Conformationally restricted angiotensin II antagonists

FIELD OF THE INVENTION
Conformationally restricted non-peptide angiotensin II (AII) antagonists are described for use in treatment of circulatory disorders such as hypertension and congestive heart failure. Of particular interest are heteroatom- containing fused bicyclic compounds having a substituted biphenyl moiety attached thereto.
BACKGROUND OF THE INVENTION
Angiotensin II is the primary hormone active in the renin-angiotensin system and elicits effects on the regulation of arterial pressure, volume homeostasis and hypertension. Activation of the renin-angiotensin cascade begins with renin secretion from the juxtaglomerular apparatus of the kidney and culminates in the formation of angiotensin II, the primary active species of this system. Angiotensin II is an octapeptide which is a potent vasoconstrictor and also promotes aldosterone secretion, promotes sodium and fluid retention, inhibits renin secretion and increases vasopressin secretion.
Previous studies have shown that antagonizing angiotensin II at the receptor level is a viable approach to controlling the renin-angiotensin system. There are several known angiotensin II antagonists, many of which are peptidic in nature. Such peptidic compounds are of limited use due to their lack of oral bioavailability or their short duration of action. Also, commercially-available peptidic angiotensin II antagonists (e.g., Saralasin) have a significant residual agonist activity which further limits their therapeutic application.
Non-peptidic compounds with angiotensin II antagonist properties are known. For example, the sodium salt of 2-n-butyl-4-chloro-1-(2-chlorobenzyl)imidazole-5-acetic acid has specific competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo tests [P. C. Wong et al, J. Pharmacol. Ext. Ther., 247(1), 1-7 (1988)]. Also, the sodium salt of 2-butyl-4-chloro-1-(2-nitrobenzyl)imidazole-5-acetic acid has specific competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo tests [A. T. Chiu et al, European J. Pharmacol., 157, 13-21 (1988)]. A family of 1-benzylimidazole-5-acetate derivatives has been shown to have competitive angiotensin II antagonist properties [A. T. Chiu et al, J. Pharmacol. Exp. Ther., 250(3), 867-874 (1989)]. U.S. Pat. No. 4,816,463 to Blankey et al describes a family of 4,5,6,7-tetrahydro-1H-imidazo(a,5-c)-tetrahydro-pyridine derivatives useful as antihypertensives, some of which are reported to antagonize the binding of labeled angiotensin II to a rat adrenal receptor preparation and thus cause a significant decrease in mean arterial blood pressure in conscious hypertensive rats. EP No. 253,310, published 20 Jan. 1988, describes a series of aralkyl imidazole compounds, including in particular a family of biphenylmethyl substituted imidazoles, as antagonists to the angiotensin II receptor. EP No. 323,841 published 12 Jul. 1989 describes four classes of angiotensin II antagonists, namely, biphenylmethylpyrroles, biphenylmethylpyrazoles, biphenylmethyl-1,2,3-triazoles and biphenylmethyl 4-substituted-4H-1,2,4-triazoles, including the compound 3,5-dibutyl-4-[(2'-carboxybiphenyl-4-yl)methyl]-4H-1,2,4-triazole. U.S. Pat. No. 4,880,804 to Carini et al describes a family of biphenylmethylbenzimidazole compounds as angiotensin II receptor blockers for use in treatment of hypertension and congestive heart failure.
There are several families of 1,2,4-triazole compounds having substituents attached to the nitrogen atom at the one-position of the 1H-triazole. For example, U.S. Pat. No. 4,118,487 to Regel et al describes a family of azol-1-yl-methane compounds for use as antimycotic and antibacterial agents including, specifically, the compound (1-biphenyl-4-yl-1-phenyl)methyl-1H-1,2,4-triazole. U.S. Pat. No. 4,381,306 to Regel et al describes a family of hydroxypropyl-triazole compounds for use as antimycotic agents including, specifically, the compound (1,2,4-triazol-1-yl)methyl-4-chlorobenzyl-biphenyl-4-yl-carbinol. U.S. Pat. No. 4,480,114 to Regel describes a family of 2-(4-biphenyl)-2-(halophenyl)-oxirane compounds having antimycotic activity including, specifically, the compound (1,2,4-triazol-1-yl)methyl-4-chlorophenyl-4-chlorobiphenyl-4-yl-carbinol.
However, not much is known about the conformations and interactions of these non-peptide antagonists with the vascular angiotensin II receptors. It has been established in the literature that there are distinct angiotensin II receptor subtypes with differing functions [A. T. Chiu et al, Biochem. Biophys. Res. Comm., 165, 196-203 (1989)]. The receptor subtypes affecting vascular constriction is believed to be an important target for the treatment of hypertension [P. C. Wong et al, J. Pharmacol. Exp. Ther., 255, 584-592 (1990)]. Compounds which conformationally restrict the possible orientations of the pharmacophores incorporated therein may maximize the interaction between those pharmacophores and the binding site of the receptor subtype or subtypes of interest. Therefore, conformationally restricted angiotensin II antagonists may increase the selectivity to the specific receptor subtype of interest, thereby reducing possible side effects associated with binding to the other receptor subtypes not involved in the hypertension pathway.
There are several families of conformationally restricted angiotensin II antagonists reported in the literature. For example, tricyclic benzoxazepines [A. P. Thomas et al, J. Med. Chem., 35, 877-885 (1992)] were used to potentially lock in a phenyl group in an energetically favorable conformation. Conformationally restricted imidazoles having a biphenyl radical substituted with bulky side groups to sterically limit the rotation of the phenyl groups and form a more rigid spatial relationship were described in P. R. Bovy et al, J. Med. Chem., 34, 2410-2414 (1991). These previous attempts to lock the conformation of angiotensin II antagonists do not stabilize conformations axial to a heterocyclic ring by means of orthogonally attaching a substituted biphenyl radical to a non-aromatic bridging ring.

DESCRIPTION OF THE INVENTION
A series of bicyclic-substituted biphenylmethylene-type compounds which exhibit angiotensin II antagonism are disclosed herein, where the compounds lock the conformation around the methylene group to better mimic high affinity angiotensin II binding site conformations. Specifically, this invention relates to compounds comprising a substituted biphenylmethylene radical attached in a conformationally restricted manner through incorporation in a heterocyclic fused ring system. More specifically, angiotensin II antagonists are described wherein the biphenyl radical may contain an acidic radical such as a tetrazole radical.
Even more specifically, the invention relates to compounds of Formula I ##STR2##
wherein W is N or CH.sub.2 ;
wherein X is N or CR.sup.2 ;
wherein Y is (CH.sub.2).sub.n and n is 1 to 3;
wherein Z is C.dbd.R.sup.3 or CR.sup.4 R.sup.5, or
wherein Y and Z together forms --CR.sup.6 .dbd.CR.sup.7 --, --CR.sup.6 .alpha.CR.sup.7 --CH.sub.2 or --CR.sup.6 .alpha.CR.sup.7 --CH.sub.2 --CH.sub.2 --;
wherein R.sup.1 is alkyl;
wherein R.sup.2 is selected from hydrido, halo, alkyl and aryl;
wherein R.sup.3 is selected from oxygen, sulfur, hydroxyamino, alkylidene, alkylcarboxyalkylidene and carboxyalkylidene;
wherein R.sup.4 is selected from hydrido, alkyl, amino, hydroxyalkyl, carboxyl, carboxyalkyl, aryl, aralkyl, aralkoxy, alkylcarboxyalkyl, hydroxyl, carboxyaralkyl, phthalimidyl, ##STR3##
wherein R.sup.5 is hydrido or hydroxyl;
wherein R.sup.6 is selected from hydrido, alkyl, halo, hydroxyalkyl, carboxyalkyl, carboxyl, alkylcarboxyalkyl, aryl and aralkyl;
wherein R.sup.7 is hydrido or halo;
wherein R.sup.8 is selected from hydrido, alkyl and aralkyl;
wherein R.sup.9 is selected from alkyl, aryl, aralkyl, carboxyl, hydrazidylcarboalkyl and carboxyalkyl;
wherein R.sup.10 is hydrido or alkyl;
wherein R.sup.11 is selected from hydrido, alkyl, hydroxyalkyl and carboxyl, or
wherein R.sup.10 and R.sup.11 taken together is .dbd.O;
wherein R.sup.12 is hydrido or alkyl; and
wherein R.sup.13 is selected from hydrido, alkyl, hydroxyalkyl and carboxyl, or
wherein R.sup.12 and R.sup.13 taken together is .dbd.O;
or a pharmaceutically suitable salt or tautemer thereof.
The compounds of Formula I are further substituted wherein R.sup.4 is selected from aryl or aralkyl only when R.sup.2 if present is hydrido or halo;
wherein R.sup.4 is alkyl when R.sup.5 is hydroxyl;
wherein R.sup.8 is aralkyl when R.sup.2, if present, is hydrido or halo;
wherein R.sup.9 and R.sup.8 are not both aralkyl; and
wherein R.sup.11 and R.sup.13 is alkyl when R.sup.2 is aryl or halo; or a pharmaceutically suitable salt thereof.
More specifically, the compounds of Formula I are further substituted wherein R.sup.1 is n-propyl or n-butyl;
wherein R.sup.2 is selected from hydrido, chloro, methyl, ethyl, n-propyl and n-butyl, 2-ethylphenyl and 2,6-dimethylphenyl;
wherein R.sup.3 is selected from oxygen, sulfur, hydroxyamino, CHCO.sub.2 H, C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, C(C.sub.2 H.sub.5)CO.sub.2 H and CHCO.sub.2 C(CH.sub.3).sub.3 ;
wherein R.sup.4 is selected from hydrido, ethyl, n-propyl, t-butoxycarbonylmethyl, t-butoxycarbonylpropyl, hydroxyl, hydroxymethyl, phenylmethoxy, --(CH.sub.2).sub.3 CO.sub.2 H, --CH.sub.2 CO.sub.2 H, amino, --(CH.sub.2).sub.2 CO.sub.2 H, --CH(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, --CH(C.sub.2 H.sub.5)CH.sub.2 CO.sub.2 H, phenethyl, --CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2 CO.sub.2 H, phenyl, 2-ethylphenyl, benzyl, 2,6 -dimethylphenyl, ##STR4## provided R.sup.4 is selected from phenyl, benzyl and phenethyl only when R.sup.2, if present, is hydrido or chloro;
wherein R.sup.5 is hydrido or hydroxyl, provided that when R.sup.5 is hydroxyl, R.sup.4 is ethyl or n-propyl;
wherein R.sup.6 is selected from hydrido, ethyl, n-propyl, hydroxymethyl, --(CH.sub.2).sub.3 CO.sub.2 H, --CH.sub.2 CO.sub.2 H, --(CH.sub.2).sub.2 CO.sub.2 H, t-butoxycarbonylmethyl, t-butoxycarbonylpropyl, --CH(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, --CH(C.sub.2 H.sub.5)CH.sub.2 CO.sub.2 H, --CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2 CO.sub.2 H, phenyl, 2-ethylphenyl, 2,6-dimethylphenyl, phenethyl and benzyl;
wherein R.sup.7 is selected from hydrido, bromo, fluoro, chloro and iodo;
wherein R.sup.8 is selected from hydrido, methyl, ethyl, propyl and benzyl, provided that R.sup.8 is benzyl where R.sup.2, if present, is hydrido or chloro;
wherein R.sup.9 is selected from methyl, ethyl, phenyl, benzyl, --(CH.sub.2).sub.2 CONHNH.sub.2, --CH.sub.2 CO.sub.2 H and --(CH.sub.2).sub.2 CO.sub.2 H, provided that R.sup.9 and R.sup.8 are not both benzyl;
wherein R.sup.10 is hydrido or methyl;
wherein R.sup.11 is selected from hydrido, methyl, ethyl, hydroxymethyl and formyl, or
wherein R.sup.10 and R.sup.11 taken together is .dbd.O;
wherein R.sup.12 is hydrido or methyl; and
wherein R.sup.13 is selected from hydrido, methyl, ethyl, hydroxymethyl and formyl, or
wherein R.sup.12 and R.sup.13 taken together is .dbd.O; or a pharmaceutically suitable salt thereof.
Within Formula I there is a sub-class of compounds represented by compounds of Formula II ##STR5##
wherein Y is (CH.sub.2).sub.n and n is 1 to 3;
wherein Z is C.dbd.R.sup.3 or CR.sup.4 R.sup.5, or
wherein Y and Z together forms --CR.sup.6 =CR.sup.7 --, --CR.sup.6 .dbd.CR.sup.7 --CH.sub.2 -- or --CR.sup.6 .dbd.CR.sup.7 --CH.sub.2 --CH.sub.2 --;
wherein R.sup.1 is alkyl;
wherein R.sup.2 is selected from hydrido, halo, alkyl and aryl;
wherein R.sup.3 is selected from oxygen, sulfur, hydroxyamino, alkylidene alkylcarboxyalkylidene and carboxyalkylidene;
wherein R.sup.4 is selected from hydrido, alkyl, amino, hydroxyalkyl, carboxyl, carboxyalkyl, alkylcarboxyalkyl, aryl, aralkyl, hydroxyl, aralkoxy, carboxyaralkyl, phthalimidyl, ##STR6##
wherein R.sup.5 is hydrido or hydroxyl;
wherein R.sup.6 is selected from hydrido, alkyl, halo, hydroxyalkyl, carboxyl, carboxyalkyl, alkylcarboxyalkyl, aryl, aralkyl and hydroxyl;
wherein R.sup.7 is hydrido or halo;
wherein R.sup.8 is selected from hydrido, alkyl and aralkyl; wherein R.sup.9 is selected from alkyl, aryl, aralkyl, carboxyl, carboxyalkyl and hydrazidylcarboalkyl;
wherein R.sup.10 is hydrido or alkyl;
wherein R.sup.11 is selected from hydrido, alkyl, hydroxyalkyl, carboxyl and carboxyalkyl, or
wherein R.sup.10 and R.sup.11 taken together is .dbd.O;
wherein R.sup.12 is hydrido or alkyl;
wherein R.sup.13 is selected from hydrido, alkyl, hydroxyalkyl, carboxyl and carboxyalkyl, or
wherein R.sup.12 and R.sup.13 taken together is .dbd.O; or a pharmaceutically suitable salt thereof.
The compounds of Formula II are further substituted wherein R.sup.4 is aryl or aralkyl only when R.sup.2 is hydrido or halo;
wherein R.sup.4 is alkyl when R.sup.5 is hydroxyl;
wherein R.sup.7 is aralkyl when R.sup.2, if present, is hydrido or halo;
wherein R.sup.8 and R.sup.9 are not both aralkyl;
wherein R.sup.11 is alkyl when R.sup.2 is aryl or halo; and
wherein R.sup.13 is alkyl when R.sup.2 is aryl or halo; or a pharmaceutically suitable salt thereof.
A more preferred class of compounds consists of those compounds of Formula II wherein R.sup.6 is selected from hydrido, ethyl, hydroxymethyl, --CH.sub.2 CO.sub.2 H, and --(CH.sub.2).sub.3 CO.sub.2 H, or R.sup.6 is aryl or aralkyl, provided R.sup.2 is hydrido, and R.sup.3 is selected from oxygen, sulfur, hydroxyamino, CHCO.sub.2 H and CHCO.sub.2 C(CH.sub.3).sub.3 ; or a pharmaceutically suitable salt thereof.
An even more preferred class of compounds consists of those compounds of Formula II wherein R.sup.1 is n-propyl or n-butyl;
wherein R.sup.2 is selected from hydrido, chloro, methyl, ethyl, n-propyl, n-butyl, 2-ethylphenyl and 2,6-dimethylphenyl;
wherein R.sup.3 is selected from oxygen, sulfur, hydroxyamino, CHCO.sub.2 H and CHCO.sub.2 C(CH.sub.3).sub.3 ;
wherein R.sup.4 is selected from hydrido, ethyl, n-propyl, hydroxymethyl, t-butoxycarbonylmethyl, hydroxyl, amino, t-butoxycarbonylpropyl, --(CH.sub.2).sub.3 CO.sub.2 H, --CH.sub.2 CO.sub.2 H, --(CH.sub.2).sub.2 CO.sub.2 H, --CH(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, --CH(C.sub.2 H.sub.5)CH.sub.2 CO.sub.2 H, --CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2 CO.sub.2 H, phenyl, 2-ethylphenyl, 2,6-dimethylphenyl, phenethyl, benzyl, phenylmethoxy, ##STR7## provided R.sup.4 is selected from phenyl, benzyl and phenethyl only when R.sup.2 is hydrido or chloro;
wherein R.sup.5 is hydrido or hydroxyl, provided that when R.sup.5 is hydroxyl, R.sup.4 is ethyl or n-propyl;
wherein R.sup.6 is selected from hydrido, ethyl, n-propyl, hydroxymethyl, --(CH.sub.2).sub.3 CO.sub.2 H, --CH.sub.2 CO.sub.2 H, --(CH.sub.2).sub.2 CO.sub.2 H, t-butoxycarbonylmethyl, t-butoxycarbonylpropyl, --CH(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, --CH(C.sub.2 H.sub.5)CH.sub.2 CO.sub.2 H, --CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2 CO.sub.2 H, phenyl, 2-ethylphenyl, 2,6-dimethylphenyl, phenethyl and benzyl;
wherein R.sup.7 is selected from hydrido, fluoro, bromo, chloro and iodo;
wherein R.sup.8 is selected from hydrido, methyl, ethyl, propyl and benzyl, provided that R.sup.8 is benzyl where R.sup.2 if present is hydrido or chloro;
wherein R.sup.9 is selected from methyl, ethyl, phenyl, benzyl, --(CH.sub.2).sub.2 CONHNH.sub.2, --CH.sub.2 CO.sub.2 H and --(CH.sub.2).sub.2 CO.sub.2 H, provided that R.sup.9 and R.sup.8 are not both benzyl;
wherein R.sup.10 is hydrido or methyl;
wherein R.sup.11 is selected from hydrido, methyl, ethyl, hydroxymethyl and carboxy, or
wherein R.sup.10 and R.sup.11 taken together is .dbd.O;
wherein R.sup.12 is hydrido or methyl; and
wherein R.sup.13 is selected from hydrido, methyl, ethyl, hydroxymethyl and formyl, or
wherein R.sup.12 and R.sup.13 taken together is .dbd.O; or a pharmaceutically suitable salt thereof.
A family of specific compounds of particular interest within Formula II consists of compounds and pharmaceutically-acceptable salts thereof, as follows:
1,3-Dibutyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl )[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridine;
7-Bromo-1,3-dibutyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridine;
1,3-Dibutyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridine;
1,3-Dibutyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8-ol;
1,3-Dibutyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin(5H)-one;
1,3-Dibutyl-5,6-dihydro-8-phenyl-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridine;
[1,3-Dibutyl-6,7-dihydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8(5H)-ylidene]acetic acid;
-[1,3-Dibutyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8-yl]-2,5-pyrrolidinedione;
4-[1,3-Dibutyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8-yl]amino]-4-oxobutanoic acid, hydrazide;
1,3-Dibutyl-6,7-dihydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]-5H-imidazo[1,5-a]azepine;
3-Butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridine;
3-Butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8(5H) -one;
3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-cis-8-ol;
3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4yl-]imidazo[1,5-a]pyridin-trans-8-ol;
1,1-Dimethylethyl [3-butyl-6,7-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8(5H)-ylidene]acetate;
[3-Butyl-6,7-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8(5H)-ylidene]acetic acid;
1,1-Dimethylethyl 3-butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8-acetate;
3-Butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8-acetic acid;
1,1-Dimethylethyl 3-butyl-5,6,7,8-tetrahydro-5-[2'-1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-cis-8-acetate;
3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-cis-8-acetic acid;
1,3-Dibutyl-5,6-dihydro-N-hydroxy-5-[2'-(1H-tetrazol-5-yl)[1.1'-biphenyl]-4-yl]imidazol[1,5-a]pyridin-8(7H )-imine;
1-[3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo [1,5-a]pyridin-8-yl]phthalimide;
3-Butyl-5,6,7,8-tetrahydro-8-amino-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridine;
1,3 -Dibutyl-8-phenyl-5,6-dihydro-5-{2'-(1H-tetrazol-5-yl){1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridine;
1-[3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8-yl]-cis-2,5-pyrrolidinedione;
1-[3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8-yl]-trans-2,5-pyrrolidinedione;
1-[3-Butyl-1-chloro-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8-yl]-cis-2,5 -pyrrolidinedione;
1-[3-Butyl-1-chloro-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5a]pyridin-8-yl]-trans-2,5-pyrrolidinedione; and
3-Butyl-8-phenylmethoxy-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridine.
Within Formula I there is another sub-class of compounds as represented by compounds of Formula III ##STR8##
wherein Y is (CH.sub.2).sub.n and n is 1 to 3;
wherein Z is C.dbd.R.sup.3 or CR.sup.4 R.sup.5, or
wherein Y and Z together forms --CR.sup.6 .dbd.CR.sup.7 --, --CR.sup.6 .dbd.CR.sup.7 --CH.sub.2 -- or --CR.sup.6 .dbd.CR.sup.7 --CH.sub.2 --CH.sub.2 --;
wherein R.sup.1 is alkyl;
wherein R.sup.3 is selected from oxygen, sulfur, hydroxyamino, alkylidene and carboxyalkylidene;
wherein R.sup.4 is selected from hydrido, alkyl, carboxyl, hydroxyalkyl, carboxyalkyl, carboxyaralkyl, aryl, aralkyl, alkylcarboxyalkyl, hydroxyl, amino, phthalimidyl, aralkoxy, ##STR9##
wherein R.sup.5 is hydrido or hydroxyl;
wherein R.sup.6 is selected from hydrido, alkyl, carboxyl, halo, hydroxyalkyl, carboxyalkyl, alkylcarboxyalkyl, hydrazidylcarboalkyl, aryl, aralkyl, hydroxyl and amino;
wherein R.sup.7 is hydrido or halo;
wherein R.sup.8 is selected from hydrido, alkyl and aralkyl;
wherein R.sup.9 is selected from alkyl, aryl, aralkyl, carboxyl and carboxyalkyl;
wherein R.sup.10 is hydrido or alkyl;
wherein R.sup.11 is selected from hydrido, alkyl, hydroxyalkyl, carboxyl and carboxyalkyl, or
wherein R.sup.11 and R.sup.10 taken together is .dbd.O;
wherein R.sup.12 is hydrido or alkyl; and
wherein R.sup.13 is selected from hydrido, alkyl, hydroxyalkyl, carboxyl and carboxyalkyl, or
wherein R.sup.12 and R.sup.13 taken together is .dbd.O; or a pharmaceutically suitable salt thereof.
A more preferred class of compounds consists of those compounds of Formula III wherein R.sup.4 is alkyl when R.sup.5 is hydroxyl, and wherein R.sup.8 and R.sup.9 are not both aralkyl; and wherein R.sup.6 is selected from hydrido, alkyl of C.sub.1 to C.sub.6, aryl, aralkyl, hydroxyalkyl and carboxyalkyl; or a pharmaceutically suitable salt thereof.
Preferably, the compounds of Formula III are substituted wherein R.sup.6 is selected from ethyl, n-propyl, 2-ethylphenyl, 2,6-dimethylphenyl, benzyl, phenethyl, hydroxymethyl and --CH.sub.2 CO.sub.2 H; and wherein R.sup.3 is selected from C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, C(C.sub.2 H.sub.5)CH.sub.2 CO.sub.2 H, C(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2 CO.sub.2 H, CHCO.sub.2 H and CHC.sub.2 H.sub.5 ; or a pharmaceutically suitable salt thereof.
An even more preferred class of compounds consists of those compounds of Formula III wherein R.sup.1 is n-propyl or n-butyl;
wherein R.sup.3 is selected from oxygen, sulfur, hydroxyamino, CHCO.sub.2 H, C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, C(C.sub.2 H.sub.5)CO.sub.2 H and CHCO.sub.2 C(CH.sub.3).sub.3 ;
wherein R.sup.4 is selected from hydrido, ethyl, n-propyl, hydroxymethyl, t-butoxycarbonylmethyl, hydroxyl, benzyl, t-butoxycarbonylpropyl, --(CH.sub.2).sub.3 CO.sub.2 H, --CH.sub.2 CO.sub.2 H, --CH.sub.2).sub.2 CO.sub.2 H, --CH(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, --CH(C.sub.2 H.sub.5)CH.sub.2 CO.sub.2 H, --CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2 CO.sub.2 H, phenylmethoxy, 2-ethylphenyl, 2,6-dimethylphenyl, amino, phenethyl, phenyl, ##STR10## provided R.sup.4 is selected from phenyl, benzyl and phenethyl only when R.sup.2 if present is hydrido or chloro;
wherein R.sup.5 is hydrido or hydroxyl, provided that when R.sup.5 is hydroxyl, R.sup.4 is ethyl or n-propyl;
wherein R.sup.6 is selected from hydrido, ethyl, n-propyl, hydroxymethyl, --(CH.sub.2).sub.3 CO.sub.2 H, --CH.sub.2 CO.sub.2 H, --(CH.sub.2).sub.2 CO.sub.2 H, t-butoxycarbonylmethyl, t-butoxycarbonylpropyl, --CH (CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, --CH(C.sub.2 H.sub.5)CH.sub.2 CO.sub.2 H, --CH(CH.sub.2 C.sub.6 H.sub.5) CH.sub.2 CO.sub.2 H, phenyl, 2-ethylphenyl, 2,6-dimethylphenyl, phenethyl and benzyl;
wherein R.sup.7 is selected from hydrido, bromo, chloro, fluoro and iodo;
wherein R.sup.8 is selected from hydrido, methyl, ethyl, propyl and benzyl, provided that R.sup.8 is benzyl where R.sup.2, if present, is hydrido or chloro;
wherein R.sup.9 is selected from methyl, ethyl, phenyl, benzyl, --(CH.sub.2).sub.2 CONHNH.sub.2, --CH.sub.2 CO.sub.2 H and --(CH.sub.2).sub.2 CO.sub.2 H, provided that R.sup.9 and R.sup.8 are not both benzyl;
wherein R.sup.10 is hydrido or methyl;
wherein R.sup.11 is selected from hydrido, methyl, ethyl, hydroxymethyl and carboxy, or
wherein R.sup.11 and R.sup.10 taken together is .dbd.O;
wherein R.sup.12 is hydrido or methyl; and
wherein R.sup.13 is selected from hydrido, methyl, ethyl, hydroxymethyl and carboxy, or wherein R.sup.13 and R.sup.12 taken together is .dbd.O; or a pharmaceutically suitable salt thereof.
Within Formula I, another preferred sub-class of compounds is represented by compounds of Formula IV ##STR11##
wherein Y is (CH.sub.2).sub.n and n is 1 to 3;
wherein Z is C.dbd.R.sup.3 or CR.sup.4 R.sup.5, or
wherein Y and Z together forms --CR.sup.6 .dbd.CR.sup.7 --, --CR.sup.6 .dbd.CR.sup.7 --CH.sub.2 -- or --CR.sup.6 .dbd.CR.sup.7 --CH.sub.2 --CH.sub.2 --;
wherein R.sup.1 is alkyl;
wherein R.sup.3 is selected from oxygen, sulfur, hydroxyamino, alkylidene and carboxyalkylidene;
wherein R.sup.4 is selected from hydrido, alkyl, carboxyl, hydroxyalkyl, carboxyalkyl, carboxyaralkyl, phthalimidyl, alkylcarboxyalkyl, aryl, aralkyl, hydroxyl, amino, aralkoxy, ##STR12##
wherein R.sup.5 is hydride or hydroxyl;
wherein R.sup.6 is selected from hydride, alkyl, carboxyl, hydroxyalkyl, carboxyalkyl, alkylcarboxyalkyl, aryl, aralkyl, hydroxyl and amine;
wherein R.sup.7 is hydride or halo;
wherein R.sup.8 is selected from hydrido, alkyl and aralkyl;
wherein R.sup.9 is selected from alkyl, aryl, aralkyl, hydrazidylcarboalkyl, carboxyl and carboxyalkyl;
wherein R.sup.10 is hydrido or alkyl;
wherein R.sup.11 is selected from hydrido, alkyl, hydroxyalkyl, carboxyl and carboxyalkyl, or
wherein R.sup.11 and R.sup.10 taken together is .dbd.O;
wherein R.sup.12 is hydrido or alkyl; and
wherein R.sup.13 is selected from hydrido, alkyl, hydroxyalkyl, carboxyl and carboxyalkyl, or
wherein R.sup.12 and R.sup.13 taken together is .dbd.O;
or a pharmaceutically suitable salt thereof.
A more preferred class of compounds consists of those compounds of Formula IV wherein R.sup.4 is alkyl when R.sup.5 is hydroxyl and wherein R.sup.8 and R.sup.9 are not both aralkyl; wherein R.sup.6 is selected from hydrido, alkyl of C.sub.1 to C.sub.6, aryl, aralkyl, hydroxyalkyl and carboxyalkyl; and wherein R.sup.3 is selected from C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, C(C.sub.2 H.sub.5)CH.sub.2 CO.sub.2 H, C(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2 CO.sub.2 H, CHCO.sub.2 H and CHC.sub.2 H.sub.5 ; or a pharmaceutically suitable salt thereof.
A further preferred class of compounds consists of those compounds of Formula IV wherein R.sup.6 is selected from ethyl, n-propyl, 2-ethylphenyl, 2,6-dimethylphenyl, benzyl, phenethyl, hydroxymethyl or --CH.sub.2 CO.sub.2 H; or a pharmaceutically suitable salt thereof.
An even more preferred class of compounds consists of those compounds of Formula IV wherein R.sup.1 is n-propyl or n-butyl;
wherein R.sup.3 is selected from oxygen, sulfur, hydroxyamino, CHCO.sub.2 H, C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, C(C.sub.2 H.sub.5)CO.sub.2 H and CHCO.sub.2 C(CH.sub.3).sub.3 ;
wherein R.sup.4 is selected from hydrido, ethyl, n-propyl, hydroxymethyl, t-butoxycarbonylmethyl, hydroxyl, amino, t-butoxycarbonylpropyl, --(CH.sub.2).sub.3 CO.sub.2 H, --CH.sub.2 CO.sub.2 H, --(CH.sub.2).sub.2 CO.sub.2 H, --CH(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, --CH(C.sub.2 H.sub.5)CH.sub.2 CO.sub.2 H, --CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2 CO.sub.2 H, phenylmethoxy, 2-ethylphenyl, 2,6-dimethylphenyl, phenyl, phenethyl, benzyl, ##STR13## provided R.sup.4 is selected from phenyl, benzyl and phenethyl only when R.sup.2, is present, is hydrido or chloro;
wherein R.sup.5 is hydrido or hydroxyl, provided that when R.sup.5 is hydroxyl, R.sup.4 is ethyl or n-propyl;
wherein R.sup.6 is selected from hydrido, ethyl, n-propyl, hydroxymethyl, --(CH.sub.2).sub.3 CO.sub.2 H, --CH.sub.2 CO.sub.2 H, --(CH.sub.2).sub.2 CO.sub.2 H, t-butoxycarbonylmethyl, t-butoxycarbonylpropyl, --CH(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, --CH(C.sub.2 H.sub.5)CH.sub.2 CO.sub.2 H, --CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2 CO.sub.2 H, phenyl, 2-ethylphenyl, 2,6-dimethylphenyl, phenethyl and benzyl;
wherein R.sup.7 is selected from hydrido, bromo, chloro, iodo and fluoro;
wherein R.sup.8 is selected from hydrido, methyl, ethyl, propyl and benzyl, provided that R.sup.8 is benzyl where R.sup.2, if present, is hydrido or chloro;
wherein R.sup.9 is selected from methyl, ethyl, phenyl, benzyl, --(CH.sub.2).sub.2 CONHNH.sub.2, --CH.sub.2 CO.sub.2 H and --(CH.sub.2).sub.2 CO.sub.2 H, provided that R.sup.9 and R.sup.8 are not both benzyl;
wherein R.sup.10 is hydrido or methyl;
wherein R.sup.11 is selected from hydrido, methyl, ethyl, hydroxymethyl and carboxy, or
wherein R.sup.11 and R.sup.10 taken together is .dbd.O;
wherein R.sup.12 is hydrido or methyl; and
wherein R.sup.13 is selected from hydrido, methyl, ethyl, hydroxymethyl and carboxy, or
wherein R.sup.13 and R.sup.12 taken together is .dbd.O; or a pharmaceutically suitable salt thereof.
Within Formula I there is a fourth sub-class of compounds of interest which consists of compounds as represented by Formula V ##STR14##
wherein Y is (CH.sub.2).sub.n and n is 1 to 3;
wherein Z is C.dbd.R.sup.3 or CR.sup.4 R.sup.5, or
wherein Y and Z together forms --CR.sup.6 .dbd.CR.sup.7 --, --CR.sup.6 .dbd.CR.sup.7 --CH.sub.2 -- or --CR.sup.6 .dbd.CR.sup.7 --CH.sub.2 --CH.sub.2 --;
wherein R.sup.1 is alkyl;
wherein R.sup.2 is selected from hydrido, halo, alkyl and aryl;
wherein R.sup.3 is selected from oxygen, sulfur, alkylidene, carboxyalkylidene and hydroxyamino;
wherein R.sup.4 is selected from hydrido, alkyl, hydroxyalkyl, carboxyl, alkylcarboxyalkyl, carboxyalkyl, carboxyaralkyl, aryl, aralkyl, hydroxyl, amino, aralkoxy, phthalimidyl, ##STR15##
wherein R.sup.5 is hydrido or hydroxyl;
wherein R.sup.6 is selected from hydrido, alkyl, hydroxyalkyl, carboxyl, alkylcarboxyalkyl, carboxyalkyl, aryl, aralkyl and hydroxyl;
wherein R.sup.7 is halo or hydrido;
wherein R.sup.8 is selected from hydrido, alkyl and aralkyl;
wherein R.sup.9 is selected from alkyl, aryl, aralkyl, hydrazidylcarboalkyl, carboxyl and carboxyalkyl;
wherein R.sup.10 is hydrido or alkyl;
wherein R.sup.11 is selected from hydrido, alkyl, hydroxyalkyl, carboxyl and carboxyalkyl, or
wherein R.sup.10 and R.sup.11 taken together is .dbd.O;
wherein R.sup.12 is hydrido or alkyl; and
wherein R.sup.13 is selected from hydrido, alkyl, hydroxyalkyl, carboxyl and carboxyalkyl, or
wherein R.sup.13 and R.sup.12 taken together is .dbd.O;
or a pharmaceutically suitable salt thereof.
A more preferred class of compounds consists of those compounds of Formula V wherein R.sup.4 is aryl or aralkyl only when R.sup.2 is hydrido or halo;
wherein R.sup.3 is selected from oxygen, sulfur, hydroxyamino, CHCO.sub.2 C(CH.sub.3) and CHCO.sub.2 H;
wherein R.sup.4 is alkyl where R.sup.5 is hydroxyl;
wherein R.sup.8 is aralkyl where R.sup.2, if present, is hydrido or halo;
wherein R.sup.8 and R.sup.9 are not both aralkyl;
wherein R.sup.11 is alkyl when R.sup.2 is aryl or halo; and
wherein R.sup.13 is alkyl when R.sup.2 is aryl or halo; or a pharmaceutically suitable salt thereof.
A further preferred class of compounds consists of those compounds of Formula V wherein R.sup.6 is selected from hydrido, ethyl, hydroxymethyl, --CH.sub.2 CO.sub.2 H and --(CH.sub.2).sub.3 CO.sub.2 H; or is aryl or aralkyl provided R.sup.2 is hydrido; or a pharmaceutically suitable salt thereof.
An even more preferred class of compounds consists of those compounds of Formula V
wherein R.sup.1 is n-propyl or n-butyl;
wherein R.sup.2 is selected from hydrido, chloro, methyl, ethyl, n-propyl, n-butyl, 2-ethylphenyl and 2,6-dimethylphenyl;
wherein R.sup.3 is selected from oxygen, sulfur, hydroxyamino, CHCO.sub.2 H and CHCO.sub.2 C (CH.sub.3).sub.3 ;
wherein R.sup.4 is selected from hydrido, ethyl, n-propyl, hydroxymethyl, t-butoxycarbonylmethyl, hydroxyl, amino, t-butoxycarbonylpropyl, --(CH.sub.2).sub.3 CO.sub.2 H, --CH.sub.2 CO.sub.2 H, --(CH.sub.2).sub.2 CO.sub.2 H, --CH(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, --CH(C.sub.2 H.sub.5)CH.sub.2 CO.sub.2 H, --CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2 CO.sub.2 H, phenylmethoxy, 2-ethylphenyl, 2,6-dimethylphenyl, phenyl phenethyl, benzyl, ##STR16## provided R.sup.4 is selected from phenyl, benzyl and phenethyl only when R.sup.2 is hydrido or chloro;
wherein R.sup.5 is hydrido or hydroxyl, provided that when R.sup.5 is hydroxyl, R.sup.4 is ethyl or n-propyl;
wherein R.sup.6 is selected from hydrido, ethyl, n-propyl, hydroxymethyl, --(CH.sub.2).sub.3 CO.sub.2 H, --CH.sub.2 CO.sub.2 H, --(CH.sub.2).sub.2 CO.sub.2 H, t-butoxycarbonylmethyl, t-butoxycarbonylpropyl, --CH(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, --CH(C.sub.2 H.sub.5)CH.sub.2 CO.sub.2 H, --CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2 CO.sub.2 H, phenyl, 2-ethylphenyl, 2,6-dimethylphenyl, phenethyl and benzyl;
wherein R.sup.7 is selected from hydrido, chloro, bromo, fluoro and iodo;
wherein R.sup.8 is selected from hydrido, methyl, ethyl, propyl and benzyl, provided that R.sup.8 is benzyl where R.sup.2, if present, is hydrido or chloro;
wherein R.sup.9 is selected from methyl, ethyl, phenyl, benzyl, --(CH.sub.2).sub.2 CONHNH.sub.2, --CH.sub.2 CO.sub.2 H and --(CH.sub.2).sub.2 CO.sub.2 H, provided that R.sup.9 and R.sup.8 are not both benzyl;
wherein R.sup.10 is hydrido or methyl;
wherein R.sup.11 is selected from hydrido, methyl, ethyl, hydroxymethyl and carboxy or
wherein R.sup.11 and R.sup.10 taken together is .dbd.O;
wherein R.sup.12 is hydrido or methyl; and
wherein R.sup.13 is selected from hydrido, methyl, ethyl, hydroxymethyl and carboxy or
wherein R.sup.13 and R.sup.12 taken together is .dbd.O; or a pharmaceutically suitable salt thereof.
The term "conformationally restricted" denotes a compound having a reduced number of possible geometries a radical can attain within the molecule. These limited conformations or orientations of the radical of interest in spatial relationship to other portions of the molecule can impact the potency of such compounds by better mimicking the binding conformation of the target, such as a receptor or enzyme. Certain radicals such as aralkyl and those including alkyl bridges, account for a substantial range of potential conformations, such as by rotation around a single methylene.
The phrase "acidic" such as used to define the substituents on the biphenyl radical is intended to embrace chemical groups which, when attached to the biphenyl radical of Formula I, confers acidic character to the compound of Formula I. "Acidic character" means proton-donor capability, that is, the capacity of the compound of Formula I to be a proton donor in the presence of a proton-receiving substance, such as water. Typically an acidic group should be selected to have proton-donor capability such that the product compound of Formula I has a PK.sub.a in a range from about one to about nine. More typically the compound of Formula I has a PK.sub.a in a range from about two to about seven. An example of an acidic group containing at least one acidic hydrogen is a carboxyl group (--COOH) or a tetrazolyl radical.
The term "alkyl", alone or in combination, means a straight-chain or branched-chain alkyl radical containing from 1 to about 10, preferably from 1 to about 8, carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. The term "alkenyl", alone or in combination, means a straight-chain or branched-chain hydrocarbon radial having one or more double bonds and containing from 2 to about 18 carbon atoms preferably from 2 to about 8 carbon atoms. The alkenyl radical may be attached through a double bond to a carbon atom in the fused ring. Examples of suitable alkenyl radicals include ethenyl, propenyl, allyl, 1,4-butadienyl and the like. The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. Examples of "aryl" include phenyl or naphthyl radicals either of which optionally carries one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro and the like, as well as p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, and the like. The term "heterocyclic ring system" means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle which contains one or more hetero atoms as ring atoms, selected from nitrogen, oxygen, silicon and sulfur, which is optionally substituted by halogen, alkyl, alkoxy, oxo and the like. Examples of such heterocyclic groups are pyrrolidinyl, imidizolyl, triazolyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, phthalimidyl, succinimidyl, maleimidyl and the like. The term "alkoxy" embraces linear or branched oxy-containing radicals each having alkyl portions of one to ten carbon atoms, such as a methoxy group. The term "aralkoxy" means a radical having an aryl group attached to an alkoxy radical as described above. Phenylmethoxy is an example of sauc a radical. The term "halo" means fluorine, chlorine, bromine or iodine. The term "aralkyl", alone or in combination, means an alkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenethyl and the like. The term "carboxyalkenyl" means a radical containing an acidic --CO.sub.2 H group attached to one carbon atom of an alkenyl group as defined above, another carbon of the alkenyl group connected via a double bond to a carbon atom on the fused ring. Examples of such "carboxyalkenyl" groups include CHCO.sub.2 H, C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, C(C.sub.2 H.sub.5)CH.sub.2 CO.sub.2 H, C(C.sub.2 H.sub.5)CO.sub.2 H and C(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2 CO.sub.2 H. The term "alkylcarboxyalkenyl" means an ester radical containing an alkyl group, as defined above, attached via a carbon atom to a "carboxyalkenyl" group as defined above. Examples of such "alkylcarboxyalkenyl" groups include CHCO.sub.2 C(CH.sub.3).sub.3. "Hydroxyalkyl" means a hydroxy substituted alkyl group wherein the hydroxy group is attached to an alkyl group as defined above. Examples of such "hydroxyalkyl" groups include --CH.sub.2 OH, --(CH.sub.2).sub.2 OH and --(CH.sub.2).sub.4 OH. "Carboxyalkyl" means a radical containing an acidic --CO.sub.2 H carboxy group attached via the carbon atom to an alkyl group as defined above. Examples of such "carboxyalkyl" groups include --CH.sub.2 CO.sub.2 H, --CH(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, --CH(C.sub.2 H.sub.5)CH.sub.2 CO.sub.2 H, --CH(C.sub.2 H.sub.5)CO.sub.2 H and CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2 CO.sub.2 H. (CH.sub.2).sub.3 CO.sub.2 H, --(CH.sub.2).sub.2 CO.sub.2 H and --CH(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H. The term "alkylcarboxyalkyl" means a radical containing an alkyl group, as defined above, attached via a carbon atom to a "carboxyalkyl" group as defined above. Examples of such "alkylcarboxyalkyl" groups include (CH.sub.3).sub.3 CO.sub.2 CCH.sub.2 --. "Carboxyaralkyl" means a radical containing an acidic --CO.sub.2 H carboxy group attached via the carbon atom to an aryl portion of an aralkyl group as defined above. Examples of such "carboxyaralkyl" groups include --CH.sub.2 C.sub.6 H.sub.4 CO.sub.2 H. 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 two hydrido groups may be attached too a carbon atom to form a methylene (--CH.sub.2) radical. The term "hydroxyamino" embraces singly or multiply hydroxy substituted amine groups, including NOH. Hydrazidocarboalkyl" denotes a radical having a carbonyl between a hydrazine portion and an alkyl portion, and includes --(CH.sub.2).sub.2 --CONHNH.sub.2.
Also included in the family of compounds of Formula I are isomeric forms including diastereoisomers, regioisomers, tautomers 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 of compounds of Formula I 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, malic, propionic, succinic, glycolic, gluconic, lactic, 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, b-hydroxybutyric, malonic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylgluca-mine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the appropriate acid or base with the compound of Formula I.
General Synthetic Procedure
General synthetic methods for preparing the compounds of the invention are illustrated in the following Schemes. It is understood by those familiar with the art of organic synthesis that some functionality present in certain compounds of the invention may be incompatible with a particular synthetic sequence. Depending on the reactions and techniques employed, an alternative route, an altered order of steps, or a strategy of protection and deprotection may be necessary to prepare those compounds. In all cases, to achieve optimal yields the reaction conditions (such as reagents, solvent, temperature, and time) may need some modification.
[1,5-a]Imidazole-based conformationally restricted angiotensin II antagonists may be prepared as shown in Scheme I to Scheme IV. Isomeric [1,2-a]imidazole-based conformationally restricted angiotensin II antagonists may be prepared as shown in Scheme V to Scheme VIII. Pyrrole-based conformationally restricted angiotensin II antagonists may be prepared as shown in Scheme IX to Scheme XII. Triazole-based conformationally restricted angiotensin II antagonists may be prepared as shown in Scheme XIII to Scheme XVI.
______________________________________Abbreviations Used in Schemes and Procedures______________________________________Reagents:NBS N-bromosuccinimideAIBN azo(bis)isobutyronitrileHOAc acetic acidNaOAc sodium acetateTEA triethylaminePPh.sub.3 triphenylphosphineTFA trifluoroacetic acidLDA lithium diisopropylamideKOt-Bu potassium tert-butoxideSolvent:DME 1,2-dimethoxyethaneDMF N,N-dimethylformamideDMSO dimethylsulfoxideIPA isopropanolEtOAc ethyl acetateTHF tetrahydrofuranOther:BOC tertiary butoxycarbonylSEM 2-trimethylsilyl-ethoxymethylMS(FAB) or FABMS Fast atom bombardment mass spectroscopyLG leaving group, e.g. halide, tosylate, triflate, etc.n- normal-Ph phenylPLG leaving group or a functionalgroup that can be easily converted to aleaving grouprt room temperaturesec- secondary-tert- tertiaryTf SO.sub.2 CF.sub.3TMS trimethylsilylTosylate (TsO) OSO.sub.2 -(4-methyl)phenylTriflate (TfO) OSO.sub.2 CF.sub.3Trityl triphenylmethylTs SO.sub.2 -(4-methyl)phenyl______________________________________
An appropriately substituted imidazole 1, the heterocyclic starting material, may be prepared as described in the literature [Klaus Hofmann, in "Imidazole and its Derivatives" of The Chemistry of Heterocyclic Compounds, Arnold Weissberger Ed., Wiley Interscience New York, 1953]. The imidazole 1 in N,N-dimethylformamide (DMF) is treated with base, such as potassium tert-butoxide, followed by addition of appropriate alkylating agent 2 to give the coupled product 3 (Scheme I). For compounds where X is a substituted phenyl group, several procedures have been published for the preparations of the alkylating agent 2 [a) D. J., Carini; J. V. Duncia, Eur. Pat. Appl. 253310, 1988; b) D. J. Carini; J. V. Duncia; P. E. Aldrich; A. T. Chiu; A. L. Johnson; M. E. Pierce; W. A. Price; J. B. Santella; G. J. Wells; R. R. Wexler; P. C. Wong; S. E. Yoo; P. B. M. W. Timmermans, J, Med. Chem., 34, 2525-2547 (1991)].
The coupled imidazole 3 itself may be an angiotensin II receptor antagonist, but it may also be used as a key intermediate in the preparation of the compounds of the invention. Imidazole 3 in THF (or DME) is treated with base (such as n-BuLi or LDA) at -78.degree. C. (or -65.degree. C., if DME is used as solvent), followed by addition of an appropriate alkylating agent or other electrophiles 4 (the acetal shown in Scheme I may be other aldehyde masking group or equivalent, and LG is a leaving group such as halide, mesylate, triflate or tosylate). The resulting masked aldehyde 5 was stirred with NaOAc in aqueous acetic acid at reflux for a few days (1 to 5 days) to give one of the compounds of the invention, a cyclized imidazole 6. ##STR17##
The imidazole 6 may be used as an intermediate to prepare other substituted compounds with appropriate functional group transformations and preparation of some of those compounds are illustrated in Scheme II and III (all of the intermediates shown in the sequences are also angiotensin II receptor antagonists). For example, The unsaturated imidazole 6 and NBS in CCl.sub.4 is stirred at reflux to give a bromide 7. The bromide 7 may be treated with organolithium, such as n-BuLi or tert-BuLi, followed by addition of an appropriate electrophile, (such as alkyl halides, carbon dioxide, aldehyde, ketone and others) to give the addition product 8. The olefin 8 may be hydrogenated to give its saturated product 9. ##STR18##
Alternatively, as illustrated in Scheme III, the unsaturated imidazole 6 may be treated with NBS in wet DMSO to give a bromohydrin which may be reduced with nBu.sub.3 SnH to an alcohol 10 and the oxidation of the alcohol with MnO.sub.2 will afford a ketone 11. The ketone 11 may be condensed with appropriately substituted amine, then reduced to an amine 12 with an appropriate reducing agent (e.g. NaBH.sub.4, or hydrogen over catalyst). The amine 12 may also be prepared directly from olefin 6 under bromination condition (NBS, CH.sub.3 CN) in the presence of large excess of succinimide. The amine 12 may be used to prepare other derivatives. Alternatively, the alcohol 10 may be treated with triphenylphosphine, diethoxyazo dicarboxylate and an imide (e.g. phthalimide) to give an imide analogue which may be converted to an amine 12 [Mitsunobu, O. Synthesis, 1981, 1-27].
The ketone 11 may be treated with appropriate organometallic reagents (such as Grignard, organolithium, organocerium, organozinc reagents or related reagents) to give the addition product, a tertiary alcohol [a) T. Imamoto; T. Kusumoto; Y. Tawarayama; Y. Sugiura; T. Mira; Y. Hatanaka; M. Yokoyama, J. Org. Chem., 49, 3904-3912 (1984). b) D. Bonneville, J. Org. Chem., 6, 462 (1941). c) T. Hirao; D. Misu; K. Yao; T. Agawa, Tetrahedron Letter, 27, 929-932 (1986)]. The alcohol may be dehydrated to give an olefin 13 or an isomeric mixture of olefins 13. The olefin 13may be treated with base, such as LDA and kinetically quenched at low temperature with either organic acid or appropriate electrophile at low temperature to give the isomerized olefin 14. The olefins 13 or 14 may be hydrogenated to its saturated analogue 15. ##STR19##
In Scheme IV, an alternative preparation for the compounds of the invention is described. An appropriately substituted imidazole 1 may be treated with one equivalent of base, then protected as SEM or BOC derivative. The protected imidazole then is treated with another equivalent of base [a) B. H. Lipshutz; B. Huff; W. Hagen, Tetrahedron Letter, 2-9, 3411-3414 (1988). b) C. C. Tang; D. Davalian; P. Huang; R. Breslow, J. American Chemical Society, 100, 3918 (1978)] followed by addition of electrophile 17 or 18. Electrophiles 17 and 18 can be prepared from HC(.dbd.O)(CR.sup.4 R.sup.5)(CH.sub.2).sub.n C(.dbd.O)LG and an appropriate organometallic reagent such as XC.sub.6 H.sub.4 MgBr. If necessary, the resulting lithium anion obtained from the procedure described above may be converted to other organometallic reagents according to well-established procedures [a) T. Imamoto; T. Kusumoto; Y. Tawarayama; Y. Sugiura; T. Mira; Y. Hatanaka; M. Yokoyama, J. Org. Chem., 49, 3904-3912 (1984) b) D. Bonneville, J. Org. Chem., 6, 462 (1941) c) T. Hirao; D. Hisu; K. Yao; T. Agawa, Tetrahedron Letter, 27, 929-932 (1986)].
If PLG is a hydroxyl group and Z is a proton, the resulting addition product 19, may be cyclized with triphenylphosphine and diethyl azodicarboxylate [Mitsunobu, O. Synthesis, 1981, 1-27]. If PLG is or is converted to a leaving group, such as halides, tosylate, and Z is a proton, the cyclization may be achieved with a weak base in DMF (e.g. K.sub.2 CO.sub.3, Cs.sub.2 CO.sub.3) to give a ketone 11. The ketone 11 may be reduced to an alcohol 10 with NaBH.sub.4 in methanol. The alcohol 10 may be dehydrated to olefin 6 with acid (e.g. HOAc and heat) or thionyl chloride and pyridine. Other compounds may be prepared from compounds 6, 10, or 11 as described in Scheme II and III. ##STR20## 1,3-Dibutyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridine
Step 1: Preparation of 2,4-dibutylimidazole
A mixture of 12 g (0.09 mol) of ethyl valeryl imidate, 8.6 g (0.074 mol) of 1-hydroxy-2-hexanone, and 100 mL of liquid ammonia was heated in a bomb at 100.degree. C. for 12 h. The bomb was cooled, vented, and the contents were concentrated. The residue was purified by chromatography, eluting with chlorformethyl acetate-TEA to give 7.2 g (44%) of the desired biphenyl dibutylimidazole intermediate as a brown oil: .sup.1 H NHR (CDCl.sub.3) .delta. 0.91 (t, J=7.31 Hz, 6H), 1.36 (septet, J=7.38 Hz, 4H), 1.50-1.75 (m, 4H), 2.55 (t, J=8.01 Hz, 2H), 2.68 (t, J=8.01 Hz, 2H), 6.61 (s, 1H).
Step 2: Preparation of Biphenyl Imidazole
To a solution of 478 mg (2.65 mmol) of 2,4-dibutylimidazole (obtained from Step 1) in 5.3 mL of DMF was added 3.45 mL (3.45 mmol) of potassium tert-butoxide (1M in THF), and the resulting solution was stirred at room temperature for 30 min. To the dark brown mixture was added 2.75 g (3.45 mmol) of the bromomethyl biphenyl. The reaction mixture was stirred at room temperature for 12 h, and concentrated in vacuo. The residue was purified by chromatography to give 737 mg (42%) of the trityl-protected biphenyl imidazole as a yellow oil which solidified as a glass: .sup.1 H NMR (CDCl.sub.3) .delta. 0.89 (q, J=7.5 Hz, 6H), 1.23-1.45 (m, 4H) , 1.50-1.73 (m, 4H), 2.53 (quintet, J=8.2 Hz, 4H), 4.85 (s, 2H), 6.36 (s, 1H), 6.79 (d, J=8.1 Hz, 2H), 6.92 (d, J=7.8 Hz, 6H), 7.09 (d, J=8.1 Hz, 2H), 7.16-7.40 (m, 10H), 7,40-7.55 (m, 2H), 7.94 (dd, J=6.9, 2.1 Hz, 1H).
Step 3: Preparation of Dimethyl Acetal Imidazole
To a solution of 2.09 g (3.18 mmol) of the biphenyl imidazole (obtained from Step 2) in 16 mL of DME cooled at -45.degree. C. (acetonitrile-dry ice) was added 2.8 mL of 1.45M (4.06 mmol) of n-butyllithium in hexane over a 4 min period. The resulting dark purple solution was stirred cold for another 15 min, followed by addition of 1.0 mL (6.59 mmol) of 3-bromopropionaldehyde dimethyl acetal in one portion. The mixture was stirred cold for 40 min, then was warmed to -10.degree. C. over a 40 min period. The reaction was quenched with aqueous NH.sub.4 Cl, extracted with three 20 mL portions of diethyl ether. The combined extracts were washed with brine, dried (MgSO.sub.4) and concentrated in vacuo. The crude acetal biphenyl imidazole was used directly in the subsequent Step 4 without purification. The .sup.1 H NMR spectrum of the crude mixture indicated a >9:1 ratio of the desired alkylated product to the recovered starting material (based on the integration areas of singlet peaks at .delta. 6.48 and 6.28, respectively). HPLC analysis also agreed with the result from the .sup.1 H NMR study (C18 column, 60% acetonitrile in water containing 0.05% of TFA, flow rate 1.5 mL/min, retention time 8.45 min and 7.21 min, respectively).
In some experiments, the acetal biphenyl imidazole was isolated by chromatography (SiO.sub.2) as a pale yellow oil: .sup.1 H NMR (CDCL.sub.3) .delta. 0.75-1.0 (m, 6H), 1.2-1.45 (m, 4H), 1.45-1.72 (m, 6H), 1.85-2.10 (m, 2H), 2,54 (t, J=7.04 Hz, 4H), 3.26 (s, 3H), 3.27 (s, 3H), 4.31 (t, J=5.45 Hz, 1H), 4.98 (dd, J=9.82, 4.95 Hz, 1H), 6.55 (s, 1H), 6.80-7.00 [m (with d at 6.89, J=7.31 Hz), 8H], 7.09 (d, J=8.08 Hz, 2H), 7.15-7.40 (m, 10H), 7.40-7.55 (m, 2H), 7.94 (dd, J=6.89, 2.16 Hz, 1H); MS(FAB) m/e (relative intensity): 759 (100, M+H), 517 (20), 474 (30).
Step 4: Preparation of Bicyclic Imidazole
A solution of 2.1 g (3.18 mmol) of the crude biphenyl acetal imidazole (obtained from Step 3) and 5.3 g (88 mmol) of NaOAc in 13 mL of water and 40 mL of glacial acetic acid was stirred at reflux for 64 h, cooled and concentrated in vacuo. The residue was dissolved in methylene chloride and filtered. The filtrate was stirred with 2 g (7.2 mmol) of trityl chloride and 3 mL (21.5 mmol) of TEA at room temperature overnight (16 h) and concentrated in vacuo. The residue was purified by chromatography to give 1.2 g (54%) of trityl-protected biphenyl bicyclic imidazole: .sup.1 H NMR (CDCl.sub.3) .delta. 0.78 (t, J=7.25 Hz, 3H), 0.96 (t, J=7.25 Hz, 3H), 1.20 (septet, J=7.65 Hz, 2H), 1.35-1.60 [m (with quintet at 1.43, J=7.65 Hz), 4H], 1.60-1.80 {m, 2H), 2.25 (dd, J=16.9, 6.54 Hz, 1H), 2.32-2.40 (m, 2H), 2.64 (t, J=7.66 Hz, 2H), 2.90 (ddt, J=16.92, 7.25, 2.82 Hz, 1H), 5.2-5.29 [m (with d at 5.21, J=6.85 Hz), 2H], 6.46 (dd, J=9.67, 2.82 Hz, 1H), 6.57 (d, J=8.46 Hz, 2H), 6.88 (d, J=7.65 Hz, 6H), 7.02 (d, J=8.06 Hz, 2H), 7.20-7.38 (m, 10 H), 7.38-7.52 (m, 2H), 7.90 (dd, J=6.85, 2.02 Hz, 1H).
Step 5: Detritylation of the Trityl Tetrazole
A solution of 100 mg (0.144 mmol) of the trityl-protected biphenyl bicyclic imidazole (obtained from Step 4) was stirred with 1 mL of water and 6 mL of acetic acid at room temperature for 18 h. The solution was concentrated in vacuo, stirred in 3 mL of aqueous NaHCO.sub.3 and washed with three 3 mL portions of ether. The aqueous residue was acidified with 3N HCl to pH 4 and extracted with methylene chloride. The combined extracts were dried (MgSO.sub.4) and concentrated to give 59 mg of the title compound of Example 1 as an oil which solidified as a glass: mp 140.2.degree.-144.0.degree. C. (decomposed); .sup.1 H NMR (CD.sub.3 OD) .delta. 0.68 (t, J=7.27 Hz, 3H), 0.83 (t, J=7.3 Hz, 3H), 1.0-1.42 (m, 8H), 2.4-2.7 (m, 5H), 2.9-3.10 (m, 1H), 5.62 (d, J=7.5 Hz, 1H), 5.7-5.82 (m, 1H), 6.52 (dd, J=10, 3 Hz, 1H), 6.69 (d, J=8.01 Hz, 2H), 6.93 (d, J=8.16 Hz, 2H), 7.2-7.5 (m, 4H); HRMS. calcd for M+H: 453.2767. Found: 453.2791.
EXAMPLE 2 ##STR21## 7-Bromo-1,3-dibutyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridine
Step 1: Preparation of Bromo Olefin Imidazole
A solution of 70 mg (0.101 mmol) of trityl-protected bicyclic imidazole {obtained from Step 4 of Example 1), 20 mg (0.112 mmol) of NBS and 7 mg (catalytic) of AIBN in 2.8 mL of CCl.sub.4 was stirred at reflux for 2 h. The reaction mixture was diluted with CCl.sub.4 and washed with water. The organic layer was dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by chromatography to give 36 mg of brominated olefin as a yellow solid: .sup.1 H NMR (CDCl.sub.3) .delta. 0.76 (t, J=7.35 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), 1.16 (septet, J=7.38 Hz, 2H), 1.20-1.32 (m, 3H), 1.35-1.55 (m, 4H), 1.60-1.75 {m, 2H), 2.20-2.35 (m, 2H), 2.58 (t, J=7.74 Hz, 2H), 2.69 (dd, J=17.3, 1.21 Hz, 1H), 3.40 (ddd, J=17.33, 7.25, 2.82 Hz, 1H), 5.20 (d, J=7.25 Hz, 1H), 6.60 {d, J=8.05 Hz, 2H), 6.80 (d, J=2.82 Hz, 1H), 6.91 (d, J=7.39 Hz, 6H), 7.05 (d, J=8.31 Hz, 2H), 7.18-7.38 {m, 10H), 7.46 (quintet of doublets, J=6.67, 1.7 Hz, 2H), 7.90 (dd, J=7.03, 2.01 Hz, 1H).
Step K: Detritylation of the Trityl Tetrazole
A solution of 33 mg (0.0427 mmol) of bromo olefin (obtained from Step 1) in 0.8 mL of water and 5 mL of acetic acid was stirred at room temperature for 5 h and concentrated in vacuo. The residue was worked up as described in Step 5 of Example 1 to give 20 mg of the title compound of Example 2 as an oil which solidified as a glass: mp 148.degree.-160.degree. C. (decomposed); .sup.1 H NMR (CDCl.sub.3) .delta. 0.68-0.85 (m,6H), 1.0-1.30 (m, 6H), 1.30-1.60 (m, 2H), 1.85-2.08 (m, 2H), 2.20 (septet, J=6.88 Hz, 2H), 2.96 (d, J=17.05 Hz, 1H), 3.39-3.53 (m, 1H), 5.34 (d, J=6.27 Hz, 1H , 6.54 (d, J=8.08 Hz, 2H), 6.63 (d, J=2.78 Hz, 1H , 7.02 (d, J=8.28 Hz, 2H), 7.42 (dd, J=7.57, 1.04 Hz, 1H), 7.45-7.60 (m, 2H), 7.76 (d, J=6.34 Hz, 1H; HRMS. calcd for M+H: 531.1872. Found: 531.1834.
EXAMPLE 3 ##STR22## 1,3-Dibutyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridine
A suspension of 45 mg (0.1 mmol) of biphenyl bicyclic imidazole (the title compound of Example 1) and 20 mg (0.019 mmol) of 10% palladium on charcoal in 2 mL of absolute ethanol was agitated on a Parr apparatus under 50 psi of hydrogen gas at room temperature for 3.5 h. The mixture was filtered through a pad of celite and concentrated in vacuo to give 39 mg of the title compound of Example 3 as an oil which solidified as a glass: mp 108.degree.-113.degree. C. (decomposed); .sup.1 H NMR (CD.sub.3 OD) .delta. 0.83 (t, J=7.22 Hz, 3H), 0.98 (t, J=7.26 Hz, 3H), 1.15-1.90 (m, 10H), 2.08-2.23 (m, 1H), 2.35-2.60 (m, 3H), 2.35-2.85 (m, 3H), 2.90-3.05 (m, 1H), 5.72 (br s, 1H), 6.96 (d, J=8.46 Hz, 2H), 7.17 (d, J=8.46 Hz, 2H), 7.50-7.63 (m, 2H), 7.63-7.78 (m, 2H); HRMS. calcd for M+H: 455.2923. Found: 455.2965.
EXAMPLE 4 ##STR23## 1,3-Dibutyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8-ol
Step 1: Preparation of the Bromohydrin Intermediate
To a solution of 1.89 g (2.72 mmol) of biphenyl olefin imidazole (obtained from Step 4 of Example 1) in 1.37 mL (0.076 mmol) of water and 19.6 mL of DMSO at room temperature was added 509 mg (2.86 mmol) of NBS in one portion. The resulting orange solution was stirred at room temperature for 1 h, quenched with 100 mL of water and 12 mL of saturated Na.sub.2 SO.sub.3, extracted with 150 mL of methylene chloride. The combined extracts were washed with two 60 mL portions of water, and the combined aqueous layers were extracted with 40 mL of methylene chloride. The combined extracts were washed with brine, dried (MgSO.sub.4) and concentrated in vacuo to give 2.12 g of the crude bromohydrin which was used directly in the subsequent Step 2 without further purification.
Step 2: Preparation of Trityl Tetrazolyl Hydroxy imidazole
To 2.12 g (2.72 mmol) of the crude bromohydrin (obtained from Step 1) in 42 mL of degassed dry benzene was added 4.3 mL (14.7 mmol) of n-Bu.sub.3 SnH and 400 mg (2.4 mmol) of AIBN in one portion and the resulting solution was stirred at reflux for 2 h. The mixture was concentrated in vacuo and partitioned between 20 mL of hexane and 80 mL of acetonitrile. The acetonitrile layer was washed with two fresh 20 mL portions of hexane, and the combined hexane layer was extracted with another 50 mL of acetonitrile. The combined acetonitrile solution was concentrated in vacuo to give 2.5 g of the crude biphenyl hydroxy imidazole. The crude product was used directly in Example 5 without further purification. However, in some experiment, the crude mixture was purified by chromatography to give trityl-protected biphenyl hydroxy imidazole as a solid: .sup.1 H NMR (CDCl.sub.3) .delta. 0.70 (t, J=7.25 Hz, 3H), 0.96 (t, J=7.31 Hz, 3H), 0.98-1.17 (m, 2H), 1.33-1.55 (m, 4H), 1.58-1.85 (m, 4H), 1.90-2.05 (m, 2H), 2.05-2.18 (m, 2H), 2.60-2.75 (m, 2H), 4.96 (br t, J=6.05 Hz, 2H), 6.81 (d, J=8.46 Hz, 2H), 6.92 (d, J=6.84 Hz, 6H), 7.12 (d, J=8.05 Hz, 2H), 7.18-7.40 (m, 10H), 7.5-7.55 (m, 2H), 7.92 (dd, J=7.25 Hz, 2.02 Hz, 1H); MS(FAB) m/e (relative intensity) 713 (75, M+H), 469 (35), 428 (100).
Step 3: Detritylation of Trityl-Protected Imidazole
A solution of 42 mg (0.059 mmol) of purified trityl tetrazolyl hydroxy imidazole (obtained from Step 2) in 0.8 mL of water and 4 mL of acetic acid was stirred at room temperature for 6 h, and concentrated in vacuo. The residue was dissolved in a minimum amount of methanol, diluted with methylene chloride, then triturated with ether to give 23 mg (82%) of the title compound of Example 4 as a solid: .sup.1 H NMR (CDCl.sub.3) .delta. 0.81 (t, J=7.25 Hz, 3H), 0.99 (t, J=7.26 Hz, 3H), 1.18-1.35 (m, 2H), 1.69 (quintet, J=7.26 Hz, 2H), 1.78-1.93 (m, 1H), 1.96-2.10 (m, 1H), 2.17-2.58 (m, 4H), 2.70-2.95 (m, 2H), 4.98 (dd, J=7.25, 5.24 Hz, 1H), 5.59 (t, J=5.0 Hz, 1H), 7.11 (d, J=8.46 Hz, 2H), 7.20 (d, J=8.46 Hz, 2H), 7.50-7.65 (m, 2H), 7.65-7.77 (m, 2H); MS(FAB) m/e (relative intensity): 471(100, M+H), 443 (13), 428(30); HRMS. calcd for M+H: 471.2872. Found: 471. 2887.
EXAMPLE 5 ##STR24## 1,3-Dibutyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8(5H)-one
Step 1: Preparation of Trityl-Protected Keto Imidazole
A suspension of 2.5 g (2.72 mmol) of the crude product (obtained from Step 2 of Example 4) and 13 g of active MnO.sub.2 in 18 mL of methylene chloride was stirred at room temperature for 4 days. The mixture was filtered through a pad of celite, rinsed with IPA-methylene chloride, and concentrated in vacuo. The residue was purified by chromatography to give 0.28 g (15%) of olefinic starting material (the trityl protected title compound of Example 1), 0.73 g (38%) of biphenyl hydroxy imidazole (the trityl protected title compound of Example 4) and 0.32 g (17%) of trityl-protected biphenyl keto imidazole as an oil which solidified as a glass: .sup.1 H NMR (CDCl.sub.3) .delta. 0.77 (t, J=7.25 Hz, 3H), 0.97 (t, J=7.25 Hz, 3H), 1.17 (septet, J=7.25 Hz, 2H), 1.33 -1.66 [m (with quintet at 1.47, J=7.65 Hz), 4H], 1.65-1.82 (m, 2H), 2.0-2.25 (m, 3H), 2.36 (t, J=7.65 Hz, 2H), 2.45-2.63 (m, 1H), 3.04 (septet, J=3.8 Hz, 2H), 5.38 (br d, J=3.22 Hz, 1H), 6.62 (d, J=8.05 Hz, 2H), 6.90 (d, J=7.65 Hz, 6H), 7.13 (d, J=8.05 Hz, 2H), 7.18-7.38 (m, 10H), 7.40-7.55 (m, 2H), 7.97 (dd, J=6.44, 2.42 Hz, 1H).
The .sup.1 H NMR spectrum of the biphenyl hydroxy imidazole obtained from the above purification indicated the presence of another compound which co-eluted with the biphenyl hydroxy imidazole. This mixture was used in Example 8 to provide the title compound of Example 8.
Step 2: Detritylation of Trityl-Protected Imidazole
A solution of 39 mg (0.055 mmol) of trityl-protected keto imidazole (obtained from Step 1) in 0.8 mL of water and 4 mL of acetic acid was stirred at room temperature for 6 h, and concentrated in vacuo. The residue was worked up as described in Step 5 of Example 1 to give 22 mg (85%) of the title compound of Example 5 as an oil which solidified as a glass: mp 107.degree.-116 .degree. C. (decomposed); .sup.1 H NMR (CD.sub.3 OD) .delta. 0.82 (t, J=7.25 Hz, 3H), 0.95 (t, J=7.25 Hz, 3H), 1.17-1.32 (m, 2H), 1.32-1.58 [m (with septet at 1.39, J=7.66 Hz), 4H], 1.66 (quintet, J=7.25 Hz, 2H), 2.28-2.45 (m, 3H), 2.53 (t, J=7.7 Hz, 2H), 2.59-2.75 (m, 1H), 2.95 (td, J=7.66, 3.62 Hz, 2H), 5.77 (d, J=3.62 Hz, 1H), 6.85 (d, J=8.06 Hz, 2H), 7.14 (d, J=8.46 Hz, 2H), 7.53 (t, J=6.84 Hz, 2H), 7.62 (td, J=6.04, 1.6 Hz, 2H); HRMS. calcd for M+H: 469.2716. Found: 469.2748.
EXAMPLE 6 ##STR25## 1,3-Dibutyl-5,6-dihydro-8-phenyl-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridine
Step 1: Preparation of Protected Phenyl Hydroxy Imidazole Biphenyl
To 105 mg (0,148 mmol) of ketone biphenyl (from step 1 of Example 5) in 1.5 mL of THF at -78.degree. C. was added dropwise 298 .mu.L (0.149 mmol) of phenyllithium (o,5M in cyclohexane/diethyl ether), and the resulting dark brown solution was stirred cold for 2 hour, then was allowed to warm to room temperature and stirred for 10 min. The reaction was quenched with aqueous NH.sub.4 Cl and extracted with methylene chloride. The combined extracts were dried and concentrated in vacuo. The crude product was used directly in the subsequent Step 2 without further purification.
Step 2: Preparation of Conjugated Phenyl Imidazole Biphenyl
To 177 mg (0.148 mmol) of phenyl hydroxy imidazole (from Step 1) and 50 .mu.L of pyridine in 1.5 mL of methylene chloride at 0.degree. C. was added 32 .mu.L of thionyl chloride, and the resulting brown solution was stirred at room temperature for 2 hour. The reaction mixture was washed with water, dried and concentrated in vacuo. The residue was purified over silica gel to give 105 mg (92%) of conjugated phenyl imidazole biphenyl as an oil which solidified upon standing.
Step 2: Detritylation of Trityl Tetrazole
A solution of 105 mg (0.136 mmol) of trityl-protected phenyl imidazole (obtained from Step 2) in 0.5 mL of water and 5 mL of acetic acid was stirred at room temperature for 16 h, and concentrated in vacuo. The residue was worked up as described in Step 5 of Example 1. The product obtained was recrystallized to give 51 mg (71%) of the title compound of Example 6 as an solid: mp 158.degree.-170.degree. C. (decomposed); .sup.1 H NMR (CDCl.sub.3) .delta. 0.47 (t, J=7.25 Hz, 3H), 0.60-0.87 [m (with t at 0.80, J=7.25 Hz), 5H], 0.88-1.13 (m, 2H), 1.22 (quintet, J=8.06 Hz, 2H), 1.42-1.63 (m, 2H), 1.63-1.85 (m, 2H), 2.12-2.33 (m, 1H), 2.40-2.60 {m, 1H), 2.82 (dd, J=16.5, 7.25 Hz, 1H), 3.07 (dd, J=16.5, 5.24 Hz, 1H), 5.42 (d, J=6.05 Hz, 1H), 5.50 (d, J=6.45 Hz, 1H), 6.73 (d, J=8.06 Hz, 2H), 7.04 (d, J=8.06 Hz, 2H), 7.14-7.22 (m, 2H), 7.38-7.55 {m, 6H), 7.70 (d, J=7.26 Hz, 1H); .sup.13 C NMR (CDCl.sub.3) .delta. 13.12 (CH.sub.3), 13.46 (CH.sub.3), 21.83 (CH.sub.2), 22.21 (CH.sub.2), 24.97 (CH.sub.2), 25.34 (CH.sub.2), 29.56 (CH.sub.2), 31.62 (CH.sub.2), 31.98 (CH.sub.2), 53.29 (CH), 118.87 (CH), 123.17 (C), 124.67 (CH), 126.05 (C), 127.50 (CH), 127.61 (CH), 128.00 (CH), 128.09 (CH), 126.20 (CH), 129.36 (CH), 129.77 (CH), 130.24 (CH), 130.97 (CH), 132.93 (C), 137.35 (C), 37.42 (C), 140.10 (C), 140.34 (C), 146.57 {C), 157.38 (C); MS(FAB) m/e (relative intensity): 529(100, M+H); HRMS. calcd for M+H: 529.3080. Found: 529.3045.
EXAMPLE 7 ##STR26## [1,3-Dibutyl-6,7-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8(5H)-ylidene]acetic acid
Step 1: Preparation of the Tert-Butyl Ester
To a suspension of 50 mg (2.058 mmol) of magnesium in 2.5 mL of THF at 45.degree. C. was added 16 .mu.L of 1,2-dibromoethane in two portions, 5 min apart. The resulting mixture was stirred at 45.degree. C. for 10 min, followed by dropwise addition of a solution of 170 mg (0.239 mmol) of biphenyl keto imidazole (obtained from Step 1 of Example 5) and 190 .mu.L (1.18 mmol) of tert-butyl bromoacetate in 1.5 mL of THF at 45.degree. C. over a 1 h period. The resulting solution was stirred for an additional 15 min, and was cooled and quenched with aqueous NH.sub.4 Cl. The mixture was extracted with ether, dried (MgSO.sub.4) and concentrated in vacuo. The crude mixture could be used in the subsequent Step 2 without further purification. In this particular experiment, the crude product was purified by chromatography to give 179 mg (91%) of the hydroxy intermediate: .sup.1 H NMR (CDCl.sub.3) .delta. 0.72 (t, J=7.65 Hz, 3H), 0.98 (t, J=7.65 Hz, 3H), 1.11 (septet, J=7.66 Hz, 2H), 1.30-1.55 [m (with s at 1.47, 9H), 14HI, 1.65-1.90 (m, 5H), 2.10-2.35 (m, 3H), 2.67 (d, J=15.7 Hz, 1H), 2.72-2.9 [m (with d at 2.83, J=15.7 Hz), 2H], 4.10-4.25 (br s, 1H), 5.13 (d, J=3.22 Hz, 1H), 6.61 (d, J=8.06 Hz, 2H), 6.93 (d, J=7.25 Hz, 6H), 7.08 (8.06 Hz, 2H), 7.18-7.38 (m, 10H), 7.46 (quintet of doublets, J=6.85, 2.02 Hz, 2H), 7.90 (dd, J=6.85, 2.01 Hz, 1H).
Step 2: Preparation of Unsaturated Tert-Butyl Ester
To a solution of 115 mg (0.139 mmol) of the biphenyl imidazolyl ester intermediate (obtained from Step 1) and 30 .mu.L (0.371 mmol) of pyridine in 1 mL of methylene chloride at 0.degree. C. was added dropwise 20 .mu.L (0.274 mmol) of thionyl chloride. The resulting dark brown solution was stirred at room temperature for 1 h, diluted with water and extracted with ether. The combined extracts were dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by chromatography to give 107 mg (95%) of the unsaturated ester intermediate as an oil which solidified as a glass: .sup.1 H NMR (CDCl.sub.3) .delta. 0.75 (t, J=7.25 Hz, 3H), 1.02 (t, J=7.25 Hz, 3H), 1.14 (septet, J=7.25 Hz, 2H), 1.35-1.65 [m (with s at 1.47), 13H], 1.77 (quintet, J=7.25 Hz, 2 H), 1.90-2.10 (m, 1H), 2.10-2.25 (m, 2H), 2.29 (t, J=7.65 Hz, 2H), 2.86 (t, J=8.06 Hz, 2H), 3.40-3.60 (m, 1H), 5.26 (s, 1H), 6.00 (s, 1H), 6.60 (d, J=8.06 Hz, 2H), 6.91 (d, J=8.1 Hz, 6H), 7.09 (d, J=8.46 Hz, 2H), 7.18 -7.49 (m, 10H), 7.47 (quintet of doublets, J=6.45, 2.01 Hz, 2H), 7.93 (dd, J=6.85, 2.02 Hz, 1H).
Step 3: Detritylation of Trityl-Protected Biphenyl and Deprotection of Tert-Butyl Ester Group
A solution of 98 mg (0,121 mmol) of trityl tetrazolyl butyl ester (obtained from Step 2) in 0.8 mL of water and 3 mL of acetic acid was stirred at room temperature for 17 h and concentrated in vacuo. The residue was worked up as described in Step 5 of Example 1 to give the free tetrazole intermediate. The intermediate was dissolved in 3 mL of CDCl.sub.3 and 1 mL of TFA, and the progress of the reaction was monitored by .sup.1 H NMR. The resulting yellow solution was stirred at room temperature for 2 h and concentrated in vacuo. The crude product was purified over reverse phase chromatography to give 30 mg of the title compound of Example 7 as a solid: mp 155.degree.-178.degree. C. (decomposed); .sup.1 H NMR (CD.sub.3 OD) .delta. 1.10 (t, j=7.31 Hz, 3H), 1.29 (t, J=7.29 Hz, 3H), 1.40-1.68 (m, 2H), 1.68-1.89 (m, 4H), 1.99 (quintet, J=7.31 Hz, 2H), 2.40 -2.75 (m, 3H), 2.78 (t, J=7.93 Hz, 2H), 3.12 t, J=7.83 Hz, 2H), 3.84 (d, J=16.47 Hz, 1H), 5.91 (s, 1H), 6.44 (s, 1H), 7.07 (d, J=8.08 Hz, 2H), 7.40 d, J=8.28 Hz, 2H), 7.68-7.78 (m, 2H), 7.78-7.90 (m, 2H); HRMS. calcd for M+H: 511.2821. Found: 511.2769.
EXAMPLE 8 ##STR27## 1-[1,3-Dibutyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8-yl]2,5-pyrrolidinedione
Step 1: Preparation of Succinimidyl Imidazole
A suspension of 727 mg (1.02 mmol) of impure biphenyl hydroxy imidazole (isolated from Step 1 of Example 5) and 7 g of active MnO.sub.2 in 10 mL of methylene chloride was stirred at room temperature for 3 h. The resulting mixture was filtered through a pad of celite, rinsed with IPA-methylene chloride, and concentrated in vacuo. The residue was purified by chromatography to give 316 mg (16% from Step 1 of Example 4) of ketone (the trityl-protected title compound of Example 5), and 130 mg (6% from Step 1 of Example 4) of the trityl-protected biphenyl succinimidyl imidazole: .sup.1 H NMR (CDCl.sub.3) .delta. 0.70 (t, J=7.31 Hz, 3H), 0.91 (t, J=7.19 Hz, 3H), 1.08 (septet, J=7.5 Hz, 2H), 1.2-1.70 (m, 6H), 1.8-1.9 (m, 1H), 2.1-2.4 (m, 7H), 2.72 (s, 4H), 5.13 (s, 1H), 5.35-5.5 (m, 1H), 6.94 (d, J=6.84 Hz, 6H), 7.09 (d, J=8.34 Hz, 2H), 7.16 (d, J=8.28 Hz, 2H), 7.20-7.55 (m, 12H), 7.86 (dd, J=6.8, 2.6 Hz, 1H).
Alternatively, the succinimide can be prepared from trityl protected title compound of Example 1 (Step 4). To a solution of 2.17 g (3.13 mmol) of biphenyl bicyclic imidazole (Example 1, Step 4) and 1.25 g (12.6 mmol) of succinimide in 20 mL of anhydrous acetonitrile is added 572 mg (3.21 mmol) of NBS in one portion. The resulting orange-red solution is stirred at room temperature for 30 min, then evaporated in vacuo. The residue is dissolved in ethyl acetate and washed with aqueous sodium bisulfite, water, and brine. The extracts are dried (MgSO.sub.4) and concentrated in vacuo. The residue is purified to give the trityl protected succinimidyl imidazole.
Step 2: Detritylation of Trityl Tetrazolyl Imidazole
A solution of 130 mg (0.16 mmol) of trityl-protected biphenyl succinimidyl imidazole (obtained from Step 1) in 0.2 mL of water and 1 mL of acetic acid was stirred at room temperature for 12 h and concentrated in vacuo. The residue was worked up as described in Step 5 of Example 1 and purified by chromatography to give 64 mg (79%) of the title compound as a solid: mp 166.8.degree.-170.0.degree. C. (decomposed); .sup.1 H NHR (CD.sub.3 OD) .delta. 1.10 (t, J=7.3 Hz, 3H), 1.22 (t, J=7.31 Hz, 3H), 1.50 (septet, J=7.4 Hz, 2H), 1.55-1.93 (m, 6H), 2.1-2.25 (m, 1H), 2.4-2.85 (m, 7H), 3.06 (s, 4H), 5.76 (dd, J=8.7, 7.8 Hz, 1H), 5.8-5.9 (m, 1H), 7.46 (d, J= 8.35 Hz, 2H), 7.60 (d, J=8.28 Hz, 2H), 7.7-7.9 (m, 4H); HRMS. calcd for M+H: 552.3087. Found: 552.3067.
EXAMPLE 9 ##STR28## 4-[1,3-Dibutyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo [1,5 -a]pyridin-8-yl]amino]-4-oxobutanoic acid, hydrazide
A solution of 34.8 mg (0.06 mmol) of succinimidyl imidazole (the title compound of Example 8 and 11 .mu.L (5.6 mmol) of hydrazine in 0.5 mL of ethanol was stirred at room temperature for 6 days and concentrated in vacuo to give the title compound as a solid: mp 136.5.degree.-139.4.degree. C. (decomposed); .sup.1 H NMR (CD.sub.3 OD) .delta. 0.68 (t, J=7.23 Hz, 3H), 0.83 (t, J=7.27 Hz, 3H), 1.00-1.43 (m, 6H), 1.40-1.57 (m, 2H), 1.58-1.75 (m, 1H), 1.80-1.93 (m, 1H), 1.98-2.12 (m, 1H), 2.20-2.65 (m, 9H), 5.10 (dd, J=8.77, 5.99 Hz, 1H), 5.54 (br s, 1H), 7.05 (qAB, J=8.35 Hz, 4H), 7.35-7.50 (m, 2H), 7.50-7.63 (m, 2H); HRMS. calcd for M+H: 584.3461. Found: 584.3525.
EXAMPLE 10 ##STR29## 1,3-Dibutyl-6,7-dihydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]-5H-imidazo[1,5-a]azepine
Step 1: Alkylation of Biphenyl Imidazole
To a solution of 100 mg (0.152 mmol) of biphenyl imidazole (obtained from Step 2 of Example 1) in 0.8 mL of DME cooled at -45.degree. C. (acetonitrile-dry ice) was added 125 .mu.L of 1.6M (0.2 mmol) of n-butyllithium in hexane over a 4-min period. The resulting dark red solution was stirred cold for another 15 min, followed by addition of 70 .mu.L (0.37 mmol) of 2-(3-bromopropyl)-5,5-dimethyl-1,3-dioxane in one portion. The mixture was stirred cold for 40 min, then was warmed to -10.degree. C. over a 40 min period. The reaction was quenched with aqueous NH.sub.4 Cl, extracted with three 20 mL portions of diethyl ether. The combined extracts were washed with brine, dried (MgSO.sub.4) and concentrated in vacuo. The crude product was used directly in the subsequent Step 2 without purification. The .sup.1 H NMR spectrum (in CDCl.sub.3) of the crude mixture indicated a >9:1 ratio of the desired alkylated product to the recovered starting material (based on the integration areas of singlet peaks at .delta. 6.55 and 6.3, respectively). HPLC analysis also agreed with the result from the .sup.1 H NMR study (C18 column, 60% acetonitrile in water containing 0.05% of TFA, flow rate 1.5 mL/min, retention time 13.5 min and 7.1 min, respectively).
Step 2: Preparation of the Bicyclic Imidazole
A solution of 135 mg (0.152 retool) of the crude biphenyl acetal imidazole (obtained from Step 1) and 255 mg (3 mmol) of NaOAc in 0.6 mL of water and 2 mL of glacial acetic acid was stirred at reflux for 22 h, cooled and concentrated in vacuo. The residue was dissolved in methylene chloride and filtered. The filtrate was stirred with 130 mg (0.46 mmol) of trityl chloride and 0.22 mL (1.6 mmol) of TEA at room temperature overnight (16 h) and concentrated in vacuo. The residue was purified by chromatography to give 25 mg (23%) of trityl-protected biphenyl bicyclic imidazole: .sup.1 H NMR (CDCl.sub.3) .delta. 0.78 (t, J=7.5 Hz, 3H), 0.87 (t, J=7.4 Hz, 3H), 1.1-1.32 (m, 2H), 1.35-1.60 (m, 4H), 1.62-1.90 (m, 3H), 1.95-2.12 (m, 1H), 2.20- 2.38 (m, 2H), 2.38-2.55 (m, 2H), 2.58-2.75 (m, 2H), 5.15-5.38 (m, 1H), 5.53 (br s, 1H), 6.27 (dd, J=17.5, 3 Hz, 1H), 6.68 (d, J=7.5 Hz, 2H), 6.93 (d, J=8.3 Hz, 6H), 7.08 (d, J=7.7 Hz, 2H), 7.20-7.38 (m, 10H), 7.40-7.55 (m, 2H), 7.9 (dd, J=7.5, 3.0 Hz, 1H).
Step 3: Detritylation of Trityl Tetrazole
A solution of 25 mg (0.035 mmol) of the bipenyl bicyclic imidazole (obtained from Step 2) was stirred with 0.4 mL of water and 2 mL of acetic acid at room temperature for 14 h. The solution was concentrated in vacuo. The residue was worked up as described in Step 5 of Example 1 to give 13 mg (80%) of the title compound of Example 10 as an oil which solidified as a glass: mp 125.degree.-130.degree. C. (decomposed); HRMS. calcd for M+H: 467.2923. Found: 467.2944.
EXAMPLE 11 ##STR30## 3-Butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridine
Step 1: Preparation of 2-Butylimidazole
To a mixture of 72.4 g (0.56 mol) of ethyl valery imidate and 63 mL {0,433 mol) of aminoacetaldehyde diethyl acetal was added slowly 50 mL of glacial acetic acid over a 20 min period, and the resulting solution was stirred at reflux for 2.5 h. To the solution was added 144 mL of 5N HCl aqueous solution, and the resulting mixture was stirred at reflux for another 2 h. The mixture was cooled and concentrated to about 200 mL, washed with 200 mL of ethyl acetate, 200 mL of ether, then basified to pH 8 with 50% NaOH, and extracted with four 225 mL portions of chloroform. The combined extracts were dried (MgSO.sub.4) and concentrated to give 30 g (56%) of 2-butyl imidazole as a light brown solid: .sup.1 H NMR (CDCl.sub.3) .delta. 0.85 (t, J=7.31 Hz, 3H), 1.31 (septet, J=7.46 Hz, 2H), 1.73 (quintet, J=7.31 Hz, 2H), 2.86 (t, J=7.39 Hz, 2H), 6.99 (s, 2H), 11.09-12.4 (br s, 1H).
Step 2: Preparation of Biphenyl Imidazole
To a solution of 4.07 g (32.8 mmol) of 2-butylimidazole (obtained from step 1) in 110 mL of DMF was added 44.3 mL (44.3 mmol) of potassium tert-butoxide (1M in THF), and the resulting solution was stirred at room temperature for 15 min. To the dark brown mixture was added 20.1 g (36.1 mmol) of the bromomethyl biphenyl. The reaction mixture was stirred at room temperature for 16 h, and concentrated in vacuo. The residue was dissolved in chloroform and washed with water. The aqueous layer was extracted with fresh chloroform, and the combined extracts were dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by chromatography to give 7.2 g (37%) of the biphenyl imidazole intermediate as a yellow oil which solidified as a glass: .sup.1 H NMR (CDCl.sub.3) .delta. 0.90 (t, J=7.31 Hz, 3H), 1.35 (septet, J=7.5 Hz, 2H), 1.71 (quintet, J=7.74 Hz, 2H), 2.61 (t, J=7.58 Hz, 2H), 4.93 (s, 2H), 6.65 (d, J=1.35 Hz, 1H), 6.79 (d, J=8.31 Hz, 2H), 6.92 (d, J=7.3 Hz, 6H), 6.97 (d, J=1.32 Hz, 1H), 7.11 (d, J=8.2 Hz, 2H), 7.2-7.4 (m, 10H), 7.4-7.55 (m, 2H), 7.95 (dd, J=6.85, 2.08 Hz, 1H); MS(FAB) m/e (relative intensity) 607 (100, M+Li), 601 (90, M+H).
Step 3: Alkylation of the Biphenyl Imidazole
To a solution of 7.5 g (12.5 mmol) of the biphenyl imidazole (obtained from Step 2) in 49 mL of DME and 86 mL of THF cooled at -45.degree. C. (acetonitrile-dry ice) was added 14.8 mL of 1.6M (24 mmol) of n-butyllithium in hexane over a 4 min period. The resulting dark red solution was stirred cold for another 15 min, followed by addition of 3.8 mL (25 mmol) of 3-bromo-proprionaldedyde dimethyl acetal in one portion. The mixture was stirred cold for 1 h, then was allowed to warm to -10.degree. C. over a 1.5-h period. The reaction was quenched with aqueous NH.sub.4 Cl, extracted with methylene chloride. The combined extracts were washed with brine, dried (MgSO.sub.4) and concentrated in vacuo to give the crude acetal biphenyl imidazole. The crude product was used directly in the subsequent Step 4 without purification. The .sup.1 H NMR spectrum of the crude mixture indicated a 9:1 ratio of the desired alkylated product to the recovered starting material [based on the integration areas of peaks at .delta. 5.13 (dd, 1H) and 4.93 (s, 2H), respectively].
Step 4: Preparation of the Bicyclic Imidazole
The crude mixture (12.5 mmol, obtained from Step 3) and 21 g (260 mol) of NaOAc in 52 mL of water and 160 mL of glacial acetic acid was stirred at reflux for 2 days, cooled and concentrated in vacuo. The residue was partitioned between chloroform and water. The combined extracts were dried (MgSO.sub.4) and concentrated in vacuo. The residue was dissolved in 40 mL of chloroform and stirred with 8.0 g (28.7 mmol) of trityl chloride and 16 mL (0.115 mol) of TEA at room temperature overnight (16 h) and concentrated in vacuo. The residue was partitioned between chloroform and water. The combined extracts were dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by chromatography (eluted with 2-propanol:hexane=1:10) to give 3.01 g (34%) of the trityl-protected biphenyl bicyclic imidazole: .sup.1 H NMR (CDCl.sub.3) .delta. 0.76 (t, J=7.31 Hz, 3H), 1.18 (septet, J=7.4 Hz, 2H), 1.43-1.62 (m, 2H), 2.20-2.49 (m, 3H), 2.83-2.97 (m, 1H), 5.22-5.31 [m (with d at 5.24, J=7.0 Hz), 2H], 6.42 (dd, J=9.82, 3.05 Hz, 1H), 6.54 (d, J=8.2 Hz, 2H), 6.84 (d, J=7.81 Hz, 6H), 6.97 (d, J=6.07 Hz, 2H), 7.01 (s, 1H), 7.09-7.33 (m, 10H), 7.34-7.50 (m, 2H), 7.88 (dd, J=6.8, 2.16 Hz, 1H).
Step 5: Detritylation of the Trityl Tetrazole
A solution of 50 mg (0.078 mmol) of the trityl-protected biphenyl bicyclic imidazole (obtained from Step 4) was stirred with 0.5 mL of water and 2 mL of acetic acid at room temperature for 18 h. The solution was concentrated in vacuo. The residue was worked up as described in Step 5 of Example 1 to give 25 mg (80%) of the title compound of Example 11 as an oil which solidified as a glass: mp: 146.degree.-156.degree. C. (decomposed); .sup.1 H NMR (CD.sub.3 OD) .delta. 0.72 (t, J=7.27 Hz, 3H), 1.10-1.50 (m, 4H), 2.55-2.80 (m, 3H), 3.00-3.21 (m, 1H), 5.82 (d, J=7.66 Hz, 1H), 5.91-6.00 (m, 1H), 6.56 (dd, J=10.1, 3.06 Hz, 1H), 6.84 (d, J=8.19 Hz, 2H), 6.99 (d, J=8.35 Hz, 2H), 7.30-7.60 [m (with s at 7.36), 5H]; HRMS. calcd. for M+H: 397.2141. Found: 97.2181.
EXAMPLE 12 ##STR31## 3-Butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8(5H) -one
Step 1: Preparation of the Bromohydrin Intermediate
To a solution of 2.0 g (3.13 mmol) of biphenyl olefin imidazole (obtained from Step 4 of Example 11) in 2.2 mL (0.122 mmol) of water and 22 mL of DMSO at room temperature was added 587 mg (3.30 mmol) of NBS in one portion. The resulting orange solution was stirred at room temperature for 40 min, quenched with 100 mL of water and 12 mL of saturated Na.sub.2 SO.sub.3, extracted with two 100 mL portions of chloroform. The combined extracts were washed with two 60 mL portions of water, and the combined aqueous layer was extracted with 40 mL of chloroform. The combined extracts were washed with brine, dried (MgSO.sub.4) and concentrated in vacuo to give a crude bromohydrin intermediate which was used directly in the subsequent Step 2 without further purification.
Step 2: Preparation of the Trityl Tetrazolyl Hydroxy Imidazole
To the crude bromohydrin intermediate (3.13 mmol, obtained from Step 1) in 42 mL of degassed dry benzene was added 4.3 mL (14.7 mmol) of n-Bu.sub.3 SnH and 456 mg (2.7 mmol) of AIBN in one portion and the resulting solution was stirred at reflux for 1 h. The mixture was concentrated in vacuo and partitioned between 20 mL of hexane and 80 mL of acetonitrile. The acetonitrile layer was washed with two fresh 20 mL portions of hexane, and the combined hexane layer was extracted with another 50 mL of acetonitrile. The combined acetonitrile extracts were concentrated in vacuo to give an isomeric mixture of both cis- and trans-hydroxy imidazole (relative to the biphenyl moiety). The .sup.1 H NMR spectrum of the crude mixture indicated a 1.8:1 ratio of the cis-hydroxy product to the trans-hydroxy product [based on the integration areas of peaks at .delta. 5.09 (t) and 5.28 (d), respectively]. The crude mixture was used directly in subsequent Step 3 without further purification. In one experiment, the mixture was used to prepare the biphenyl trans-hydroxy imidazole (the title compound of Example 14).
Step 3: Preparation of the Keto Imidazole
A suspension of the crude product (2.72 mmol, obtained from Step 2 and 13 g of active MnO.sub.2 in 15 mL of methylene chloride was stirred at room temperature for 17 h. The mixture was filtered through a pad of celite, rinsed with IPA-methylene chloride, and concentrated in vacuo. The residue was purified by chromatography to give 0.24 g (12%) of olefinic starting material (the trityl protected title compound of Example 11 ), and 1.01 g (57% ) of trityl-protected keto imidazole as a solid: .sup.1 H NMR (CDCl.sub.3) .delta. 0.72 (t, J=7.25 Hz, 3H), 1.13 (septet, J=7.26 Hz, 2H), 1.40-1.65 (m, 2H), 1.95-2.22 (m, 3H), 2.25-2.42 (m, 2H), 2.45-2.60 (m, 1H), 5.36 (br d, J=3.22 Hz, 1H), 6.54 (d, J=8.06 Hz, 2H), 6.83 (d, J=7.66 Hz, 6H), 7.08 (d, J=8.06 Hz, 2H), 7.13-7.35 (m, 10H), 7.42 (quintet, J=3.63 Hz, 2H), 7.86 (s, 1H), 7.92 (dd, J=6.85, 1.61 Hz, 1H).
Step 4: Detritylation of Trityl Tetrazolyl Imidazole
A solution of 86 mg (0.131 mmol of trityl-protected keto imidazole (obtained from Step 3) in 1.0 mL of water and 5.0 mL of acetic acid was stirred at room temperature for 20 h, and concentrated in vacuo. The residue was worked up as described in Step 5 of Example 1 to give 54 mg (quantitative) of the title compound of Example 12 as a solid: mp 128.degree.-144.degree. C. (decomposed); .sup.1 H NMR (CD.sub.3 OD) .delta. 0.82 (t, J=7.25 Hz, 3H), 1.15-1.35 (m, 2H), 1.35-1.65 (m, 2H), 2.3-2.8 (m, 6H), 5.84 (d, J=3.23 Hz, 1H), 6.88 (d, J=8.46 Hz, 2H), 7.13 (d, J=8.06 Hz, 2H), 7.49-7.60 (m, 2H), 7.60-7.70 (m, 2H), 7.80 (s, 1H); HRMS. calcd for M+H: 413.2090. Found: 413.2016.
EXAMPLE 13 ##STR32## 3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-cis-8-ol
Step 1: Preparation of Biphenyl Cis-Hydroxy Imidazole
To a solution of 298 mg (0.456 mmol) of ketone (obtained from Step 3 of Example 12) in 0.5 mL of methanol and 2.0 mL of THF at 0.degree. C. was added in small portions 34 mg (0.899 mmol) of NaBH.sub.4. The resulting solution was stirred at 0.degree. C. and slowly warmed to room temperature for 17 h. The reaction was quenched with aqueous NH.sub.4 Cl, extracted with methylene chloride, dried (MgSO.sub.4) and concentrated in vacuo. The residue was chromatography to give 273 mg (91%) of the biphenyl cis-hydroxy imidazole (relative to the biphenyl moiety) as a solid: .sup.1 H NMR (CDCl.sub.3) .delta. 0.68 (t, J=7.46 Hz, 3H), 1.07 (septet, J=7.38 Hz, 2H), 1.25-1.64 (m, 3H), 1.68-1.82 (m, 2H), 1.82-1.96 (m, 2H), 1.96-2.15 [m (with t at 2.10, J=8.4 Hz,), 3H], 4.84 (dd, J=8.7, 5.57 Hz, 1H), 5.03 (t, J=5.06 Hz, 1H), 6.63 (d, J=8.27 Hz, 2H), 6.89 (d, J=7.08 Hz, 6H), 6.98-7.08 [m (with s at 7.03 and d at 7.03, J=8.27 Hz), 3H], 7.15-7.32 (m, 10H), 7.32-7.45 (m, 2H), 7.85 (dd, J=6.85, 2.17 Hz, 1H).
Step 2: Detritylation of Trityl Tetrazolyl Imidazole
A solution of 170 mg (0.259 mmol) of trityl-protected biphenyl hydroxy imidazole (obtained from Step 1) in 0.4 mL of water and 2.0 mL of acetic acid was stirred at room temperature for 16 h and concentrated in vacuo. The residue was dissolved in a minimum amount of methanol, diluted with methylene chloride, then triturated with ether to give 92 mg (86%) of the title compound of Example 13 as a solid: mp 175.5.degree.-180.degree. C.; .sup.1 H NMR (CD.sub.3 OD) .delta. 0.80 (t, J=7.26 Hz, 3H), 1.15-1.28 (m, 2H), 1.28-1.43 (m, 1H), 1.43 -1.60 (m, 1H), 1.69-1.86 (m, 1H), 1.92-2.05 (m, 1H), 2.13-2.28 (m 1H), 2.28-2.55 (m, 3H), 4.81-4.95 (m, 1H), 5.57 (t, J=4.80 Hz, 1H), 6.90 (d, J=8.46 Hz, 2H), 7.14 (d, J=8.06 Hz, 2H), 7.36 (s, 1H), 7.40-7.62 (m, 4H); HRMS. calcd for M+Li: 421.2328. Found: 421.2306.
EXAMPLE 14 ##STR33## 3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-trans-8-ol
Step 1: Preparation of Biphenyl Trans-Hydroxy Imidazole
A suspension of the crude biphenyl hydroxy imidazole (1.307 mmol, obtained from Step 2 of Example 12) and 3.0 g of active MnO.sub.2 in 5.0 mL of methylene chloride was stirred at room temperature. The reaction was stopped before its completion (in this particular experiment, the reaction time was 14 h). The mixture was filtered through a pad of celite, rinsed with IPA-methylene chloride, and concentrated in vacuo. The residue was purified by chromatography to give 190 mg of olefinic starting material (23% from Step 1 of Example 12), 341 mg of trityl-protected ketone (40% from Step 1 of Example 12), and 74 mg of the trityl protected biphenyl trans-hydroxy imidazole (9% from Step 1 of Example 12) as a solid: .sup.1 H NMR (CDCl.sub.3) .delta. 0.76 (t, J=7.25 Hz, 3H), 1.16 (septet, J=7.25 Hz, 2H), 1.23 -1.62 (m, 4H), 1.68 (br d, J=12.09 Hz, 1H), 2.07-2.34 (m, 2H), 2.56-2.73 (m, 1H), 2.73 -2.95 (br s, 1 H). 4.94 (br s, 1H), 5.26 (br d, J=3.62 Hz, 1H), 6.47 (d, J=8.06 Hz, 2H), 6.90 (d, J=7.25 Hz, 6H), 7.05 (s, 1H), 7.07 (d, J=8.06 Hz, 2H), 7.17-7.38 (m, 10H), 7.40-7.55 (m, 2H), 7.93 (dd, J=7.25, 2.02 Hz, 1H).
Alternatively, the biphenyl trans-hydroxy imidazole can be prepared using the Mitsunobu reaction conditions. To a solution of diethyl azodicarboxylate (2.0 mmol) and 3-nitrobenzoic acid (2.0 mmol) in 2.0 mL of THP is added dropwise a solution of the biphenyl hydroxy imidazole (2.0 mmol, obtained from Step 1 of Example 13), and triphenylphosphine (2.0 mmol) in 1.0 mL of THF at room temperature. The resulting solution is stirred at room temperature until the reaction is complete. The resulting mixture is diluted with ether or ethyl acetate, and washed with water. The extracts are dried (MgSO.sub.4) and concentrated in vacuo to give the biphenyl imidazolyl nitrobenzoate. The crude benzoate is hydrolyzed with LiOH in aqueous THF at room temperature and purified to give the biphenyl trans-hydroxy imidazole.
Step2: Detritylation of Trityl Tetrazole
A solution of 52 mg 0.079 mmol) of biphenyl trans-hydroxy imidazole (obtained from Step 1) in 0.4 mL of water and 2.0 mL of acetic acid was stirred at room temperature for 17 h and concentrated in vacuo. The residue was dissolved in a minimum amount of methanol, diluted with methylene chloride, then triturated with ether to give 23 mg (70%) of the title compound of Example 14 as a solid: mp 185.2.degree.-188.0.degree. C. (decomposed); .sup.1 H NMR (CD.sub.3 OD) .delta. 0.82 (t, J=7.26 Hz, 3H), 1.15-1.62 (m, 4H), 1.72-1.87 (m, 1H), 1.90-2.10 (m, 2H), 2.35-2.60 (m, 2H), 2.63-2.80 (m, 1H), 5.01 (t, J=3.9 Hz, 1H), 5.65 (br t, J=5.1 Hz, 1H), 6.81 (d, J=8.40 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 7.39 (s, 1H), 7.42-7.65 (m, 4H); MS (FAB) m/e (relative intensity): 415 (100, M+H), 372 (20), 359 (18); HRMS. calcd for M+Li: 421.2328. Found: 421.2373.
EXAMPLE 15 ##STR34## 1,1-Dimethylethyl [3-butyl-6,7-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8(5H)-ylidene]acetate
Step 1: Preparation of Tert-Butyl Ester
To a suspension of 64 mg (2.63 mmol) of magnesium in 3.0 mL of THF at 55.degree. C. was added two 10 .mu.L portions of 1,2-dibromoethane, 5 min apart. The resulting mixture was stirred at 45.degree. C. for 10 min, followed by dropwise addition of a solution of 200 mg (0.306 mmol) of trityl-protected keto imidazole (obtained from Step 3 of Example 12) and 242 .mu.L (1.50 mmol) of tert-butyl bromoacetate in 2.0 mL of THF at 55.degree. C. over a 1 h period. The resulting solution was stirred for an additional 20 min, cooled and quenched with aqueous NH.sub.4 Cl. The mixture was extracted with ether, dried (MgSO.sub.4) and concentrated in vacuo. The crude mixture was used directly in the subsequent Step 2 without further purification.
Step 2: Preparation of Unsaturated Butyl Ester
To a solution of the crude alcohol (0.306 mmol) (obtained from Step 1) and 200 .mu.L (2.47 mmol) of pyridine in 2 mL of methylene chloride at 0.degree. C. was added dropwise 80 .mu.L (1.1 mmol) of thionyl chloride. The resulting dark brown solution was stirred an 0.degree. C. for 1 h, diluted with water and extracted with methylene chloride. TLC analysis indicated that some product was detritylated. The methylene chloride solution was treated with 100 mg of trityl chloride and 200 .mu.L of TEA, stirred at room temperature for 16 h, and concentrated in vacuo. The residue was purified by chromatography to give 164 mg (71%) of the biphenyl imidazolyl unsaturated ester as an oil which solidified as a glass: .sup.1 H NMR (CDCl.sub.3) .delta. 0.77 (t, J=7.26 Hz, 3H), 1.17 (septet, J=7.25 Hz, 2H), 1.40-1.70 [m (with s at 1.47), 11H], 1.96-2.12 (m, 1H), 2.12-2.32 (m, 2H), 2.32 -2.52 (m, 2H), 3.50 (d, J=15.7 Hz, 1H), 5.28-5.40 (br s, 1H), 6.23 (s, 1H), 6.60 (d, J=8.47 Hz, 2H), 6.90 (d, J=7.25 Hz, 6H), 7.14 (d, J=8.06 Hz, 2H), 7.20-7.40 (m, 10H), 7.42-7.56 (m, 2H), 7.60 (s, 1H), 7.97 (dd, J=7.25, 2.01 Hz, 1H).
Step 3: Detritylation of Trityl Tetrazolyl Imidazole
A solution of 100 mg (0.133 mmol of trityl-protected imidazolyl butyl ester {obtained from Step 2) in 1.0 mL of water and 5.0 mL of acetic acid was stirred at room temperature for 20 h and concentrated in vacuo. The residue was worked up as described in Step 5 of Example 1 to give 66 mg (97%) of the title compound of Example 15 as a solid: mp 205.degree.-212.degree. C. (decomposed); .sup.1 H NMR (CD.sub.3 OD) .delta. 1.09 (t, J=7.31 Hz, 3H), 1.43-1.65 (m, 2H), 1.65-1.95 [m {with s at 1.76), 11H], 2.45-2.65 (m, 3H), 2.68-2.95 (m, 2H), 3.73-3.92 (m, 1H), 5.95-6.02 (br s, 1H), 6.61 (s, 1H), 7.12 (d, J=8.09 Hz, 2H), 7.40 (d, J=8.28 Hz, 2H), 7.79 (t, J=7.58 Hz, 2H), 7.89 (t, J=7.81 Hz, 2H), 7.97 (s, 1H), 8.17 (s, 1H); HRMS. calcd for M+H: 511.2821. Found: 511.2793.
EXAMPLE 16 ##STR35## [3 -Butyl-6,7-dihydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8(5H)-ylidene]acetic acid
To a solution of 32 mg (0.0627 mmol) of tert-butyl ester (the title compound of Example 15) in 2 mL of CDCl.sub.3 at room temperature was added 0.5 mL of TFA, and the progress of the reaction was monitored by .sup.1 H NMR. The resulting yellow solution was stirred at room temperature for 1 h and concentrated in vacuo. The crude product was dissolved in a minimum amount of methanol, diluted with methylene chloride, then triturated with ether and hexane at 5.degree. C. to give 27 mg (96%) of the title compound of Example 16 as a solid: mp 154.0.degree.-155.5.degree. C. (decomposed); .sup.1 H NMR (CD.sub.3 OD) .delta. 0.84 (t, J=7.5 Hz, 3H), 1.2-1.45 (m, 2H), 1.45-1.63 (m, 2H), 2.25-2.55 (m, 3H), 2.60-2.9 (m, 2H), 3.52-3.7 (m, 1H), 5.95 (br s, 1 H), 6.59 (s, 1H), 6.99 (d, J=7.5 Hz, 2H), 7.19 (d, J=7.7 Hz, 2H), 7.50-7.62 (m, 2H, 7.67 (d, J=7.2 Hz, 2H), 8.16 (s, 1H); HRMS. calcd for M+H: 455.2195. Found: 455.2195.
EXAMPLE 17 ##STR36## 1,1-Dimethylethyl 3-butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8-acetate
Step 1: Preparation of Deconjugated Ester
To a solution of 178 mg (0,237 mmol) of conjugated butyl ester (obtained from Step 2 of Example 15) in 4 mL of THF at 0.degree. C. was added 310 .mu.L of 1.5M (0.467 mmol) LDA over a 2 min period, and the resulting solution was stirred at 0.degree. C. for 10 min. The mixture was cooled to -78.degree. C., stirred cold for 5 min, and quenched at -78.degree. C. with dropwise addition of 100 .mu.L of acetic acid in 1 mL of hexane. The mixture was stirred cold for 15 min, then warmed to room temperature and treated with aqueous NaHCO.sub.3. The mixture was extracted with three 5 mL portions of methylene chloride. The combined extracts were washed with water, dried (MgSO.sub.4) and concentrated in vacuo to give a crude biphenyl imidazolyl deconjugated ester. No starting material could be detected by the .sup.1 H NMR spectrum. The crude product was purified by chromatography to give 145 mg (81%) of the biphenyl imidazolyl deconjugated ester as a solid: .sup.1 H NMR (CDCl.sub.3) .delta. 0.74 (t, J=7.23 Hz, 3H), 1.16 (septet, 7.39 Hz, 2H), 1.41 (s, 9H), 1.42-1.60 (m, 2H), 2.20 (dd, J=17.05, 6.61 Hz, 1H), 2.23-2.50 (m, 2H), 2.93 (ddd, J=17.3, 7.65, 1.74 Hz, 1H), 3.20 (s, 2H), 5.12-5.25 [m (with d at 5.17, J=7.66 Hz), 2H], 6.58 (d, J=8.0 Hz, 2H), 6.82 (d, J=7.84 Hz, 6H), 6.99 (d, J=8.27 Hz, 2H), 7.05 (s, 1H), 7.15-7.35 (m, 10H), 7.35-7.50 (m, 2H), 7.88 (dd, J=6.69, 2.24 Hz, 1H).
Step 2: Detritylation of Trityl Tetrazolyl Imidazole
A solution of 124 mg (0.165 mmol) of trityl biphenyl imidazole (obtained from Step 1) in 1 mL of water and 3 mL of acetic acid was stirred at room temperature for 2 days, and concentrated in vacuo. The residue was worked up as described in Step 5 of Example 1. The crude product was recrystallized from methylene chloride-ether to give 78 mg (93%) of the title compound of Example 17 as a solid: mp 221.degree.-223.degree. C. (decomposed); .sup.1 H NMR (CD.sub.3 OD) .delta. 0.83 (t, J=7.25 Hz, 3H), 1.15-1.60 [m (with s at 1.44), 13H), 2.72-2.97 (m, 3H), 3.19-3.3 (m, 1H), 3,40 (d, J=16.5 Hz, 1H), 3.49 (d, J=15.71 Hz, 1H), 5.88-6.0 [m (with d at 5.92, J=7.26 Hz), 2H], 7.11 (s, 4H), 7.51 (d, J=7.65 Hz, 1H), 7.55-7.62 (m, 2H), 7.62-7.73 (m, 2H); HRMS. calcd for M+H: 511.2821. Found: 511.2847.
EXAMPLE 18 ##STR37## 3-Butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-8-acetic acid
To a solution of 20 mg (0.039 mmol) of biphenyl imidazolyl tert-butyl ester (the title compound of Example 17) in 0.5 mL of chloroform was added 0.25 mL of TFA, and the progress of the reaction was monitored by .sup.1 H NMR. The resulting solution was stirred at room temperature for 75 min. The mixture was quenched with methanol and concentrated in vacuo. The residue was dissolved in a minimum amount of methanol and triturated with dropwise addition of methylene chloride-ether-hexane to give 15 mg (84%) of the title compound of Example 18 as a solid: mp 148.degree.-171.degree. C. (decomposed); .sup.1 H NMR (CD.sub.3 OD) .delta. 0.83 (t, J=7.25 Hz, 3H), 1.10-1.60 (m, 4H), 2.68-2.95 (m, 3H), 3.13 -3.35 (m, 1H), 3.48-3.60 (m, 2H), 5.80-6.0 [m (with d at 5.87, J=7.66 Hz), 2H], 7.10 (br s, 4H), 7.40-7.75 (m, 5H); HRMS. calcd for M+H: 455.2195. Found: 455.2215.
EXAMPLE 19 ##STR38## 1,1-Dimethylethyl 3-butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-cis-8-acetate
A suspension of 30 mg (0.059 mmol) of the imidazolyl unsaturated butyl ester (the title compound of Example 17) and 20 mg (0.0188 mmol) of 10% palladium on charcoal in 1.5 mL of methanol was stirred at room temperature under an atmosphere of hydrogen gas for 4 h. The mixture was filtered through a pad of celite and concentrated in vacuo. The residue was recrystallized from methanol, ether and hexane to give 28 mg (93%) of the title compound as a solid: mp 194.degree.-203.degree. C. (decomposed); .sup.1 H NMR (CD.sub.3 OD) .delta. 0.84 (t, J=7.25 Hz, 3H), 1.15-1.75 (m, 15H), 1.82-2.00 (m, 1H), 2.20 (br d, J=14.1 Hz, 1H), 2.38-2.59 (m, 2H), 2.59-2.78 [m (with dd at 2.68, J=16.5, 6.85 Hz), 2H], 2.86 (br dd, J=16.1, 4.84 Hz, 1H), 5.80 (br d, J=4.03 Hz, 1H), 6.95 (d, J=7.65 Hz, 2H), 7.16 (d, J=7.66 Hz, 2H), 7.40 (s, 1H), 7.46-7.63 (m, 2H), 7.63-7.75 (m, 2H); HRMS. calcd for M+H: 513.2978. Found: 513.2992.
EXAMPLE 20 ##STR39## 3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridin-cis-8-acetic acid
To a solution of 17 mg (0.0332 mmol) of biphenyl imidazolyl tert-butyl ester (the title compound of Example 19) in 0.4 mL of CDCl.sub.3 was added 0.2 mL of TFA, and the progress of the reaction was monitored by .sup.1 H NMR. The resulting solution was allowed to stand at room temperature for 1.5 h. The reaction mixture was diluted with methanol and concentrated. The residue was recrystallized from methanol, methylene chloride and ether to give 13 mg (87%) of the title compound of Example 20 as a solid: mp 119.5.degree.-122.degree. C.; .sup.1 H NMR (CD.sub.3 OD) .delta. 0.84 (t, J=7.25 Hz, 3H), 1.13-1.73 (m, 6H), 1.87-2.00 (m, 1H), 2.20 (br d, J=14.1 Hz, 1H), 2.40 -2.57 (m, 2H), 2.57-2.70 (m, 1H), 2.7 6 (dd, J=16.5, 6.45 Hz, 1H), 2.90 (dd, J=16.51, 5.23 Hz, 1H), 5.78 (d, J=4.43 Hz, 1H), 6.96 (d, J=8.05 Hz, 2H), 7.16 (d, J=8.46 Hz, 2H), 7.42 (s, 1H), 7.48-7.62 (m, 2H), 7.62-7.72 (m, 2H); HRMS. calcd for M+H: 457.2352. Found: 457.2371.
EXAMPLE 21 ##STR40## 1,3-Dibutyl-5,6-dihydro-N-hydroxy-5-[2'-(1H-tetrazol-5-yl) [1.1'-biphenyl]-4-yl]imidazol[1,5-a]pyridin-8(7H)-imine
A mixture of 44 mg (0.094 mmol) of biphenyl keto imidazole (the title compound of Example 5), 20 mg (0.29 mmol) of N-hydroxyamine (hydrochloride salt) and 30 mg of NaOAc in 2 mL of methanol was stirred at 60.degree. C. for 16 h. The mixture was diluted with chloroform and filtered. The solid was washed with methanol. The filtrate was concentrated in vacuo and recrystallized from methanol and chloroform at 5.degree. C. to give 33 mg of the oxime as a solid: .sup.1 H NMR (CD.sub.3 OD) .delta. 0.68 (t, J=7.31 Hz, 3H), 0.82 (t, J=7.30 Hz, 3H), 1.11 (quintet, J=7.65 Hz, 2H), 1.19-1.45 (m, 4H), 1.53 (quintet, J=7.66 Hz, 2H), 1.85-2.07 (m, 1H), 2.12-2.35 (br s, 2H), 2.56 (t, J=7.85 Hz, 2 H), 2.83 (septet, J=8.28 Hz, 2H), 2.95 (d, J=17.50 Hz, 1H), 5.68 (s, 1H), 6.70 (d, J=8.00 Hz, 2H), 6.99 (d, J=8.20 Hz, 2H), 7.25-7.55 [m (with t at 7.33, J=7.38 Hz), 5H]; .sup.13 C NMR (CD.sub.3 OD) .delta. 12.22, 12.59, 15.93, 21.51, 21.85, 24.05, 25.34, 27.70, 28.42, 30.15, 55.53, 121.60, 124.73, 127.01, 127.07, 127.44, 127.67, 129.24, 129.40, 129.74, 130.19, 132.79, 136.43, 140.60, 140.80, 145.59, 145.86, 159.37; MS (FAB) m/e (relative intensity): 484 (100, M+H), 456 (60), 427 (30); HRMS. calcd for M+H: 484.2825. Found: 484.2837.
EXAMPLE 22 ##STR41## 1-[3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,5 -a]pyridin-8 -yl]phthalimide
Step 1: Preparation of Biphenyl Phthalimidyl Imidazole
To a solution of the biphenyl hydroxy imidazole (2.0 mmol, obtained from Step 1 of Example 13 or 14), phthalimide (2.0 mmol), and triphenylphosphine (2.0 mmol) in 2.0 mL of THF is added dropwise a solution of diethyl azodicarboxylate (2.0 mmol) in 1 mL of THF at room temperature. The resulting solution is stirred at room temperature until the reaction is complete. The resulting mixture is diluted with ether or ethyl acetate and washed with water. The extracts are dried (MgSO.sub.4) and concentrated in vacuo. The residue is purified to give the trityl protected phthalimidyl imidazole.
Step 2: Detritylation of Trityl Tetrazole
A solution of trityl-protected biphenyl phthalimidyl imidazole (2.0 mmol, obtained from Step 1) in 2 mL of water and 10 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 5 of Example 1 and purified give the title compound of Example 22.
EXAMPLE 23 ##STR42## 3 -Butyl-5,6,7,8-tetrahydro-8-amino-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,5-a]pyridine
A solution of phthalimidyl imidazole (0.6 mmol, the title compound of Example 22) and 3 .mu.L (1.5 mmol) of hydrazine in 1.0 mL of ethanol is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo, and purified to give the title compound of Example 23.
Alternatively, the title compound of Example 23 can be prepared from the corresponding oxime. A suspension of the biphenyl imidazolyl oxime (0.059 mmol, can be prepared from biphenyl ketone imidazole, the title compound of Example 12, according to the procedure described in Example 21) and 20 mg (0.0188 mmol) of 10% palladium on charcoal in 1.5 mL of methanol is stirred at room temperature under 50 psi of hydrogen gas until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 23.
The following examples, 24-1433, located in Tables I-XXIV, are further conformationally restricted angiotensin II antagonists embraced by Formula II above.
TABLE I______________________________________ ##STR43##EX. # R.sup.1 R.sup.2 R.sup.3______________________________________24 H C.sub.3 H.sub.7 (n) H25 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.526 H C.sub.3 H.sub.7 (n) CH.sub.2 OH27 H C.sub.3 H.sub.7 (n) CO.sub.2 H28 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H29 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.330 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H31 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3 432 H C.sub.3 H.sub.7 (n) phenyl33 H C.sub.3 H.sub.7 (n) benzyl34 H C.sub.3 H.sub.7 (n) phenylethyl35 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.536 H C.sub.4 H.sub.9 (n) CH.sub.2 OH37 H C.sub.4 H.sub.9 (n) CO.sub.2 H38 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H39 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3 240 H C.sub.4 H.sub.9 (n) phenyl41 H C.sub.4 H.sub.9 (n) benzyl42 H C.sub.4 H.sub.9 (n) phenylethyl43 Cl C.sub.3 H.sub.7 (n) H44 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.545 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH46 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H47 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H48 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.349 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H50 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3 051 Cl C.sub.4 H.sub.9 (n) H52 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.553 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH54 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H55 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H56 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.357 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H58 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3 .59 ethyl C.sub.3 H.sub.7 (n) H60 ethyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.561 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 OH62 ethyl C.sub.3 H.sub.7 (n) CO.sub.2 H63 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H64 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.365 ethyl C.sub.4 H.sub.9 (n) H66 ethyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.567 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 OH68 ethyl C.sub.4 H.sub.9 (n) CO.sub.2 H69 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H70 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.371 n-butyl C.sub.3 H.sub.7 (n) H72 n-butyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.573 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 OH74 n-butyl C.sub.3 H.sub.7 (n) CO.sub.2 H75 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H76 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.377 n-butyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.578 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 OH79 n-butyl C.sub.4 H.sub.9 (n) CO.sub.2 H80 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H81 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.382 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H83 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.584 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH85 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H86 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H87 (2-ethylphenyl) C.sub.3 H.sub. 7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.388 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H89 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.590 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH91 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H92 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H93 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.394 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H95 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.596 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH97 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H98 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H99 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3100 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H101 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5102 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH103 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H104 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H105 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3______________________________________
TABLE II______________________________________ ##STR44##EX. # R.sup.4 R.sup.5 R.sup.6______________________________________106 H C.sub.3 H.sub.7 (n) O107 H C.sub.3 H.sub.7 (n) S108 H C.sub.3 H.sub.7 (n) CHCO.sub.2 H109 H C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.3110 H C.sub.3 H.sub.7 (n) NOH111 H C.sub.4 H.sub.9 (n) S112 H C.sub.4 H.sub.9 (n) NOH113 Cl C.sub.3 H.sub.7 (n) O114 Cl C.sub.3 H.sub.7 (n) S115 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 H116 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.3117 Cl C.sub.3 H.sub.7 (n) NOH118 Cl C.sub. 4 H.sub.9 (n) O119 Cl C.sub.4 H.sub.9 (n) S120 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 H121 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.3122 Cl C.sub.4 H.sub.9 (n) NOH123 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O124 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) S125 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 H126 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.3127 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NOH128 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O129 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) S130 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 H131 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.3132 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NOH133 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O134 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) S135 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 H136 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.3137 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) S138 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.3139 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NOH140 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O141 (2-ethylphenyl) C.sub.3 H.sub.7 (n) S142 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 H143 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NOH144 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O145 (2-ethylphenyl) C.sub.4 H.sub.9 (n) S146 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H147 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NOH148 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) O149 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) S150 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 H151 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) NOH152 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) O153 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) S154 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H155 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) NOH______________________________________
TABLE III______________________________________ ##STR45##EX. # R.sup.7 R.sup.8 R.sup.9______________________________________156 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5157 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)158 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5159 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)160 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5161 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)162 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5163 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)164 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5165 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)166 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5167 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)168 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5169 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5170 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5171 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5172 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5173 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5______________________________________
TABLE IV______________________________________ ##STR46##EX. # R.sup.10 R.sup.11 R.sup.12______________________________________174 H C.sub.3 H.sub.7 (n) H175 H C.sub.3 H.sub.7 (n) NH.sub.2176 H C.sub.3 H.sub.7 (n) OH177 H C.sub.3 H.sub.7 (n) CH.sub.2 OH178 H C.sub.3 H.sub.7 (n) CO.sub.2 H179 H C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.3180 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5181 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)182 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5183 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub. 2184 H C.sub.3 H.sub.7 (n) (2-ethylphenyl)185 H C.sub.4 H.sub.9 (n) H186 H C.sub.4 H.sub.9 (n) CH.sub.2 OH187 H C.sub.4 H.sub.9 (n) CO.sub.2 H188 H C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.3189 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5190 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)191 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5192 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2193 H C.sub.4 H.sub.9 (n) (2-ethylphenyl)194 Cl C.sub.3 H.sub.7 (n) H195 Cl C.sub.3 H.sub.7 (n) NH.sub.2196 Cl C.sub.3 H.sub.7 (n) OH197 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH198 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H199 Cl C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.3200 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5201 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)202 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5203 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2204 Cl C.sub.3 H.sub.7 (n) (2-ethylphenyl)205 Cl C.sub.4 H.sub.9 (n) H206 Cl C.sub.4 H.sub.9 (n) NH.sub.2207 Cl C.sub.4 H.sub.9 (n) OH208 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH209 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H210 Cl C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.3211 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5212 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)213 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5214 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2215 Cl C.sub.4 H.sub.9 (n) (2-ethylphenyl)216 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H217 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NH.sub.2218 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) OH219 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 OH220 C.sub.2 H.sub.5 C.sub.3 H.sub. 7 (n) CO.sub.2 H221 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.3222 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5223 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H224 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NH.sub.2225 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) OH226 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 OH227 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CO.sub.2 H228 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.3229 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5230 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H231 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NH.sub.2232 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) OH233 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 OH234 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CO.sub.2 H235 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CO.sub. 2 C(CH.sub.3).sub.3236 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5237 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2238 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NH.sub.2239 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 OH240 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CO.sub.2 H241 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.3242 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5243 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H244 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.2245 (2-ethylphenyl) C.sub.3 H.sub.7 (n) OH246 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH247 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H248 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.3249 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5250 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H251 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.2252 (2-ethylphenyl) C.sub.4 H.sub.9 (n) OH253 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH254 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H255 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.3256 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5257 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H258 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.2259 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) OH260 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH261 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H262 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.3263 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5264 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H265 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.2266 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) OH267 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH268 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H269 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.3270 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5______________________________________
TABLE V______________________________________ ##STR47##EX. # R.sup.13 R.sup.14 R.sup.15 R.sup.16______________________________________271 H C.sub.3 H.sub.7 (n) H CH.sub.3272 H C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3273 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.3274 H C.sub.4 H.sub.9 (n) H CH.sub.3275 H C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3276 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.3277 Cl C.sub.3 H.sub.7 (n) H CH.sub.3278 Cl C.sub.3 H.sub.7 (n) CH.sub. 3 CH.sub.3279 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.3280 Cl C.sub.4 H.sub.9 (n) H CH.sub.3281 Cl C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3282 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.3283 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H CH.sub.3284 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3285 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H CH.sub.3286 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3287 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H CH.sub.3288 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3289 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.3290 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3291 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.3292 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3293 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.3294 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3295 (2,6-dimethyl- C.sub.3 H.sub.7 (n) H CH.sub.3 phenyl)296 (2,6-dimethyl- C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3 phenyl)297 (2,6-dimethyl- C.sub.4 H.sub.9 (n) H CH.sub.3 phenyl)298 (2,6-dimethyl- C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3 phenyl)299 H C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5300 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.5301 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.5302 H C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5303 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.5304 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.5305 Cl C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5306 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.5307 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.5308 Cl C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5309 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.5310 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.5311 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5312 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.5313 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5314 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.5315 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5316 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5317 (2,6-dimethyl- C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5 phenyl)318 (2,6-dimethyl- C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5 phenyl)319 H C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5320 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5321 H C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5322 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5323 Cl C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5324 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5325 Cl C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5326 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5327 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5328 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5329 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5330 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5331 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5332 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5333 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5334 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5335 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H336 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H337 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H338 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H339 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H340 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H341 (2,6-dimethyl- C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H phenyl)342 (2,6-dimethyl- C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H phenyl)343 (2,6-dimethyl- C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H phenyl)344 (2,6-dimethyl- C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H phenyl)______________________________________
TABLE VI______________________________________ ##STR48##EX. # R.sup.17 R.sup.18 R.sup.19, R.sup.20______________________________________345 H C.sub.3 H.sub.7 (n) O346 H C.sub.3 H.sub.7 (n) H, H347 H C.sub.3 H.sub.7 (n) H, CH.sub.3348 H C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.5349 H C.sub.3 H.sub.7 (n) H, CH.sub.2 OH350 H C.sub.3 H.sub.7 (n) H, CO.sub.2 H351 H C.sub.4 H.sub.9 (n) O352 H C.sub.4 H.sub.9 (n) H, H353 H C.sub.4 H.sub.9 (n) H, CH.sub.3354 H C.sub.4 H.sub. 9 (n) H, C.sub.2 H.sub.5355 H C.sub.4 H.sub.9 (n) H, CH.sub.2 OH356 H C.sub.4 H.sub.9 (n) H, CO.sub.2 H357 Cl C.sub.3 H.sub.7 (n) O358 Cl C.sub.3 H.sub.7 (n) H, H359 Cl C.sub.3 H.sub.7 (n) H, CH.sub.3360 Cl C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.5361 Cl C.sub.3 H.sub.7 (n) H, CH.sub.2 OH362 Cl C.sub.3 H.sub.7 (n) H, CO.sub.2 H363 Cl C.sub.4 H.sub.9 (n) O364 Cl C.sub.4 H.sub.9 (n) H, H365 Cl C.sub.4 H.sub.9 (n) H, CH.sub.3366 Cl C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.5367 Cl C.sub.4 H.sub.9 (n) H, CH.sub.2 OH368 Cl C.sub.4 H.sub.9 (n) H, CO.sub.2 H369 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O370 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, H371 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CH.sub.3372 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.5373 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CH.sub.2 OH374 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CO.sub.2 H375 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O376 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, H377 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CH.sub.3378 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.5379 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CH.sub.2 OH380 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CO.sub.2 H381 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O382 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, H383 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CH.sub.3384 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CH.sub.2 OH385 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CO.sub.2 H386 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, H387 C.sub.4 H.sub.9 (n) C.sub.4 H.sub. 9 (n) H, CH.sub.3388 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CH.sub.2 OH389 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CO.sub.2 H390 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O391 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, H392 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CH.sub.3393 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3, CH.sub.3394 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CH.sub.2 OH395 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CO.sub.2 H396 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O397 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, H398 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CH.sub.3399 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3, CH.sub.3400 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CH.sub.2 OH401 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CO.sub.2 H______________________________________
TABLE VII______________________________________ ##STR49##EX. # R.sup.21 R.sup.22 R.sup.23, R.sup.24______________________________________402 H C.sub.3 H.sub.7 (n) O403 H C.sub.3 H.sub.7 (n) H, H404 H C.sub.3 H.sub.7 (n) H, CH.sub.3405 H C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.5406 H C.sub.3 H.sub.7 (n) H, CH.sub.2 OH407 H C.sub.3 H.sub.7 (n) H, CO.sub.2 H408 H C.sub.4 H.sub.9 (n) O409 H C.sub.4 H.sub.9 (n) H, H410 H C.sub.4 H.sub.9 (n) H, CH.sub.3411 H C.sub.4 H.sub. 9 (n) H, C.sub.2 H.sub.5412 H C.sub.4 H.sub.9 (n) H, CH.sub.2 OH413 H C.sub.4 H.sub.9 (n) H, CO.sub.2 H414 Cl C.sub.3 H.sub.7 (n) O415 Cl C.sub.3 H.sub.7 (n) H, H416 Cl C.sub.3 H.sub.7 (n) H, CH.sub.3417 Cl C.sub.3 H.sub.7 (n) CH.sub.3, CH.sub.3418 Cl C.sub.3 H.sub.7 (n) H, CH.sub.2 OH419 Cl C.sub.3 H.sub.7 (n) H, CO.sub.2 H420 Cl C.sub.4 H.sub.9 (n) O421 Cl C.sub.4 H.sub.9 (n) H, H422 Cl C.sub.4 H.sub.9 (n) H, CH.sub.3423 Cl C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.5424 Cl C.sub.4 H.sub.9 (n) H, CH.sub.2 OH425 Cl C.sub.4 H.sub.9 (n) H, CO.sub.2 H426 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O427 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, H428 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CH.sub.3429 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.5430 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CH.sub.2 OH431 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CO.sub.2 H432 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O433 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, H434 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CH.sub.3435 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.5436 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CH.sub.2 OH437 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CO.sub.2 H438 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O439 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, H440 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CH.sub.3441 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CH.sub.2 OH442 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CO.sub.2 H443 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O444 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, H445 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CH.sub.3446 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CH.sub.2 OH447 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CO.sub.2 H448 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O449 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, H450 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CH.sub.3451 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3, CH.sub.3452 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CH.sub.2 OH453 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CO.sub.2 H454 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O455 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, H456 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CH.sub.3457 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3, CH.sub.3458 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CH.sub.2 OH459 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CO.sub.2 H______________________________________
TABLE VIII______________________________________ ##STR50##EX. # R.sup.25 R.sup.26 R.sup.27______________________________________460 H C.sub.3 H.sub.7 (n) CH.sub.2461 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)462 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)463 H C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2464 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.2465 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2466 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)467 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)468 H C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2469 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.2470 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2471 Cl C.sub.3 H.sub.7 (n) CH.sub.2472 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)473 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)474 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2475 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.2476 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2477 Cl C.sub.4 H.sub.9 (n) CH.sub.2478 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)479 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)480 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2481 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.2482 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2483 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2484 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)485 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)486 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2487 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.2488 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2489 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2490 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)491 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)492 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2493 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.2494 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2495 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2496 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub. 2 CH.sub.2497 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2498 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2499 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2500 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2501 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2502 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2503 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2504 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2505 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2506 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2______________________________________
TABLE IX______________________________________ ##STR51##EX. # R.sup.28 R.sup.29 R.sup.30______________________________________507 H C.sub.3 H.sub.7 (n) H508 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5509 H C.sub.3 H.sub.7 (n) CH.sub.2 OH510 H C.sub.3 H.sub.7 (n) CO.sub.2 H511 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H512 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3513 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H514 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3515 H C.sub.3 H.sub.7 (n) phenyl516 H C.sub.3 H.sub.7 (n) benzyl517 H C.sub.3 H.sub.7 (n) phenylethyl518 H C.sub.4 H.sub.9 (n) H519 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5520 H C.sub.4 H.sub.9 (n) CH.sub.2 OH521 H C.sub.4 H.sub.9 (n) CO.sub.2 H522 H C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H523 H C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3524 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H525 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3526 H C.sub.4 H.sub.9 (n) phenyl527 H C.sub.4 H.sub.9 (n) benzyl528 H C.sub.4 H.sub.9 (n) phenylethyl529 Cl C.sub.3 H.sub.7 (n) H530 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5531 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH532 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H533 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H534 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3535 Cl C.sub. 3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H536 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3537 Cl C.sub.4 H.sub.9 (n) H538 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5539 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH540 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H541 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H542 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3543 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H544 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3545 ethyl C.sub.3 H.sub.7 (n) H546 ethyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5547 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 OH548 ethyl C.sub.3 H.sub.7 (n) CO.sub.2 H549 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H550 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3551 ethyl C.sub.4 H.sub.9 (n) H552 ethyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5553 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 OH554 ethyl C.sub.4 H.sub.9 (n) CO.sub.2 H555 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H556 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3557 n-butyl C.sub.3 H.sub.7 (n) H558 n-butyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5559 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 OH560 n-butyl C.sub.3 H.sub.7 (n) CO.sub.2 H561 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H562 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3563 n-butyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5564 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 OH565 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H566 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3567 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H568 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5569 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH______________________________________
TABLE X______________________________________ ##STR52##EX. # R.sup.31 R.sup.32 R.sup.33______________________________________570 H C.sub.3 H.sub.7 (n) O571 H C.sub.3 H.sub.7 (n) S572 H C.sub.3 H.sub.7 (n) CHCO.sub.2 H573 H C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.3574 H C.sub.3 H.sub.7 (n) NOH575 H C.sub.4 H.sub.9 (n) O576 H C.sub.4 H.sub.9 (n) S577 H C.sub.4 H.sub.9 (n) CHCO.sub.2 H578 H C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.3579 H C.sub.4 H.sub.9 (n) NOH580 Cl C.sub.3 H.sub.7 (n) O581 Cl C.sub.3 H.sub.7 (n) S582 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 H583 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.3584 Cl C.sub.3 H.sub.7 (n) NOH585 Cl C.sub.4 H.sub.9 (n) O586 Cl C.sub.4 H.sub.9 (n) S587 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 H588 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.3589 Cl C.sub.4 H.sub.9 (n) NOH590 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O591 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) S592 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 H593 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.3594 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NOH595 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O596 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) S597 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 H598 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.3599 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NOH600 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O601 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) S602 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 H603 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.3604 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NOH605 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O606 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) S607 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 H608 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.3609 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NOH610 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O611 (2-ethylphenyl) C.sub.3 H.sub.7 (n) S612 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 H613 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NOH614 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O615 (2-ethylphenyl) C.sub.4 H.sub.9 (n) S616 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H617 (2-ethylphenyl) C.sub.4 H.sub. 9 (n) NOH618 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) O619 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) S620 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 H621 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) NOH622 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) O623 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) S624 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H625 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) NOH______________________________________
TABLE XI______________________________________ ##STR53##EX. # R.sup.34 R.sup.35 R.sup.36______________________________________626 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5627 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)628 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5629 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)630 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5631 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)632 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5633 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)634 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5635 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)636 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5637 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)638 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5639 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5640 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5641 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5642 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5643 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5______________________________________
TABLE XII______________________________________ ##STR54##EX. # R.sup.37 R.sup.38 R.sup.39______________________________________644 H C.sub.3 H.sub.7 (n) H645 H C.sub.3 H.sub.7 (n) NH.sub.2646 H C.sub.3 H.sub.7 (n) OH647 H C.sub.3 H.sub.7 (n) CH.sub.2 OH648 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5649 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)650 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5651 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2652 H C.sub.3 H.sub.7 (n) (2-ethylphenyl)653 H C.sub.4 H.sub.9 (n) H654 H C.sub.4 H.sub.9 (n) NH.sub.2655 H C.sub.4 H.sub.9 (n) OH656 H C.sub.4 H.sub.9 (n) CH.sub.2 OH657 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5658 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)659 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5660 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2661 H C.sub.4 H.sub.9 (n) (2-ethylphenyl)662 Cl C.sub.3 H.sub.7 (n) H663 Cl C.sub.3 H.sub.7 (n) NH.sub.2664 Cl C.sub.3 H.sub.7 (n) OH665 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH666 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5667 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)668 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5669 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2670 Cl C.sub.3 H.sub.7 (n) (2-ethylphenyl)671 Cl C.sub.4 H.sub.9 (n) H672 Cl C.sub.4 H.sub.9 (n) NH.sub.2673 Cl C.sub.4 H.sub.9 (n) OH674 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH675 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5676 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)677 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5678 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2679 Cl C.sub.4 H.sub.9 (n) (2-ethylphenyl)680 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H681 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NH.sub.2682 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) OH683 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 OH684 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5685 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H686 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NH.sub.2687 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) OH688 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 OH689 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5690 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H691 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NH.sub.2692 C.sub.4 H.sub. 9 (n) C.sub.3 H.sub.7 (n) OH693 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 OH694 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5695 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2696 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H697 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NH.sub.2698 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) OH699 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 OH700 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5701 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H702 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.2703 (2-ethylphenyl) C.sub.3 H.sub.7 (n) OH704 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH705 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5706 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H707 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.2708 (2-ethylphenyl) C.sub.4 H.sub.9 (n) OH709 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH710 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5711 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H712 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.2713 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) OH714 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH715 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5716 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H717 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.2718 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) OH719 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH720 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5______________________________________
TABLE XIII______________________________________ ##STR55##EX.# R.sup.40 R.sup.41 R.sup.42 R.sup.43______________________________________721 H C.sub.3 H.sub.7 (n) H CH.sub.3722 H C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3723 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.3724 H C.sub.4 H.sub.9 (n) H CH.sub.3725 H C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3726 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.3727 Cl C.sub.3 H.sub.7 (n) H CH.sub.3728 Cl C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3729 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.3730 Cl C.sub.4 H.sub.9 (n) H CH.sub.3731 Cl C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3732 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.3733 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H CH.sub.3734 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3735 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H CH.sub.3736 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3737 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H CH.sub.3738 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3739 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.3740 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3741 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.3742 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3743 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.3744 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3745 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.3746 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3747 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.3748 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3749 H C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5750 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.5751 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.5752 H C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5753 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.5754 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.5755 Cl C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5756 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.5757 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.5758 Cl C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5759 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.5760 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.5761 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5762 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.5763 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5764 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.5765 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5766 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5767 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5768 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5769 H C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5770 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5771 H C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5772 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5773 Cl C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5774 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5775 Cl C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5776 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5777 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5778 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5779 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5780 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5781 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5782 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5783 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5784 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5785 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H786 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H787 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H788 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H789 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H790 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H791 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H792 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H793 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H794 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H______________________________________
TABLE XIV______________________________________ ##STR56##EX. # R.sup.44 R.sup.45 R.sup.46, R.sup.47______________________________________795 H C.sub.3 H.sub.7 (n) O796 H C.sub.3 H.sub.7 (n) H,H797 H C.sub.3 H.sub.7 (n) H,CH.sub.3798 H C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.5799 H C.sub.3 H.sub.7 (n) H,CH.sub.2 OH800 H C.sub.3 H.sub.7 (n) H,CO.sub.2 H801 H C.sub.4 H.sub.9 (n) O802 H C.sub.4 H.sub.9 (n) H,H803 H C.sub.4 H.sub.9 (n) H,CH.sub.3804 H C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub. 5805 H C.sub.4 H.sub.9 (n) H,CH.sub.2 OH806 H C.sub.4 H.sub.9 (n) H,CO.sub.2 H807 Cl C.sub.3 H.sub.7 (n) O808 Cl C.sub.3 H.sub.7 (n) H,H809 Cl C.sub.3 H.sub.7 (n) H,CH.sub.3810 Cl C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.5811 Cl C.sub.3 H.sub.7 (n) H,CH.sub.2 OH812 Cl C.sub.3 H.sub.7 (n) H,CO.sub.2 H813 Cl C.sub.4 H.sub.9 (n) O814 Cl C.sub.4 H.sub.9 (n) H,H815 Cl C.sub.4 H.sub.9 (n) H,CH.sub.3816 Cl C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.5817 Cl C.sub.4 H.sub.9 (n) H,CH.sub.2 OH818 Cl C.sub.4 H.sub.9 (n) H,CO.sub.2 H819 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O820 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,H821 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.3822 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.5823 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH824 C.sub.2 H.sub.5 C.sub. 3 H.sub.7 (n) H,CO.sub.2 H825 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O826 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,H827 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.3828 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.5829 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH830 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CO.sub.2 H831 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O832 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,H833 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.3834 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH835 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CO.sub.2 H836 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O837 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,H838 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.3839 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH840 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CO.sub.2 H841 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O842 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,H843 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.3844 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.3845 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH846 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CO.sub.2 H847 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O848 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,H849 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.3850 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3,CH.sub.3851 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH852 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE XV______________________________________ ##STR57##EX. # R.sup.48 R.sup.49 R.sup.50, R.sup.51______________________________________853 H C.sub.3 H.sub.7 (n) O854 H C.sub.3 H.sub.7 (n) H,H855 H C.sub.3 H.sub.7 (n) H,CH.sub.3856 H C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.5857 H C.sub.3 H.sub.7 (n) H,CH.sub.2 OH858 H C.sub.3 H.sub.7 (n) H,CO.sub.2 H859 H C.sub.4 H.sub.9 (n) O860 H C.sub.4 H.sub.9 (n) H,H861 H C.sub.4 H.sub.9 (n) H,CH.sub.3862 H C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub. 5863 H C.sub.4 H.sub.9 (n) H,CH.sub.2 OH864 H C.sub.4 H.sub.9 (n) H,CO.sub.2 H865 Cl C.sub.3 H.sub.7 (n) O866 Cl C.sub.3 H.sub.7 (n) H,H867 Cl C.sub.3 H.sub.7 (n) H,CH.sub.3868 Cl C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.3869 Cl C.sub.3 H.sub.7 (n) H,CH.sub.2 OH870 Cl C.sub.3 H.sub.7 (n) H,CO.sub.2 H871 Cl C.sub.4 H.sub.9 (n) O872 Cl C.sub.4 H.sub.9 (n) H,H873 Cl C.sub.4 H.sub.9 (n) H,CH.sub.3874 Cl C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.5875 Cl C.sub.4 H.sub.9 (n) H,CH.sub.2 OH876 Cl C.sub.4 H.sub.9 (n) H,CO.sub.2 H877 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O878 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,H879 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.3880 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.5881 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH882 C.sub.2 H.sub.5 C.sub. 3 H.sub.7 (n) H,CO.sub.2 H883 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O884 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,H885 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.3886 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.5887 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH888 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CO.sub.2 H889 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O890 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,H891 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.3892 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH893 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CO.sub.2 H894 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O895 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,H896 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.3897 C.sub. 4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH898 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CO.sub.2 H899 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O900 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,H901 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.3902 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.3903 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH904 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CO.sub.2 H905 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O906 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,H907 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.3908 (2-ethylphenyi) C.sub.4 H.sub.9 (n) CH.sub.3,CH.sub.3909 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH910 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE XVI______________________________________ ##STR58##EX. # R.sup.52 R.sup.53 R.sup.54______________________________________911 H C.sub.3 H.sub.7 (n) CH.sub.2912 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)913 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)914 H C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2915 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.2916 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2917 H C.sub.4 H.sub.9 (n) CH.sub.2918 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)919 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5 )920 H C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2921 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.2922 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2923 Cl C.sub.3 H.sub.7 (n) CH.sub.2924 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)925 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)926 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2927 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.2928 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2929 Cl C.sub.4 H.sub.9 (n) CH.sub.2930 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)931 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)932 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2933 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.2934 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2935 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2936 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)937 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)938 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2939 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.2940 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2941 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2942 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)943 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)944 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2945 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.2946 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2947 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2948 C.sub. 4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2949 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2950 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2951 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2952 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2953 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2954 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2955 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2956 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2957 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2958 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2______________________________________
TABLE XVII______________________________________ ##STR59##EX. # R.sup.55 R.sup.56 R.sup.57______________________________________ 959 H C.sub.3 H.sub.7 (n) H 960 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 961 H C.sub.3 H.sub.7 (n) CH.sub.2 OH 962 H C.sub.3 H.sub.7 (n) CO.sub.2 H 963 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H 964 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3 965 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H 966 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3 967 H C.sub.3 H.sub.7 (n) phenyl 968 H C.sub.3 H.sub.7 (n) benzyl 969 H C.sub.3 H.sub.7 (n) phenylethyl 970 H C.sub.4 H.sub.9 (n) H 971 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 972 H C.sub.4 H.sub.9 (n) CH.sub.2 OH 973 H C.sub.4 H.sub.9 (n) CO.sub.2 H 974 H C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H 975 H C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3 976 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H 977 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3 978 H C.sub.4 H.sub.9 (n) phenyl 979 H C.sub.4 H.sub.9 (n) benzyl 980 H C.sub.4 H.sub.9 (n) phenylethyl 981 Cl C.sub.3 H.sub.7 (n) H 982 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 983 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH 984 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H 985 Cl C.sub.3 H.sub. 7 (n) CH.sub.2 CO.sub.2 H 986 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3 987 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H 988 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3 989 Cl C.sub.4 H.sub.9 (n) H 990 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 991 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH 992 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H 993 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H 994 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3 995 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H 996 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3 997 ethyl C.sub.3 H.sub.7 (n) H 998 ethyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 999 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 OH1000 ethyl C.sub.3 H.sub.7 (n) CO.sub.2 H1001 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1002 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31003 ethyl C.sub.4 H.sub.9 (n) H1004 ethyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51005 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 OH1006 ethyl C.sub.4 H.sub.9 (n) CO.sub.2 H1007 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H1008 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31009 n-butyl C.sub.3 H.sub.7 (n) H1010 n-butyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51011 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 OH1012 n-butyl C.sub.3 H.sub.7 (n) CO.sub.2 H1013 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1014 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31015 n-butyl C.sub.4 H.sub.9 (n) H1016 n-butyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51017 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 OH1018 n-butyl C.sub.4 H.sub.9 (n) CO.sub.2 H1019 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H1020 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31021 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H1022 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51023 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH1024 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H1025 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1026 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31027 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H1028 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51029 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH1030 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H1031 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H1032 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31033 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H1034 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51035 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH1036 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H1037 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1038 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31039 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H1040 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51041 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH1042 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H1043 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H1044 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3______________________________________
TABLE XVIII______________________________________ ##STR60##EX. # R.sup.58 R.sup.59 R.sup.60______________________________________1045 H C.sub.3 H.sub.7 (n) O1046 H C.sub.3 H.sub.7 (n) S1047 H C.sub.3 H.sub.7 (n) CHCO.sub.2 H1048 H C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.31049 H C.sub.3 H.sub.7 (n) NOH1050 H C.sub.4 H.sub.9 (n) O1051 H C.sub.4 H.sub.9 (n) S1052 H C.sub.4 H.sub.9 (n) CHCO.sub.2 H1053 H C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.31054 H C.sub.4 H.sub.9 (n) NOH1055 Cl C.sub.3 H.sub.7 (n) O1056 Cl C.sub.3 H.sub.7 (n) S1057 Cl C.sub. 3 H.sub.7 (n) CHCO.sub.2 H1058 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.31059 Cl C.sub.3 H.sub.7 (n) NOH1060 Cl C.sub.4 H.sub.9 (n) O1061 Cl C.sub.4 H.sub.9 (n) S1062 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 H1063 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.31064 Cl C.sub.4 H.sub.9 (n) NOH1065 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O1066 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) S1067 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 H1068 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.31069 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NOH1070 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O1071 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) S1072 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 H1073 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.31074 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NOH1075 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O1076 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) S1077 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 H1078 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.31079 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NOH1080 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O1081 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) S1082 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 H1083 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.31084 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NOH1085 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O1086 (2-ethylphenyl) C.sub.3 H.sub.7 (n) S1087 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 H1088 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NOH1089 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O1090 (2-ethylphenyl) C.sub.4 H.sub.9 (n) S1091 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H1092 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NOH1093 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) O1094 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) S1095 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 H1096 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) NOH1097 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) O1098 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) S1099 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H1100 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) NOH______________________________________
TABLE XIX______________________________________ ##STR61##EX. # R.sup.61 R.sup.62 R.sup.63______________________________________1101 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51102 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1103 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51104 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1105 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51106 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1107 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51108 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1109 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51110 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1111 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51112 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1113 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51114 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51115 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51116 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51117 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51118 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5______________________________________
TABLE XX______________________________________ ##STR62##EX. # R.sup.64 R.sup.65 R.sup.66______________________________________1119 H C.sub.3 H.sub.7 (n) H1120 H C.sub.3 H.sub.7 (n) NH.sub.21121 H C.sub.3 H.sub.7 (n) OH1122 H C.sub.3 H.sub.7 (n) CH.sub.2 OH1123 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51124 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1125 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.51126 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.21127 H C.sub.3 H.sub.7 (n) (2-ethylphenyl)1128 H C.sub.4 H.sub.9 (n) H1129 H C.sub.4 H.sub.9 (n) NH.sub.21130 H C.sub.4 H.sub.9 (n) OH1131 H C.sub.4 H.sub.9 (n) CH.sub.2 OH1132 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51133 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1134 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.51135 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.21136 H C.sub.4 H.sub.9 (n) (2-ethylphenyl)1137 Cl C.sub.3 H.sub.7 (n) H1138 Cl C.sub.3 H.sub.7 (n) NH.sub.21139 Cl C.sub.3 H.sub.7 (n) OH1140 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH1141 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51142 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1143 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.51144 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.21145 Cl C.sub.3 H.sub.7 (n) (2-ethylphenyl)1146 Cl C.sub.4 H.sub.9 (n) H1147 Cl C.sub.4 H.sub.9 (n) NH.sub.21148 Cl C.sub.4 H.sub.9 (n) OH1149 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH1150 Cl C.sub.4 H.sub.9 (n) C.sub. 2 H.sub.51151 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1152 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.51153 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.21154 Cl C.sub.4 H.sub.9 (n) (2-ethylphenyl)1155 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H1156 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NH.sub.21157 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) OH1158 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 OH1159 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51160 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H1161 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NH.sub.21162 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) OH1163 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 OH1164 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51165 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H1166 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NH.sub.21167 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) OH1168 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 OH1169 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51170 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.21171 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H1172 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NH.sub.21173 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) OH1174 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 OH1175 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51176 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H1177 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.21178 (2-ethylphenyl) C.sub.3 H.sub.7 (n) OH1179 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH1180 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51181 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H1182 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.21183 (2-ethylphenyl) C.sub.4 H.sub.9 (n) OH1184 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH1185 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51186 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H1187 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.21188 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) OH1189 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH1190 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51191 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H1192 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.21193 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) OH1194 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH1195 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5______________________________________
TABLE XXI______________________________________ ##STR63##EX. # R.sup.67 R.sup.68 R.sup.69 R.sup.70______________________________________1196 H C.sub.3 H.sub.7 (n) H CH.sub.31197 H C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.31198 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.31199 H C.sub.4 H.sub.9 (n) H CH.sub.31200 H C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.31201 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.31202 Cl C.sub.3 H.sub.7 (n) H CH.sub.31203 Cl C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.31204 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.31205 Cl C.sub.4 H.sub.9 (n) H CH.sub.31206 Cl C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.31207 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.31208 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H CH.sub.31209 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.31210 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H CH.sub.31211 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.31212 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H CH.sub.31213 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.31214 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.31215 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.31216 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.31217 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.31218 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.31219 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub. 31220 (2,6-dimethyl- C.sub.3 H.sub.7 (n) H CH.sub.3 phenyl)1221 (2,6-dimethyl- C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3 phenyl)1222 (2,6-dimethyl- C.sub.4 H.sub.9 (n) H CH.sub.3 phenyl)1223 (2,6-dimethyl- C.sub.4 H.sub.9 (n) CH3 CH.sub.3 phenyl)1224 H C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.51225 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.51226 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51227 H C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.51228 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.51229 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51230 Cl C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.51231 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.51232 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51233 Cl C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.51234 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.51235 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51236 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.51237 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.51238 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.51239 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.51240 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.51241 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.51242 (2,6-dimethyl- C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5 phenyl)1243 (2,6-dimethyl- C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5 phenyl)1244 H C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.51245 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.51246 H C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.51247 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.51248 Cl C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.51249 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.51250 Cl C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.51251 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.51252 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.51253 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.51254 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.51255 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.51256 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.51257 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.51258 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.51259 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.51260 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1261 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1262 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1263 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1264 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1265 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1266 (2,6-dimethyl- C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H phenyl)1267 (2,6-dimethyl- C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H phenyl)1268 (2,6-dimethyl- C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H phenyl)1269 (2,6-dimethyl- C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H phenyl)______________________________________
TABLE XXII______________________________________ ##STR64##EX. # R.sup.71 R.sup.72 R.sup.73, R.sup.74______________________________________1270 H C.sub.3 H.sub.7 (n) O1271 H C.sub.3 H.sub.7 (n) H, H1272 H C.sub.3 H.sub.7 (n) H, CH.sub.31273 H C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.51274 H C.sub.3 H.sub.7 (n) H, CH.sub.2 OH1275 H C.sub.3 H.sub.7 (n) H, CO.sub.2 H1276 H C.sub.4 H.sub.9 (n) O1277 H C.sub.4 H.sub.9 (n) H, H1278 H C.sub.4 H.sub.9 (n) H, CH.sub.31279 H C.sub.4 H.sub. 9 (n) H, C.sub.2 H.sub.51280 H C.sub.4 H.sub.9 (n) H, CH.sub.2 OH1281 H C.sub.4 H.sub.9 (n) H, CO.sub.2 H1282 Cl C.sub.3 H.sub.7 (n) O1283 Cl C.sub.3 H.sub.7 (n) H, H1284 Cl C.sub.3 H.sub.7 (n) H, CH.sub.31285 Cl C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.51286 Cl C.sub.3 H.sub.7 (n) H, CH.sub.2 OH1287 Cl C.sub.3 H.sub.7 (n) H, CO.sub.2 H1288 Cl C.sub.4 H.sub.9 (n) O1289 Cl C.sub.4 H.sub.9 (n) H, H1290 Cl C.sub.4 H.sub.9 (n) H, CH.sub.31291 Cl C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.51292 Cl C.sub.4 H.sub.9 (n) H, CH.sub.2 OH1293 Cl C.sub.4 H.sub.9 (n) H, CO.sub.2 H1294 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O1295 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, H1296 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CH.sub.31297 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.51298 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CH.sub.2 OH1299 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CO.sub.2 H1300 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O1301 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, H1302 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CH.sub.31303 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.51304 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CH.sub.2 OH1305 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CO.sub.2 H1306 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O1307 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, H1308 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CH.sub.31309 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CH.sub.2 OH1310 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CO.sub.2 H1311 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O1312 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, H1313 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CH.sub.31314 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CH.sub.2 OH1315 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CO.sub.2 H1316 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O1317 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, H1318 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CH.sub.31319 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3, CH.sub.31320 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CH.sub.2 OH1321 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CO.sub.2 H1322 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O1323 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, H1324 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CH.sub.31325 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3, CH.sub.31326 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CH.sub.2 OH1327 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CO.sub.2 H______________________________________
TABLE XXIII______________________________________ ##STR65##EX. # R.sup.75 R.sup.76 R.sup.77, R.sup.78______________________________________1328 H C.sub.3 H.sub.7 (n) O1329 H C.sub.3 H.sub.7 (n) H, H1330 H C.sub.3 H.sub.7 (n) H, CH.sub.31331 H C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.51332 H C.sub.3 H.sub.7 (n) H, CH.sub.2 OH1333 H C.sub.3 H.sub.7 (n) H, CO.sub.2 H1334 H C.sub.4 H.sub.9 (n) O1335 H C.sub.4 H.sub.9 (n) H, H1336 H C.sub.4 H.sub.9 (n) H, CH.sub.31337 H C.sub.4 H.sub. 9 (n) H, C.sub.2 H.sub.51338 H C.sub.4 H.sub.9 (n) H, CH.sub.2 OH1339 H C.sub.4 H.sub.9 (n) H, CO.sub.2 H1340 Cl C.sub.3 H.sub.7 (n) O1341 Cl C.sub.3 H.sub.7 (n) H, H1342 Cl C.sub.3 H.sub.7 (n) H, CH.sub.31343 Cl C.sub.3 H.sub.7 (n) CH.sub.3, CH.sub.31344 Cl C.sub.3 H.sub.7 (n) H, CH.sub.2 OH1345 Cl C.sub.3 H.sub.7 (n) H, CO.sub.2 H1346 Cl C.sub.4 H.sub.9 (n) O1347 Cl C.sub.4 H.sub.9 (n) H, H1348 Cl C.sub.4 H.sub.9 (n) H, CH.sub.31349 Cl C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.51350 Cl C.sub.4 H.sub.9 (n) H, CH.sub.2 OH1351 Cl C.sub.4 H.sub.9 (n) H, CO.sub.2 H1352 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O1353 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, H1354 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CH.sub.31355 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.51356 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CH.sub.2 OH1357 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CO.sub.2 H1358 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O1359 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, H1360 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CH.sub.31361 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.51362 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CH.sub.2 OH1363 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CO.sub.2 H1364 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O1365 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, H1366 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CH.sub.31367 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CH.sub.2 OH1368 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CO.sub.2 H1369 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O1370 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, H1371 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CH.sub.31372 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CH.sub.2 OH1373 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CO.sub.2 H1374 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O1375 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, H1376 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CH.sub.31377 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3, CH.sub.31378 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CH.sub.2 OH1379 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CO.sub.2 H1380 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O1381 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, H1382 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CH.sub.31383 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3, CH.sub.31384 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CH.sub.2 OH1385 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CO.sub.2 H______________________________________
TABLE XXIV______________________________________ ##STR66##EX. # R.sup.79 R.sup.80 R.sup.81______________________________________1386 H C.sub.3 H.sub.7 (n) CH.sub.21387 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)1388 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1389 H C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21390 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.21391 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.21392 H C.sub.4 H.sub.9 (n) CH.sub.21393 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)1394 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1395 H C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.21396 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.21397 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.21398 Cl C.sub.3 H.sub.7 (n) CH.sub.21399 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)1400 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1401 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21402 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.21403 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.21404 Cl C.sub.4 H.sub.9 (n) CH.sub.21405 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)1406 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1407 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.21408 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.21409 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.21410 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.21411 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)1412 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1413 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21414 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.21415 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.21416 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.21417 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)1418 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1419 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.21420 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.21421 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.21422 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.21423 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21424 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.21425 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.21426 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.21427 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21428 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.21429 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.21430 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.21431 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21432 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.21433 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2______________________________________
An appropriately substituted imidazole 31, the heterocyclic starting material, may be prepared as described in the literature [Klaus Hofmann, in "Imidazole and its Derivatives" of The Chemistry of Heterocyclic Compounds, Arnold Weissberger Ed., Wiley Interscience New York, 1953]. The imidazole 31 in N,N-dimethylformamide (DMF) is treated with base, such as potassium tert-butoxide, followed by addition of appropriate alkylating agent 32 to give the coupled product 33 (Scheme V). For compounds where X is a substituted phenyl group, several procedures have been published for the preparations of the alkylating agent 32 [see references for compound 2]. ##STR67##
The arylated imidazole 33 itself may be an angiotensin II receptor antagonist, but it may also be used as a key intermediate in the preparation of the compounds of the invention. Imidazole 33 in THF (or DME) is treated with base (such as n-BuLi or LDA) at -78.degree. C. (or -65.degree. C.), followed by addition of an appropriate alkylating agent or other electrophiles 34 (the acetal shown in Scheme V may be other aldehyde masking group or equivalent, and LG is a leaving group such as halide, triflate or rosylate). The resulting masked aldehyde 35 was stirred with NaOAc in aqueous acetic acid at reflux for a few days (1 to 5 days) to give one of the described invention compounds, a cyclized imidazole 36.
The imidazole 36 may be used as an intermediate to prepare other substituted compounds with appropriate functional group transformations and preparations of some of those compounds are illustrated in Scheme VI (all of the intermediates shown in the sequences are also angiotensin II receptor antagonists). For example, The unsaturated imidazole 36 and NBS in CCl.sub.4 is stirred at reflux to give a bromide 37. The bromide 37 may be treated with organolithium, such as n-BuLi or tert-BuLi, followed by addition of an appropriate electrophile, (such as alkyl halide, carbon dioxide, aldehyde, ketone and others) to give the addition product 38. The olefin 38 may be hydrogenated to give its saturated product 39. ##STR68##
Alternatively, as illustrated in Scheme VII, the unsaturated imidazole 36 may be treated with NBS in wet DMSO to give a bromohydrin which may be reduced with nBu.sub.3 SnH to an alcohol 40 and the oxidation of the alcohol with MnO.sub.2 will afford a ketone 41. The ketone 41 may be condensed with appropriately substituted amine, then reduced to an amine 42 with an appropriate reducing agent (e.g. NaBH.sub.4, or hydrogen over catalyst). The amine 42 may also be prepared directly from olefin 36 under bromination condition (NBS, CH.sub.3 CN) with a large excess of succinimide. The amine 42 may be used to prepare other derivatives. Alternatively, the alcohol 40 may be treated with triphenylphosphine, diethoxyazo dicarboxylate and an imide (e.g. phthalimide) to give an imide analogue which may be converted to an amine 42.
The ketone 41 may be treated with appropriate organometallic reagents (such as Grignard, organolithium, organocerium or organozinc reagents) to give the additional product, a tertiary alcohol. The alcohol may be dehydrated to give an olefin 43 or an isomeric mixture of olefins 43. The olefin 43 may be treated with base, such as LDA and kinetically quenched with either organic acid or appropriate electrophile at low temperature to give the isomerized olefin 44. The olefins 43 or 44 may be hydrogenated to its saturated analogue 45. ##STR69##
In Scheme VIII, an alternative preparation for the compounds of the invention is described. An appropriately substituted imidazole 31 may be treated with one equivalent of base, then protected as SEM or BOC derivative. The protected imidazole then is treated with another equivalent of base followed by addition of electrophile 46 or 47. If necessary, the resulting lithium anion obtained from the procedure described above may be converted to other organometallic reagents according to well-established procedures. Electrophiles 47 and 48 can be prepared from HC(.dbd.O)(CR.sup.4 R.sup.5)(CH.sub.2).sub.n C(.dbd.O)LG and an appropriate organometallic reagent such as XC.sub.6 H.sub.4 MgBr.
If PLG is an hydroxyl group and Z is a proton, the resulting addition product 49, may be cyclized with triphenylphosphine and diethyl azodicarboxylate (Mitsunobu reaction or other modified conditions). If PLG is or is converted to a leaving group, such as halides, rosylate, and Z is a proton, the cyclization may be achieved with a weak base in DMF (e.g. K.sub.2 CO.sub.3), CsCO.sub.3) to give a ketone 41. The ketone 41 may be reduced to an alcohol 40 with NaBH.sub.4 in methanol. The alcohol 40 may be dehydrated to olefin 36 with acid (e.g. HOAc and heat) or thionyl chloride and pyridine. Other compounds may be prepared from compounds 36, 40, or 41 as described in Scheme VI and VII. ##STR70##
EXAMPLE 1434 ##STR71## 3-Butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,2-a]pyridine
Step 1: Preparation of Biphenyl Imidazole To a solution of 4-butylimidazole (2.65 mmol) in 5.3 ml of DMF is added 3.45 ml (3.45 mmol) of potassium tert-butoxide (1M in THF), and the resulting solution is stirred at room temperature for 30 min. To the dark brown mixture is added 2.75 g (3.45 mmol) of the bromomethyl biphenyl. The reaction mixture is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is purified to give the trityl-protected biphenyl imidazole.
Step 2: Preparation of Dimethyl Acetal Imidazole
To a solution of biphenyl imidazole (3.18 mmol, obtained from Step 1) in 16 mL of THF cooled at -45.degree. C. (acetonitrile-dry ice) is added 2.8 mL (4.06 mmol) of n-butyllithium (1.45M in hexane) over a 4 minute period. The resulting dark purple solution is stirred cold for another 15 minutes, followed by addition of 1.0 mL (6.59 mmol) of 3-bromopropionaldehyde dimethyl acetal in one portion. The mixture is stirred cold for 40 minutes, then is slowly warmed to -10.degree. C. The reaction is quenched with aqueous NH.sub.4 Cl, extracted with diethyl ether. The combined extracts are washed with brine, dried (MgSO.sub.4), concentrated in vacuo and purified to give the biphenyl dimethyl acetal imidazole intermediate.
Step 3: Preparation of Biphenyl Bicyclic Imidazole
A solution of the crude biphenyl dimethyl acetal imidazole (3.18 mmol, obtained from Step 2) and 5.3 g (88 mmol) of NaOAc in 13 mL of water and 40 mL of glacial acetic acid is stirred at reflux until the reaction is complete. The solution is cooled and concentrated in vacuo. The residue is dissolved in methylene chloride and filtered. The filtrate is stirred with 2 g (7.2 mmol) of trityl chloride and 3 mL (21.5 mmol) of TEA at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is purified to give the biphenyl bicyclic imidazole.
Step 4: Detritylation of Trityl Tetrazole
A solution of the biphenyl bicyclic imidazole (0.144 mmol, obtained from Step 3) is stirred with 1 mL of water and 6 mL of acetic acid at room temperature until the reaction is complete. The solution is concentrated in vacuo, stirred in aqueous NaHCO.sub.3 and washed with ether. The aqueous residue is acidified with 3N HCl to pH 4 and extracted with methylene chloride. The combined extracts are dried (MgSO.sub.4), concentrated and purified to give the title compound of Example 1434.
EXAMPLE 1435 ##STR72## 7-Bromo-3-butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,2-a]pyridine
Step 1: Preparation of Bromo Olefin Imidazole
A solution of trityl-protected bicyctic imidazole (0.101 mmol, obtained from Step 3 of Example 1434), 20 mg (0.112 mmol) of NBS and 7 mg (catalytic) of AIBN in 2.8 mL of CCl.sub.4 is stirred at reflux until the reaction is complete. The reaction mixture is diluted with CCl.sub.4 and washed with water. The organic layer is dried (MgSO.sub.4) and concentrated in vacuo. The residue is purified to give the biphenyl bromo olefin imidazole.
Step 2: Detritylation of the Trityl Tetrazole
A solution of bromo olefin imidazole (0.0427 mmol, obtained from Step 1) in 0.8 mL of water and 5 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 4 of Example 1434 and purified to give the title compound of Example 1435.
EXAMPLE 1436 ##STR73## 3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,2-a]pyridine
A suspension of bicyclic olefin imidazole (0.1 mmol, the title compound of Example 1434) and 20 mg (0,019 mmol) of 10% palladium on charcoal in 2 mL of absolute ethanol is agitated on a Parr apparatus under 50 psi of hydrogen gas at room temperature until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 1436.
EXAMPLE 1437 ##STR74## 3-Butyl-5,6-dihydro-5 -[2'-(1H-tetrazol-5-yl )[1,1'-biphenyl]-4-yl]imidazo[1,2-a]pyridin-8(5H)-one
Step 1: Preparation of the Bromohydrin Intermediate
To a solution of biphenyl olefin imidazole (3.13 mmol, obtained from Step 4 of Example 1434) in 2.2 mL (0.122 mmol) of water and 22 mL of DMSO at room temperature is added 587 mg (3.30 mmol) of NBS in one portion. The resulting orange solution is stirred at room temperature for 40 min, quenched with aqueous Na.sub.2 SO.sub.3, and extracted with chloroform. The combined extracts are washed with water, and the combined aqueous layers are extracted with chloroform. The combined extracts are washed with brine, dried (MgSO.sub.4) and concentrated in vacuo to give a crude bromohydrin intermediate which can be used directly in the subsequent Step 2 without further purification.
Step 2: Preparation of the Biphenyl Hydroxy Imidazole
To the crude bromohydrin (3.13 mmol, obtained from Step 1) in 42 mL of degassed dry benzene is added 4.3 mL (14.7 mmol) of n-Bu.sub.3 SnH and 456 mg (2.7 mmol) of AIBN in one portion and the resulting solution is stirred at reflux until the reaction is complete. The mixture is concentrated in vacuo and partitioned between hexane and acetonitrile. The acetonitrile layer is washed with hexane, and the combined hexane layers are extracted with acetonitrile. The combined acetonitrile extracts are concentrated in vacuo to give an isomeric mixture of both cis- and trans-hydroxy imidazoles (relative to the biphenyl moiety). The crude mixture can be used directly in subsequent Step 3 without further purification. The mixture may also be used to prepare the trans-hydroxy title compound of Example 1439.
Step 3: Preparation of the Keto Imidazole
A suspension of the crude biphenyl hydroxy imidazole (2.72 mmol, obtained from Step 2) and 13 g of active MnO.sub.2 in 15 mL of methylene chloride is stirred at room temperature until the reaction is complete. The mixture is filtered through a pad of celite, rinsed with IPA-methylene chloride, and concentrated in vacuo. The residue is purified to give the trityl-protected biphenyl keto imidazole.
Step 4: Detritylation of Trityl Tetrazole
A solution of trityl-protected keto imidazole (0.131 mmol, obtained from Step 3) in 1.0 mL of water and 5.0 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 4 of Example 1434 to give the title compound of Example 1437.
EXAMPLE 1438 ##STR75## 3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,2-a]pyridin-cis-8-ol
Step 1: Preparation of Cis-Hydroxy Imidazole
To a solution of biphenyl keto imidazole (0.456 mmol, obtained from Step 3 of Example 1437) in 0.5 mL of methanol and 2.0 mL of THF at 0.degree. C. is added in small portions 34 mg (0.899 mmol) of NaBH.sub.4. The resulting solution is stirred at 0.degree. C., and slowly warmed to room temperature. The reaction is quenched with aqueous NH.sub.4 Cl, extracted with methylene chloride, dried (MgSO.sub.4) and concentrated in vacuo. The residue is purified to give the biphenyl hydroxy imidazole.
Step 2: Detritylation of Trityl Tetrazole
A solution of the biphenyl hydroxy imidazole (0.259 mmol, obtained from Step 1) in 0.4 mL of water and 2.0 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is purified to give the title compound of Example 1438.
EXAMPLE 1439 ##STR76## 3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,2-a]pyridin-trans-8-ol
Step 1: Preparation of Biphenyl Trans-Hydroxy Imidazole
A suspension of the crude biphenyl hydroxy imidazole (1,307 mmol, obtained from Step 2 of Example 1437) and 3.0 g of active MnO.sub.2 in 5.0 mL of methylene chloride is stirred at room temperature. The reaction is worked up before its completion. The mixture is filtered through a pad of celite, rinsed with IPA-methylene chloride, and concentrated in vacuo. The residue is purified to give the trityl protected biphenyl trans-hydroxy imidazole.
Alternatively, the biphenyl trans-hydroxy imidazole can be prepared using the Mitsunobu reaction conditions, To a solution of diethyl azodicarboxylate (2.0 mmol) and 3-nitrobenzoic acid (2.0 mmol) in 2.0 mL of THF is added dropwise a solution of the biphenyl hydroxy imidazole (2.0 mmol, obtained from Step 1 of Example 1438), and triphenylphosphine (2.0 mmol) in 1.0 mL of THF at room temperature. The resulting solution is stirred at room temperature until the reaction is complete. The resulting mixture is diluted with ether or ethyl acetate, and washed with water. The extracts are dried MgSO.sub.4) and concentrated in vacuo to give the biphenyl imidazolyl nitrobenzoate. The crude benzoate is hydrolyzed with LiOH in aqueous THF at room temperature and purified to give the biphenyl trans-hydroxy imidazole.
Step 2: Detritylation of Trityl Tetrazole
A solution of the trityl protected biphenyl trans-hydroxy imidazole (0,079 mmol, obtained from Step i) in 0.4 mL of water and 2.0 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is purified to give the title compound of Example 1439.
EXAMPLE 1440 ##STR77## 1-[3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,2-a]pyridin-8-yl]-2,5-pyrrolidinedione
Step 1: Preparation of Succinimidyl Imidazole
To a solution of 2.00 g 3.13 mmol) of biphenyl bicyclic imidazole (Example 1434, Step 3) and 1.25 g (12.6 mmol) of succinimide in 20 mL of anhydrous acetonitrile is added 572 mg (3.21 mmol) of NBS in one portion. The resulting orange-red solution is stirred at room temperature for 30 min, then evaporated in vacuo. The residue is dissolved in ethyl acetate and washed with aqueous sodium bisulfite, water, and brine. The extracts are dried (MgSO.sub.4) and concentrated in vacuo The residue is purified to give the trityl protected succinimidyl imidazole.
Alternatively, the succinimide can be prepared from its corresponding hydroxy imidazole. To a solution of the biphenyl hydroxy imidazole (2.0 mmol, obtained from Step 1 of Example 1438 or 1439), succinimide (2.0 mmol), and triphenylphosphine (2.0 mmol) in 2.0 mL of THF is added dropwise a solution of diethyl azodicarboxylate (2.0 mmol) in 1 mL of THF at room temperature. The resulting solution is stirred at room temperature until the reaction is complete. The resulting mixture is diluted with ether or ethyl acetate and washed with water. The extracts are dried (MgSO.sub.4) and concentrated in vacuo. The residue is purified to give the trityl protected succinimidyl imidazole.
Step 2: Detritylation of Trityl Tetrazole
A solution of trityl protected succinimidyl imidazole (0.16 mmol, obtained from Step 1) in 0.2 mL of water and 1 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 4 of Example 1434 and purified to give the title compound of Example 1440.
EXAMPLE 1441 ##STR78## 4-[3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,2-a]pyridin-8-yl]amino]-4-oxobutanoic acid, hydrazide
A solution of succinimidyl imidazole (0.06 mmol, obtained from Example 1440 ) and 11 .mu.L (5.6 mmol) of hydrazine in 0.5 mL of ethanol is stirred at room temperature until the reaction is complete and concentrated in vacuo to give the title compound of Example 1441.
EXAMPLE 1442 ##STR79## 3-Butyl-6,7-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-5H-imidazo[1,2-a]azepine
Step 1: Alkylation of Biphenyl Imidazole
To a solution of biphenyl imidazole (0.152 mmol, obtained from Step 2 of Example 1434) in 0.8 mL of DME cooled at -45.degree. C. (acetonitrile-dry ice) is added 125 .mu.L (0.2 mmol) of n-butyllithium (1.6M in hexane) over a 4-min period. The resulting dark red solution is stirred cold for another 15 min, followed by addition of 70 .mu.L (0.37 mmol) of 2-(3-bromopropyl)-5,5-dimethyl-1,3-dioxane in one portion. The mixture is stirred cold for 40 min, then is slowly warmed to -10.degree. C. The reaction is quenched with aqueous NH.sub.4 Cl, extracted with diethyl ether. The combined extracts are washed with brine, dried (MgSO.sub.4) and concentrated in vacuo. The crude product can be used directly in the subsequent Step 2 without purification.
Step 2: Preparation of the Bicyclic Imidazole
A solution of the crude mixture (0.152 mmol, obtained from Step 1) and 255 mg (3 mmol) of NaOAc in 0.6 mL of water and 2 mL of glacial acetic acid is stirred at reflux until the reaction is complete. The mixture is cooled and concentrated in vacuo. The residue is dissolved in methylene chloride and filtered. The filtrate is stirred with 130 mg (0.46 mmol) of trityl chloride and 0.22 mL (1.6 mmol) of TEA at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is purified to give the biphenyl bicyclic imidazole.
Step 3: Detritylation of Trityl Tetrazole
A solution of the biphenyl bicyclic imidazole (0.035 mmol, obtained from Step 2) is stirred with 0.4 mL of water and 2 mL of acetic acid at room temperature until the reaction is complete. The solution is concentrated in vacuo. The residue is worked up as described in Step 4 of Example 1434 to give the title compound of Example 1442.
EXAMPLE 1443 ##STR80## 1,1-Dimethylethyl [3-butyl-6,7-dihydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,2-a]pyridin-8(5H)-ylidene]acetate
Step 1: Preparation of Tert-Butyl Ester
To a suspension of 64 mg (2.63 mmol) of magnesium in 3.0 mL of THF at 55.degree. C. is added two 10.mu.L portions of 1,2-dibromoethane, 5 min apart. The resulting mixture is stirred at 45.degree. C. for 10 min, followed by dropwise addition of a solution of biphenyl keto imidazole (0.306 mmol, obtained from Step 3 of Example 1436) and 242 .mu.L (1.50 mmol) of tert-butyl bromoacetate in 2.0 mL of THF at 55.degree. C. over a 1 h period. The resulting solution is stirred until the reaction is complete. The mixture is cooled and quenched with aqueous NH.sub.4 Cl. The mixture is extracted with ether, dried (MgSO.sub.4) and concentrated in vacuo. The crude mixture can be used directly in the subsequent Step 2 without further purification.
Step 2: Preparation of Unsaturated Butyl Ester
To a solution of the crude hydroxy butyl ester (0.306 mmol, obtained from Step 1) and 200 .mu.L (2.47 mmol) of pyridine in 2 mL of methylene chloride at 0.degree. C. is added dropwise 80 .mu.L (1.1 mmol) of thionyl chloride. The resulting dark brown solution is stirred at 0.degree. C. for 1 h, diluted with water and extracted with methylene chloride. The residue is purified to give the biphenyl imidazolyl unsaturated ester.
Step 3: Detritylation of Trityl Tetrazole
A solution of biphenyl imidazolyl unsaturated ester (0.133 mmol, obtained from Step 2) in 1.0 mL of water and 5.0 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 4 of Example 1434 to give the title compound of Example 1443.
EXAMPLE 1444 ##STR81## [3-Butyl -6,7-dihydro-5 -[2'-(1H-tetrazol -5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,2-a]pyridin-8(5H) -ylidene]acetic acid
To a solution of unsaturated tert-butyl ester (0.0627 mmol, the title compound of Example 1443) in 2 mL of CDCl.sub.3 at room temperature is added 0.5 mL of TFA, and the progress of the reaction is monitored by .sup.1 H NMR. The resulting yellow solution is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The crude product is purified to give the title compound of Example 1444.
EXAMPLE 1445 ##STR82## 1,1-Dimethylethyl 3-butyl-5,6-dihydro-5-[2 '-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,2-a]pyridin-8-acetate
Step 1: Preparation of Deconjugated Ester
To a solution of ester (0.237 mmol, obtained from Step 2 of Example 1443) in 4 mL of THP at 0.degree. C. is added 310 .mu.L of 1.5M (0,467 mmol) LDA over a 2-min period, and the resulting solution is stirred at 0.degree. C. for 10 min. The mixture is cooled to -78.degree. C., stirred cold for 5 min, and quenched dropwise at -78.degree. C. with 100 .mu.L of acetic acid in 1 mL of hexane. The mixture is stirred cold, then warmed to room temperature and treated with aqueous NaHCO.sub.3. The mixture is extracted with methylene chloride. The combined extracts are washed with water, dried (MgSO.sub.4) and concentrated in vacuo to give a crude mixture. The crude product is purified to give the biphenyl imidazolyl deconjugated ester.
Step 2: Detritylation of Trityl Tetrazole
A solution of trityl-protected biphenyl imidazolyl deconjugated ester (0.165 mmol, obtained from Step 1) in 1 mL of water and 3 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture was concentrated in vacuo. The residue is worked up as described in Step 4 of Example 1448. The crude product is purified to give the title compound of Example 1445.
EXAMPLE 1446 ##STR83## 3-Butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1-biphenyl]-4-yl]imidazo[1,2-a]pyridin-8-acetic acid
To a solution of biphenyl imidazolyl tert-butyl ester (0,039 mmol, the title compound of Example 1445) in 0.5 mL of chloroform is added 0.25 mL of TFA, and the progress of the reaction is monitored by .sup.1 H NMR. The resulting solution is stirred at room temperature until the reaction is complete. The mixture is quenched with methanol and concentrated in vacuo. The residue is purified to give the title compound of Example 1446.
EXAMPLE 1447 ##STR84## 1,1-Dimethylethyl 3-butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,2-a]pyridin-cis-acetate
A suspension of the biphenyl imidazolyl unsaturated ester (0.059 mmol, the title compound of Example 1445) and 20 mg (0.0188 mmol) of 10% palladium on charcoal in 1.5 mL of methanol is stirred at room temperature under an atmosphere of hydrogen gas until the reaction is complete. The mixture is filtered through a pad of celite and concentrated in vacuo. The residue is purified to give the title compound of Example 1447.
EXAMPLE 1448 ##STR85## 3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,2-a]pyridin-cis-8-acetic acid
To a solution of tert-butyl ester (0.0332 mmol, obtained from Example 1447) in 0.4 mL of CDCl.sub.3 is added 0.2 mL of TFA, and the progress of the reaction is monitored by .sup.1 H NMR. The resulting solution is allowed to stand at room temperature until the reaction is complete. The reaction mixture is diluted with methanol and concentrated. The residue is purified to give the title compound of Example 1448.
EXAMPLE 1449 ##STR86## 3-Butyl-5,6-dihydro-N-hydroxy-5-[2'-(1H-tetrazol-5-yl)[1.1'-biphenyl]-4-yl]imidazol[1,2-a]pyridin-8(7H)-imine
A mixture of biphenyl keto imidazole (0.094 mmol, the title compound of Example 1437), 20 mg (0.29 mmol) of N-hydroxyamine (hydrochloride salt) and 30 mg of NaOAc in 2 mL of methanol is stirred at 60.degree. C. until the reaction is complete. The mixture is diluted with chloroform and filtered. The solid is washed with methanol. The filtrate is concentrated in vacuo and purified to give the title compound of Example 1449.
EXAMPLE 1450 ##STR87## 1-[3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]imidazo[1,2-a]pyridin-8-yl]phthalimide
Step 1: Preparation of Biphenyl Phthalimidyl Imidazole
To a solution of the hydroxy imidazole (2.0 mmol, obtained from Step 1 of Example 1438 or 1439), phthalimide (2.0 mmol), and triphenylphosphine (2.0 mmol) in 2.0 mL of THF is added dropwise a solution of diethyl azodicarboxylate (2.0 mmol) in 1 mL of THF at room temperature. The resulting solution is stirred at room temperature until the reaction is complete. The resulting mixture is diluted with ether or ethyl acetate and washed with water. The extracts are dried (MgSO.sub.4) and concentrated in vacuo. The residue is purified to give the trityl protected phthalimidyl imidazole.
Step 2: Detritylation of Trityl Tetrazole
A solution of trityl-protected biphenyl phthalimidyl imidazole (2.0 mmol, obtained from Step 1) in 2 mL of water and 10 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 5 of Example 1 and purified give the title compound of Example 1450.
EXAMPLE 1451 ##STR88## 3-Butyl-5,6,7,8-tetrahydro-8-amino-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]imidazo[1,2-a]pyridine
A solution of phthalimidyl imidazole (0.6 mmol, the title compound of Example 1450) and 3 .mu.L (1.5 mmol) of hydrazine in 1.0 mL of ethanol is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo, and purified to give the title compound of Example 1451.
Alternatively, the title compound of Example 1451 can be prepared from the corresponding oxime. A suspension of the biphenyl imidazolyl oxime (0.059 mmol, the title compound of Example 1449) and 20 mg (0.0188 mmol) of 10% palladium on charcoal in 1.5 mL of methanol is stirred at room temperature under 50 psi of hydrogen gas until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 1451.
Examples 1452-1914, located in Tables XXV-XLVIII, are additional conformationally restricted angiotensin II antagonists embraced by Formula III above.
TABLE XXV______________________________________ ##STR89##EX.# R.sup.82 R.sup.83______________________________________1452 C.sub.3 H.sub.7 (n) H1453 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51454 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1455 C.sub.3 H.sub.7 (n) (2-ethylphenyl)1456 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)1457 C.sub.3 H.sub.7 (n) phenyl1458 C.sub.3 H.sub.7 (n) benzyl1459 C.sub.3 H.sub.7 (n) phenylethyl1460 C.sub.3 H.sub.7 (n) CH.sub.2 OH1461 C.sub.3 H.sub.7 (n) CO.sub.2 H1462 C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1463 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51464 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1465 C.sub.4 H.sub.9 (n) (2-ethylphenyl)1466 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)1467 C.sub.4 H.sub.9 (n) phenyl1468 C.sub.4 H.sub.9 (n) benzyl1469 C.sub.4 H.sub.9 (n) phenylethyl1470 C.sub.4 H.sub.9 (n) CH.sub.2 OH1471 C.sub.4 H.sub.9 (n) CO.sub.2 H______________________________________
TABLE XXVI______________________________________ ##STR90##EX.# R.sup.84 R.sup.85______________________________________1472 C.sub.3 H.sub.7 (n) O1473 C.sub.3 H.sub.7 (n) S1474 C.sub.3 H.sub.7 (n) NOH1475 C.sub.3 H.sub.7 (n) CHCO.sub.2 H1476 C.sub.3 H.sub.7 (n) C(C.sub.2 H.sub.5)CO.sub.2 H1477 C.sub.3 H.sub.7 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H1478 C.sub.3 H.sub.7 (n) CHC.sub.2 H.sub.51479 C.sub.4 H.sub.9 (n) S1480 C.sub.4 H.sub.9 (n) C(C.sub.2 H.sub.5)CO.sub.2 H1481 C.sub.4 H.sub.9 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H1482 C.sub.4 H.sub.9 (n) CHC.sub.2 H.sub.5______________________________________
TABLE XXVII______________________________________ ##STR91##EX.# R.sup.86 R.sup.87______________________________________1483 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51484 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1485 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51486 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)______________________________________
TABLE XXVIII______________________________________ ##STR92##EX.# R.sup.88 R.sup.89______________________________________1487 C.sub.3 H.sub.7 (n) H1488 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51489 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1490 C.sub.3 H.sub.7 (n) (2-ethylphenyl)1491 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)1492 C.sub.3 H.sub.7 (n) phenyl1493 C.sub.3 H.sub.7 (n) benzyl1494 C.sub.3 H.sub.7 (n) phenylethyl1495 C.sub.3 H.sub.7 (n) NH.sub.21496 C.sub.3 H.sub.7 (n) OH1497 C.sub.3 H.sub.7 (n) CH.sub.2 OH1498 C.sub.3 H.sub.7 (n) CO.sub.2 H1499 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51500 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1501 C.sub.4 H.sub.9 (n) (2-ethylphenyl)1502 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)1503 C.sub.4 H.sub.9 (n) phenyl1504 C.sub.4 H.sub.9 (n) benzyl1505 C.sub.4 H.sub.9 (n) phenylethyl1506 C.sub.4 H.sub.9 (n) CH.sub.2 OH1507 C.sub.4 H.sub.9 (n) CO.sub.2 H______________________________________
TABLE XXIX______________________________________ ##STR93##EX.# R.sup.90 R.sup.91 R.sup.92______________________________________1508 C.sub.3 H.sub.7 (n) H CH.sub.31509 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.51510 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.51511 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5 CH.sub.21512 C.sub.3 H.sub.7 (n) H CH.sub.2 CO.sub.2 H1513 C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1514 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.31515 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.51516 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.51517 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5 CH.sub.21518 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CO.sub.2 H1519 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1520 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.31521 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51522 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.51523 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.5 CH.sub.21524 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H1525 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H1526 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.31527 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51528 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.51529 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.21530 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1531 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H1532 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.31533 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.51534 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.51535 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H1536 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H1537 C.sub.4 H.sub.9 (n) H CH.sub.31538 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.51539 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.51540 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5 CH.sub.21541 C.sub.4 H.sub.9 (n) H CH.sub.2 CO.sub.2 H1542 C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1543 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.31544 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.51545 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.51546 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5 CH.sub.21547 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CO.sub.2 H1548 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1549 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.31550 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51551 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.51552 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.5 CH.sub.21553 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H1554 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H1555 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.31556 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51557 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.51558 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.21559 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1560 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H1561 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.31562 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.51563 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.51564 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H1565 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H______________________________________
TABLE XXX______________________________________ ##STR94##EX.# R.sup.93 R.sup.94, R.sup.95______________________________________1566 C.sub.3 H.sub.7 (n) O1567 C.sub.3 H.sub.7 (n) H,H1568 C.sub.3 H.sub.7 (n) H,CH.sub.31569 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.51570 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1571 C.sub.3 H.sub.7 (n) H,CO.sub.2 H1572 C.sub.4 H.sub.9 (n) H,H1573 C.sub.4 H.sub.9 (n) H,CH.sub.31574 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51575 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1576 C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE XXXI______________________________________ ##STR95##EX.# R.sup.96 R.sup.97, R.sup.98______________________________________1577 C.sub.3 H.sub.7 (n) O1578 C.sub.3 H.sub.7 (n) H,H1579 C.sub.3 H.sub.7 (n) H,CH.sub.31580 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.51581 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1582 C.sub.3 H.sub.7 (n) H,CO.sub.2 H1583 C.sub.4 H.sub.9 (n) O1584 C.sub.4 H.sub.9 (n) H,H1585 C.sub.4 H.sub.9 (n) H,CH.sub.31586 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51587 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1588 C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE XXXII______________________________________ ##STR96##EX.# R.sup.99 R.sup.100______________________________________1589 C.sub.3 H.sub.7 (n) CH.sub.21590 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)1591 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1592 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21593 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.21594 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.21595 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)1596 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1597 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.21598 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.21599 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub. 6 H.sub.5)CH.sub.2______________________________________
TABLE XXXIII______________________________________ ##STR97##EX.# R.sup.101 R.sup.102______________________________________1600 C.sub.3 H.sub.7 (n) H1601 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51602 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1603 C.sub.3 H.sub.7 (n) (2-ethylphenyl)1604 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)1605 C.sub.3 H.sub.7 (n) phenyl1606 C.sub.3 H.sub.7 (n) benzyl1607 C.sub.3 H.sub.7 (n) phenylethyl1608 C.sub.3 H.sub.7 (n) CH.sub.2 OH1609 C.sub.3 H.sub.7 (n) CO.sub.2 H1610 C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1611 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51612 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1613 C.sub.4 H.sub.9 (n) (2-ethylphenyl)1614 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)1615 C.sub.4 H.sub.9 (n) phenyl1616 C.sub.4 H.sub.9 (n) benzyl1617 C.sub.4 H.sub.9 (n) phenylethyl1618 C.sub.4 H.sub.9 (n) CH.sub.2 OH1619 C.sub.4 H.sub.9 (n) CO.sub.2 H1620 C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H______________________________________
TABLE XXXIV______________________________________ ##STR98##EX.# R.sup.103 R.sup.104______________________________________1621 C.sub.3 H.sub.7 (n) O1622 C.sub.3 H.sub.7 (n) S1623 C.sub.3 H.sub.7 (n) NOH1624 C.sub.3 H.sub.7 (n) CHCO.sub.2 H1625 C.sub.3 H.sub.7 (n) C(C.sub.2 H.sub.5)CO.sub.2 H1626 C.sub.3 H.sub.7 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H1627 C.sub.3 H.sub.7 (n) CHC.sub.2 H.sub.51628 C.sub.4 H.sub.9 (n) O1629 C.sub.4 H.sub.9 (n) S1630 C.sub.4 H.sub.9 (n) NOH1631 C.sub.4 H.sub.9 (n) CHCO.sub.2 H1632 C.sub.4 H.sub.9 (n) C(C.sub.2 H.sub.5)CO.sub.2 H1633 C.sub.4 H.sub.9 (n) C(CH.sub.2 C.sub.6 H.sub.5 )CO.sub.2 H1634 C.sub.4 H.sub.9 (n) CHC.sub.2 H.sub.5______________________________________
TABLE XXXV______________________________________ ##STR99##EX.# R.sup.105 R.sup.106______________________________________1635 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51636 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1637 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51638 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)______________________________________
TABLE XXXVI______________________________________ ##STR100##EX.# R.sup.107 R.sup.108______________________________________1639 C.sub.3 H.sub.7 (n) H1640 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51641 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1642 C.sub.3 H.sub.7 (n) (2-ethylphenyl)1643 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)1644 C.sub.3 H.sub.7 (n) phenyl1645 C.sub.3 H.sub.7 (n) benzyl1646 C.sub.3 H.sub.7 (n) phenylethyl1647 C.sub.3 H.sub.7 (n) NH.sub.21648 C.sub.3 H.sub.7 (n) OH1649 C.sub.3 H.sub.7 (n) CH.sub.2 OH1650 C.sub.3 H.sub.7 (n) CO.sub.2 H1651 C.sub.4 H.sub.9 (n) H1652 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51653 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1654 C.sub.4 H.sub.9 (n) (2-ethylphenyl)1655 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)1656 C.sub.4 H.sub.9 (n) phenyl1657 C.sub.4 H.sub.9 (n) benzyl1658 C.sub.4 H.sub.9 (n) phenylethyl1659 C.sub.4 H.sub.9 (n) NH.sub.21660 C.sub.4 H.sub.9 (n) OH1661 C.sub.4 H.sub.9 (n) CH.sub.2 OH1662 C.sub.4 H.sub.9 (n) CO.sub.2 H______________________________________
TABLE XXXVII______________________________________ ##STR101##EX.# R.sup.109 R.sup.110 R.sup.111______________________________________1663 C.sub.3 H.sub.7 (n) H CH.sub.31664 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.51665 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.51666 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5 CH.sub.21667 C.sub.3 H.sub.7 (n) H CH.sub.2 CO.sub.2 H1668 C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1669 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.31670 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.51671 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.51672 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5 CH.sub.21673 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CO.sub.2 H1674 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1675 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.31676 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51677 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.51678 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.5 CH.sub.21679 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H1680 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H1681 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.31682 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51683 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.51684 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.21685 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1686 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H1687 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.31688 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.51689 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.51690 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H1691 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H1692 C.sub.4 H.sub.9 (n) H CH.sub.31693 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.51694 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.51695 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5 CH.sub.21696 C.sub.4 H.sub.9 (n) H CH.sub.2 CO.sub.2 H1697 C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1698 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.31699 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.51700 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.51701 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5 CH.sub.21702 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CO.sub.2 H1703 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1704 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.31705 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51706 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.51707 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.5 CH.sub.21708 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H1709 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H1710 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.31711 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51712 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.51713 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.21714 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1715 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H1716 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.31717 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.51718 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.51719 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H1720 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H______________________________________
TABLE XXXVIII______________________________________ ##STR102##EX.# R.sup.112 R.sup.113, R.sup.114______________________________________1721 C.sub.3 H.sub.7 (n) O1722 C.sub.3 H.sub.7 (n) H,H1723 C.sub.3 H.sub.7 (n) H,CH.sub.31724 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.51725 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1726 C.sub.3 H.sub.7 (n) H,CO.sub.2 H1727 C.sub.4 H.sub.9 (n) O1728 C.sub.4 H.sub.9 (n) H,H1729 C.sub.4 H.sub.9 (n) H,CH.sub.31730 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51731 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1732 C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE XXXIX______________________________________ ##STR103##EX.# R.sup.115 R.sup.116, R.sup.117______________________________________1733 C.sub.3 H.sub.7 (n) O1734 C.sub.3 H.sub.7 (n) H,H1735 C.sub.3 H.sub.7 (n) H,CH.sub.31736 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.51737 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1738 C.sub.3 H.sub.7 (n) H,CO.sub.2 H1739 C.sub.4 H.sub.9 (n) O1740 C.sub.4 H.sub.9 (n) H,H1741 C.sub.4 H.sub.9 (n) H,CH.sub.31742 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51743 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1744 C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE XL______________________________________ ##STR104##EX.# R.sup.118 R.sup.119______________________________________1745 C.sub.3 H.sub.7 (n) CH.sub.21746 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)1747 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1748 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21749 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.21750 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.21751 C.sub.4 H.sub.9 (n) CH.sub.21752 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)1753 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1754 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.21755 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5 )CH.sub.21756 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2______________________________________
TABLE XLI______________________________________ ##STR105##EX.# R.sup.120 R.sup.121______________________________________1757 C.sub.3 H.sub.7 (n) H1758 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51759 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1760 C.sub.3 H.sub.7 (n) (2-ethylphenyl)1761 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)1762 C.sub.3 H.sub.7 (n) phenyl1763 C.sub.3 H.sub.7 (n) benzyl1764 C.sub.3 H.sub.7 (n) phenylethyl1765 C.sub.3 H.sub.7 (n) CH.sub.2 OH1766 C.sub.3 H.sub.7 (n) CO.sub.2 H1767 C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1768 C.sub.4 H.sub.9 (n) H1769 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51770 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1771 C.sub.4 H.sub.9 (n) (2-ethylphenyl)1772 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)1773 C.sub.4 H.sub.9 (n) phenyl1774 C.sub.4 H.sub.9 (n) benzyl1775 C.sub.4 H.sub.9 (n) phenylethyl1776 C.sub.4 H.sub.9 (n) CH.sub.2 OH1777 C.sub.4 H.sub.9 (n) CO.sub.2 H1778 C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H______________________________________
TABLE XLII______________________________________ ##STR106##EX.# R.sup.122 R.sup.123______________________________________1779 C.sub.3 H.sub.7 (n) O1780 C.sub.3 H.sub.7 (n) S1781 C.sub.3 H.sub.7 (n) NOH1782 C.sub.3 H.sub.7 (n) CHCO.sub.2 H1783 C.sub.3 H.sub.7 (n) C(C.sub.2 H.sub.5)CO.sub.2 H1784 C.sub.3 H.sub.7 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H1785 C.sub.3 H.sub.7 (n) CHC.sub.2 H.sub.51786 C.sub.4 H.sub.9 (n) O1787 C.sub.4 H.sub.9 (n) S1788 C.sub.4 H.sub.9 (n) NOH1789 C.sub.4 H.sub.9 (n) CHCO.sub.2 H1790 C.sub.4 H.sub.9 (n) C(C.sub.2 H.sub.5)CO.sub.2 H1791 C.sub.4 H.sub.9 (n) C(CH.sub.2 C.sub.6 H.sub.5 )CO.sub.2 H1792 C.sub.4 H.sub.9 (n) CHC.sub.2 H.sub.5______________________________________
TABLE XLIII______________________________________ ##STR107##EX.# R.sup.124 R.sup.125______________________________________1793 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51794 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1795 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51796 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)______________________________________
TABLE XLIV______________________________________ ##STR108##EX.# R.sup.126 R.sup.127______________________________________1797 C.sub.3 H.sub.7 (n) H1798 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51799 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1800 C.sub.3 H.sub.7 (n) (2-ethylphenyl)1801 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)1802 C.sub.3 H.sub.7 (n) phenyl1803 C.sub.3 H.sub.7 (n) benzyl1804 C.sub.3 H.sub.7 (n) phenylethyl1805 C.sub.3 H.sub.7 (n) NH.sub.21806 C.sub.3 H.sub.7 (n) OH1807 C.sub.3 H.sub.7 (n) CH.sub.2 OH1808 C.sub.3 H.sub.7 (n) CO.sub.2 H1809 C.sub.4 H.sub.9 (n) H1810 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51811 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1812 C.sub.4 H.sub.9 (n) (2-ethylphenyl)1813 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)1814 C.sub.4 H.sub.9 (n) phenyl1815 C.sub.4 H.sub.9 (n) benzyl1816 C.sub.4 H.sub.9 (n) phenylethyl1817 C.sub.4 H.sub.9 (n) NH.sub.21818 C.sub.4 H.sub.9 (n) OH1819 C.sub.4 H.sub.9 (n) CH.sub.2 OH1820 C.sub.4 H.sub.9 (n) CO.sub.2 H______________________________________
TABLE XLV______________________________________ ##STR109##EX.# R.sup.128 R.sup.129 R.sup.130______________________________________1821 C.sub.3 H.sub.7 (n) H CH.sub.31822 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.51823 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.51824 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5 CH.sub.21825 C.sub.3 H.sub.7 (n) H CH.sub.2 CO.sub.2 H1826 C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1827 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.31828 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.51829 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.51830 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5 CH.sub.21831 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CO.sub.2 H1832 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1833 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.31834 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51835 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.51836 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.5 CH.sub.21837 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H1838 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H1839 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.31840 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51841 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.51842 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.21843 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1844 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H1845 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.31846 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.51847 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.51848 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H1849 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H1850 C.sub.4 H.sub.9 (n) H CH.sub.31851 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.51852 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.51853 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5 CH.sub.21854 C.sub.4 H.sub.9 (n) H CH.sub.2 CO.sub.2 H1855 C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1856 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.31857 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.51858 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.51859 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5 CH.sub.21860 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CO.sub.2 H1861 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1862 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.31863 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51864 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.51865 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.5 CH.sub.21866 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H1867 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H1868 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.31869 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51870 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.51871 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.21872 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1873 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H1874 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.31875 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.51876 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.51877 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H1878 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H______________________________________
TABLE XLVI______________________________________ ##STR110##EX.# R.sup.131 R.sup.132 ,R.sup.133______________________________________1879 C.sub.3 H.sub.7 (n) O1880 C.sub.3 H.sub.7 (n) H,H1881 C.sub.3 H.sub.7 (n) H,CH.sub.31882 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.51883 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1884 C.sub.3 H.sub.7 (n) H,CO.sub.2 H1885 C.sub.4 H.sub.9 (n) O1886 C.sub.4 H.sub.9 (n) H,H1887 C.sub.4 H.sub.9 (n) H,CH.sub.31888 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51889 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1890 C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE XLVII______________________________________ ##STR111##EX.# R.sup.134 R.sup.135 ,R.sup.136______________________________________1891 C.sub.3 H.sub.7 (n) O1892 C.sub.3 H.sub.7 (n) H,H1893 C.sub.3 H.sub.7 (n) H,CH.sub.31894 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.51895 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1896 C.sub.3 H.sub.7 (n) H,CO.sub.2 H1897 C.sub.4 H.sub.9 (n) O1898 C.sub.4 H.sub.9 (n) H,H1899 C.sub.4 H.sub.9 (n) H,CH.sub.31900 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51901 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1902 C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE XLVIII______________________________________ ##STR112##EX.# R.sup.137 R.sup.138______________________________________1903 C.sub.3 H.sub.7 (n) CH.sub.21904 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)1905 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1906 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21907 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.21908 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.21909 C.sub.4 H.sub.9 (n) CH.sub.21910 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)1911 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1912 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.21913 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5 )CH.sub.21914 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2______________________________________
An appropriately substituted pyrrole 61, the heterocyclic starting material, may be prepared as described in the literature [G. P. Bean and A. H. Jackson; M. Artico; H. J. Anderson; C. E. Loader, A. Gossauer, P. Nesvadba; and N. Dennis in "Pyrroles", Vol 48 of The Chemistry of Heterocyclic Compounds, E. C. Taylor, A. Weissberger Eds., Wiley-Interscience, New York, 1990, pp 105-497]. The pyrrole 1 in N,N-dimethylformamide (DMF) is treated with base, such as potassium tert-butoxide, followed by addition of appropriate alkylating agent 62 to give the coupled product 63 (Scheme IX). For compounds where X is a substituted phenyl group, several procedures have been published for the preparations of the alkylating agent 62 [see references for compound 2]. ##STR113##
The coupled pyrrole 63 itself may be an angiotensin II receptor antagonist, but it may also be used as a key intermediate in the preparation of the compounds of the invention. Pyrrole 63 in THF (or DME) is treated with base (such as n-BuLi or LDA) at -78.degree. C. (or -65.degree. C.), followed by addition of an appropriate alkylating agent or other electrophiles 64 (the acetal shown in Scheme I may be other aldehyde masking group or equivalent, and LG is a leaving group such as halide, mesylate, triflate or tosylate). The resulting masked aldehyde 65 was stirred with NaOAc in aqueous acetic acid at reflux for a few days (1 to 5 days) to give one of the compounds of the invention, a cyclized pyrrole 66.
The pyrrole 66 may be used as an intermediate to prepare other substituted compounds with appropriate functional group transformations and preparations of some of those compounds are illustrated in Scheme X and XI (all of the intermediates shown in the sequences are also angiotensin II receptor antagonists). For example, The unsaturated pyrrole 66 and NBS in CCl.sub.4 is stirred at reflux to give a bromide 67. The bromide 67 may be treated with organolithium, such as n-BuLi or tert-BuLi, followed by addition of an appropriate electrophile, (such as alkyl halides, carbon dioxide, aldehyde, ketone and others) to give the addition product 68. The olefin 68 may be hydrogenated to give its saturated product 69. ##STR114##
Alternatively, as illustrated in Scheme XI, the unsaturated pyrrole 66 may be treated with NBS in wet DMSO to give a bromohydrin which may be reduced with nBu.sub.3 SnH to an alcohol 70 and the oxidation of the alcolol with MnO.sub.2 will afford a ketone 71. The ketone 71 may be condensed with appropriately substituted amine, then reduced to an amine 72 with an appropriate reducing agent (e.g. NaBH.sub.4, or hydrogen over catalyst). The amine 72 may also be prepared directly from olefin 66 under bromination condition (NBS, CH.sub.3 CN) in the presence of large excess of succinimide. The amine 72may be used to prepare other derivatives. Alternatively, the alcohol 70 may be treated with triphenylphosphine, diethoxyazo dicarboxylate and an imide (e.g. phthalimide) to give an imide analogue which may be converted to an amine 72.
The ketone 71 may be treated with appropriate organometallic reagents (such as Grignard, organolithium, organocerium, organozinc reagents or related reagents) to give the addition product, a tertiary alcohol. The alcohol may be dehydrated to give an olefin 73 or an isomeric mixture of olefins 73. The olefin 73 may be treated with base, such as LDA and kinetically quenched at low temperature with either organic acid or appropriate electrophile at low temperature to give the isomerized olefin 74. The olefins 73 or 74 may be hydrogenated to its saturated analogue 75. ##STR115##
In Scheme XII, an alternative preparation for the compounds of the invention is described. An appropriately substituted pyrrole 61. may be treated with one equivalent of base, then protected as SEM or BOC derivative. The protected pyrrole then is treated with another equivalent of base followed by addition of electrophile 76 or 77. If necessary, the resulting lithium anion obtained from the two procedures described above may be converted to other organometallic reagents according to well-established procedures. Electrophiles 77 and 78 can be prepared from HC(.dbd.O)(CR.sup.4 R.sup.5)(CH.sub.2).sub.n C(.dbd.O)LG and an appropriate organometallic reagent such as XC.sub.6 H.sub.4 MgBr.
If PLG is a hydroxyl group and Z is a proton, the resulting addition product 79, may be cyclized with triphenylphosphine and diethyl azodicarboxylate (Mitsunobu reaction or other modified conditions). If PLG is or is converted to a leaving group, such as halides, tosylate, and Z is a proton, the cyclization may be achieved with a weak base in DMF (e.g. K.sub.2 CO.sub.3, CsCO.sub.3) to give a ketone 71. The ketone 71 may be reduced to an alcohol 70 with NaBH.sub.4 in methanol. The alcohol 70 may be dehydrated to olefin 66 with acid (e.g. HOAc and heat) or thionyl chloride and pyridine. Other compounds may be prepared from compounds 66, 70, or 71 as described in Scheme X and XI. ##STR116##
EXAMPLE 1915 ##STR117## 3-Butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]indolizine
Step 1: Preparation of Biphenyl Pyrrole
To a solution of 2-butylpyrrole (2.65 mmol) in 5.3 mL of DMF is added 3.45 mL (3.45 mmol) of potassium tert-butoxide (1M in THF), and the resulting solution is stirred at room temperature for 30 min. To the dark brown mixture is added 2.75 g (3.45 mmol) of the bromomethyl biphenyl. The reaction mixture is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is purified to give the trityl-protected biphenyl pyrrole.
Step 2: Preparation of Biphenyl Dimethyl Acetal Pyrrole
To a solution of biphenyl pyrrole (3.18 mmol, obtained from Step 1) in 16 mL of THF cooled at -45.degree. C. (acetonitrile-dry ice) is added 2.8 mL (4.06 mmol) of n-butyllithium (1.45M in hexane) over a 4-min period. The resulting dark purple solution is stirred cold for another 15 min, followed by addition of 1.0 mL (6.59 mmol) of 3-bromopropionaldehyde dimethyl acetal in one portion. The mixture is stirred cold for 40 min, then is slowly warmed to -10.degree. C. The reaction is quenched with aqueous NH.sub.4 Cl, extracted with diethyl ether. The combined extracts are washed with brine, dried (MgSO.sub.4), concentrated in vacuo and purified to give the biphenyl dimethyl acetal pyrrole intermediate.
Step 3: Preparation of Biphenyl Indolizine
A solution of the crude biphenyl dimethyl acetal pyrrole (3.18 mmol, obtained from Step 2) and 5.3 g (88 mmol) of NaOAc in 13 mL of water and 40 mL of glacial acetic acid is stirred at reflux until the reaction is complete. The solution is cooled and concentrated in vacuo. The residue is dissolved in methylene chloride and filtered. The filtrate is stirred with 2 g (7.2 mmol) of trityl chloride and 3 mL (21.5 mmol) of TEA at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is purified to give the biphenyl indolizine.
Step 4: Detritylation of Trityl Tetrazole
A solution of the biphenyl indolizine (0.144 mmol, obtained from Step 3) is stirred with 1 mL of water and 6 mL of acetic acid at room temperature until the reaction is complete. The solution is concentrated in vacuo, stirred in aqueous NaHCO.sub.3 and washed with ether. The aqueous residue is acidified with 3N HCl to pH 4 and extracted with methylene chloride. The combined extracts are dried (MgSO.sub.4), concentrated and purified to give the title compound of Example 1915.
EXAMPLE 1916 ##STR118## 7-Bromo-3-butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]indolizine
Step 1: Preparation of Bromo Olefin Indolizine
A solution of biphenyl indolizine (0.101 mmol, obtained from Step 3 of Example 1915), 20 mg (0.112 mmol) of NBS and 7 mg (catalytic) of AIBN in 2.8 mL of CCl.sub.4 is stirred at reflux until the reaction is complete. The reaction mixture is diluted with CCl.sub.4 and washed with water. The organic layer is dried (MgSO.sub.4) and concentrated in vacuo. The residue is purified to give the biphenyl bromo olefin indolizine.
Step 2: Detritylation of the Trityl Tetrazole
A solution of bromo olefin indolizine (0.0427 mmol, obtained from Step 1) in 0.8 mL of water and 5 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 4 of Example 1915 and purified to give the title compound of Example 1916.
EXAMPLE 1917 ##STR119## 3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]indolizine
A suspension of olefin indolizine (0.1 mmol, the title compound of Example 1915) and 20 mg (0.019 mmol) of 10% palladium on charcoal in 2 mL of absolute ethanol is agitated on a Parr apparatus under 50 psi of hydrogen gas at room temperature until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 1917.
EXAMPLE 1918 ##STR120## 3-Butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]indolizin-8(5H) -one
Step 1: Preparation of the Bromohydrin Intermediate
To a solution of biphenyl indolizine (3.13 mmol, obtained from Step 4 of Example 1915) in 2.2 mL (0.122 mmol) of water and 22 mL of DMSO at room temperature is added 587 mg (3.30 mmol) of NBS in one portion. The resulting orange solution is stirred at room temperature for 40 min, quenched with aqueous Na.sub.2 SO.sub.3, and extracted with chloroform. The combined extracts are washed with water, and the combined aqueous layers are extracted with chloroform. The combined extracts are washed with brine, dried (MgSO.sub.4) and concentrated in vacuo to give a crude bromohydrin intermediate which can be used directly in the subsequent Step 2 without further purification.
Step 2: Preparation of the Trityl-Protected Biphenyl Hydroxy Indolizine
To the crude bromohydrin (3.13 mmol, obtained from Step 1) in 42 mL of degassed dry benzene is added 4.3 mL (14.7 mmol) of n-Bu.sub.3 SnH and 456 mg (2.7 mmol) of AIBN in one portion and the resulting solution is stirred at reflux until the reaction is complete. The mixture is concentrated in vacuo and partitioned between hexane and acetonitrile. The acetonitrile layer is washed with hexane, and the combined hexane layers are extracted with acetonitrile. The combined acetonitrile extracts are concentrated in vacuo to give an isomeric mixture of both cis- and trans-hydroxy indolizines (relative to the biphenyl moiety). The crude mixture can be used directly in subsequent Step 3 without further purification. The mixture may also be used to prepare the biphenyl trans-hydroxy indolizine (the title compound of Example 1920).
Step 3: Preparation of the Keto Indolizine
A suspension of the crude biphenyl hydroxy indolizine (2.72 mmol, obtained from Step 2) and 13 g of active MnO.sub.2 in 15 mL of methylene chloride is stirred at room temperature until the reaction is complete. The mixture is filtered through a pad of celite, rinsed with IPA-methylene chloride, and concentrated in vacuo. The residue is purified to give the trityl-protected biphenyl keto indolizine.
Step 4: Detritylation of Trityl Tetrazole
A solution of trityl tetrazolyl keto indolizine (0.131 mmol, obtained from Step 3) in 1.0 mL of water and 5.0 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 4 of Example 1915 and purified to give the title compound of Example 1918.
EXAMPLE 1919 ##STR121## 3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]indolizin-cis-8-ol
Step 1: Preparation of Biphenyl Cis-Hydroxy Indolizine
To a solution of biphenyl keto indolizine (0.456 mmol, obtained from Step 3 of Example 1918) in 0.5 mL of methanol and 2.0 mL of THF at 0.degree. C. is added in small portions 34 mg (0.899 mmol) of NaBH.sub.4. The resulting solution is stirred at 0.degree. C., and slowly warmed to room temperature. The reaction is quenched with aqueous NH.sub.4 Cl, extracted with methylene chloride, dried (MgSO.sub.4) and concentrated in vacuo. The residue is purified to give the biphenyl hydroxy indolizine.
Step 2: Detritylation of Trityl Tetrazole
A solution of the biphenyl hydroxy indolizine (0.259 mmol, obtained from Step 1) in 0.4 mL of water and 2.0 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is purified to give the title compound of Example 1919.
EXAMPLE 1920 ##STR122## 3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]indolizin-trans-8-ol
Step 1: Preparation of Biphenyl Trans-Hydroxy Indolizine
A suspension of the crude biphenyl hydroxy indolizine (1.307 mmol, obtained from Step 2 of Example 1918) and 3.0 g of active MnO.sub.2 in 5.0 mL of methylene chloride is stirred at room temperature. The reaction is worked up before its completion. The mixture is filtered through a pad of celite, rinsed with IPA-methylene chloride, and concentrated in vacuo. The residue is purified to give the trityl protected biphenyl trans-hydroxy indolizine.
Alternatively, the biphenyl trans-hydroxy indolizine can be prepared using the Mitsunobu reaction conditions. To a solution of diethyl azodicarboxylate (2.0 mmol) and 3-nitrobenzoic acid (2.0 mmol) in 2.0 mL of THF is added dropwise a solution of the biphenyl hydroxy indolizine (2.0 mmol, obtained from Step 1 of Example 1919), and triphenylphosphine (2.0 mmol) in 1.0 mL of THF at room temperature. The resulting solution is stirred at room temperature until the reaction is complete. The resulting mixture is diluted with ether or ethyl acetate, and washed with water. The extracts are dried (MgSO.sub.4) and concentrated in vacuo to give the biphenyl indolizinyl nitrobenzoate. The crude benzoate is hydrolyzed with LiOH in aqueous THF at room temperature and purified to give the biphenyl trans-hydroxy indolizine.
Step 2: Detritylation of Trityl Tetrazole
A solution of the trityl protected biphenyl trans-hydroxy indolizine (0.079 mmol, obtained from Step 1) in 0.4 mL of water and 2.0 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is purified to give the title compound of Example 1920.
EXAMPLE 1921 ##STR123## 1-[3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]indolizin-8-yl]-2,5-pyrrolidinedione
Step 1: Preparation of Succinimidyl Indolizine
To a solution of biphenyl indolizine (3.13 mmol, Example 1915, Step 3) and 1.25 g (12.6 mmol) of succinimide in 20 mL of anhydrous acetonitrile is added 572 mg (3.21 mmol) of NBS in one portion. The resulting orange-red solution is stirred at room temperature for 30 min, then evaporated in vacuo. The residue is dissolved in ethyl acetate and washed with aqueous sodium bisulfite, water, and brine. The extracts are dried (MgSO.sub.4) and concentrated in vacuo. The residue is purified to give the trityl protected succinimidyl indolizine.
Alternatively, the succinimide can be prepared from its corresponding hydroxy indolizine. To a solution of the biphenyl hydroxy indolizine (2.0 mmol, obtained from Step 1 of Example 1919 or 1920), succinimide (2.0 mmol), and triphenylphosphine (2.0 mmol) in 2.0 mL of THF is added dropwise a solution of diethyl azodicarboxylate (2.0 mmol) in 1 mL of THF at room temperature. The resulting solution is stirred at room temperature until the reaction is complete. The resulting mixture is diluted with ether or ethyl acetate and washed with water. The extracts are dried (HgSO.sub.4) and concentrated in vacuo. The residue is purified to give the trityl protected succinimidyl indolizine.
Step 2: Detritylation of Trityl Tetrazole
A solution of trityl protected succinimidyl indolizine (0.16 mmol, obtained from Step 1) in 0.2 mL of water and 1 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 4 of Example 1915 and purified to give the title compound of Example 1921.
EXAMPLE 1922 ##STR124## 4-[3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]indolizin-8-yl]amino]-4-oxobutanoic acid, hydrazide
A solution of succinimidyl indolizine (0.06 mmol, obtained from Example 1921) and 11 .mu.L (5.6 mmol) of hydrazine in 0.5 mL of ethanol is stirred at room temperature until the reaction is complete and concentrated in vacuo to give the title compound of Example 1922.
EXAMPLE 1923 ##STR125## 3-Butyl-6,7-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-5H-pyrrolo[1,5-a]azepine
Step 1: Alkylation of Biphenyl Pyrrole
To a solution of biphenyl pyrrole (0.152 mmol, obtained from Step 2 of Example 1915) in 0.8 mL of DME cooled at -45.degree. C. (acetonitrile-dry ice) is added 125 .mu.L (0.2 mmol) of n-butyllithium (1.6 M in hexane) over a 4-min period. The resulting dark red solution is stirred cold for another 15 min, followed by addition of 70 .mu.L (0.37 mmol) of 2-(3-bromopropyl)-5,5-dimethyl-1,3-dioxane in one portion. The mixture is stirred cold for 40 min, then is slowly warmed to -10.degree. C. The reaction is quenched with aqueous NH.sub.4 Cl, extracted with diethyl ether. The combined extracts are washed with brine, dried (MgSO.sub.4) and concentrated in vacuo. The crude product can be used directly in the subsequent Step 2 without purification.
Step 2: Preparation of the Indolizine
A solution of the crude mixture (0.152 mmol, obtained from Step 1) and 255 mg (3 mmol) of NaOAc in 0.6 mL of water and 2 mL of glacial acetic acid is stirred at reflux until the reaction is complete. The mixture is cooled and concentrated in vacuo. The residue is dissolved in methylene chloride and filtered. The filtrate is stirred with 130 mg (0.46 mmol) of trityl chloride and 0.22 mL (1.6 mmol) of TEA at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is purified to give the biphenyl indolizine.
Step 3: Detritylation of Trityl Tetrazole
A solution of the biphenyl indolizine (0,035 mmol, obtained from Step 2) is stirred with 0.4 mL of water and 2 mL of acetic acid at room temperature until the reaction is complete. The solution is concentrated in vacuo. The residue is worked up as described in Step 4 of Example 1915 and purified to give the title compound of Example 1923.
EXAMPLE 1924 ##STR126## 1,1-Dimethylethyl [3-Butyl-6,7-dihydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]-8(5H)-indolizinylidene]acetate
Step 1: Preparation of Tert-Butyl Ester
To a suspension of 64 mg (2.63 mmol) of magnesium in 3.0 mL of THF at 55.degree. C. is added two 10-.mu.L portions of 1,2-dibromoethane, 5 min apart. The resulting mixture is stirred at 45.degree. C. for 10 min, followed by dropwise addition of a solution of biphenyl keto indolizine (0.306 mmol, obtained from Step 3 of Example 1918) and 242 .mu.L (1.50 mmol) of tert-butyl bromoacetate in 2.0 mL of THF at 55.degree. C. over a 1 h period. The resulting solution is stirred until the reaction is complete. The mixture is cooled and quenched with aqueous NH.sub.4 Cl. The mixture is extracted with ether, dried (MgSO.sub.4) and concentrated in vacuo. The crude mixture can be used directly in the subsequent Step 2 without further purification.
Step 2: Preparation of Unsaturated Butyl Ester
To a solution of the crude biphenyl tert-butyl ester intermediate (0.306 mmol, obtained from Step 1) and 200 .mu.L (2.47 mmol) of pyridine in 2 mL of methylene chloride at 0.degree. C. is added dropwise 80 .mu.L (1.1 mmol) of thionyl chloride. The resulting dark brown solution is stirred at 0.degree. C. for 1 h, diluted with water and extracted with methylene chloride. The residue is purified to give the biphenyl indolizinyl unsaturated ester.
Step 3: Detritylation of Trityl Tetrazole
A solution of biphenyl indolizinyl unsaturated ester (0.133 mmol, obtained from Step 2) in 1.0 mL of water and 5.0 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 4 of Example 1915 and purified to give the title compound of Example 1924.
EXAMPLE 1925 ##STR127## [3-Butyl-6,7-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-8(5H) -indolizinylidene]acetic acid
To a solution of unsaturated tert-butyl ester (0.0627 mmol, the title compound of Example 1924) in 2 mL of CDCl.sub.3 at room temperature is added 0.5 mL of TFA, and the progress of the reaction is monitored by .sup.1 H NMR. The resulting yellow solution is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The crude product is purified to give the title compound of Example 1925.
EXAMPLE 1926 ##STR128## 1,1-Dimethylethyl 3-butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]indolizin-8-acetate
Step 1: Preparation of Deconjugated Ester
To a solution of ester (0.237 mmol, obtained from Step 2 of Example 1924) in 4 mL of THF at 0.degree. C. is added 10 .mu.L of 1.5M (0.467 mmol) LDA over a 2-min period, and the resulting solution is stirred at 0.degree. C. for 10 min. The mixture is cooled to -78.degree. C., stirred cold for 5 min, and quenched dropwise at -78.degree. C. with 100 .mu.L of acetic acid in 1 mL of hexane. The mixture is stirred cold, then warmed to room temperature and treated with aqueous NaHCO.sub.3. The mixture is extracted with methylene chloride. The combined extracts are washed with water, dried (MgSO.sub.4) and concentrated in vacuo to give a crude mixture. The crude product is purified to give the biphenyl indolizinyl deconjugated ester.
Step 2: Detritylation of Trityl Tetrazole
A solution of trityl-protected biphenyl indolizinyl deconjugated ester (0.165 mmol, obtained from Step 1) in 1 mL of water and 3 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 4 of Example 1915. The crude product is purified to give the title compound of Example 1926.
EXAMPLE 1927 ##STR129## 3-Butyl -5,6-dihydro-5-[2'-(1H-tetrazol -5-yl)[1,1'-biphenyl]-4-yl]indolizin-8-acetic acid
To a solution of biphenyl indolizinyl tert-butyl ester (0.039 mmol, the title compound of Example 1926) in 0.5 mL of chloroform is added 0.25 mL of TFA, and the progress of the reaction is monitored by .sup.1 H NMR. The resulting solution is stirred at room temperature until the reaction is complete. The mixture is quenched with methanol and concentrated in vacuo. The residue is purified to give the title compound of Example 1927.
EXAMPLE 1928 ##STR130## 1,1-Dimethylethyl 3-butyl-5,6,7,8-tetrahydro-5-[2 '-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]indolizin-cis-8-acetate
A suspension of the biphenyl indolizinyl unsaturated ester (0.059 mmol, the title compound of Example 1926) and 20 mg (0.0188 mmol) of 10% palladium on charcoal in 1.5 mL of methanol is stirred at room temperature under an atmosphere of hydrogen gas until the reaction is complete. The mixture is filtered through a pad of celite and concentrated in vacuo. The residue is purified to give the title compound of Example 1928.
EXAMPLE 1929 ##STR131## 3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]indolizin-cis-8-acetic acid
To a solution of tert-butyl ester (0.0332 mmol, obtained from Example 1928) in 0.4 mL of CDCl.sub.3 is added 0.2 mL of TFA, and the progress of the reaction is monitored by .sup.1 H NMR. The resulting solution is allowed to stand at room temperature until the reaction is complete. The reaction mixture is diluted with methanol and concentrated. The residue is purified to give the title compound of Example 1929.
EXAMPLE 1930 ##STR132## 3-Butyl-5,6-dihydro-N-hydroxy-5-[2'-1H-tetrazol-5-yl)[1.1'-biphenyl]-4-yl]indolizin-8 (7H)-imine
A mixture of biphenyl keto indolizine (0.094 mmol, the title compound of Example 1918), 20 mg (0.29 mmol) of N-hydroxyamine (hydrochloride salt) and 30 mg of NaOAc in 2 mL of methanol is stirred at 60.degree. C. until the reaction is complete. The mixture is diluted with chloroform and filtered. The solid is washed with methanol. The filtrate is concentrated in vacuo and purified to give the title compound of Example 1930.
EXAMPLE 1931 ##STR133## 1-[3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]indolizin-8-yl]phthalimide
Step 1: Preparation of Biphenyl Phthalimidyl Indolizine
To a solution of the biphenyl hydroxy indolizine (2.0 mmol, obtained from Step 1 of Example 1919 or 1920), phthalimide (2.0 mmol), and triphenylphosphine (2.0 mmol) in 2.0 mL of THF is added dropwise a solution of diethyl azodicarboxylate (2.0 mmol) in 1 mL of THF at room temperature. The resulting solution is stirred at room temperature until the reaction is complete. The resulting mixture is diluted with ether or ethyl acetate and washed with water. The extracts are dried (MgSO.sub.4) and concentrated in vacuo. The residue is purified to give the trityl protected phthalimidyl indolizine.
Step 2: Detritylation of Trityl Tetrazole
A solution of trityl-protected biphenyl phthalimidyl indolizine (2.0 mmol, obtained from Step 1) in 2 mL of water and 10 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 5 of Example 1915 and purified give the title compound of Example 1931.
EXAMPLE 1932 ##STR134## 3-Butyl-5,6,7,8-tetrahydro-8-amino-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]indolizine
A solution of phthalimidyl indolizine (0.6 mmol, the title compound of Example 1931) and 3 .mu.L (1.5 mmol) of hydrazine in 1.0 mL of ethanol is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo, and purified to give the title compound of Example 1932.
Alternatively, the title compound of Example 1932 can be prepared from the corresponding oxime. A suspension of the biphenyl imidazolyl oxime (0.059 mmol, the title compound of Example 1930) and 20 mg (0.0188 mmol) of 10% palladium on charcoal in 1.5 mL of methanol is stirred at room temperature under 50 psi of hydrogen gas until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 1932.
Examples 1933-3219 located in Tables XLIV-LXXII, are further examples of conformationally restricted angiotensin II antagonists embraced by Formula IV.
TABLE XLIX______________________________________ ##STR135##EX.# R.sup.139 R.sup.140 R.sup.141______________________________________1933 H C.sub.3 H.sub.7 (n) H1934 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51935 H C.sub.3 H.sub.7 (n) CH.sub.2 OH1936 H C.sub.3 H.sub.7 (n) CO.sub.2 H1937 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1938 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31939 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H1940 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.31941 H C.sub.3 H.sub.7 (n) phenyl1942 H C.sub.3 H.sub.7 (n) benzyl1943 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51944 H C.sub.4 H.sub.9 (n) CH.sub.2 OH1945 H C.sub.4 H.sub.9 (n) CO.sub.2 H1946 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H1947 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.31948 H C.sub.4 H.sub.9 (n) phenyl1949 H C.sub.4 H.sub.9 (n) benzyl1950 Cl C.sub.3 H.sub.7 (n) H1951 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51952 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH1953 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H1954 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1955 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31956 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H1957 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.31958 Cl C.sub.4 H.sub.9 (n) H1959 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51960 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH1961 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H1962 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H1963 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31964 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H1965 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.31966 ethyl C.sub.3 H.sub.7 (n) H1967 ethyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51968 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 OH1969 ethyl C.sub.3 H.sub.7 (n) CO.sub.2 H1970 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1971 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31972 ethyl C.sub.4 H.sub.9 (n) H1973 ethyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51974 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 OH1975 ethyl C.sub.4 H.sub.9 (n) CO.sub.2 H1976 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H1977 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31978 n-butyl C.sub.3 H.sub.7 (n) H1979 n-butyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51980 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 OH1981 n-butyl C.sub.3 H.sub.7 (n) CO.sub.2 H1982 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1983 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31984 n-butyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51985 n-butyl C.sub.4 H.sub.9 (n) H1986 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 OH1987 n-butyl C.sub.4 H.sub.9 (n) CO.sub.2 H1988 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H1989 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31990 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H1991 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51992 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH1993 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H1994 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1995 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31996 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H1997 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51998 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH1999 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H2000 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2001 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3______________________________________
TABLE L______________________________________ ##STR136##EX.# R.sup.142 R.sup.143 R.sup.144______________________________________2002 H C.sub.3 H.sub.7 (n) O2003 H C.sub.3 H.sub.7 (n) S2004 H C.sub.3 H.sub.7 (n) CHCO.sub.2 H2005 H C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32006 H C.sub.3 H.sub.7 (n) NOH2007 H C.sub.4 H.sub.9 (n) S2008 Cl C.sub.3 H.sub.7 (n) O2009 Cl C.sub.3 H.sub.7 (n) S2010 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 H2011 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32012 Cl C.sub.3 H.sub.7 (n) NOH2013 Cl C.sub.4 H.sub.9 (n) O2014 Cl C.sub.4 H.sub.9 (n) S2015 Cl C.sub. 4 H.sub.9 (n) CHCO.sub.2 H2016 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32017 Cl C.sub.4 H.sub.9 (n) NOH2018 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O2019 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) S2020 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 H2021 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32022 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NOH2023 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O2024 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) S2025 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 H2026 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32027 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NOH2028 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O2029 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) S2030 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 H2031 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32032 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NOH2033 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O2034 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) S2035 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 H2036 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32037 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NOH2038 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O2039 (2-ethylphenyl) C.sub.3 H.sub.7 (n) S2040 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 H2041 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NOH2042 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O2043 (2-ethylphenyl) C.sub.4 H.sub.9 (n) S2044 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H2045 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NOH______________________________________
TABLE LI______________________________________ ##STR137##EX.# R.sup.145 R.sup.146 R.sup.147______________________________________2046 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52047 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2048 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52049 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2050 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52051 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2052 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52053 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2054 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52055 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub. 3 H.sub.7 (n)2056 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52057 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2058 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52059 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52060 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52061 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5______________________________________
TABLE LII______________________________________ ##STR138##EX.# R.sup.148 R.sup.149 R.sup.150______________________________________2062 H C.sub.3 H.sub.7 (n) H2063 H C.sub.3 H.sub.7 (n) NH.sub.22064 H C.sub.3 H.sub.7 (n) OH2065 H C.sub.3 H.sub.7 (n) CH.sub.2 OH2066 H C.sub.3 H.sub.7 (n) CO.sub.2 H2067 H C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32068 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52069 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2070 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.52071 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.22072 H C.sub.3 H.sub.7 (n) (2-ethylphenyl)2073 H C.sub.4 H.sub.9 (n) CH.sub. 2 OH2074 H C.sub.4 H.sub.9 (n) CO.sub.2 H2075 H C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32076 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52077 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2078 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.52079 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.22080 H C.sub.4 H.sub.9 (n) (2-ethylphenyl)2081 Cl C.sub.3 H.sub.7 (n) H2082 Cl C.sub.3 H.sub.7 (n) NH.sub.22083 Cl C.sub.3 H.sub.7 (n) OH2084 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH2085 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H2086 Cl C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32087 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52088 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2089 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.52090 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.22091 Cl C.sub.3 H.sub.7 (n) (2-ethylphenyl)2092 Cl C.sub.4 H.sub.9 (n) H2093 Cl C.sub.4 H.sub.9 (n) NH.sub.22094 Cl C.sub.4 H.sub.9 (n) OH2095 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH2096 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H2097 Cl C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32098 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52099 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2100 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.52101 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.22102 Cl C.sub.4 H.sub.9 (n) (2-ethylphenyl)2103 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H2104 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NH.sub.22105 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) OH2106 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 OH2107 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CO.sub.2 H2108 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32109 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52110 C.sub.2 H.sub. 5 C.sub.4 H.sub.9 (n) H2111 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NH.sub.22112 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) OH2113 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 OH2114 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CO.sub.2 H2115 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32116 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52117 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H2118 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NH.sub.22119 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) OH2120 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 OH2121 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CO.sub.2 H2122 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32123 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52124 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.22125 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H2126 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NH.sub.22127 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) OH2128 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 OH2129 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CO.sub.2 H2130 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32131 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52132 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H2133 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.22134 (2-ethylphenyl) C.sub.3 H.sub.7 (n) OH2135 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH2136 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H2137 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32138 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52139 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H2140 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.22141 (2-ethylphenyl) C.sub.4 H.sub.9 (n) OH2142 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH2143 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H2144 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32145 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5______________________________________
TABLE LIII______________________________________ ##STR139##EX. # R.sup.151 R.sup.152 R.sup.153 R.sup.154______________________________________2146 H C.sub.3 H.sub.7 (n) H CH.sub.32147 H C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32148 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.32149 H C.sub.4 H.sub.9 (n) H CH.sub.32150 H C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32151 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.32152 Cl C.sub.3 H.sub.7 (n) H CH.sub.32153 Cl C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32154 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.32155 Cl C.sub.4 H.sub.9 (n) H CH.sub.32156 Cl C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32157 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.32158 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H CH.sub.32159 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32160 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H CH.sub.32161 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32162 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H CH.sub.32163 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32164 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.32165 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32166 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.32167 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32168 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.32169 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32170 H C.sub.3 H.sub. 7 (n) H C.sub.2 H.sub.52171 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.52172 H C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.52173 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.52174 Cl C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.52175 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.52176 Cl C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.52177 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.52178 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.52179 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.52180 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.52181 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.52182 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.52183 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.52184 H C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.52185 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.52186 H C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.52187 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.52188 Cl C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.52189 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.52190 Cl C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.52191 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.52192 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.52193 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.52194 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.52195 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.52196 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.52197 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.52198 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.52199 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.52200 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H2201 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H2202 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H2203 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H2204 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H2205 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H______________________________________
TABLE LIV______________________________________ ##STR140##EX. # R.sup.155 R.sup.156 R.sup.157, R.sup.158______________________________________2206 H C.sub.3 H.sub.7 (n) O2207 H C.sub.3 H.sub.7 (n) H, H2208 H C.sub.3 H.sub.7 (n) H, CH.sub.32209 H C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.52210 H C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2211 H C.sub.3 H.sub.7 (n) H, CO.sub.2 H2212 H C.sub.4 H.sub.9 (n) H, H2213 H C.sub.4 H.sub.9 (n) H, CH.sub.32214 H C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.52215 H C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2216 H C.sub.4 H.sub.9 (n) H, CO.sub.2 H2217 Cl C.sub.3 H.sub.7 (n) O2218 Cl C.sub.3 H.sub.7 (n) H, H2219 Cl C.sub.3 H.sub.7 (n) H, CH.sub.32220 Cl C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.52221 Cl C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2222 Cl C.sub.3 H.sub.7 (n) H, CO.sub.2 H2223 Cl C.sub.4 H.sub.9 (n) O2224 Cl C.sub.4 H.sub.9 (n) H, H2225 Cl C.sub.4 H.sub.9 (n) H, CH.sub.32226 Cl C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.52227 Cl C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2228 Cl C.sub.4 H.sub.9 (n) H, CO.sub.2 H2229 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O2230 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, H2231 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CH.sub.32232 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.52233 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2234 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CO.sub.2 H2235 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O2236 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, H2237 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CH.sub.32238 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.52239 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2240 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CO.sub.2 H2241 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O2242 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, H2243 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CH.sub.32244 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2245 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CO.sub.2 H2246 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O2247 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, H2248 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CH.sub.32249 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2250 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CO.sub.2 H2251 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O2252 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, H2253 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CH.sub.32254 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3, CH.sub.32255 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2256 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CO.sub.2 H2257 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O2258 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, H2259 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CH.sub.32260 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3, CH.sub.32261 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2262 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CO.sub.2 H______________________________________
TABLE LV______________________________________ ##STR141##EX. # R.sup.159 R.sup.160 R.sup.161, R.sup.162______________________________________2263 H C.sub.3 H.sub.7 (n) O2264 H C.sub.3 H.sub.7 (n) H, H2265 H C.sub.3 H.sub.7 (n) H, CH.sub.32266 H C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.52267 H C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2268 H C.sub.3 H.sub.7 (n) H, CO.sub.2 H2269 H C.sub.4 H.sub.9 (n) O2270 H C.sub.4 H.sub.9 (n) H, H2271 H C.sub.4 H.sub.9 (n) H, CH.sub.32272 H C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.52273 H C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2274 H C.sub.4 H.sub.9 (n) H, CO.sub.2 H2275 Cl C.sub.3 H.sub.7 (n) O2276 Cl C.sub.3 H.sub.7 (n) H, H2277 Cl C.sub.3 H.sub.7 (n) H, CH.sub.32278 Cl C.sub.3 H.sub.7 (n) CH.sub.3, CH.sub.32279 Cl C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2280 Cl C.sub.3 H.sub.7 (n) H, CO.sub.2 H2281 Cl C.sub.4 H.sub.9 (n) O2282 Cl C.sub.4 H.sub.9 (n) H, H2283 Cl C.sub.4 H.sub.9 (n) H, CH.sub.32284 Cl C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.52285 Cl C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2286 Cl C.sub.4 H.sub.9 (n) H, CO.sub.2 H2287 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O2288 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, H2289 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CH.sub.32290 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.52291 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2292 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CO.sub.2 H2293 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O2294 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, H2295 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CH.sub.32296 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.52297 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2298 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CO.sub.2 H2299 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O2300 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, H2301 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CH.sub.32302 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2303 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CO.sub.2 H2304 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O2305 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, H2306 C.sub.4 H.sub. 9 (n) C.sub.4 H.sub.9 (n) H, CH.sub.32307 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2308 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CO.sub.2 H2309 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O2310 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, H2311 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CH.sub.32312 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3, CH.sub.32313 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2314 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CO.sub.2 H2315 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O2316 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, H2317 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CH.sub.32318 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3, CH.sub.32319 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2320 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CO.sub.2 H______________________________________
TABLE LVI______________________________________ ##STR142##EX. # R.sup.163 R.sup.164 R.sup.165______________________________________2321 H C.sub.3 H.sub.7 (n) CH.sub.22322 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)2323 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)2324 H C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22325 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.22326 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.22327 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)2328 H C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.22329 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.22330 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.22331 Cl C.sub.3 H.sub.7 (n) CH.sub.22332 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)2333 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)2334 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22335 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.22336 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.22337 Cl C.sub.4 H.sub.9 (n) CH.sub.22338 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)2339 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)2340 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.22341 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.22342 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.22343 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.22344 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22345 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.22346 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.22347 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.22348 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22349 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.22350 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.22351 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.22352 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22353 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.22354 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2______________________________________
TABLE LVII______________________________________ ##STR143##EX. # R.sup.166 R.sup.167 R.sup.168______________________________________2355 H C.sub.3 H.sub.7 (n) H2356 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52357 H C.sub.3 H.sub.7 (n) CH.sub.2 OH2358 H C.sub.3 H.sub.7 (n) CO.sub.2 H2359 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2360 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32361 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H2362 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.32363 H C.sub.3 H.sub.7 (n) phenyl2364 H C.sub.3 H.sub.7 (n) benzyl2365 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52366 H C.sub.4 H.sub.9 (n) CH.sub.2 OH2367 H C.sub.4 H.sub.9 (n) CO.sub.2 H2368 H C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2369 H C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32370 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H2371 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.32372 H C.sub.4 H.sub.9 (n) phenyl2373 H C.sub.4 H.sub.9 (n) benzyl2374 Cl C.sub.3 H.sub.7 (n) H2375 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52376 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH2377 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H2378 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2379 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32380 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H2381 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.32382 Cl C.sub.4 H.sub. 9 (n) H2383 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52384 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH2385 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H2386 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2387 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32388 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H2389 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.32390 ethyl C.sub.3 H.sub.7 (n) H2391 ethyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52392 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 OH2393 ethyl C.sub.3 H.sub.7 (n) CO.sub.2 H2394 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2395 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32396 ethyl C.sub.4 H.sub.9 (n) H2397 ethyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52398 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 OH2399 ethyl C.sub.4 H.sub.9 (n) CO.sub.2 H2400 ethyl C.sub. 4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2401 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32402 n-butyl C.sub.3 H.sub.7 (n) H2403 n-butyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52404 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 OH2405 n-butyl C.sub.3 H.sub.7 (n) CO.sub.2 H2406 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2407 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32408 n-butyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52409 n-butyl C.sub.4 H.sub.9 (n) H2410 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 OH2411 n-butyl C.sub.4 H.sub.9 (n) CO.sub.2 H2412 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2413 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32414 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H2415 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52416 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH2417 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H2418 (2-ethylphenyl) C.sub.3 H.sub. 7 (n) CH.sub.2 CO.sub.2 H2419 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32420 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H2421 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52422 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH2423 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H2424 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2425 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3______________________________________
TABLE LVIII______________________________________ ##STR144##EX. # R.sup.169 R.sup.170 R.sup.171______________________________________2426 H C.sub.3 H.sub.7 (n) O2427 H C.sub.3 H.sub.7 (n) S2428 H C.sub.3 H.sub.7 (n) CHCO.sub.2 H2429 H C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32430 H C.sub.3 H.sub.7 (n) NOH2431 H C.sub.4 H.sub.9 (n) O2432 H C.sub.4 H.sub.9 (n) S2433 H C.sub.4 H.sub.9 (n) CHCO.sub.2 H2434 H C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32435 Cl C.sub.3 H.sub.7 (n) O2436 Cl C.sub.3 H.sub.7 (n) S2437 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 H2438 Cl C.sub.3 H.sub.7 (n) CHCO.sub. 2 C(CH.sub.3).sub.32439 Cl C.sub.3 H.sub.7 (n) NOH2440 Cl C.sub.4 H.sub.9 (n) O2441 Cl C.sub.4 H.sub.9 (n) S2442 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 H2443 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32444 Cl C.sub.4 H.sub.9 (n) NOH2445 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O2446 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) S2447 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 H2448 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32449 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NOH2450 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O2451 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) S2452 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 H2453 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32454 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NOH2455 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O2456 C.sub.4 H.sub. 9 (n) C.sub.3 H.sub.7 (n) S2457 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 H2458 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32459 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NOH2460 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O2461 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) S2462 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 H2463 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32464 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NOH2465 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O2466 (2-ethylphenyl) C.sub.3 H.sub.7 (n) S2467 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 H2468 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NOH2469 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O2470 (2-ethylphenyl) C.sub.4 H.sub.9 (n) S2471 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H2472 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NOH______________________________________
TABLE LIX______________________________________ ##STR145##EX. # R.sup.172 R.sup.173 R.sup.174______________________________________2473 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52474 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2475 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52476 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2477 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52478 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2479 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52480 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2481 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52482 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2483 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52484 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2485 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52486 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52487 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52488 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5______________________________________
TABLE LX______________________________________ ##STR146##EX. # R.sup.175 R.sup.176 R.sup.177______________________________________2489 H C.sub.3 H.sub.7 (n) H2490 H C.sub.3 H.sub.7 (n) NH.sub.22491 H C.sub.3 H.sub.7 (n) OH2492 H C.sub.3 H.sub.7 (n) CH.sub.2 OH2493 H C.sub.3 H.sub.7 (n) CO.sub.2 H2494 H C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32495 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52496 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2497 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.52498 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.22499 H C.sub.3 H.sub.7 (n) (2-ethylphenyl)2500 H C.sub.3 H.sub.7 (n) H2501 H C.sub.3 H.sub.7 (n) NH.sub.22502 H C.sub.3 H.sub.7 (n) OH2503 H C.sub.4 H.sub.9 (n) CH.sub.2 OH2504 H C.sub.4 H.sub.9 (n) CO.sub.2 H2505 H C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32506 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52507 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2508 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.52509 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.22510 H C.sub.4 H.sub.9 (n) (2-ethylphenyl)2511 Cl C.sub.4 H.sub.9 (n) H2512 Cl C.sub.4 H.sub.9 (n) NH.sub.22513 Cl C.sub.3 H.sub.7 (n) OH2514 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH2515 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H2516 Cl C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32517 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52518 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2519 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.52520 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.22521 Cl C.sub.3 H.sub.7 (n) (2-ethylphenyl)2522 Cl C.sub.4 H.sub.9 (n) H2523 Cl C.sub.4 H.sub.9 (n) NH.sub.22524 Cl C.sub.4 H.sub.9 (n) OH2525 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH2526 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H2527 Cl C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32528 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52529 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2530 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.52531 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.22532 Cl C.sub.4 H.sub.9 (n) (2-ethylphenyl)2533 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H2534 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NH.sub.22535 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) OH2536 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 OH2537 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CO.sub.2 H2538 C.sub.2 H.sub.5 C.sub.3 H.sub. 7 (n) CO.sub.2 C(CH.sub.3).sub.32539 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52540 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H2541 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NH.sub.22542 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) OH2543 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 OH2544 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CO.sub.2 H2545 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32546 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52547 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H2548 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NH.sub.22549 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) OH2550 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 OH2551 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CO.sub.2 H2552 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32553 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52554 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.22555 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H2556 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NH.sub.22557 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) OH2558 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 OH2559 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CO.sub.2 H2560 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32561 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52562 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H2563 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.22564 (2-ethylphenyl) C.sub.3 H.sub.7 (n) OH2565 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH2566 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H2567 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32568 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52569 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H2570 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.22571 (2-ethylphenyl) C.sub.4 H.sub.9 (n) OH2572 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH2573 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H2574 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32575 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5______________________________________
TABLE LXI______________________________________ ##STR147##EX. # R.sup.178 R.sup.179 R.sup.180 R.sup.181______________________________________2576 H C.sub.3 H.sub.7 (n) H CH.sub.32577 H C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32578 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.32579 H C.sub.4 H.sub.9 (n) H CH.sub.32580 H C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32581 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.32582 Cl C.sub.3 H.sub.7 (n) H CH.sub.32583 Cl C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32584 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.32585 Cl C.sub.4 H.sub.9 (n) H CH.sub.32586 Cl C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32587 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.32588 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H CH.sub.32589 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32590 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H CH.sub.32591 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32592 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H CH.sub.32593 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32594 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.32595 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32596 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.32597 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32598 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.32599 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32600 H C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.52601 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.52602 H C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.52603 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.52604 Cl C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.52605 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.52606 Cl C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.52607 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.52608 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.52609 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.52610 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.52611 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.52612 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.52613 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.52614 H C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.52615 H C.sub.3 H.sub.7 (n) CH.sub. 3 C.sub.6 H.sub.52616 H C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.52617 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.52618 Cl C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.52619 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.52620 Cl C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.52621 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.52622 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.52623 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.52624 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.52625 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.52626 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.52627 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.52628 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.52629 C.sub.4 H.sub.9 (n) C.sub.4 H.sub. 9 (n) CH.sub.3 C.sub.6 H.sub.52630 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H2631 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H2632 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H2633 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H2634 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H2635 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H______________________________________
TABLE LXII______________________________________ ##STR148##EX. # R.sup.182 R.sup.183 R.sup.184, R.sup.185______________________________________2636 H C.sub.3 H.sub.7 (n) O2637 H C.sub.3 H.sub.7 (n) H, H2638 H C.sub.3 H.sub.7 (n) H, CH.sub.32639 H C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.52640 H C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2641 H C.sub.3 H.sub.7 (n) H, CO.sub.2 H2642 H C.sub.4 H.sub.9 (n) O2643 H C.sub.4 H.sub.9 (n) H, H2644 H C.sub.4 H.sub.9 (n) H, CH.sub.32645 H C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.52646 H C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2647 H C.sub.4 H.sub.9 (n) H, CO.sub.2 H2648 Cl C.sub.3 H.sub.7 (n) O2649 Cl C.sub.3 H.sub.7 (n) H, H2650 Cl C.sub.3 H.sub.7 (n) H, CH.sub.32651 Cl C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.52652 Cl C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2653 Cl C.sub.3 H.sub.7 (n) H, CO.sub.2 H2654 Cl C.sub.4 H.sub.9 (n) O2655 Cl C.sub.4 H.sub.9 (n) H, H2656 Cl C.sub.4 H.sub.9 (n) H, CH.sub.32657 Cl C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.52658 Cl C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2659 Cl C.sub.4 H.sub.9 (n) H, CO.sub.2 H2660 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O2661 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, H2662 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CH.sub.32663 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.52664 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2665 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CO.sub.2 H2666 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O2667 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, H2668 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CH.sub.32669 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.52670 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2671 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CO.sub.2 H2672 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O2673 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, H2674 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CH.sub.32675 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2676 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CO.sub.2 H2677 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O2678 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, H2679 C.sub.4 H.sub. 9 (n) C.sub.4 H.sub.9 (n) H, CH.sub.32680 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2681 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CO.sub.2 H2682 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O2683 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, H2684 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CH.sub.32685 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3, CH.sub.32686 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2687 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CO.sub.2 H2688 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O2689 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, H2690 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CH.sub.32691 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3, CH.sub.32692 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2693 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CO.sub.2 H______________________________________
TABLE LXIII______________________________________ ##STR149##EX. # R.sup.186 R.sup.187 R.sup.188, R.sup.189______________________________________2694 H C.sub.3 H.sub.7 (n) O2695 H C.sub.3 H.sub.7 (n) H, H2696 H C.sub.3 H.sub.7 (n) H, CH.sub.32697 H C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.52698 H C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2699 H C.sub.3 H.sub.7 (n) H, CO.sub.2 H2700 H C.sub.4 H.sub.9 (n) O2701 H C.sub.4 H.sub.9 (n) H, H2702 H C.sub.4 H.sub.9 (n) H, CH.sub.32703 H C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.52704 H C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2705 H C.sub.4 H.sub.9 (n) H, CO.sub.2 H2706 Cl C.sub.3 H.sub.7 (n) O2707 Cl C.sub.3 H.sub.7 (n) H, H2708 Cl C.sub.3 H.sub.7 (n) H, CH.sub.32709 Cl C.sub.3 H.sub.7 (n) CH.sub.3, CH.sub.32710 Cl C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2711 Cl C.sub.3 H.sub.7 (n) H, CO.sub.2 H2712 Cl C.sub.4 H.sub.9 (n) O2713 Cl C.sub.4 H.sub.9 (n) H, H2714 Cl C.sub.4 H.sub.9 (n) H, CH.sub.32715 Cl C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.52716 Cl C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2717 Cl C.sub.4 H.sub.9 (n) H, CO.sub.2 H2718 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O2719 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, H2720 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CH.sub.32721 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.52722 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2723 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H, CO.sub.2 H2724 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O2725 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, H2726 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CH.sub.32727 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.52728 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2729 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H, CO.sub.2 H2730 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O2731 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, H2732 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CH.sub.32733 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2734 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H, CO.sub.2 H2735 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O2736 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, H2737 C.sub.4 H.sub. 9 (n) C.sub.4 H.sub.9 (n) H, CH.sub.32738 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2739 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H, CO.sub.2 H2740 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O2741 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, H2742 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CH.sub.32743 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3, CH.sub.32744 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CH.sub.2 OH2745 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H, CO.sub.2 H2746 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O2747 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, H2748 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CH.sub.32749 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3, CH.sub.32750 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CH.sub.2 OH2751 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H, CO.sub.2 H______________________________________
TABLE LXIV______________________________________ ##STR150##EX. # R.sup.190 R.sup.191 R.sup.192______________________________________2752 H C.sub.3 H.sub.7 (n) CH.sub.22753 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)2754 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)2755 H C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22756 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.22757 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.22758 H C.sub.4 H.sub.9 (n) CH.sub.22759 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)2760 H C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.22761 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub. 5)CH.sub.22762 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.22763 Cl C.sub.3 H.sub.7 (n) CH.sub.22764 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)2765 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)2766 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22767 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.22768 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.22769 Cl C.sub.4 H.sub.9 (n) CH.sub.22770 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)2771 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)2772 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.22773 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.22774 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.22775 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.22776 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22777 C.sub.2 H.sub.5 C.sub.4 H.sub. 9 (n) CH.sub.22778 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.22779 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.22780 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22781 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.22782 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.22783 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.22784 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22785 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.22786 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2______________________________________
TABLE LXV______________________________________ ##STR151##EX. # R.sup.193 R.sup.194 R.sup.195______________________________________2787 H C.sub.3 H.sub.7 (n) H2788 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52789 H C.sub.3 H.sub.7 (n) CH.sub.2 OH2790 H C.sub.3 H.sub.7 (n) CO.sub.2 H2791 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2792 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32793 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H2794 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.32795 H C.sub.3 H.sub.7 (n) phenyl2796 H C.sub.3 H.sub.7 (n) benzyl2797 H C.sub.4 H.sub.9 (n) H2798 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52799 H C.sub.4 H.sub.9 (n) CH.sub.2 OH2800 H C.sub.4 H.sub.9 (n) CO.sub.2 H2801 H C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2802 H C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32803 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H2804 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.32805 H C.sub.4 H.sub.9 (n) phenyl2806 H C.sub.4 H.sub.9 (n) benzyl2807 Cl C.sub.3 H.sub.7 (n) H2808 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52809 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH2810 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H2811 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2812 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32813 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H2814 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub. 3).sub.32815 Cl C.sub.4 H.sub.9 (n) H2816 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52817 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH2818 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H2819 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2820 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32821 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H2822 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.32823 ethyl C.sub.3 H.sub.7 (n) H2824 ethyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52825 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 OH2826 ethyl C.sub.3 H.sub.7 (n) CO.sub.2 H2827 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2828 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32829 ethyl C.sub.4 H.sub.9 (n) H2830 ethyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52831 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 OH2832 ethyl C.sub.4 H.sub. 9 (n) CO.sub.2 H2833 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2834 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32835 n-butyl C.sub.3 H.sub.7 (n) H2836 n-butyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52837 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 OH2838 n-butyl C.sub.3 H.sub.7 (n) CO.sub.2 H2839 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2840 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32841 n-butyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52842 n-butyl C.sub.4 H.sub.9 (n) H2843 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 OH2844 n-butyl C.sub.4 H.sub.9 (n) CO.sub.2 H2845 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2846 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32847 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H2848 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52849 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH2850 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H2851 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2852 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32853 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H2854 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52855 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH2856 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H2857 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2858 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3______________________________________
TABLE LXVI______________________________________ ##STR152##EX. # R.sup.196 R.sup.197 R.sup.198______________________________________2859 H C.sub.3 H.sub.7 (n) O2860 H C.sub.3 H.sub.7 (n) S2861 H C.sub.3 H.sub.7 (n) CHCO.sub.2 H2862 H C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32863 H C.sub.3 H.sub.7 (n) NOH2864 H C.sub.4 H.sub.9 (n) O2865 H C.sub.4 H.sub.9 (n) S2866 H C.sub.4 H.sub.9 (n) CHCO.sub.2 H2867 H C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32868 Cl C.sub.3 H.sub.7 (n) O2869 Cl C.sub.3 H.sub.7 (n) S2870 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 H2871 Cl C.sub.3 H.sub.7 (n) CHCO.sub. 2 C(CH.sub.3).sub.32872 Cl C.sub.3 H.sub.7 (n) NOH2873 Cl C.sub.4 H.sub.9 (n) O2874 Cl C.sub.4 H.sub.9 (n) S2875 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 H2876 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32877 Cl C.sub.4 H.sub.9 (n) NOH2878 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O2879 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) S2880 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 H2881 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32992 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NOH2883 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O2884 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) S2885 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 H2886 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32887 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NOH2888 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O2889 C.sub.4 H.sub. 9 (n) C.sub.3 H.sub.7 (n) S2890 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 H2891 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32892 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NOH2893 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O2894 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) S2895 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 H2896 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32897 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NOH2898 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O2899 (2-ethylphenyl) C.sub.3 H.sub.7 (n) S2900 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 S2901 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NOH2902 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O2903 (2-ethylphenyl) C.sub.4 H.sub.9 (n) S2904 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H2905 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NOH______________________________________
TABLE LXVII______________________________________ ##STR153##EX. # R.sup.199 R.sup.200 R.sup.201______________________________________2906 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52907 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2908 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52909 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2910 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52911 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2912 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52913 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2914 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52915 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2916 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52917 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2918 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52919 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52920 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52921 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5______________________________________
TABLE LXVIII______________________________________ ##STR154##EX. # R.sup.202 R.sup.203 R.sup.204______________________________________2922 H C.sub.3 H.sub.7 (n) H2923 H C.sub.3 H.sub.7 (n) NH.sub.22924 H C.sub.3 H.sub.7 (n) OH2925 H C.sub.3 H.sub.7 (n) CH.sub.2 OH2926 H C.sub.3 H.sub.7 (n) CO.sub.2 H2927 H C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32928 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52929 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2930 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.52931 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.22932 H C.sub.3 H.sub.7 (n) (2-ethylphenyl)2933 H C.sub.3 H.sub.7 (n) H2934 H C.sub.3 H.sub.7 (n) NH.sub.22935 H C.sub.3 H.sub.7 (n) OH2936 H C.sub.4 H.sub.9 (n) CH.sub.2 OH2937 H C.sub.4 H.sub.9 (n) CO.sub.2 H2938 H C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32939 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52940 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2941 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.52942 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.22943 H C.sub.4 H.sub.9 (n) (2-ethylphenyl)2944 Cl C.sub.4 H.sub.9 (n) H2945 Cl C.sub.4 H.sub.9 (n) NH.sub.22946 Cl C.sub.3 H.sub.7 (n) OH2947 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH2948 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H2949 Cl C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32950 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52951 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2952 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.52953 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.22954 Cl C.sub.3 H.sub.7 (n) (2-ethylphenyl)2955 Cl C.sub.4 H.sub.9 (n) H2956 Cl C.sub.4 H.sub.9 (n) NH.sub.22957 Cl C.sub.4 H.sub.9 (n) OH2958 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH2959 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H2960 Cl C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32961 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52962 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2963 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.52964 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.22965 Cl C.sub.4 H.sub.9 (n) (2-ethylphenyl)2966 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H2967 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NH.sub.22968 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) OH2969 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 OH2970 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CO.sub.2 H2971 C.sub.2 H.sub.5 C.sub.3 H.sub. 7 (n) CO.sub.2 C(CH.sub.3).sub.32972 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52973 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H2974 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NH.sub.22975 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) OH2976 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 OH2977 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CO.sub.2 H2978 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32979 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52980 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H2981 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NH.sub.22982 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) OH2983 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 OH2984 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CO.sub.2 H2985 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32986 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52987 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.22988 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H2989 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NH.sub.22990 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) OH2991 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 OH2992 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CO.sub.2 H2993 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32994 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52995 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H2996 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.22997 (2-ethylphenyl) C.sub.3 H.sub.7 (n) OH2998 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH2999 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H3000 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.33001 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53002 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H3003 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.23004 (2-ethylphenyl) C.sub.4 H.sub.9 (n) OH3005 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH3006 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H3007 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.33008 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5______________________________________
TABLE LXIX______________________________________ ##STR155##EX. # R.sup.205 R.sup.206 R.sup.207 R.sup.208______________________________________3009 H C.sub.3 H.sub.7 (n) H CH.sub.33010 H C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.33011 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.33012 H C.sub.4 H.sub.9 (n) H CH.sub.33013 H C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.33014 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.33015 Cl C.sub.3 H.sub.7 (n) H CH.sub.33016 Cl C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.33017 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub. 5 CH.sub.2 CH.sub.33018 Cl C.sub.4 H.sub.9 (n) H CH.sub.33019 Cl C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.33020 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.33021 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H CH.sub.33022 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.33023 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H CH.sub.33024 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.33025 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H CH.sub.33026 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.33027 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.33028 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.33029 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.33030 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.33031 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.33032 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.33033 H C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.53034 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.53035 H C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.53036 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.53037 Cl C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.53038 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.53039 Cl C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.53040 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.53041 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.53042 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.53043 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.53044 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.53045 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.53046 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.53047 H C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.53048 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.53049 H C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.53050 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.53051 Cl C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.53052 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.53053 Cl C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.53054 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.53055 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.53056 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.53057 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.53058 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.53059 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.53060 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.53061 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.53062 C.sub.4 H.sub.9 (n) C.sub. 4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.53063 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3064 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H3065 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3066 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H3067 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3068 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H______________________________________
TABLE LXX______________________________________ ##STR156##EX. # R.sup.209 R.sup.210 R.sup.211, R.sup.212______________________________________3069 H C.sub.3 H.sub.7 (n) O3070 H C.sub.3 H.sub.7 (n) H,H3071 H C.sub.3 H.sub.7 (n) H,CH.sub.33072 H C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.53073 H C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3074 H C.sub.3 H.sub.7 (n) H,CO.sub.2 H3075 H C.sub.4 H.sub.9 (n) O3076 H C.sub.4 H.sub.9 (n) H,H3077 H C.sub.4 H.sub.9 (n) H,CH.sub.33078 H C.sub.4 H.sub.9 (n) H,C.sub. 2 H.sub.53079 H C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3080 H C.sub.4 H.sub.9 (n) H,CO.sub.2 H3081 Cl C.sub.3 H.sub.7 (n) O3082 Cl C.sub.3 H.sub.7 (n) H,H3083 Cl C.sub.3 H.sub.7 (n) H,CH.sub.33084 Cl C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.53085 Cl C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3086 Cl C.sub.3 H.sub.7 (n) H,CO.sub.2 H3087 Cl C.sub.4 H.sub.9 (n) O3088 Cl C.sub.4 H.sub.9 (n) H,H3089 Cl C.sub.4 H.sub.9 (n) H,CH.sub.33090 Cl C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53091 Cl C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3092 Cl C.sub.4 H.sub.9 (n) H,CO.sub.2 H3093 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O3094 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,H3095 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.33096 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub. 53097 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3098 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CO.sub.2 H3099 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O3100 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,H3101 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.33102 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53103 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3104 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CO.sub.2 H3105 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O3106 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,H3107 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.33108 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3109 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CO.sub.2 H3110 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O3111 C.sub.4 H.sub.9 (n) C.sub. 4 H.sub.9 (n) H,H3112 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.33113 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3114 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CO.sub.2 H3115 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O3116 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,H3117 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.33118 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.33119 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3120 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CO.sub.2 H3121 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O3122 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,H3123 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.33124 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3,CH.sub.33125 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3126 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE LXXI______________________________________ ##STR157##EX. # R.sup.213 R.sup.214 R.sup.215, R.sup.216______________________________________3127 H C.sub.3 H.sub.7 (n) O3128 H C.sub.3 H.sub.7 (n) H,H3129 H C.sub.3 H.sub.7 (n) H,CH.sub.33130 H C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.53131 H C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3132 H C.sub.3 H.sub.7 (n) H,CO.sub.2 H3133 H C.sub.4 H.sub.9 (n) O3134 H C.sub.4 H.sub.9 (n) H,H3135 H C.sub.4 H.sub.9 (n) H,CH.sub.33136 H C.sub.4 H.sub.9 (n) H,C.sub. 2 H.sub.53137 H C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3138 H C.sub.4 H.sub.9 (n) H,CO.sub.2 H3139 Cl C.sub.3 H.sub.7 (n) O3140 Cl C.sub.3 H.sub.7 (n) H,H3141 Cl C.sub.3 H.sub.7 (n) H,CH.sub.33142 Cl C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.33143 Cl C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3144 Cl C.sub.3 H.sub.7 (n) H,CO.sub.2 H3145 Cl C.sub.4 H.sub.9 (n) O3146 Cl C.sub.4 H.sub.9 (n) H,H3147 Cl C.sub.4 H.sub.9 (n) H,CH.sub.33148 Cl C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53149 Cl C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3150 Cl C.sub.4 H.sub.9 (n) H,CO.sub.2 H3151 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O3152 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,H3153 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.33154 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub. 53155 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3156 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CO.sub.2 H3157 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O3158 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,H3159 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.33160 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53161 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3162 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CO.sub.2 H3163 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O3164 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,H3165 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.33166 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3167 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CO.sub.2 H3168 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O3169 C.sub.4 H.sub.9 (n) C.sub. 4 H.sub.9 (n) H,H3170 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.33171 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3172 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CO.sub.2 H3173 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O3174 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,H3175 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.33176 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.33177 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3178 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CO.sub.2 H3179 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O3180 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,H3181 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.33182 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3,CH.sub.33183 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3184 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE LXXII______________________________________ ##STR158##EX. # R.sup.217 R.sup.218 R.sup.219______________________________________3185 H C.sub.3 H.sub.7 (n) CH.sub.23186 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)3187 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3188 H C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.23189 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.23190 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.23191 H C.sub.4 H.sub.9 (n) CH.sub.23192 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)3193 H C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.23194 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.23195 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.23196 Cl C.sub.3 H.sub.7 (n) CH.sub.23197 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)3198 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3199 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.23200 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.23201 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.23202 Cl C.sub.4 H.sub.9 (n) CH.sub.23203 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)3204 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3205 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.23206 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.23207 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.23208 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub. 23209 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.23210 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.23211 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.23212 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.23213 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.23214 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.23215 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.23216 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.23217 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.23218 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.23219 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2______________________________________
An appropriately substituted triazole 91, the heterocyclic starting material, may be prepared as described in the literature [E. C. Taylor in "Triazoles: 1,2,4" Vol. 37 of The Chemistry of Heterocyclic Compounds. A. Weissberger Eds., Wiley-Interscience, New York, 1981]. The triazole 1 in N,N-dimethylformamide (DMF) is treated with base, such as potassium tert-butoxide, followed by addition of appropriate alkylating agent 92 to give the coupled product 93 (Scheme XIII). For compounds where X is a substituted phenyl group, several procedures have been published for the preparations of the alkylating agent 92 [see references for compound 2]. ##STR159##
The coupled triazole 93 itself may be an angiotensin II receptor antagonist, but it may also be used as a key intermediate in the preparation of the compounds of the invention. Triazole 93 in THF (or DME) is treated with base (such as n-BuLi or LDA) at -78.degree. C. (or -65.degree. C.), followed by addition of an appropriate alkylating agent or other electrophiles 94 (the acetal shown in Scheme I may be other aldehyde masking group or equivalent, and LG is a leaving group such as halide, mesylate, triflate or tosylate). The resulting masked aldehyde 95 was stirred with NaOAc in aqueous acetic acid at reflux for a few days (1 to 5 days) to give one of the compounds of the invention, a cyclized triazole 96.
The triazole 96 may be used as an intermediate to prepare other substituted compounds with appropriate functional group transformations and preparations of some of those compounds are illustrated in Scheme XIV and XV (all of the intermediates shown in the sequences are also angiotensin II receptor antagonists). For example, The unsaturated triazole 96, NaHCO.sub.3 and NBS in CCl.sub.4 is stirred at reflux to give a bromide 97. The bromide 97 may be treated with organolithium, such as n-BuLi or tert-BuLi, followed by addition of an appropriate electrophile, (such as alkyl halides, carbon dioxide, aldehyde, ketone and others) to give the addition product 98. The olefin 98 may be hydrogenated to give its saturated product 99. ##STR160##
Alternatively, as illustrated in Scheme XV, the unsaturated triazole 96 may be treated with NBS in wet DMSO to give a bromohydrin which may be reduced with nBu.sub.3 SnH to an alcohol 100 and the oxidation of the alcolol with MnO.sub.2 will afford a ketone 101. The ketone 101 may be condensed with appropriately substituted amine, then reduced to an amine 102 with an appropriate reducing agent (e.g. NaBH.sub.4, or hydrogen over catalyst). The amine 102 may also be prepared directly from olefin 96 under bromination condition (NBS, CH.sub.3 CN) with a large excess of succinimide. The amine 102 may be used to prepare other derivatives. Alternatively, the alcohol 100 may be treated with triphenylphosphine, diethoxyazo dicarboxylate and an imide (e.g. phthalimide) to give an imide analogue which may be converted to an amine 102. ##STR161##
In Scheme XVI, an alternative preparation for the compounds of the invention is described. An appropriately substituted triazole 91 may be treated with one equivalent of base, then protected as SEM or BOC derivative. The protected triazole then is treated with another equivalent of base followed by addition of electrophile 107 or 108. Electrophiles 107 and 108 can be prepared from HC(.dbd.O)(CR.sup.4 R.sup.5)(CH.sub.2).sub.n C(.dbd.O)LG and an appropriate organometallic reagent such as XC.sub.6 H.sub.4 MgBr. If necessary, the resulting lithium anion obtained from the procedure described above may be converted to other organometallic reagents according to well-established procedures.
If PLG is a hydroxyl group and Z is a proton, the resulting addition product 109, may be cyclized with triphenylphosphine and diethyl azodicarboxylate [Hitsunobu, O. Synthesis, 1981, 1-27; or other modified conditions]. If PLG is or is converted to a leaving group, such as halides, tosylate, and Z is a proton, the cyclization may be achieved with a weak base in DHF (e.g. K.sub.2 CO.sub.3, Cs.sub.2 CO.sub.3) to give a ketone 101. The ketone 101 may be reduced to an alcohol 100 with NaBH.sub.4 in methanol. The alcohol 100 may be dehydrated to olefin 96 with acid (e.g. HOAc and heat) or thionyl chloride and pyridine. Other compounds may be prepared from compounds 96, 100, or 101 as described in Scheme XIV and XV. ##STR162##
EXAMPLE 3220 ##STR163## 3-Butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-1,2,4-triazolo[4,3-a]pyridine
Step 1: Preparation of Biphenyl Triazole
To a solution of 2-butylpyrrole (2.65 mmol) in 5.3 mL of DHF is added 3.45 mL (3.45 mmol) of potassium tert-butoxide (1M in THF), and the resulting solution is stirred at room temperature for 30 min. To the dark brown mixture is added 2.75 g (3.45 mmol) of the bromomethyl biphenyl. The reaction mixture is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is purified to give the trityl-protected biphenyl triazole.
Step 2: Preparation of Dimethyl Acetal Triazole
To a solution of biphenyl triazole (3.18 mmol, obtained from Step 1) in 16 mL of THF cooled at -45.degree. C. (acetonitrile-dry ice) is added 2.8 mL (4.06 mmol) of n-butyllithium (1.45 H in hexane) over a 4-min period. The resulting dark purple solution is stirred cold for another 15 min, followed by addition of 1.0 mL (6.59 mmol) of 3-bromopropionaldehyde dimethyl acetal in one portion. The mixture is stirred cold for 40 min, then is slowly warmed to -10.degree. C. The reaction is quenched with aqueous NH.sub.4 Cl, extracted with diethyl ether. The combined extracts are washed with brine, dried (HgSO.sub.4), concentrated in vacuo and purified to give the biphenyl dimethyl acetal triazole intermediate.
Step 3: Preparation of Biphenyl Bicyclic Triazole
A solution of the crude biphenyl dimethyl acetal triazole (3.18 mmol, obtained from Step 2) and 5.3 g (88 mmol) of NaOAc in 13 mL of water and 40 mL of glacial acetic acid is stirred at reflux until the reaction is complete. The solution is cooled and concentrated in vacuo. The residue is dissolved in methylene chloride and filtered. The filtrate is stirred with 2 g (7.2 mmol) of trityl chloride and 3 mL (21.5 mmol) of TEA at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is purified to give the biphenyl bicyclic triazole.
Step 4: Detritylation of Trityl Tetrazole
A solution of the biphenyl bicyclic triazole (0.144 mmol, obtained from Step 3) is stirred with 1 mL of water and 6 mL of acetic acid at room temperature until the reaction is complete. The solution is concentrated in vacuo, stirred in aqueous NaHCO.sub.3 and washed with ether. The aqueous residue is acidified with 3N HCl to pH 4 and extracted with methylene chloride. The combined extracts are dried (MgSO.sub.4), concentrated and purified to give the title compound of Example 3220.
EXAMPLE 3221 ##STR164## 7-Bromo-3-butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-1,2,4-triazolo[4,3-a]pyridine
Step 1: Preparation of Bromo Olefin Triazole
A solution of trityl-protected bicyclic triazole (0.101 mmol, obtained from Step 3 of Example 3220), 20 mg (0.112 mmol) of NBS and 7 mg (catalytic) of AIBN in 2.8 mL of CCl.sub.4 is stirred at reflux until the reaction is complete. The reaction mixture is diluted with CCl.sub.4 and washed with water. The organic layer is dried (MgSO.sub.4) and concentrated in vacuo. The residue is purified to give the biphenyl bromo olefin triazole.
Step 2: Detritylation of the Trityl Tetrazole
A solution of bromo olefin triazole (0.0427 mmol, obtained from Step 1) in 0.8 mL of water and 5 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 4 of Example 3220 and purified to give the title compound of Example 3221.
EXAMPLE 3222 ##STR165## 3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-1,2,4-triazolo[4,3-a]pyridine
A suspension of bicyclic olefin triazole (0.1 mmol, the title compound of Example 3220) and 20 mg (0.019 mmol) of 10% palladium on charcoal in 2 mL of absolute ethanol is agitated on a Parr apparatus under 50 psi of hydrogen gas at room temperature until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 3222.
EXAMPLE 3223 ##STR166## 3-Butyl -5,6-dihydro-5-[2'-(1H-tetrazol -5-yl)[1,1'-biphenyl]-4-yl]-1,2,4-triazolo[4,3-a]pyridin-8(5H) -one
Step 1: Preparation of the Bromohydrin Intermediate
To a solution of biphenyl olefin triazole (3.13 mmol, obtained from Step 4 of Example 3220) in 22 mL (0,122 mmol) of water and 22 mL of DMSO at room temperature is added 587 mg (3.30 mmol) of NBS in one portion. The resulting orange solution is stirred at room temperature for 40 min, quenched with aqueous Na.sub.2 SO.sub.3, and extracted with chloroform. The combined extracts are washed with water, and the combined aqueous layers are extracted with chloroform. The combined extracts are washed with brine, dried (MgSO.sub.4) and concentrated in vacuo to give a crude bromohydrin intermediate which can be used directly in the subsequent Step 2 without further purification.
Step 2: Preparation of the Trityl-Protected Biphenyl Hydroxy Triazole
To the crude bromohydrin (3.13 mmol, obtained from Step 1) in 42 mL of degassed dry benzene is added 4.3 mL (14.7 mmol) of n-Bu.sub.3 SnH and 456 mg (2.7 mmol) of AIBN in one portion and the resulting solution is stirred at reflux until the reaction is complete. The mixture is concentrated in vacuo and partitioned between hexane and acetonitrile. The acetonitrile layer is washed with hexane, and the combined hexane layers are extracted with acetonitrile. The combined acetonitrile extracts are concentrated in vacuo to give an isomeric mixture of both cis- and trans-hydroxy triazoles (relative to the biphenyl moiety). The crude mixture can be used directly in subsequent Step 3 without further purification. The mixture may also be used to prepare the biphenyl trans-hydroxy triazole (the title compound of Example 3225).
Step 3: Preparation of the Keto Triazole
A suspension of the crude biphenyl hydroxy triazole (2.72 mmol, obtained from Step 2) and 13 g of active MnO.sub.2 in 15 mL of methylene chloride is stirred at room temperature until the reaction is complete. The mixture is filtered through a pad of celite, rinsed with IPA-methylene chloride, and concentrated in vacuo. The residue is purified to give the trityl-protected biphenyl keto triazole.
Step 4: Detritylation of Trityl Tetrazole
A solution of trityl-protected biphenyl keto triazole (0.131 mmol, obtained from Step 3) in 1.0 mL of water and 5.0 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 4 of Example 3220 and purified to give the title compound of Example 3223.
EXAMPLE 3224 ##STR167## 3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-1,2,4-triazolo[4,3-a]pyridin-cis-8-ol
Step 1: Preparation of Biphenyl Cis-Hydroxy Triazole
To a solution of biphenyl keto triazole (0.456 mmol, obtained from Step 3 of Example 3223) in 0.5 mL of methanol and 2.0 mL of THF at 0.degree. C. is added in small portions 34 mg (0.899 mmol) of NaBH.sub.4. The resulting solution is stirred at 0.degree. C., and slowly warmed to room temperature. The reaction is quenched with aqueous NH.sub.4 Cl, extracted with methylene chloride, dried (MgSO.sub.4) and concentrated in vacuo. The residue is purified to give the biphenyl hydroxy triazole.
Step 2: Detritylation of Trityl Tetrazole
A solution of the biphenyl hydroxy triazole (0.259 mmol, obtained from Step 1) in 0.4 mL of water and 2.0 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is purified to give the title compound of Example 3224.
EXAMPLE 3225 ##STR168## 3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-1,2,4-triazolo[4,3-a]pyridin-trans-8-ol
Step 1: Preparation of Biphenyl Trans-Hydroxy Triazole
A suspension of the crude biphenyl hydroxy triazole (1.307 mmol, obtained from Step 2 of Example 3223) and 3.0 g of active MnO.sub.2 in 5.0 mL of methylene chloride is stirred at room temperature. The reaction is worked up before its completion. The mixture is filtered through a pad of celite, rinsed with IPA-methylene chloride, and concentrated in vacuo. The residue is purified to give the trityl protected biphenyl trans-hydroxy triazole.
Alternatively, the biphenyl trans-hydroxy triazole can be prepared using the Mitsunobu reaction conditions. To a solution of diethyl azodicarboxylate (2.0 mmol) and 3-nitrobenzoic acid (2.0 mmol) in 2.0 mL of THF is added dropwise a solution of the biphenyl hydroxy triazole (2.0 mmol, obtained from Step 1 of Example 3224), and triphenylphosphine (2.0 mmol) in 1.0 mL of THF at room temperature. The resulting solution is stirred at room temperature until the reaction is complete. The resulting mixture is diluted with ether or ethyl acetate, and washed with water. The extracts are dried (MgSO.sub.4) and concentrated in vacuo to give the biphenyl indolizinyl nitrobenzoate. The crude benzoate is hydrolyzed with LiOH in aqueous THF at room temperature and purified to give the biphenyl trans-hydroxy triazole.
Step 2: Detritylation of Trityl Tetrazole
A solution of the trityl protected biphenyl trans-hydroxy triazole (0.079 mmol, obtained from Step 1) in 0.4 mL of water and 2.0 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in Vacuo. The residue is purified to give the title compound of Example 3225.
EXAMPLE 3226 ##STR169## 1-[3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-1,2,4-triazolo[4,3-a]pyridin-8-yl]-2,5-pyrrolidinedione
Step 1: Preparation of Succinimidyl Triazole
To a solution of biphenyl triazole (3.13 mmol, Example 3220, Step 3) and 1.25 g (12.6 mmol) of succinimide in 20 mL of anhydrous acetonitrile is added 572 mg (3.21 mmol) of NBS in one portion. The resulting orange-red solution is stirred at room temperature for 30 min, then evaporated in vacuo. The residue is dissolved in ethyl acetate and washed with aqueous sodium bisulfite, water, and brine. The extracts are dried (MgSO.sub.4) and concentrated in vacuo. The residue is purified to give the trityl protected succinimidyl triazole.
Alternatively, the succinimide can be prepared from its corresponding hydroxy triazole. To a solution of the biphenyl hydroxy triazole (2.0 mmol, obtained from Step i of Example 3224 or 3225), succinimide (2.0 mmol), and triphenylphosphine (2.0 mmol) in 2.0 mL of THF is added dropwise a solution of diethyl azodicarboxylate (2.0 mmol) in 1 mL of THF at room temperature. The resulting solution is stirred at room temperature until the reaction is complete. The resulting mixture is diluted with ether or ethyl acetate and washed with water. The extracts are dried (MgSO.sub.4) and concentrated in vacuo. The residue is purified to give the trityl protected succinimidyl triazole.
Step 2: Detritylation of Trityl Tetrazole
A solution of trityl protected succinimidyl triazole (0.16 mmol, obtained from Step 1) in 0.2 mL of water and 1 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 4 of Example 3220 and purified to give the title compound of Example 3226.
EXAMPLE 3227 ##STR170## 4-[3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-1,2,4-triazolo[4,3- a]pyridin-8-yl]amino]-4-oxobutanoic acid, hydrazide
A solution of succinimidyl triazole (0.06 mmol, obtained from Example 3226) and 11 .mu.L (5.6 mmol) of hydrazine in 0.5 mL of ethanol is stirred at room temperature until the reaction is complete and concentrated in vacuo to give the title compound of Example 3227.
EXAMPLE 3228 ##STR171## 3-Butyl-6,7-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-5H-1,2,4-triazolo[4,3-a]azepine
Step 1: Alkylation of Biphenyl Triazole
To a solution of biphenyl triazole (0.152 mmol, obtained from Step 2 of Example 3220) in 0.8 mL of DME cooled at -45.degree. C. (acetonitrile-dry ice) is added 125 .mu.L (0.2 mmol) of n-butyllithium (1.6M in hexane) over a 4-min period. The resulting dark red solution is stirred cold for another 15 min, followed by addition of 70 .mu.L (0.37 mmol) of 2-(3-bromopropyl)-5,5-dimethyl-1,3-dioxane in one portion. The mixture is stirred cold for 40 min, then is slowly warmed to -10.degree. C. The reaction is quenched with aqueous NH.sub.4 Cl, extracted with diethyl ether. The combined extracts are washed with brine, dried (MgSO.sub.4) and concentrated in vacuo. The crude product can be used directly in the subsequent Step 2 without purification.
Step 2: Preparation of the Bicyclic Triazole
A solution of the crude mixture (0.152 mmol, obtained from Step 1) and 255 mg (3 mmol) of NaOAc in 0.6 mL of water and 2 mL of glacial acetic acid is stirred at reflux until the reaction is complete. The mixture is cooled and concentrated in vacuo. The residue is dissolved in methylene chloride and filtered. The filtrate is stirred with 130 mg (0.46 mmol) of trityl chloride and 0.22 mL (1.6 mmol) of TEA at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is purified to give the biphenyl bicyclic triazole.
Step 3: Detritylation of Trityl Tetrazole
A solution of the biphenyl bicyclic triazole (0.035 mmol, obtained from Step 2) is stirred with 0.4 mL of water and 2 mL of acetic acid at room temperature until the reaction is complete. The solution is concentrated in vacuo. The residue is worked up as described in Step 4 of Example 3220 and purified to give the title compound of Example 3228.
EXAMPLE 3229 ##STR172## 1,1-Dimethylethyl [3-butyl-6,7-dihydro-5-[2'-(1H-tetrazol-5 -yl) [1,1'-biphenyl]-4-yl]-1,2,4-triazolo[4,3-a]pyridin-8(5H)-ylidene]acetate
Step 1: Preparation of Tert-Butyl Ester
To a suspension of 64 mg (2.63 mmol) of magnesium in 3.0 mL of THF at 55.degree. C. is added two 10-.mu.L portions of 1,2-dibromoethane, 5 min apart. The resulting mixture is stirred at 45.degree. C. for 10 min, followed by dropwise addition of a solution of biphenyl keto triazole (0.306 mmol, obtained from Step 3 of Example 3223) and 242 .mu.L (1.50 mmol) of tert-butyl bromoacetate in 2.0 mL of THF at 55.degree. C. over a 1-h period. The resulting solution is stirred until the reaction is complete. The mixture is cooled and quenched with aqueous NH.sub.4 Cl. The mixture is extracted with ether, dried (MgSO.sub.4) and concentrated in vacuo. The crude mixture can be used directly in the subsequent Step 2 without further purification.
Step 2: Preparation of Unsaturated Butyl Ester
To a solution of the crude biphenyl tert-butyl ester intermediate (0.306 mmol, obtained from Step 1) and 200 .mu.L (2.47 mmol) of pyridine in 2 mL of methylene chloride at 0.degree. C. is added dropwise 80 .mu.L (1.1 mmol) of thionyl chloride. The resulting dark brown solution is stirred at 0.degree. C. for 1 h, diluted with water and extracted with methylene chloride. The residue is purified to give the biphenyl indolizinyl unsaturated ester.
Step 3: Detritylation of Trityl Tetrazole
A solution of biphenyl indolizinyl unsaturated ester (0.133 mmol, obtained from Step 2) in 1.0 mL of water and 5.0 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 4 of Example 3220 and purified to give the title compound of Example 3229.
EXAMPLE 3230 ##STR173## [3-Butyl-6,7-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-1,2,4-triazolo[4,3-a]pyridin-8(5H)-ylidene]acetic acid
To a solution of unsaturated tert-butyl ester (0.0627 mmol, the title compound of Example 3229) in 2 mL of CDCl.sub.3 at room temperature is added 0.5 mL of TFA, and the progress of the reaction is monitored by .sup.1 H NMR. The resulting yellow solution is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The crude product is purified to give the title compound of Example 3230.
EXAMPLE 3231 ##STR174## 1,1-Dimethylethyl 3-butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]-1,2,4-triazolo[4,3-a]pyridin-8-acetate
Step 1: Preparation of Deconjugated Ester
To a solution of ester (0.237 mmol, obtained from Step 2 of Example 3229) in 4 mL of THF at 0.degree. C. is added 310 .mu.L of 1.5M (0.467 mmol) LDA over a 2-min period, and the resulting solution is stirred at 0.degree. C. for 10 min. The mixture is cooled to -78.degree. C., stirred cold for 5 min, and quenched dropwise at -78.degree. C. with 100 .mu.L of acetic acid in 1 mL of hexane. The mixture is stirred cold, then warmed to room temperature and treated with aqueous NaHCO.sub.3. The mixture is extracted with methylene chloride. The combined extracts are washed with water, dried (MgSO.sub.4) and concentrated in vacuo to give a crude mixture. The crude product is purified to give the biphenyl indolizinyl deconjugated ester.
Step 2: Detritylation of Trityl Tetrazole
A solution of trityl-protected biphenyl indolizinyl deconjugated ester (0.165 mmol, obtained from Step 1) in 1 mL of water and 3 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 4 of Example 3220. The crude product is purified to give the title compound of Example 3231.
EXAMPLE 3232 ##STR175## 3-Butyl-5,6-dihydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-1,2,4-triazolo[4,3-a]pyridin-8-acetic acid
To a solution of biphenyl indolizinyl tert-butyl ester (0.039 mmol, the title compound of Example 3231) in 0.5 mL of chloroform is added 0.25 mL of TFA, and the progress of the reaction is monitored by .sup.1 H NMR. The resulting solution is stirred at room temperature until the reaction is complete. The mixture is quenched with methanol and concentrated in vacuo. The residue is purified to give the title compound of Example 3232.
EXAMPLE 3233 ##STR176## 1,1-Dimethylethyl 3-butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-1,2,4-triazolo[4,3-a]pyridin-cis-8-acetate
A suspension of the biphenyl indolizinyl unsaturated ester (0.059 mmol, the title compound of Example 3231) and 20 mg (0.0188 mmol) of 10% palladium on charcoal in 1.5 mL of methanol is stirred at room temperature under an atmosphere of hydrogen gas until the reaction is complete. The mixture is filtered through a pad of celite and concentrated in vacuo. The residue is purified to give the title compound of Example 3233.
EXAMPLE 3234 ##STR177## 3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-1,2,4-triazolo[4,3-a]pyridin-cis-8-acetic acid
To a solution of tert-butyl ester (0.0332 mmol, obtained from Example 3233) in 0.4 mL of CDCl.sub.3 is added 0.2 mL of TFA, and the progress of the reaction is monitored by .sup.1 H NMR. The resulting solution is allowed to stand at room temperature until the reaction is complete. The reaction mixture is diluted with methanol and concentrated. The residue is purified to give the title compound of Example 3234.
EXAMPLE 3235 ##STR178## 3-Butyl-5,6-dihydro-N-hydroxy-5-[2'-(1H-tetrazol-5-yl)[1.1'-biphenyl]-4-yl]triazolo[4,3-a]pyridin-8(7H) -imine
A mixture of biphenyl keto imidazole (0.094 mmol, the title compound of Example 3223), 20 mg (0.29 mmol) of N-hydroxyamine (hydrochloride salt) and 30 mg of NaOAc in 2 mL of methanol is stirred at 60.degree. C. until the reaction is complete. The mixture is diluted with chloroform and filtered. The solid is washed with methanol. The filtrate is concentrated in vacuo and purified to give the title compound of Example 3235.
EXAMPLE 3236 ##STR179## 1-[3-Butyl-5,6,7,8-tetrahydro-5-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-1,2,4-triazolo[4,3- a]pyridin-8-yl]phthalimide
Step 1: Preparation of Biphenyl Phthalimidyl Triazole
To a solution of the biphenyl hydroxy triazole (2.0 mmol, obtained from Step 1 of Example 3224 or 3225), phthalimide (2.0 mmol), and triphenylphosphine (2.0 mmol) in 2.0 mL of THF is added dropwise a solution of diethyl azodicarboxylate (2.0 mmol) in 1 mL of THF at room temperature. The resulting solution is stirred at room temperature until the reaction is complete. The resulting mixture is diluted with ether or ethyl acetate and washed with water. The extracts are dried (MgSO.sub.4) and concentrated in vacuo. The residue is purified to give the trityl protected phthalimidyl triazole.
Step 2: Detritylation of Trityl Tetrazole
A solution of trityl-protected biphenyl phthalimidyl triazole (2.0 mmol, obtained from Step 1) in 2 mL of water and 10 mL of acetic acid is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The residue is worked up as described in Step 5 of Example 3220 and purified give the title compound of Example 3236.
EXAMPLE 3237 ##STR180## 3-Butyl-5,6,7,8-tetrahydro-8-amino-5-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]triazole
A solution of phthalimidyl triazole (0.6 mmol, the title compound of Example 3236) and 3 .mu.L (1.5 mmol) of hydrazine in 1.0 mL of ethanol is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo, and purified to give the title compound of Example 3237.
Alternatively, the title compound of Example 3237 can be prepared from the corresponding oxime. A suspension of the biphenyl imidazolyl oxime (0.059 mmol, the title compound of Example 3235) and 20 mg (0.0188 mmol) of 10% palladium on charcoal in 1.5 mL of methanol is stirred at room temperature under 50 psi of hydrogen gas until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 3237.
Further examples of conformationally restricted angiotensin II antagonists (3238-3700) embraced by Formula V above are located in Tables LXXIII-XCVI.
TABLE LXXIII______________________________________ ##STR181##EX. # R.sup.220 R.sup.221______________________________________3238 C.sub.3 H.sub.7 (n) H3239 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53240 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3241 C.sub.3 H.sub.7 (n) (2-ethylphenyl)3242 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)3243 C.sub.3 H.sub.7 (n) phenyl3244 C.sub.3 H.sub.7 (n) benzyl3245 C.sub.3 H.sub.7 (n) phenylethyl3246 C.sub.3 H.sub.7 (n) CH.sub.2 OH3247 C.sub.3 H.sub.7 (n) CO.sub.2 H3248 C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3249 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53250 C.sub. 4 H.sub.9 (n) C.sub.3 H.sub.7 (n)3251 C.sub.4 H.sub.9 (n) (2-ethylphenyl)3252 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)3253 C.sub.4 H.sub.9 (n) phenyl3254 C.sub.4 H.sub.9 (n) benzyl3255 C.sub.4 H.sub.9 (n) phenylethyl3256 C.sub.4 H.sub.9 (n) CH.sub.2 OH3257 C.sub.4 H.sub.9 (n) CO.sub.2 H______________________________________
TABLE LXXIV______________________________________ ##STR182##EX. # R.sup.222 R.sup.223______________________________________3258 C.sub.3 H.sub.7 (n) O3259 C.sub.3 H.sub.7 (n) S3260 C.sub.3 H.sub.7 (n) NOH3261 C.sub.3 H.sub.7 (n) CHCO.sub.2 H3262 C.sub.3 H.sub.7 (n) C(C.sub.2 H.sub.5)CO.sub.2 H3263 C.sub.3 H.sub.7 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H3264 C.sub.3 H.sub.7 (n) CHC.sub.2 H.sub.53265 C.sub.4 H.sub.9 (n) S3266 C.sub.4 H.sub.9 (n) C(C.sub.2 H.sub.5)CO.sub.2 H3267 C.sub.4 H.sub.9 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H3268 C.sub.4 H.sub.9 (n) CHC.sub.2 H.sub.5______________________________________
TABLE LXXV______________________________________ ##STR183##EX. # R.sup.224 R.sup.225______________________________________3269 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53270 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3271 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53272 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)______________________________________
TABLE LXXVI______________________________________ ##STR184##EX. # R.sup.226 R.sup.227______________________________________3273 C.sub.3 H.sub.7 (n) H3274 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53275 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3276 C.sub.3 H.sub.7 (n) (2-ethylphenyl)3277 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)3278 C.sub.3 H.sub.7 (n) phenyl3279 C.sub.3 H.sub.7 (n) benzyl3280 C.sub.3 H.sub.7 (n) phenylethyl3281 C.sub.3 H.sub.7 (n) NH.sub.23282 C.sub.3 H.sub.7 (n) OH3283 C.sub.3 H.sub.7 (n) CH.sub.2 OH3284 C.sub.3 H.sub.7 (n) CO.sub.2 H3285 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53286 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)3287 C.sub.4 H.sub.9 (n) (2-ethylphenyl)3288 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)3289 C.sub.4 H.sub.9 (n) phenyl3290 C.sub.4 H.sub.9 (n) benzyl3291 C.sub.4 H.sub.9 (n) phenylethyl3292 C.sub.4 H.sub.9 (n) CH.sub.2 OH3293 C.sub.4 H.sub.9 (n) CO.sub.2 H______________________________________
TABLE LXXVII______________________________________ ##STR185##EX. # R.sup.228 R.sup.229 R.sup.230______________________________________3294 C.sub.3 H.sub.7 (n) H CH.sub.33295 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.53296 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.53297 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5 CH.sub.23298 C.sub.3 H.sub.7 (n) H CH.sub.2 CO.sub.2 H3299 C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3300 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.33301 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.53302 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.53303 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5 CH.sub.23304 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CO.sub.2 H3305 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H3306 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.33307 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.53308 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.53309 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.5 CH.sub.23310 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H3311 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H3312 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.33313 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53314 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.53315 C.sub. 3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.23316 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3317 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H3318 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.33319 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.53320 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.53321 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H3322 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H3323 C.sub.4 H.sub.9 (n) H CH.sub.33324 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.53325 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.53326 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5 CH.sub.23327 C.sub.4 H.sub.9 (n) H CH.sub.2 CO.sub.2 H3328 C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3329 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.33330 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.53331 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.53332 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5 CH.sub.23333 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CO.sub.2 H3334 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H3335 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.33336 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.53337 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.53338 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.5 CH.sub.23339 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H3340 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H3341 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.33342 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53343 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.53344 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.23345 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3346 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H3347 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.33348 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.53349 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.53350 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H3351 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H______________________________________
TABLE LXXVIII______________________________________ ##STR186##EX. # R.sup.231 R.sup.232, R.sup.233______________________________________3352 C.sub.3 H.sub.7 (n) O3353 C.sub.3 H.sub.7 (n) H,H3354 C.sub.3 H.sub.7 (n) H,CH.sub.33355 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.53356 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3357 C.sub.3 H.sub.7 (n) H,CO.sub.2 H3358 C.sub.4 H.sub.9 (n) H,H3359 C.sub.4 H.sub.9 (n) H,CH.sub.33360 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53361 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3362 C.sub. 4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE LXXIX______________________________________ ##STR187##EX. # R.sup.234 R.sup.235, R.sup.236______________________________________3363 C.sub.3 H.sub.7 (n) O3364 C.sub.3 H.sub.7 (n) H,H3365 C.sub.3 H.sub.7 (n) H,CH.sub.33366 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.53367 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3368 C.sub.3 H.sub.7 (n) H,CO.sub.2 H3369 C.sub.4 H.sub.9 (n) O3370 C.sub.4 H.sub.9 (n) H,H3371 C.sub.4 H.sub.9 (n) H,CH.sub.33372 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53373 C.sub.4 H.sub. 9 (n) H,CH.sub.2 OH3374 C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE LXXX______________________________________ ##STR188##EX. # R.sup.237 R.sup.238______________________________________3375 C.sub.3 H.sub.7 (n) CH.sub.23376 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)3377 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3378 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.23379 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.23380 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.23381 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)3382 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3383 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.23384 C.sub. 4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.23385 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2______________________________________
TABLE LXXXI______________________________________ ##STR189##EX. # R.sup.239 R.sup.240______________________________________3386 C.sub.3 H.sub.7 (n) H3387 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53388 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3389 C.sub.3 H.sub.7 (n) (2-ethylphenyl)3390 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)3391 C.sub.3 H.sub.7 (n) phenyl3392 C.sub.3 H.sub.7 (n) benzyl3393 C.sub.3 H.sub.7 (n) phenylethyl3394 C.sub.3 H.sub.7 (n) CH.sub.2 OH3395 C.sub.3 H.sub.7 (n) CO.sub.2 H3396 C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3397 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53398 C.sub. 4 H.sub.9 (n) C.sub.3 H.sub.7 (n)3399 C.sub.4 H.sub.9 (n) (2-ethylphenyl)3400 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)3401 C.sub.4 H.sub.9 (n) phenyl3402 C.sub.4 H.sub.9 (n) benzyl3403 C.sub.4 H.sub.9 (n) phenylethyl3404 C.sub.4 H.sub.9 (n) CH.sub.2 OH3405 C.sub.4 H.sub.9 (n) CO.sub.2 H3406 C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H______________________________________
TABLE LXXXII______________________________________ ##STR190##EX. # R.sup.241 R.sup.242______________________________________3407 C.sub.3 H.sub.7 (n) O3408 C.sub.3 H.sub.7 (n) S3409 C.sub.3 H.sub.7 (n) NOH3410 C.sub.3 H.sub.7 (n) CHCO.sub.2 H3411 C.sub.3 H.sub.7 (n) C(C.sub.2 H.sub.5)CO.sub.2 H3412 C.sub.3 H.sub.7 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H3413 C.sub.3 H.sub.7 (n) CHC.sub.2 H.sub.53414 C.sub.4 H.sub.9 (n) O3415 C.sub.4 H.sub.9 (n) S3416 C.sub.4 H.sub.9 (n) NOH3417 C.sub.4 H.sub.9 (n) CHCO.sub.2 H3418 C.sub.4 H.sub.9 (n) C(C.sub.2 H.sub.5)CO.sub.2 H3419 C.sub.4 H.sub.9 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H3420 C.sub.4 H.sub.9 (n) CHC.sub.2 H.sub.5______________________________________
TABLE LXXXIII______________________________________ ##STR191##EX. # R.sup.243 R.sup.244______________________________________3421 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53422 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3423 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53424 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)______________________________________
TABLE LXXXIV______________________________________ ##STR192##EX. # R.sup.245 R.sup.246______________________________________3425 C.sub.3 H.sub.7 (n) H3426 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53427 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3428 C.sub.3 H.sub.7 (n) (2-ethylphenyl)3429 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)3430 C.sub.3 H.sub.7 (n) phenyl3431 C.sub.3 H.sub.7 (n) benzyl3432 C.sub.3 H.sub.7 (n) phenylethyl3433 C.sub.3 H.sub.7 (n) NH.sub.23434 C.sub.3 H.sub.7 (n) OH3435 C.sub.3 H.sub.7 (n) CH.sub.2 OH3436 C.sub.3 H.sub.7 (n) CO.sub.2 H3437 C.sub.4 H.sub.9 (n) H3438 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53439 C.sub.4 H.sub. 9 (n) C.sub.3 H.sub.7 (n)3440 C.sub.4 H.sub.9 (n) (2-ethylphenyl)3441 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)3442 C.sub.4 H.sub.9 (n) phenyl3443 C.sub.4 H.sub.9 (n) benzyl3444 C.sub.4 H.sub.9 (n) phenylethyl3445 C.sub.4 H.sub.9 (n) NH.sub.23446 C.sub.4 H.sub.9 (n) OH3447 C.sub.4 H.sub.9 (n) CH.sub.2 OH3448 C.sub.4 H.sub.9 (n) CO.sub.2 H______________________________________
TABLE LXXXV______________________________________ ##STR193##EX. # R.sup.247 R.sup.248 R.sup.249______________________________________3449 C.sub.3 H.sub.7 (n) H CH.sub.33450 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.53451 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.53452 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5 CH.sub.23453 C.sub.3 H.sub.7 (n) H CH.sub.2 CO.sub.2 H3454 C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3455 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.33456 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.53457 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.53458 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5 CH.sub.23459 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CO.sub.2 H3460 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H3461 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.33462 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.53463 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.53464 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.5 CH.sub.23465 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H3466 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H3467 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.33468 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53469 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.53470 C.sub. 3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.23471 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3472 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H3473 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.33474 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.53475 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.53476 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H3477 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H3478 C.sub.4 H.sub.9 (n) H CH.sub.33479 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.53480 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.53481 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5 CH.sub.23482 C.sub.4 H.sub.9 (n) H CH.sub.2 CO.sub.2 H3483 C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3484 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.33485 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.53486 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.53487 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5 CH.sub.23488 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CO.sub.2 H3489 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H3490 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.33491 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.53492 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.53493 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.5 CH.sub.23494 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H3495 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H3496 C.sub.4 H.sub.9 (n) C.sub.3 H.sub. 7 (n) CH.sub.33497 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53498 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.53499 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.23500 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3501 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H3502 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.33503 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.53504 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.53505 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H3506 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H______________________________________
TABLE LXXXVI______________________________________ ##STR194##EX. # R.sup.250 R.sup.251, R.sup.252______________________________________3507 C.sub.3 H.sub.7 (n) O3508 C.sub.3 H.sub.7 (n) H,H3509 C.sub.3 H.sub.7 (n) H,CH.sub.33510 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.53511 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3512 C.sub.3 H.sub.7 (n) H,CO.sub.2 H3513 C.sub.4 H.sub.9 (n) O3514 C.sub.4 H.sub.9 (n) H,H3515 C.sub.4 H.sub.9 (n) H,CH.sub.33516 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53517 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3518 C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE LXXXVII______________________________________ ##STR195##EX. # R.sup.253 R.sup.254, R.sup.255______________________________________3519 C.sub.3 H.sub.7 (n) O3520 C.sub.3 H.sub.7 (n) H,H3521 C.sub.3 H.sub.7 (n) H,CH.sub.33522 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.53523 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3524 C.sub.3 H.sub.7 (n) H,CO.sub.2 H3525 C.sub.4 H.sub.9 (n) O3526 C.sub.4 H.sub.9 (n) H,H3527 C.sub.4 H.sub.9 (n) H,CH.sub.33528 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53529 C.sub.4 H.sub. 9 (n) H,CH.sub.2 OH3530 C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE LXXXVIII______________________________________ ##STR196##EX. # R.sup.256 R.sup.257______________________________________3531 C.sub.3 H.sub.7 (n) CH.sub.23532 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)3533 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3534 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.23535 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.23536 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.23537 C.sub.4 H.sub.9 (n) CH.sub.23538 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)3539 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3540 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.23541 C.sub.4 H.sub. 9 (n) CH(C.sub.2 H.sub.5)CH.sub.23542 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2______________________________________
TABLE LXXXIX______________________________________ ##STR197##EX. # R.sup.258 R.sup.259______________________________________3543 C.sub.3 H.sub.7 (n) H3544 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53545 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3546 C.sub.3 H.sub.7 (n) (2-ethylphenyl)3547 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)3548 C.sub.3 H.sub.7 (n) phenyl3549 C.sub.3 H.sub.7 (n) benzyl3550 C.sub.3 H.sub.7 (n) phenylethyl3551 C.sub.3 H.sub.7 (n) CH.sub.2 OH3552 C.sub.3 H.sub.7 (n) CO.sub.2 H3553 C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3554 C.sub.4 H.sub.9 (n) H3555 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53556 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)3557 C.sub.4 H.sub.9 (n) (2-ethylphenyl)3558 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)3559 C.sub.4 H.sub.9 (n) phenyl3560 C.sub.4 H.sub.9 (n) benzyl3561 C.sub.4 H.sub.9 (n) phenylethyl3562 C.sub.4 H.sub.9 (n) CH.sub.2 OH3563 C.sub.4 H.sub.9 (n) CO.sub.2 H3564 C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H______________________________________
TABLE XC______________________________________ ##STR198##EX. # R.sup.260 R.sup.261______________________________________3565 C.sub.3 H.sub.7 (n) O3566 C.sub.3 H.sub.7 (n) S3567 C.sub.3 H.sub.7 (n) NOH3568 C.sub.3 H.sub.7 (n) CHCO.sub.2 H3569 C.sub.3 H.sub.7 (n) C(C.sub.2 H.sub.5)CO.sub.2 H3570 C.sub.3 H.sub.7 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H3571 C.sub.3 H.sub.7 (n) CHC.sub.2 H.sub.53572 C.sub.4 H.sub.9 (n) O3573 C.sub.4 H.sub.9 (n) S3574 C.sub.4 H.sub.9 (n) NOH3575 C.sub.4 H.sub.9 (n) CHCO.sub.2 H3576 C.sub.4 H.sub.9 (n) C(C.sub. 2 H.sub.5)CO.sub.2 H3577 C.sub.4 H.sub.9 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H3578 C.sub.4 H.sub.9 (n) CHC.sub.2 H.sub.5______________________________________
TABLE XCI______________________________________ ##STR199##EX. # R.sup.262 R.sup.263______________________________________3579 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53580 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3581 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53582 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)______________________________________
TABLE XCII______________________________________ ##STR200##EX. # R.sup.264 R.sup.265______________________________________3583 C.sub.3 H.sub.7 (n) H3584 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53585 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3586 C.sub.3 H.sub.7 (n) (2-ethylphenyl)3587 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)3588 C.sub.3 H.sub.7 (n) phenyl3589 C.sub.3 H.sub.7 (n) benzyl3590 C.sub.3 H.sub.7 (n) phenylethyl3591 C.sub.3 H.sub.7 (n) NH.sub.23592 C.sub.3 H.sub.7 (n) OH3593 C.sub.3 H.sub.7 (n) CH.sub.2 OH3594 C.sub.3 H.sub.7 (n) CO.sub.2 H3595 C.sub.4 H.sub.9 (n) H3596 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53597 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)3598 C.sub.4 H.sub.9 (n) (2-ethylphenyl)3599 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)3600 C.sub.4 H.sub.9 (n) phenyl3601 C.sub.4 H.sub.9 (n) benzyl3602 C.sub.4 H.sub.9 (n) phenylethyl3603 C.sub.4 H.sub.9 (n) NH.sub.23604 C.sub.4 H.sub.9 (n) OH3605 C.sub.4 H.sub.9 (n) CH.sub.2 OH3606 C.sub.4 H.sub.9 (n) CO.sub.2 H______________________________________
TABLE XCIII______________________________________ ##STR201##EX. # R.sup.266 R.sup.267 R.sup.268______________________________________3607 C.sub.3 H.sub.7 (n) H CH.sub.33608 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.53609 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.53610 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5 CH.sub.23611 C.sub.3 H.sub.7 (n) H CH.sub.2 CO.sub.2 H3612 C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3613 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.33614 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.53615 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.53616 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5 CH.sub.23617 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CO.sub.2 H3618 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H3619 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.33620 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.53621 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.53622 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.5 CH.sub.23623 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H3624 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H3625 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.33626 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53627 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.53628 C.sub. 3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.23629 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3630 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H3631 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.33632 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.53633 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.53634 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H3635 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H3636 C.sub.4 H.sub.9 (n) H CH.sub.33637 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.53638 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.53639 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5 CH.sub.23640 C.sub.4 H.sub.9 (n) H CH.sub.2 CO.sub.2 H3641 C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3642 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.33643 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.53644 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.53645 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5 CH.sub.23646 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CO.sub.2 H3647 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H3648 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.33649 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.53650 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.53651 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.5 CH.sub.23652 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H3653 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H3654 C.sub.4 H.sub.9 (n) C.sub.3 H.sub. 7 (n) CH.sub.33655 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53656 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.53657 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.23658 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3659 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H3660 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.33661 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.53662 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.53663 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H3664 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H______________________________________
TABLE XCIV______________________________________ ##STR202##EX. # R.sup.269 R.sup.270, R.sup.271______________________________________3665 C.sub.3 H.sub.7 (n) O3666 C.sub.3 H.sub.7 (n) H,H3667 C.sub.3 H.sub.7 (n) H,CH.sub.33668 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.53669 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3670 C.sub.3 H.sub.7 (n) H,CO.sub.2 H3671 C.sub.4 H.sub.9 (n) O3672 C.sub.4 H.sub.9 (n) H,H3673 C.sub.4 H.sub.9 (n) H,CH.sub.33674 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53675 C.sub.4 H.sub. 9 (n) H,CH.sub.2 OH3676 C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE XCV______________________________________ ##STR203##EX. # R.sup.272 R.sup.273, R.sup.274______________________________________3677 C.sub.3 H.sub.7 (n) O3678 C.sub.3 H.sub.7 (n) H,H3679 C.sub.3 H.sub.7 (n) H,CH.sub.33680 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.53681 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3682 C.sub.3 H.sub.7 (n) H,CO.sub.2 H3683 C.sub.4 H.sub.9 (n) O3684 C.sub.4 H.sub.9 (n) H,H3685 C.sub.4 H.sub.9 (n) H,CH.sub.33686 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53687 C.sub.4 H.sub. 9 (n) H,CH.sub.2 OH3688 C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE XCVI______________________________________ ##STR204##EX. # R.sup.275 R.sup.276______________________________________3689 C.sub.3 H.sub.7 (n) CH.sub.23690 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)3691 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3692 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.23693 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.23694 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.23695 C.sub.4 H.sub.9 (n) CH.sub.23696 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)3697 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3698 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.23699 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.23700 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2______________________________________
BIOLOGICAL EVALUATION
Assay A: Angiotensin II Binding Activity
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. .sup.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.degree. 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.times.g for 20 min., and the supernatant was recentrifuged at 100,000.times.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 mgCl.sub.2, 2 mM EDTA, 0.5% bovine serum albumin, 50 mM Tris-HCl, pH 7.5 and .sup.125 I-AII (approximately 10.sup.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.degree. 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 labeled 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 .mu.M 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.sub.50) of the tested AII antagonist which gives 50% displacement of the total specifically bound .sup.125 I-AII from the high affinity AII receptor. Binding data were analyzed by a nonlinear least-squares curve fitting program. Results are reported in Table XCVII.
Assay B: In Vitro Vascular Smooth Muscle-Response for AII
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.degree. C., between movable and fixed ends of a stainless steel wire with the movable 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.sub.3, 15 KCl, 1.2 NaH.sub.2 PO.sub.4, 1.2 MgSO.sub.4, 2.5 CaCl.sub.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.times.10.sup.-10 to 1.times.10.sup.-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 All. Aorta rings were exposed to the test antagonist at 10.sup.-5 M for 5 minutes before challenging with All. 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.sub.2 values and were calculated according to H. O. Schild [Br. J. Pharmacol. Chemother., 2,189-206 (1947)]. The pA.sub.2 value is the concentration of the antagonist which increases the IC50 value for All by a factor of two. Each test antagonist was evaluated in aorta rings from two rabbits. Results are reported in Table XCVII.
TABLE XCVII______________________________________In Vitro Angiotensin IIActivity of Compounds of the InventionTest Compound .sup.1 Assay A .sup.2 Assay BExample # IC.sub.50 (nM) pA.sub.2______________________________________ 1 190 6.40/6.27 2 2100 5.84/6.58 3 270 7.27/6.65 4 51 7.65/7.84 5 60 7.86/8.15 6 2800 NA 7 15000 NA 8 27 NA 9 44 7.15/7.2410 330 NA11 120 NA12 110 6.66/7.0513 23 7.00/6.8614 120 6.48/6.2615 160 6.46/6.7316 440 8.11/7.7917 41 7.79/7.2718 200 NA19 67 7.15/6.8520 240 6.89/6.8521 66 6.98/6.13______________________________________ .sup.1 Assay A: Angiotensin II Binding Activity .sup.2 Assay B: In Vitro Vascular Smooth Muscle Response * NA = Not Assayed
Also embraced within this invention is a class of pharmaceutical compositions comprising one or more compounds of Formula I in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. The compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds and composition may, for example, be administered intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.
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 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 0.1 to 3000 mg/kg body weight, particularly from about 1 to 100 mg/kg body weight, may be appropriate.
The active ingredient 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 is from about 0.1 to 100 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 30 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 100 mg per kilogram of body weight per day. A more preferred dosage will be a range from about 1 mg to about 100 mg per kilogram of body weight. Most preferred is a dosage in a range from about 1 to about 50 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.
The dosage regimen for treating a disease condition with the compounds and/or compositions 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 compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds 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 compounds 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.

Conformationally restricted angiotensin II antagonists

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