at 25 °C.
• the ability of the compounds of the invention to lower blood pressure can be demonstrated according to the methods described in Matsumura, et al., Eur. J. Pharmacol.185103 (1990) and Takata, et al., Clin. Exp. Pharmacol. Physiol.10131 (1983).
• the ability of the compounds of the invention to treat congestive heart failure can be demonstrated according to the method described in Margulies, et al., Circulation 82 2226 (1990).
• the ability of the compounds of the invention to treat coronary angina can be demonstrated according to the method described in Heistad, et al., Circ. Res. 54 711 (1984).
• the ability of the compounds of the invention to treat cerebral vasospasm can be demonstrated according to the methods described in Nakagomi, et al., J. Neurosurg. 6j3 915 (1987) or Matsumura, et al., Life Sci. 49 841 -848 (1991 ).
• the ability of the compounds of the invention to treat gastric ulceration can be demonstrated according to the method described in Wallace, et al., Am. J. Physiol. 256 G661 (1989).
• the ability of the compounds of the invention to treat cyclosporin-induced nephrotoxicity can be demonstrated according to the method described in Kon, et al., Kidney Int. 37 1487 (1990).
• the ability of the compounds of the invention to treat asthma can be demonstrated according to the method described in Potvin and Varma, Can. J. Physiol. and Pharmacol. 67 1213 (1989).
• the ability of the compounds of the invention to treat transplant-induced atherosclerosis can be demonstrated according to the method described in Foegh, et al., Atherosclerosis 78 229-236 (1989).
• the ability of the compounds of the invention to treat LPL-related lipoprotein disorders can be demonstrated according to the method described in Ishida, et al., Biochem. Pharmacol. 44 1431 -1436 (1992).
• the ability of the compounds of the invention to treat proliferative diseases can be demonstrated according to the methods described in Bunchman ET and CA Brookshire, Transplantation Proceed. 23 967-968 (1991 ); Yamagishi, et al., Biochem. Biophys. Res. Comm. 191840-846 (1993); and Shichiri, et al., J. Clin. Invest. 87 1867-1871 (1991 ).
• Proliferative diseases include smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels.
• the ability of the compounds of the invention to treat acute or chronic pulmonary hypertension can be demonstrated according to the method described in Bonvallet et al., Am. J. Physiol. 266 H1327 (1994).
• Pulmonary hypertension can be associated with congestive heart failure, mitral valve stenosis, emphysema, lung fibrosis, chronic obstructive pulmonary disease (COPD), acute repiratory distress syndrome (ARDS), altitude sickness, chemical exposure, or may be idiopathic.
• COPD chronic obstructive pulmonary disease
• ARDS acute repiratory distress syndrome
• altitude sickness chemical exposure
• chemical exposure or may be idiopathic.
• the ability of the compounds of the invention to treat plaletet aggregation, and thrombosis can be demonstrated according to the method described in McMurdo et al. Eu. J. Pharmacol. 259 51 (1994).
• the ability of the compounds of the invention to treat angina, pulmonary hypertension, Raynaud's disease, and migraine can be demonstrated according to the method described in Ferro and Webb (Drugs 1996, 51,12-27).
• the compounds of the present invention can be used in the form of salts derived from inorganic or organic acids.
• salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thio
• the basic nitrogen- containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
• loweralkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
• dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
• long chain halides
• acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
• Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula (I), or separately by reacting the carboxylic acid function with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine.
• Such pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
• Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
• the compounds of the invention are useful for antagonizing endothelin in a human or other mammal.
• the compounds of the present invention are useful (in a human or other mammal) for the treatment of hypertension, acute or chronic pulmonary hypertension, Raynaud's disease, congestive heart failure, myocardial ischemia, reperfusion injury, coronary angina, cerebral ischemia, cerebral vasospasm, chronic or acute renal failure, non-steroidal antiinflammatory drug induced gastric ulceration, cyclosporin induced nephrotoxicity, endotoxin- induced toxicity, asthma, fibrotic or proliferative diseases, including smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, restenos
• Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg/kg body weight daily and more usually 0.1 to 100 mg/kg for oral administration or 0.01 to 10 mg/kg for parenteral administration. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
• the compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
• parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
• sterile injectable preparations for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-propanediol.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid find use in the preparation of injectables.

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