Compositions including and methods of using conformationally restricted angiotensin II antagonist

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. Exp. 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(4,5-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. Commun., 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)! are described to potentially lock in a phenyl group in an energetically favorable conformation. P. A. Carpino et al �Biorg.& Med. Chem. Lett., 4, 93 (1994)! describe conformationally restricted compounds incorporating fused rings between a pyridylimidazole and a tetrazolylphenyl radical. 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 are 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, this invention relates to compounds comprising a substituted biphenyl radical attached directly to a heterocyclic fused ring system. Even 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 ##STR1## 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.7 .dbd.CR.sup.6 --, --CH.sub.2 --CR.sup.7 .dbd.CR.sup.6 -- or --CH.sub.2 --CH.sub.2 --CR.sup.7 .dbd.CR.sup.6 --;
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, alkylcarboxyalkyl, hydroxyl, carboxyaralkyl, phthalimidyl, aralkoxy, ##STR2## wherein R.sup.5 is hydrido or hydroxyl; wherein R.sup.6 is selected from hydrido, alkyl, 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 tautomer 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, phenyl, --(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2 CO.sub.2 H, 2-ethylphenyl, benzyl, 2,6-dimethylphenyl, ##STR3## 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 carboxyl, 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 carboxyl, 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 ##STR4## 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.7 .dbd.CR.sup.6 --, --CH.sub.2 --CR.sup.7 .dbd.CR.sup.6 -- or --CH.sub.2 --CH.sub.2 --CR.sup.7 .dbd.CR.sup.6 --;
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, ##STR5## wherein R.sup.5 is hydrido or hydroxyl; wherein R.sup.6 is selected from hydrido, alkyl, hydroxyalkyl, carboxyl, carboxyalkyl, 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, 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.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, --(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, ##STR6## 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 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 carboxyl, or herein 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 carboxyl, 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-8(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-�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!-4-yl!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�1,5-a!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 ##STR7## 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.7 .dbd.CR.sup.6 --, --CH.sub.2 --CR.sup.7 .dbd.CR.sup.6 -- or --CH.sub.2 --CH.sub.2 --CR.sup.7 .dbd.CR.sup.6 --;
wherein R.sup.1 is alkyl;
wherein R.sup.3 is selected from oxygen, sulfur, hydroxyamino, alkylidene, alkylcarboxyalkylidene and carboxyalkylidene;
wherein R.sup.4 is selected from hydrido, alkyl, carboxyl, hydroxyalkyl, carboxyalkyl, carboxyaralkyl, aryl, aralkyl, alkylcarboxyalkyl, hydroxyl, amino, phthalimidyl, aralkoxy, ##STR8## wherein R.sup.5 is hydrido or hydroxyl wherein R.sup.6 is selected from hydrido, alkyl, carboxyl, hydroxyalkyl, carboxyalkyl, 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 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.
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(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, 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, ##STR9## 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.sub.2 C.sub.6 H.sub.5)CO.sub.2 H, --(C.sub.2 H.sub.5)CH.sub.2 CO.sub.2 H, --(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; 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 carboxyl, 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 carboxyl, 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 ##STR10## 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.7 .dbd.CR.sup.6 --, --CH.sub.2 --CR.sup.7 .dbd.CR.sup.6 -- or --CH.sub.2 --CH.sub.2 --CR.sup.7 .dbd.CR.sup.6 --;
wherein R.sup.1 is alkyl;
wherein R.sup.3 is selected from oxygen, sulfur, hydroxyamino, alkylidene, alkylcarboxyalkylidene and carboxyalkylidene;
wherein R.sup.4 is selected from hydrido, alkyl, carboxyl, hydroxyalkyl, carboxyalkyl, carboxyaralkyl, phthalimidyl, alkylcarboxyalkyl, aryl, aralkyl, hydroxyl, amino, aralkoxy, ##STR11## wherein R.sup.5 is hydrido or hydroxyl; wherein R.sup.6 is selected from hydrido, alkyl, carboxyl, hydroxyalkyl, carboxyalkyl, 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, 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.
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, ##STR12## 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; 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 carboxyl, 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 carboxyl, or wherein R.sup.13 and R.sup.12 taken together is .dbd.O; or a pharmaceutically suitable salt thereof.
Within Formula I thereis a fourth sub-class of compounds of interest which consists of compounds as represented by Formula V ##STR13## 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.7 .dbd.CR.sup.6 --, --CH.sub.2 --CR.sup.7 .dbd.CR.sup.6 -- or --CH.sub.2 --CH.sub.2 --CR.sup.7 .dbd.CR.sup.6 --;
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, alkylcarboxyalkylidene, carboxyalkylidene and hydroxyamino;
wherein R.sup.4 is selected from hydrido, alkyl, amino, hydroxyalkyl, carboxyl, alkylcarboxyalkyl, carboxyalkyl, carboxyaralkyl, aryl, aralkyl, hydroxyl, phthalimidyl, aralkoxy, ##STR14## wherein R.sup.5 is hydrido or hydroxyl; wherein R.sup.6 is selected from hydrido, alkyl, hydroxyalkyl, carboxyl, alkylcarboxyalkyl, carboxyalkyl, aryl, and aralkyl;
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, ##STR15## provided R.sup.4 is selected from phenyl, benzyl and phenethyl only when R.sub.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, propyl, hydroxylethyl, --(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 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 carboxyl, 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 carboxyl, 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, isoamyl, 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 "heterocyclic fused ring system" means a heterocyclic ring as described above, fused to a second ring at more than one ring position. Examples of such fused ring systems include imidazopyridines, dihydroimidazopyridines, tetrahydroimidazopyridines, imidazoazepines, dihydroimidazoazepines, tetrahydroimidazoazepines, triazolopyridines, dihydrotriazolopyridines, tetrahydrotriazolopyridines, triazoloazepines, dihydrotriazoloazepines, tetrahydrotriazoloazepines, indolizines, dihydroindolizines, tetrahydroindolizines, pyrroloazepines, dihydropyrroloazepines, and tetrahydropyrroloazepines. 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, .beta.-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-methylglucamine) 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 Procedures
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-bromosuccinimide
AIBN azo(bis)isobutyronitrile
HOAc acetic acid
NaOAc sodium acetate
TEA triethylamine
Abbreviations Used in Schemes and Procedures
Reagents:
PPh.sub.3 triphenylphosphine
TFA trifluoroacetic acid
LDA lithium diisopropylamide
KOt-Bu potassium tert-butoxide
Solvent:
DME 1,2-dimethoxyethane
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
IPA isopropanol
EtOAc ethyl acetate
THF tetrahydrofuran
Other:
BOC tertiary butoxycarbonyl
SEM 2-trimethylsilyl-ethoxymethyl
MS (FAB) or FABMS Fast atom bombardment mass spectroscopy
LG leaving group, e.g. halide, tosylate, triflate, etc.
n- normal-
Ph phenyl
PLG leaving group or a functional group
that can be easily converted to a
leaving group
rt room temperature
sec- secondary-
tert- or t- tertiary-
Tf SO.sub.2 CF.sub.3
TMS trimethylsilyl
Tosylate (TsO) OSO.sub.2 -(4-methyl)phenyl
Triflate (TfO) OSO.sub.2 CF.sub.3
Trityl triphenylmethyl
Ts 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. ##STR16##
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 imidazole 6 may be hydrogenated to give its saturated product 9. ##STR17##
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. Mita; 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 13 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 14. The olefins 13 or 14 may be hydrogenated to its saturated analogue 15. Alternatively, olefin 14 can be prepared from ketone 11 by treatment with an appropriate organometallic reagent, such as a Grignard reagent. ##STR18##
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, 29, 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. Mita; Y. Hatanaka; M. Yokoyama, J. Org. Chem., 49, 3904-3912 (1984) b) D. Bonneville, J. Org. Chem., 462 (1941) c) T. Hirao; D. Misu; 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 �O. Mitsunobu, 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. ##STR19##

EXAMPLE 1 ##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 chlorform-ethyl acetate-TEA to give 7.2 g (44%) of the desired biphenyl dibutylimidazole intermediate as a brown oil: .sup.1 H NMR (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 (C.sub.18 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, 10H), 7.38-7.52 (m, 2H), 7.90 (dd, J=6.85, 2.02 Hz, 1H).
Steps: 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 2: 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 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 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 solidfied upon standing.
Step3: 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), 137.42 (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), 14H!, 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, 2H), 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.30 D) .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. To the resulting crude bromide (3.13 mmol) in 30 mL of degassed dry benzene is added 1.5 mL (5.2 mmol) of n-Bu.sub.3 SnH and 150 mg (0.91 mmol) of AIBN in one portion and the resulting solution is stirred at reflux for 2 h. The mixture is concentrated in vacuo and partitioned between 15 mL of hexane and 15 mL of acetonitrile. The acetonitrile layer is washed with two fresh 12-mL portions of hexane, and the combined hexane layer is extracted with another 15 mL of acetonitrile. The combined acetonitrile solution is concentrated in vacuo and purified to give the 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 NMR (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), 5.8-0.59 (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), 0.198-2.12 (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 (q.sub.AB, 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 mmol) 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: 397.2181.
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, 1H). 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 THF 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 temperture and purified to give the biphenyl trans-hydroxy imidazole.
Step 2: 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 at 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 205-212.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, 1H), 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), 2.76 (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, 2H), 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 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.
EXAMPLE 24 ##STR43##
3-Butyl-5,6,7,8-tetrahydro-5-�2'-(1H-tetrazol-5-yl)�1,1'-biphenyl!-4-yl!-cis-8-phenylmethoxy-imidazo�1,5-a!pyridine
Step 1: Preparation of biphenyl phenylmethoxyimidazole
To a solution of 203 mg (0.318 mmol) of biphenyl bicyclic imidazole (trityl protected Example 11) and 200 .mu.L (1.9 mmol) of benzyl alcohol in 0.5 mL of anhydrous chloroform was added 57 mg (0.32 mmol) of NBS in one portion. The resulting orange-red solution was stirred at room temperature for 2 hours, and the reaction mixture was washed with aqueous sodium bisulfite, water,and brine. The combined extracts were dried (MgSO.sub.4) and concentrated in vacuo. The residue was used directly in the subsequent Step 2 without further purification.
Step 2: Preparation of trityl tetrazolyl phenylmethoxy imidazole
To the crude bromohydrin (0.318 mmol, obtained from Step 1) in 3 mL of degassed dry benzene was added 150 .mu.L (0.52 mmol) of n-Bu.sub.3 SnH and 30 mg (0.18 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 5 mL of hexane and 5 mL of acetonitrile. The acetonitrile layer was washed with two fresh 2-mL portions of hexane, and the combined hexane layer was extracted with another 5 mL of acetonitrile. The combined acetonitrile solution was concentrated in vacuo and purified by chromatography to give 131 mg (55%) of the biphenyl phenylmethoxy imidazole as a colorless oil: .sup.1 H NMR (CDCl.sub.3) .delta. 0.73 (t, J=7.26 Hz, 3H), 1.12 (septet, J=7.66 Hz, 2H), 1.16-1.60 (m, 3H), 1.70-2.20 (m, 6H), 4.61 (d, J=11.7 Hz, 1H), 4.66 (t, J=5.24 Hz, 1H), 4.72 (d, J=11.7 Hz, 1H), 4.97 (t, J=7.50 Hz, 1H), 6.81 (d, J=8.1 Hz, 2H), 6.91 (d, J=7.9 Hz, 6H), 7.10 (d, J=8.46 Hz, 2H), 7.15-7.41 (m, 15H), 7.4-7.53 (m, 2H), 7.92 (d, J=3.8 Hz, 1H).
Step 3: Detritylation of trityl tetrazole
A solution of trityl-protected biphenyl phenylmethoxy imidazole (0.176 mmol, obtained from Step 2) in 0.4 mL of water and 2 mL of acetic acid was stirred at room temperature until the reaction was complete. The mixture was concentrated in vacuo, stirred in 2 mL of aqueous NaHCO.sub.3 and washed with three 2-mL portions of ether and the ether extracts were discarded. The aqueous residue was acidified with 3N HCl to pH 4 and extracted with methylene chloride. The combined methylene chloride extracts were dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by chromatography to give 71 mg (80% ) of the biphenyl phenylmethoxy imidazole, the title compound of Example 1, as an oil which solidified as a glass: .sup.1 H NMR (CDCl.sub.3) .delta. 0.78 (t, J=7.05 Hz, 3H), 1.15 (septet, J=7.25 Hz, 2H), 1.3-1.6 (m, 2H), 1.75-1,95 (m, 2H), 2.0-2.12 (m, 2H), 2.17 (q, J=5.64 Hz, 2H), 4.45-4.63 �m (with q.sub.AB at 4.56, J=12 Hz), 3H!, 5.07 (t, J=5.63 Hz, 1H), 6.24 (br s, 1H), 6.73 (d, J=7.85 Hz, 2H), 6.98 (d, J=8.06 Hz, 2H), 7.25-7.45 (m, 6H), 7.47-7.60 (m, 2H), 7.78 (d, J=6.45 Hz, 1H).
The following examples, 25-1450, located in Tables I-XXIV, are further conformationally restricted angiotensin II antagonists embraced by Formula II above.
TABLE I______________________________________ ##STR44##EX. # R.sup.1 R.sup.2 R.sup.3______________________________________25 H C.sub.3 H.sub.7 (n) H26 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.527 H C.sub.3 H.sub.7 (n) CH.sub.2 OH28 H C.sub.3 H.sub.7 (n) CO.sub.2 H29 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H30 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.331 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H32 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3 133 H C.sub.3 H.sub.7 (n) phenyl34 H C.sub.3 H.sub.7 (n) benzyl35 H C.sub.3 H.sub.7 (n) phenylethyl36 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.537 H C.sub.4 H.sub.9 (n) CH.sub.2 OH38 H C.sub.4 H.sub.9 (n) CO.sub.2 H39 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H40 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3 241 H C.sub.4 H.sub.9 (n) phenyl42 H C.sub.4 H.sub.9 (n) benzyl43 H C.sub.4 H.sub.9 (n) phenylethyl44 Cl C.sub.3 H.sub.7 (n) H45 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.546 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH47 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H48 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H49 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.350 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H51 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3 152 Cl C.sub.4 H.sub.9 (n) H53 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.554 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH55 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H56 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H57 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.358 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H59 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3 .60 ethyl C.sub.3 H.sub.7 (n) H61 ethyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.562 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 OH63 ethyl C.sub.3 H.sub.7 (n) CO.sub.2 H64 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H65 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.366 ethyl C.sub.4 H.sub.9 (n) H67 ethyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.568 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 OH69 ethyl C.sub.4 H.sub.9 (n) CO.sub.2 H70 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H71 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.372 n-butyl C.sub.3 H.sub.7 (n) H73 n-butyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.574 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 OH75 n-butyl C.sub.3 H.sub.7 (n) CO.sub.2 H76 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H77 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.378 n-butyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.579 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 OH80 n-butyl C.sub.4 H.sub.9 (n) CO.sub.2 H81 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H82 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.383 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H84 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.585 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH86 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H87 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H88 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.389 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H90 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.591 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH92 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H93 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H94 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.395 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H96 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.597 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH98 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H99 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H100 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3101 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H102 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5103 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH104 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H105 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H106 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3______________________________________
TABLE II______________________________________ ##STR45##EX. # R.sup.4 R.sup.5 R.sup.6______________________________________107 H C.sub.3 H.sub.7 (n) O108 H C.sub.3 H.sub.7 (n) S109 H C.sub.3 H.sub.7 (n) CHCO.sub.2 H110 H C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.3111 H C.sub.3 H.sub.7 (n) NOH112 H C.sub.4 H.sub.9 (n) S113 H C.sub.4 H.sub.9 (n) NOH114 Cl C.sub.3 H.sub.7 (n) O115 Cl C.sub.3 H.sub.7 (n) S116 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 H117 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.3118 Cl C.sub.3 H.sub.7 (n) NOH119 Cl C.sub.4 H.sub.9 (n) O120 Cl C.sub.4 H.sub.9 (n) S121 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 H122 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.3123 Cl C.sub.4 H.sub.9 (n) NOH124 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O125 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) S126 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 H127 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.3128 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NOH129 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O130 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) S131 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 H132 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.3133 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NOH134 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O135 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) S136 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 H137 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.3138 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) S139 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.3140 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NOH141 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O142 (2-ethylphenyl) C.sub.3 H.sub.7 (n) S143 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 H144 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NOH145 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O146 (2-ethylphenyl) C.sub.4 H.sub.9 (n) S147 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H148 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NOH149 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) O150 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) S151 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 H152 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) NOH153 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) O154 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) S155 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H156 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) NOH______________________________________
TABLE III______________________________________ ##STR46##EX. # R.sup.7 R.sup.8 R.sup.9______________________________________157 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5158 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)159 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5160 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)161 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5162 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)163 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5164 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)165 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5166 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)167 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5168 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)169 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5170 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5171 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5172 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5173 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5174 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5______________________________________
TABLE IV______________________________________ ##STR47##EX. # R.sup.10 R.sup.11 R.sup.12______________________________________175 H C.sub.3 H.sub.7 (n) H176 H C.sub.3 H.sub.7 (n) NH.sub.2177 H C.sub.3 H.sub.7 (n) OH178 H C.sub.3 H.sub.7 (n) CH.sub.2 OH179 H C.sub.3 H.sub.7 (n) CO.sub.2 H180 H C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.3181 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5182 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)183 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5184 H C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5185 H C.sub.3 H.sub.7 (n) (2-ethylphenyl)186 H C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H.sub.5187 H C.sub.4 H.sub.9 (n) H188 H C.sub.4 H.sub.9 (n) CH.sub.2 OH189 H C.sub.4 H.sub.9 (n) CO.sub.2 H190 H C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.3191 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5192 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)193 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5194 H C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5195 H C.sub.4 H.sub.9 (n) (2-ethylphenyl)196 Cl C.sub.3 H.sub.7 (n) H197 Cl C.sub.3 H.sub.7 (n) NH.sub.2198 Cl C.sub.3 H.sub.7 (n) OH199 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH200 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H201 Cl C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.3202 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5203 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)204 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5205 Cl C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5206 Cl C.sub.3 H.sub.7 (n) (2-ethylphenyl)207 Cl C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H.sub.5208 Cl C.sub.4 H.sub.9 (n) H209 Cl C.sub.4 H.sub.9 (n) NH.sub.2210 Cl C.sub.4 H.sub.9 (n) OH211 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH212 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H213 Cl C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.3214 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5215 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)216 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5217 Cl C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5218 Cl C.sub.4 H.sub.9 (n) (2-ethylphenyl)219 Cl C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H.sub.5220 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H221 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NH.sub.2222 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) OH223 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 OH224 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CO.sub.2 H225 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.3226 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5227 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H228 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NH.sub.2229 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) OH230 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 OH231 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CO.sub.2 H232 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.3233 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5234 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H235 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NH.sub.2236 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) OH237 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 OH238 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CO.sub.2 H239 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.3240 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5241 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5242 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NH.sub.2243 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 OH244 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CO.sub.2 H245 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.3246 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5247 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H248 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.2249 (2-ethylphenyl) C.sub.3 H.sub.7 (n) OH250 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH251 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H252 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.3253 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5254 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H255 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.2256 (2-ethylphenyl) C.sub.4 H.sub.9 (n) OH257 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH258 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H259 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.3260 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5261 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H262 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.2263 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) OH264 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH265 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H266 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.3267 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5268 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H269 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.2270 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) OH271 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH272 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H273 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.3274 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5______________________________________
TABLE V______________________________________ ##STR48##EX. # R.sup.13 R.sup.14 R.sup.15 R.sup.16______________________________________275 H C.sub.3 H.sub.7 (n) H CH.sub.3276 H C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3277 H C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.3278 H C.sub.4 H.sub.9 (n) H CH.sub.3279 H C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3280 H C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.3281 Cl C.sub.3 H.sub.7 (n) H CH.sub.3282 Cl C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3283 Cl C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.3284 Cl C.sub.4 H.sub.9 (n) H CH.sub.3285 Cl C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3286 Cl C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.3287 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H CH.sub.3288 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3289 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H CH.sub.3290 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3291 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H CH.sub.3292 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3293 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.3294 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3295 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.3296 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3297 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.3298 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3299 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.3300 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3301 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.3302 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3303 H C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5304 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.5305 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.5306 H C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5307 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.5308 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.5309 Cl C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5310 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.5311 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.5312 Cl C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5313 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.5314 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.5315 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5316 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.5317 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5318 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.5319 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5320 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5321 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5322 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5323 H C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5324 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5325 H C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5326 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5327 Cl C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5328 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5329 Cl C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5330 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5331 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5332 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5333 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5334 C.sub.2 H.sub.5 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.3 H.sub.7 (n) H C.sub.6 H.sub.5336 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5337 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5338 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5339 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H340 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 H341 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H342 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H343 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H344 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H345 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H346 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H347 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H348 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H______________________________________
TABLE VI______________________________________ ##STR49##EX. # R.sup.17 R.sup.18 R.sup.19, R.sup.20______________________________________349 H C.sub.3 H.sub.7 (n) O350 H C.sub.3 H.sub.7 (n) H,H351 H C.sub.3 H.sub.7 (n) H,CH.sub.3352 H C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.5353 H C.sub.3 H.sub.7 (n) H,CH.sub.2 OH354 H C.sub.3 H.sub.7 (n) H,CO.sub.2 H355 H C.sub.4 H.sub.9 (n) O356 H C.sub.4 H.sub.9 (n) H,H357 H C.sub.4 H.sub.9 (n) H,CH.sub.3358 H C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.5359 H C.sub.4 H.sub.9 (n) H,CH.sub.2 OH360 H C.sub.4 H.sub.9 (n) H,CO.sub.2 H361 Cl C.sub.3 H.sub.7 (n) O362 Cl C.sub.3 H.sub.7 (n) H,H363 Cl C.sub.3 H.sub.7 (n) H,CH.sub.3364 Cl C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.5365 Cl C.sub.3 H.sub.7 (n) H,CH.sub.2 OH366 Cl C.sub.3 H.sub.7 (n) H,CO.sub.2 H367 Cl C.sub.4 H.sub.9 (n) O368 Cl C.sub.4 H.sub.9 (n) H,H369 Cl C.sub.4 H.sub.9 (n) H,CH.sub.3370 Cl C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.5371 Cl C.sub.4 H.sub.9 (n) H,CH.sub.2 OH372 Cl C.sub.4 H.sub.9 (n) H,CO.sub.2 H373 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O374 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,H375 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.3376 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.5377 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH378 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CO.sub.2 H379 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O380 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,H381 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.3382 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.5383 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH384 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CO.sub.2 H385 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O386 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,H387 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.3388 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH389 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CO.sub.2 H390 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,H391 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.3392 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH393 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CO.sub.2 H394 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O395 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,H396 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.3397 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.3398 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH399 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CO.sub.2 H400 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O401 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,H402 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.3403 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3,CH.sub.3404 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH405 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CO.sub.2 H406 H C.sub.3 H.sub.7 (n) O407 H C.sub.3 H.sub.7 (n) H,H408 H C.sub.3 H.sub.7 (n) H,CH.sub.3409 H C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.5410 H C.sub.3 H.sub.7 (n) H,CH.sub.2 OH411 H C.sub.3 H.sub.7 (n) H,CO.sub.2 H412 H C.sub.4 H.sub.9 (n) O413 H C.sub.4 H.sub.9 (n) H,H414 H C.sub.4 H.sub.9 (n) H,CH.sub.3415 H C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.5416 H C.sub.4 H.sub.9 (n) H,CH.sub.2 OH417 H C.sub.4 H.sub.9 (n) H,CO.sub.2 H418 Cl C.sub.3 H.sub.7 (n) O419 Cl C.sub.3 H.sub.7 (n) H,H420 Cl C.sub.3 H.sub.7 (n) H,CH.sub.3421 Cl C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.3422 Cl C.sub.3 H.sub.7 (n) H,CH.sub.2 OH423 Cl C.sub.3 H.sub.7 (n) H,CO.sub.2 H424 Cl C.sub.4 H.sub.9 (n) O425 Cl C.sub.4 H.sub.9 (n) H,H426 Cl C.sub.4 H.sub.9 (n) H,CH.sub.3427 Cl C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.5428 Cl C.sub.4 H.sub.9 (n) H,CH.sub.2 OH429 Cl C.sub.4 H.sub.9 (n) H,CO.sub.2 H430 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O431 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,H432 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.3433 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.5434 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH435 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CO.sub.2 H436 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O437 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,H438 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.3439 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.5440 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH441 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CO.sub.2 H442 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O443 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,H444 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.3445 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH446 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CO.sub.2 H447 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O448 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,H449 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.3450 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH451 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CO.sub.2 H452 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O453 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,H454 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.3455 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.3456 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH457 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CO.sub.2 H458 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O459 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,H460 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.3461 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3,CH.sub.3462 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH463 (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______________________________________464 H C.sub.3 H.sub.7 (n) CH.sub.2465 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)466 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)467 H C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2468 H C.sub.3 H.sub.7 (n) CH(C.sub.2 C.sub.6 H.sub.5)CH.sub.2469 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2470 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)471 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)472 H C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2473 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.2474 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2475 Cl C.sub.3 H.sub.7 (n) CH.sub.2476 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)477 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)478 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2479 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.2480 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2481 Cl C.sub.4 H.sub.9 (n) CH.sub.2482 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)483 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)484 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2485 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.2486 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2487 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2488 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)489 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5490 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2491 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.2492 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.2493 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2494 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)495 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)496 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2497 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.2498 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.2499 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2500 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2501 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2502 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2503 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2504 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2505 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2506 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2507 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2508 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2509 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2510 (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______________________________________511 H C.sub.3 H.sub.7 (n) H512 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5513 H C.sub.3 H.sub.7 (n) CH.sub.2 OH514 H C.sub.3 H.sub.7 (n) CO.sub.2 H515 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H516 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3517 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H518 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3519 H C.sub.3 H.sub.7 (n) phenyl520 H C.sub.3 H.sub.7 (n) benzyl521 H C.sub.3 H.sub.7 (n) phenylethyl522 H C.sub.4 H.sub.9 (n) H523 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.9524 H C.sub.4 H.sub.9 (n) CH.sub.2 OH525 H C.sub.4 H.sub.9 (n) CO.sub.2 H526 H C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H527 H C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3528 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H529 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3530 H C.sub.4 H.sub.9 (n) phenyl531 H C.sub.4 H.sub.9 (n) benzyl532 H C.sub.4 H.sub.9 (n) phenylethyl533 Cl C.sub.3 H.sub.7 (n) H534 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5535 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH536 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H537 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H538 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3539 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H540 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3541 Cl C.sub.4 H.sub.9 (n) H542 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5543 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH544 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H545 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H546 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3547 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H548 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.3549 ethyl C.sub.3 H.sub.7 (n) H550 ethyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5551 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 OH552 ethyl C.sub.3 H.sub.7 (n) CO.sub.2 H553 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H554 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3555 ethyl C.sub.4 H.sub.9 (n) H556 ethyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5557 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 OH558 ethyl C.sub.4 H.sub.9 (n) CO.sub.2 H559 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H560 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3561 n-butyl C.sub.3 H.sub.7 (n) H562 n-butyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5563 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 OH564 n-butyl C.sub.3 H.sub.7 (n) CO.sub.2 H565 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H566 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3567 n-butyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5568 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 OH569 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H570 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3571 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H572 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5273 (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______________________________________574 H C.sub.3 H.sub.7 (n) O575 H C.sub.3 H.sub.7 (n) S576 H C.sub.3 H.sub.7 (n) CHCO.sub.2 H577 H C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.3578 H C.sub.3 H.sub.7 (n) NOH579 H C.sub.4 H.sub.9 (n) O580 H C.sub.4 H.sub.9 (n) S581 H C.sub.4 H.sub.9 (n) CHCO.sub.2 H582 H C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.3583 H C.sub.4 H.sub.9 (n) NOH584 Cl C.sub.3 H.sub.7 (n) O585 Cl C.sub.3 H.sub.7 (n) S586 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 H587 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.3588 Cl C.sub.3 H.sub.7 (n) NOH589 Cl C.sub.4 H.sub.9 (n) O590 Cl C.sub.4 H.sub.9 (n) S591 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 H592 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.3593 Cl C.sub.4 H.sub.9 (n) NOH594 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O595 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) S596 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 H597 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.3598 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NOH599 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O600 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) S601 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 H602 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.3603 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NOH604 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O605 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) S606 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 H607 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.3608 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NOH609 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O610 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) S611 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 H612 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.3613 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NOH614 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O615 (2-ethylphenyl) C.sub.3 H.sub.7 (n) S616 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 H617 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NOH618 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O619 (2-ethylphenyl) C.sub.4 H.sub.9 (n) S620 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H621 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NOH622 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) O623 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) S624 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 H625 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) NOH626 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) O627 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) S628 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H629 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) NOH______________________________________
TABLE XI______________________________________ ##STR53##EX. # R.sup.34 R.sup.35 R.sup.36______________________________________630 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5631 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)632 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5633 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)634 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5635 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)636 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5637 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)638 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5639 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)640 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5641 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)642 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5643 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5644 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5645 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5646 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5647 (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______________________________________648 H C.sub.3 H.sub.7 (n) H649 H C.sub.3 H.sub.7 (n) NH.sub.2650 H C.sub.3 H.sub.7 (n) OH651 H C.sub.3 H.sub.7 (n) CH.sub.2 OH652 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5653 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)654 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5655 H C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5656 H C.sub.3 H.sub.7 (n) (2-ethylphenyl)657 H C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H.sub.5658 H C.sub.4 H.sub.9 (n) H659 H C.sub.4 H.sub.9 (n) NH.sub.2660 H C.sub.4 H.sub.9 (n) OH661 H C.sub.4 H.sub.9 (n) CH.sub.2 OH662 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5663 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)664 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5665 H C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5666 H C.sub.4 H.sub.9 (n) (2-ethylphenyl)667 H C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H.sub.5668 Cl C.sub.3 H.sub.7 (n) H669 Cl C.sub.3 H.sub.7 (n) NH.sub.2670 Cl C.sub.3 H.sub.7 (n) OH671 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH672 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5673 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)674 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5675 Cl C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5676 Cl C.sub.3 H.sub.7 (n) (2-ethylphenyl)677 Cl C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H.sub.5678 Cl C.sub.4 H.sub.9 (n) H679 Cl C.sub.4 H.sub.9 (n) NH.sub.2680 Cl C.sub.4 H.sub.9 (n) OH681 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH682 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5683 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)684 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5685 Cl C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5686 Cl C.sub.4 H.sub.9 (n) (2-ethylphenyl)687 Cl C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H.sub.5688 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H689 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NH.sub.2690 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) OH691 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 OH692 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5693 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H.sub.5694 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H695 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NH.sub.2696 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) OH697 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 OH698 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5699 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H.sub.5700 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H701 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NH.sub.2702 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) OH703 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 OH704 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5705 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5706 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H.sub.5707 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H708 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NH.sub.2709 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) OH710 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 OH711 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5712 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H713 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.2714 (2-ethylphenyl) C.sub.3 H.sub.7 (n) OH715 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH716 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5717 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H718 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.2719 (2-ethylphenyl) C.sub.4 H.sub.9 (n) OH720 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH721 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5722 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H723 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.2724 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) OH725 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH726 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5727 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H728 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.2729 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) OH730 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH731 (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______________________________________732 H C.sub.3 H.sub.7 (n) H CH.sub.3733 H C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3734 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.3735 H C.sub.4 H.sub.9 (n) H CH.sub.3736 H C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3737 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.3738 Cl C.sub.3 H.sub.7 (n) H CH.sub.3739 Cl C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3740 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.3741 Cl C.sub.4 H.sub.9 (n) H CH.sub.3742 Cl C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3743 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.3744 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H CH.sub.3745 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3746 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H CH.sub.3747 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3748 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H CH.sub.3749 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3750 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.3751 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3752 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.3753 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3754 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.3755 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3756 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.3757 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.3758 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.3759 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.3760 H C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5761 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.5762 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.5763 H C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5764 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.5765 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.5766 Cl C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5767 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.5768 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.5769 Cl C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5770 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.5771 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.5772 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5773 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.5774 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5775 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.5776 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5777 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5778 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.5779 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.5780 H C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5781 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5782 H C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5783 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5784 Cl C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5785 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5786 Cl C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5787 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5788 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5789 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5790 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5791 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5792 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.5793 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.5794 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.5795 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.5796 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H797 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 H798 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H799 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H800 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H801 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H802 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H803 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H804 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H805 (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______________________________________806 H C.sub.3 H.sub.7 (n) O807 H C.sub.3 H.sub.7 (n) H,H808 H C.sub.3 H.sub.7 (n) H,CH.sub.3809 H C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.5810 H C.sub.3 H.sub.7 (n) H,CH.sub.2 OH811 H C.sub.3 H.sub.7 (n) H,CO.sub.2 H812 H C.sub.4 H.sub.9 (n) O813 H C.sub.4 H.sub.9 (n) H,H814 H C.sub.4 H.sub.9 (n) H,CH.sub.3815 H C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.5816 H C.sub.4 H.sub.9 (n) H,CH.sub.2 OH817 H C.sub.4 H.sub.9 (n) H,CO.sub.2 H818 Cl C.sub.3 H.sub.7 (n) O819 Cl C.sub.3 H.sub.7 (n) H,H820 Cl C.sub.3 H.sub.7 (n) H,CH.sub.3821 Cl C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.5822 Cl C.sub.3 H.sub.7 (n) H,CH.sub.2 OH823 Cl C.sub.3 H.sub.7 (n) H,CO.sub.2 H824 Cl C.sub.4 H.sub.9 (n) O825 Cl C.sub.4 H.sub.9 (n) H,H826 Cl C.sub.4 H.sub.9 (n) H,CH.sub.3827 Cl C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.5828 Cl C.sub.4 H.sub.9 (n) H,CH.sub.2 OH829 Cl C.sub.4 H.sub.9 (n) H,CO.sub.2 H830 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O831 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,H832 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.3833 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.5834 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH835 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CO.sub.2 H836 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O837 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,H838 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.3839 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.5840 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH841 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CO.sub.2 H842 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O843 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,H844 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.3845 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH846 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CO.sub.2 H847 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O848 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,H849 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.3850 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH851 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CO.sub.2 H852 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O853 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,H854 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.3855 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.3856 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH857 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CO.sub.2 H858 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O859 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,H860 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.3861 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3,CH.sub.3862 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH863 (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______________________________________864 H C.sub.3 H.sub.7 (n) O865 H C.sub.3 H.sub.7 (n) H,H866 H C.sub.3 H.sub.7 (n) H,CH.sub.3867 H C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.5868 H C.sub.3 H.sub.7 (n) H,CH.sub.2 OH869 H C.sub.3 H.sub.7 (n) H,CO.sub.2 H870 H C.sub.4 H.sub.9 (n) O871 H C.sub.4 H.sub.9 (n) H,H872 H C.sub.4 H.sub.9 (n) H,CH.sub.3873 H C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.5874 H C.sub.4 H.sub.9 (n) H,CH.sub.2 OH875 H C.sub.4 H.sub.9 (n) H,CO.sub.2 H876 Cl C.sub.3 H.sub.7 (n) O877 Cl C.sub.3 H.sub.7 (n) H,H878 Cl C.sub.3 H.sub.7 (n) H,CH.sub.3879 Cl C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.3880 Cl C.sub.3 H.sub.7 (n) H,CH.sub.2 OH881 Cl C.sub.3 H.sub.7 (n) H,CO.sub.2 H882 Cl C.sub.4 H.sub.9 (n) O883 Cl C.sub.4 H.sub.9 (n) H,H884 Cl C.sub.4 H.sub.9 (n) H,CH.sub.3885 Cl C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.5886 Cl C.sub.4 H.sub.9 (n) H,CH.sub.2 OH887 Cl C.sub.4 H.sub.9 (n) H,CO.sub.2 H888 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O889 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,H890 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.3891 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.5892 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH893 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CO.sub.2 H894 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O895 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,H896 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.3897 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.5898 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH899 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CO.sub.2 H900 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O901 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,H902 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.3903 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH904 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CO.sub.2 H905 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O906 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,H907 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.3908 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH909 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CO.sub.2 H910 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O911 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,H912 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.3913 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.3914 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH915 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CO.sub.2 H916 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O917 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,H918 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.3919 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3,CH.sub.3920 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH921 (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______________________________________922 H C.sub.3 H.sub.7 (n) CH.sub.2923 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)924 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)925 H C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2926 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.2927 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2928 H C.sub.4 H.sub.9 (n) CH.sub.2929 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)930 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)931 H C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2932 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.2933 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2934 Cl C.sub.3 H.sub.7 (n) CH.sub.2935 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)936 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)937 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2938 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.2939 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2940 Cl C.sub.4 H.sub.9 (n) CH.sub.2941 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)942 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)943 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2944 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.2945 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.2946 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2947 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)948 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)949 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2950 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.2951 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.2952 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2953 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)954 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)955 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2956 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.2957 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.2958 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2959 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2960 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2961 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2962 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2963 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2964 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2965 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.2966 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2967 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2968 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2969 (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______________________________________970 H C.sub.3 H.sub.7 (n) H971 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5972 H C.sub.3 H.sub.7 (n) CH.sub.2 OH973 H C.sub.3 H.sub.7 (n) CO.sub.2 H974 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H975 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3976 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H977 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub. 3978 H C.sub.3 H.sub.7 (n) phenyl979 H C.sub.3 H.sub.7 (n) benzyl980 H C.sub.3 H.sub.7 (n) phenylethyl981 H C.sub.4 H.sub.9 (n) H982 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5983 H C.sub.4 H.sub.9 (n) CH.sub.2 OH984 H C.sub.4 H.sub.9 (n) CO.sub.2 H985 H C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H986 H C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3987 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H988 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub. 3989 H C.sub.4 H.sub.9 (n) phenyl990 H C.sub.4 H.sub.9 (n) benzyl991 H C.sub.4 H.sub.9 (n) phenylethyl992 Cl C.sub.3 H.sub.7 (n) H993 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5994 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH995 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H996 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H997 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3998 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H999 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub. 31000 Cl C.sub.4 H.sub.9 (n) H1001 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51002 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH1003 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H1004 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H1005 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31006 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H1007 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub. 31008 ethyl C.sub.3 H.sub.7 (n) H1009 ethyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51010 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 OH1011 ethyl C.sub.3 H.sub.7 (n) CO.sub.2 H1012 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1013 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31014 ethyl C.sub.4 H.sub.9 (n) H1015 ethyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51016 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 OH1017 ethyl C.sub.4 H.sub.9 (n) CO.sub.2 H1018 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H1019 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31020 n-butyl C.sub.3 H.sub.7 (n) H1021 n-butyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51022 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 OH1023 n-butyl C.sub.3 H.sub.7 (n) CO.sub.2 H1024 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1025 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31026 n-butyl C.sub.4 H.sub.9 (n) H1027 n-butyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51028 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 OH1029 n-butyl C.sub.4 H.sub.9 (n) CO.sub.2 H1030 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H1031 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31032 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H1033 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51034 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH1035 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H1036 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1037 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31038 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H1039 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51040 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH1041 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H1042 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H1043 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31044 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H1045 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51046 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH1047 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H1048 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1049 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31050 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H1051 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51052 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH1053 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H1054 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H1055 (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______________________________________1056 H C.sub.3 H.sub.7 (n) O1057 H C.sub.3 H.sub.7 (n) S1058 H C.sub.3 H.sub.7 (n) CHCO.sub.2 H1059 H C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.31060 H C.sub.3 H.sub.7 (n) NOH1061 H C.sub.4 H.sub.9 (n) O1062 H C.sub.4 H.sub.9 (n) S1063 H C.sub.4 H.sub.9 (n) CHCO.sub.2 H1064 H C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.31065 H C.sub.4 H.sub.9 (n) NOH1066 Cl C.sub.3 H.sub.7 (n) O1067 Cl C.sub.3 H.sub.7 (n) S1068 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 H1069 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.31070 Cl C.sub.3 H.sub.7 (n) NOH1071 Cl C.sub.4 H.sub.9 (n) O1072 Cl C.sub.4 H.sub.9 (n) S1073 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 H1074 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.31075 Cl C.sub.4 H.sub.9 (n) NOH1076 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O1077 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) S1078 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 H1079 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.31080 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NOH1081 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O1082 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) S1083 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 H1084 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.31085 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NOH1086 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O1087 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) S1088 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 H1089 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.31090 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NOH1091 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O1092 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) S1093 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 H1094 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.31095 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NOH1096 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O1097 (2-ethylphenyl) C.sub.3 H.sub.7 (n) S1098 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 H1099 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NOH1100 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O1101 (2-ethylphenyl) C.sub.4 H.sub.9 (n) S1102 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H1103 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NOH1104 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) O1105 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) S1106 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 H1107 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) NOH1108 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) O1109 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) S1110 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H1111 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) NOH______________________________________
TABLE XIX______________________________________ ##STR61##EX. # R.sup.61 R.sup.62 R.sup.63______________________________________1112 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51113 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1114 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51115 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1116 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51117 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1118 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51119 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1120 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51121 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1122 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51123 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1124 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51125 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51126 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51127 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51128 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51129 (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______________________________________1130 H C.sub.3 H.sub.7 (n) H1131 H C.sub.3 H.sub.7 (n) NH.sub.21132 H C.sub.3 H.sub.7 (n) OH1133 H C.sub.3 H.sub.7 (n) CH.sub.2 OH1134 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51135 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1136 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.51137 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.21138 H C.sub.3 H.sub.7 (n) (2-ethylphenyl)1139 H C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H1140 H C.sub.4 H.sub.9 (n) H1141 H C.sub.4 H.sub.9 (n) NH.sub.21142 H C.sub.4 H.sub.9 (n) OH1143 H C.sub.4 H.sub.9 (n) CH.sub.2 OH1144 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51145 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1146 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.51147 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.21148 H C.sub.4 H.sub.9 (n) (2-ethylphenyl)1149 H C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H1150 Cl C.sub.3 H.sub.7 (n) H1151 Cl C.sub.3 H.sub.7 (n) NH.sub.21152 Cl C.sub.3 H.sub.7 (n) OH1153 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH1154 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51155 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1156 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.51157 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.21158 Cl C.sub.3 H.sub.7 (n) (2-ethylphenyl)1159 Cl C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H1160 Cl C.sub.4 H.sub.9 (n) H1161 Cl C.sub.4 H.sub.9 (n) NH.sub.21162 Cl C.sub.4 H.sub.9 (n) OH1163 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH1164 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51165 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1166 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.51167 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.5 CH.sub.21168 Cl C.sub.4 H.sub.9 (n) (2-ethylphenyl)1169 Cl C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H1170 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H1171 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NH.sub.21172 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) OH1173 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 OH1174 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51175 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H1176 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H1177 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NH.sub.21178 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) OH1179 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 OH1180 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51181 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H1182 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H1183 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NH.sub.21184 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) OH1185 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 OH1186 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51187 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.21188 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H1189 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NH.sub.21190 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) OH1191 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 OH1192 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51193 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H1194 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.21195 (2-ethylphenyl) C.sub.3 H.sub.7 (n) OH1196 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH1197 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51198 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H1199 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.21200 (2-ethylphenyl) C.sub.4 H.sub.9 (n) OH1201 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH1202 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51203 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H1204 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.21205 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) OH1206 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH1207 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51208 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H1209 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.21210 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) OH1211 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH1212 (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______________________________________1213 H C.sub.3 H.sub.7 (n) H CH.sub.31214 H C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.31215 H C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.31216 H C.sub.4 H.sub.9 (n) H CH.sub.31217 H C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.31218 H C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.31219 Cl C.sub.3 H.sub.7 (n) H CH.sub.31220 Cl C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.31221 Cl C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.31222 Cl C.sub.4 H.sub.9 (n) H CH.sub.31223 Cl C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.31224 Cl C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.31225 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H CH.sub.31226 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.31227 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H CH.sub.31228 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.31229 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H CH.sub.31230 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.31231 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.31232 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.31233 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.31234 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.31235 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.31236 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.31237 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.31238 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.31239 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.31240 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.31241 H C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.51242 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.51243 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51244 H C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.51245 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.51246 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51247 Cl C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.51248 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.51249 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51250 Cl C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.51251 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.51252 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51253 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.51254 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.51255 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.51256 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.51257 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.51258 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.51259 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.51260 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.51261 H C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.51262 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.51263 H C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.51264 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.51265 Cl C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.51266 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.51267 Cl C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.51268 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.51269 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.51270 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.51271 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.51272 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.51273 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.51274 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.51275 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.51276 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.51277 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1278 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 H1279 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1280 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1281 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1282 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1283 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1284 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1285 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1286 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H______________________________________
TABLE XXII______________________________________ ##STR64##EX. # R.sup.71 R.sup.72 R.sup.73,R.sup.74______________________________________1287 H C.sub.3 H.sub.7 (n) O1288 H C.sub.3 H.sub.7 (n) H,H1289 H C.sub.3 H.sub.7 (n) H,CH.sub.31290 H C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.51291 H C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1292 H C.sub.3 H.sub.7 (n) H,CO.sub.2 H1293 H C.sub.4 H.sub.9 (n) O1294 H C.sub.4 H.sub.9 (n) H,H1295 H C.sub.4 H.sub.9 (n) H,CH.sub.31296 H C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51297 H C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1298 H C.sub.4 H.sub.9 (n) H,CO.sub.2 H1299 Cl C.sub.3 H.sub.7 (n) O1300 Cl C.sub.3 H.sub.7 (n) H,H1301 Cl C.sub.3 H.sub.7 (n) H,CH.sub.31302 Cl C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.51303 Cl C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1304 Cl C.sub.3 H.sub.7 (n) H,CO.sub.2 H1305 Cl C.sub.4 H.sub.9 (n) O1306 Cl C.sub.4 H.sub.9 (n) H,H1307 Cl C.sub.4 H.sub.9 (n) H,CH.sub.31308 Cl C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51309 Cl C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1310 Cl C.sub.4 H.sub.9 (n) H,CO.sub.2 H1311 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O1312 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,H1313 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.31314 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.51315 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1316 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CO.sub.2 H1317 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O1318 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,H1319 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.31320 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51321 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1322 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CO.sub.2 H1323 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O1324 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,H1325 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.31326 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1327 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CO.sub.2 H1328 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O1329 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,H1330 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.31331 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1332 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CO.sub.2 H1333 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O1334 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,H1335 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.31336 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.31337 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1338 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CO.sub.2 H1339 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O1340 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,H1341 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.31342 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3,CH.sub.31343 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1344 (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______________________________________1345 H C.sub.3 H.sub.7 (n) O1346 H C.sub.3 H.sub.7 (n) H,H1347 H C.sub.3 H.sub.7 (n) H,CH.sub.31348 H C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.51349 H C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1350 H C.sub.3 H.sub.7 (n) H,CO.sub.2 H1351 H C.sub.4 H.sub.9 (n) O1352 H C.sub.4 H.sub.9 (n) H,H1353 H C.sub.4 H.sub.9 (n) H,CH.sub.31354 H C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51355 H C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1356 H C.sub.4 H.sub.9 (n) H,CO.sub.2 H1357 Cl C.sub.3 H.sub.7 (n) O1358 Cl C.sub.3 H.sub.7 (n) H,H1359 Cl C.sub.3 H.sub.7 (n) H,CH.sub.31360 Cl C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.31361 Cl C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1362 Cl C.sub.3 H.sub.7 (n) H,CO.sub.2 H1363 Cl C.sub.4 H.sub.9 (n) O1364 Cl C.sub.4 H.sub.9 (n) H,H1365 Cl C.sub.4 H.sub.9 (n) H,CH.sub.31366 Cl C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51367 Cl C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1368 Cl C.sub.4 H.sub.9 (n) H,CO.sub.2 H1369 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O1370 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,H1371 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.31372 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.51373 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1374 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CO.sub.2 H1375 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O1376 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,H1377 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.31378 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51379 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1380 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CO.sub.2 H1381 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O1382 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,H1383 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.31384 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1385 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CO.sub.2 H1386 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O1387 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,H1388 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.31389 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1390 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CO.sub.2 H1391 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O1392 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,H1393 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.31394 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.31395 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1396 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CO.sub.2 H1397 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O1398 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,H1399 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.31400 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3,CH.sub.31401 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1402 (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______________________________________1403 H C.sub.3 H.sub.7 (n) CH.sub.21404 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)1405 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1406 H C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21407 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.21408 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.21409 H C.sub.4 H.sub.9 (n) CH.sub.21410 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)1411 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1412 H C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.21413 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.21414 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.21415 Cl C.sub.3 H.sub.7 (n) CH.sub.21416 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)1417 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1418 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21419 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.21420 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.21421 Cl C.sub.4 H.sub.9 (n) CH.sub.21422 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)1423 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1424 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.21425 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.21426 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.21427 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.21428 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)1429 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1430 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21431 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.21432 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.21433 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.21434 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)1435 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1436 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.21437 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.21438 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.21439 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.21440 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21441 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.21442 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.21443 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.21444 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21445 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.21446 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.21447 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.21448 (2,6-dimethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21449 (2,6-dimethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.21450 (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 32 (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!.
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 tosylate). 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. ##STR67##
The imidazole 36may 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 imidazole 36 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. Alternatively, olefin 44 can be prepared from ketone 41 by treatment with an appropriate organometallic reagent, such as a Grignard reagent. ##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, 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 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 1451 ##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 1451.
EXAMPLE 1452 ##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 bicyclic imidazole (0.101 mmol, obtained from Step 3 of Example 1451), 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 1451 and purified to give the title compound of Example 1452.
EXAMPLE 1453 ##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 amidazole (0.1 mmol, the title compound of Example 1451) 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 1453.
EXAMPLE 1454 ##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 1451) 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 1456.
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 1451 to give the title compound of Example 1454.
EXAMPLE 1455 ##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 1454) 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 1455.
EXAMPLE 1456 ##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 1454) 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 1454), and triphenyl-phosphine (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 temperture 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 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 1456.
EXAMPLE 1457 ##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 1451, 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 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 1455 or 1456), 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 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 1451 and purified to give the title compound of Example 1457.
EXAMPLE 1458 ##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 1457) 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 1458.
EXAMPLE 1459 ##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 1451) 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 1451 to give the title compound of Example 1459.
EXAMPLE 1460 ##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 1453) 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 1451 to give the title compound of Example 1460.
EXAMPLE 1461 ##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 1460) 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 1461.
EXAMPLE 1462 ##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 1460) 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 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 1451. The crude product is purified to give the title compound of Example 1462.
EXAMPLE 1463 ##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 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 1463.
EXAMPLE 1464 ##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-8-acetate
A suspension of the biphenyl imidazolyl unsaturated ester (0.059 mmol, the title compound of Example 1462) 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 1464.
EXAMPLE 1465 ##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 1464) 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 1465.
EXAMPLE 1466 ##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 1454), 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 1466.
EXAMPLE 1467 ##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 1455 or 1456), 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 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 1467.
EXAMPLE 1468 ##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 1467) 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 1468.
Alternatively, the title compound of Example 1468 can be prepared from the corresponding oxime. A suspension of the biphenyl imidazolyl oxime (0.059 mmol, the title compound of Example 1466) 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 1468.
Examples 1469-1937, 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______________________________________1469 C.sub.3 H.sub.7 (n) H1470 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51471 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1472 C.sub.3 H.sub.7 (n) (2-ethylphenyl)1473 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)1474 C.sub.3 H.sub.7 (n) phenyl1475 C.sub.3 H.sub.7 (n) benzyl1476 C.sub.3 H.sub.7 (n) phenylethyl1477 C.sub.3 H.sub.7 (n) CH.sub.2 OH1478 C.sub.3 H.sub.7 (n) CO.sub.2 H1479 C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1480 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51481 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1482 C.sub.4 H.sub.9 (n) (2-ethylphenyl)1483 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)1484 C.sub.4 H.sub.9 (n) phenyl1485 C.sub.4 H.sub.9 (n) benzyl1486 C.sub.4 H.sub.9 (n) phenylethyl1487 C.sub.4 H.sub.9 (n) CH.sub.2 OH1488 C.sub.4 H.sub.9 (n) CO.sub.2 H______________________________________
TABLE XXVI______________________________________ ##STR90##EX. # R.sup.84 R.sup.85______________________________________1489 C.sub.3 H.sub.7 (n) O1490 C.sub.3 H.sub.7 (n) S1491 C.sub.3 H.sub.7 (n) NOH1492 C.sub.3 H.sub.7 (n) CHCO.sub.2 H1493 C.sub.3 H.sub.7 (n) C(C.sub.2 H.sub.5)CO.sub.2 H1494 C.sub.3 H.sub.7 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H1495 C.sub.3 H.sub.7 (n) CHC.sub.2 H.sub.51496 C.sub.4 H.sub.9 (n) S1497 C.sub.4 H.sub.9 (n) C(C.sub.2 H.sub.5)CO.sub.2 H1498 C.sub.4 H.sub.9 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H1499 C.sub.4 H.sub.9 (n) CHC.sub.2 H.sub.5______________________________________
TABLE XXVII______________________________________ ##STR91##EX. # R.sup.86 R.sup.87______________________________________1500 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51501 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1502 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51503 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)______________________________________
TABLE XXVIII______________________________________ ##STR92##EX. # R.sup.88 R.sup.89______________________________________1504 C.sub.3 H.sub.7 (n) H1505 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51506 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1507 C.sub.3 H.sub.7 (n) (2-ethylphenyl)1508 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)1509 C.sub.3 H.sub.7 (n) phenyl1510 C.sub.3 H.sub.7 (n) benzyl1511 C.sub.3 H.sub.7 (n) phenylethyl1512 C.sub.3 H.sub.7 (n) NH.sub.21513 C.sub.3 H.sub.7 (n) OH1514 C.sub.3 H.sub.7 (n) CH.sub.2 OH1515 C.sub.3 H.sub.7 (n) CO.sub.2 H1516 C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H1517 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51518 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1519 C.sub.4 H.sub.9 (n) (2-ethylphenyl)1520 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)1521 C.sub.4 H.sub.9 (n) phenyl1522 C.sub.4 H.sub.9 (n) benzyl1523 C.sub.4 H.sub.9 (n) phenylethyl1524 C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H1525 C.sub.4 H.sub.9 (n) CH.sub.2 OH1526 C.sub.4 H.sub.9 (n) CO.sub.2 H______________________________________
TABLE XXIX______________________________________ ##STR93##EX. # R.sup.90 R.sup.91 R.sup.92______________________________________1527 C.sub.3 H.sub.7 (n) H CH.sub.31528 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.51529 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.51530 C.sub.3 H.sub.7 (n) H CH.sub.2 C.sub.6 H.sub.51531 C.sub.3 H.sub.7 (n) H CH.sub.2 CO.sub.2 H1532 C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1533 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.31534 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.51535 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.51536 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 C.sub.6 H.sub.51537 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CO.sub.2 H1538 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1539 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.31540 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51541 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.51542 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 C.sub.6 H.sub.51543 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H1544 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H1545 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.31546 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51547 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.51548 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.51549 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1550 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H1551 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.31552 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.51553 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.51554 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H1555 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 H1556 C.sub.4 H.sub.9 (n) H CH.sub.31557 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.51558 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.51559 C.sub.4 H.sub.9 (n) H CH.sub.2 C.sub.6 H.sub.51560 C.sub.4 H.sub.9 (n) H CH.sub.2 CO.sub.2 H1561 C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1562 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.31563 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.51564 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.51565 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 C.sub.6 H.sub.51566 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CO.sub.2 H1567 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1568 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.31569 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51570 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.51571 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 C.sub.6 H.sub.51572 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H1573 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H1574 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.31575 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51576 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.51577 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.51578 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1579 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H1580 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.31581 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.51582 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.51583 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H1584 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______________________________________1585 C.sub.3 H.sub.7 (n) O1586 C.sub.3 H.sub.7 (n) H,H1587 C.sub.3 H.sub.7 (n) H,CH.sub.31588 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.51589 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1590 C.sub.3 H.sub.7 (n) H,CO.sub.2 H1591 C.sub.4 H.sub.9 (n) H,H1592 C.sub.4 H.sub.9 (n) H,CH.sub.31593 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51594 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1595 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______________________________________1596 C.sub.3 H.sub.7 (n) O1597 C.sub.3 H.sub.7 (n) H,H1598 C.sub.3 H.sub.7 (n) H,CH.sub.31599 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.51600 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1601 C.sub.3 H.sub.7 (n) H,CO.sub.2 H1602 C.sub.4 H.sub.9 (n) O1603 C.sub.4 H.sub.9 (n) H,H1604 C.sub.4 H.sub.9 (n) H,CH.sub.31605 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51606 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1607 C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE XXXII______________________________________ ##STR96##EX. # R.sup.99 R.sup.100______________________________________1608 C.sub.3 H.sub.7 (n) CH.sub.21609 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)1610 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1611 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21612 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.21613 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.21614 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)1615 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1616 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.21617 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.21618 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______________________________________1619 C.sub.3 H.sub.7 (n) H1620 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51621 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1622 C.sub.3 H.sub.7 (n) (2-ethylphenyl)1623 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)1624 C.sub.3 H.sub.7 (n) phenyl1625 C.sub.3 H.sub.7 (n) benzyl1626 C.sub.3 H.sub.7 (n) phenylethyl1627 C.sub.3 H.sub.7 (n) CH.sub.2 OH1628 C.sub.3 H.sub.7 (n) CO.sub.2 H1629 C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1630 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51631 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1632 C.sub.4 H.sub.9 (n) (2-ethylphenyl)1633 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)1634 C.sub.4 H.sub.9 (n) phenyl1635 C.sub.4 H.sub.9 (n) benzyl1636 C.sub.4 H.sub.9 (n) phenylethyl1637 C.sub.4 H.sub.9 (n) CH.sub.2 OH1638 C.sub.4 H.sub.9 (n) CO.sub.2 H1639 C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H______________________________________
TABLE XXXIV______________________________________ ##STR98##EX. # R.sup.103 R.sup.104______________________________________1640 C.sub.3 H.sub.7 (n) O1641 C.sub.3 H.sub.7 (n) S1642 C.sub.3 H.sub.7 (n) NOH1643 C.sub.3 H.sub.7 (n) CHCO.sub.2 H1644 C.sub.3 H.sub.7 (n) C(C.sub.2 H.sub.5)CO.sub.2 H1645 C.sub.3 H.sub.7 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H1646 C.sub.3 H.sub.7 (n) CHC.sub.2 H.sub.51647 C.sub.4 H.sub.9 (n) O1648 C.sub.4 H.sub.9 (n) S1649 C.sub.4 H.sub.9 (n) NOH1650 C.sub.4 H.sub.9 (n) CHCO.sub.2 H1651 C.sub.4 H.sub.9 (n) C(C.sub.2 H.sub.5)CO.sub.2 H1652 C.sub.4 H.sub.9 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H1653 C.sub.4 H.sub.9 (n) CHC.sub.2 H.sub.5______________________________________
TABLE XXXV______________________________________ ##STR99##EX. # R.sup.105 R.sup.106______________________________________1654 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51655 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1656 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51657 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)______________________________________
TABLE XXXVI______________________________________ ##STR100##EX. # R.sup.107 R.sup.108______________________________________1658 C.sub.3 H.sub.7 (n) H1659 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51660 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1661 C.sub.3 H.sub.7 (n) (2-ethylphenyl)1662 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)1663 C.sub.3 H.sub.7 (n) phenyl1664 C.sub.3 H.sub.7 (n) benzyl1665 C.sub.3 H.sub.7 (n) phenylethyl1666 C.sub.3 H.sub.7 (n) NH.sub.21667 C.sub.3 H.sub.7 (n) OH1668 C.sub.3 H.sub.7 (n) CH.sub.2 OH1669 C.sub.3 H.sub.7 (n) CO.sub.2 H1670 C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H1671 C.sub.4 H.sub.9 (n) H1672 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51673 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1674 C.sub.4 H.sub.9 (n) (2-ethylphenyl)1675 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)1676 C.sub.4 H.sub.9 (n) phenyl1677 C.sub.4 H.sub.9 (n) benzyl1678 C.sub.4 H.sub.9 (n) phenylethyl1679 C.sub.4 H.sub.9 (n) NH.sub.21680 C.sub.4 H.sub.9 (n) OH1681 C.sub.4 H.sub.9 (n) CH.sub.2 OH1682 C.sub.4 H.sub.9 (n) CO.sub.2 H1683 C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H______________________________________
TABLE XXXVII______________________________________ ##STR101##EX. # R.sup.109 R.sup.110 R.sup.111______________________________________1684 C.sub.3 H.sub.7 (n) H CH.sub.31685 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.51686 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.51687 C.sub.3 H.sub.7 (n) H CH.sub.2 C.sub.6 H.sub.51688 C.sub.3 H.sub.7 (n) H CH.sub.2 CO.sub.2 H1689 C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1690 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.21691 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.51692 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.51693 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 C.sub.6 H.sub.51694 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CO.sub.2 H1695 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1696 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.31697 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51698 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.51699 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 C.sub.6 H.sub.51700 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H1701 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H1702 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.31703 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51704 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.51705 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.51706 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1707 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H1708 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.31709 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.51710 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.51711 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H1712 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 H1713 C.sub.4 H.sub.9 (n) H CH.sub.31714 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.51715 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.51716 C.sub.4 H.sub.9 (n) H CH.sub.2 C.sub.6 H.sub.51717 C.sub.4 H.sub.9 (n) H CH.sub.2 CO.sub.2 H1718 C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1719 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.31720 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.51721 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.51722 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 C.sub.6 H.sub.51723 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CO.sub.2 H1724 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1725 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.31726 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51727 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.51728 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 C.sub.6 H.sub.51729 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H1730 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H1731 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.31732 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51733 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.51734 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.51735 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1736 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H1737 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.31738 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.51739 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.51740 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H1741 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______________________________________1742 C.sub.3 H.sub.7 (n) O1743 C.sub.3 H.sub.7 (n) H,H1744 C.sub.3 H.sub.7 (n) H,CH.sub.31745 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.51746 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1747 C.sub.3 H.sub.7 (n) H,CO.sub.2 H1748 C.sub.4 H.sub.9 (n) O1749 C.sub.4 H.sub.9 (n) H,H1750 C.sub.4 H.sub.9 (n) H,CH.sub.31751 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51752 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1753 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______________________________________1754 C.sub.3 H.sub.7 (n) O1755 C.sub.3 H.sub.7 (n) H,H1756 C.sub.3 H.sub.7 (n) H,CH.sub.31757 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.51758 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1759 C.sub.3 H.sub.7 (n) H,CO.sub.2 H1760 C.sub.4 H.sub.9 (n) O1761 C.sub.4 H.sub.9 (n) H,H1762 C.sub.4 H.sub.9 (n) H,CH.sub.31763 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51764 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1765 C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE XL______________________________________ ##STR104##EX. # R.sup.118 R.sup.119______________________________________1766 C.sub.3 H.sub.7 (n) CH.sub.21767 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)1768 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1769 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21770 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.21771 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.21772 C.sub.4 H.sub.9 (n) CH.sub.21773 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)1774 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1775 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.21776 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.21777 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______________________________________1778 C.sub.3 H.sub.7 (n) H1779 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51780 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1781 C.sub.3 H.sub.7 (n) (2-ethylphenyl)1782 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)1783 C.sub.3 H.sub.7 (n) phenyl1784 C.sub.3 H.sub.7 (n) benzyl1785 C.sub.3 H.sub.7 (n) phenylethyl1786 C.sub.3 H.sub.7 (n) CH.sub.2 OH1787 C.sub.3 H.sub.7 (n) CO.sub.2 H1788 C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1789 C.sub.4 H.sub.9 (n) H1790 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51791 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1792 C.sub.4 H.sub.9 (n) (2-ethylphenyl)1793 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)1794 C.sub.4 H.sub.9 (n) phenyl1795 C.sub.4 H.sub.9 (n) benzyl1796 C.sub.4 H.sub.9 (n) phenylethyl1797 C.sub.4 H.sub.9 (n) CH.sub.2 OH1798 C.sub.4 H.sub.9 (n) CO.sub.2 H1799 C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H______________________________________
TABLE XLII______________________________________ ##STR106##EX. # R.sup.122 R.sup.123______________________________________1800 C.sub.3 H.sub.7 (n) O1801 C.sub.3 H.sub.7 (n) S1802 C.sub.3 H.sub.7 (n) NOH1803 C.sub.3 H.sub.7 (n) CHCO.sub.2 H1804 C.sub.3 H.sub.7 (n) C(C.sub.2 H.sub.5)CO.sub.2 H1805 C.sub.3 H.sub.7 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H1806 C.sub.3 H.sub.7 (n) CHC.sub.2 H.sub.51807 C.sub.4 H.sub.9 (n) O1808 C.sub.4 H.sub.9 (n) S1809 C.sub.4 H.sub.9 (n) NOH1810 C.sub.4 H.sub.9 (n) CHCO.sub.2 H1811 C.sub.4 H.sub.9 (n) C(C.sub.2 H.sub.5)CO.sub.2 H1812 C.sub.4 H.sub.9 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H1813 C.sub.4 H.sub.9 (n) CHC.sub.2 H.sub.5______________________________________
TABLE XLIII______________________________________ ##STR107##EX. # R.sup.124 R.sup.125______________________________________1814 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51815 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1816 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51817 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)______________________________________
TABLE XLIV______________________________________ ##STR108##EX. # R.sup.126 R.sup.127______________________________________1818 C.sub.3 H.sub.7 (n) H1819 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51820 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)1821 C.sub.3 H.sub.7 (n) (2-ethylphenyl)1822 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)1823 C.sub.3 H.sub.7 (n) phenyl1824 C.sub.3 H.sub.7 (n) benzyl1825 C.sub.3 H.sub.7 (n) phenylethyl1826 C.sub.3 H.sub.7 (n) NH.sub.21827 C.sub.3 H.sub.7 (n) OH1828 C.sub.3 H.sub.7 (n) CH.sub.2 OH1829 C.sub.3 H.sub.7 (n) CO.sub.2 H1830 C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H1831 C.sub.4 H.sub.9 (n) H1832 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51833 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)1834 C.sub.4 H.sub.9 (n) (2-ethylphenyl)1835 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)1836 C.sub.4 H.sub.9 (n) phenyl1837 C.sub.4 H.sub.9 (n) benzyl1838 C.sub.4 H.sub.9 (n) phenylethyl1839 C.sub.4 H.sub.9 (n) NH.sub.21840 C.sub.4 H.sub.9 (n) OH1841 C.sub.4 H.sub.9 (n) CH.sub.2 OH1842 C.sub.4 H.sub.9 (n) CO.sub.2 H1843 C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H______________________________________
TABLE XLV______________________________________ ##STR109##EX. # R.sup.128 R.sup.129 R.sup.130______________________________________1844 C.sub.3 H.sub.7 (n) H CH.sub.31845 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.51846 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.51847 C.sub.3 H.sub.7 (n) H CH.sub.2 C.sub.6 H.sub.51848 C.sub.3 H.sub.7 (n) H CH.sub.2 CO.sub.2 H1849 C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1850 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.31851 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.51852 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.51853 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 C.sub.6 H.sub.51854 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CO.sub.2 H1855 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1856 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.31857 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51858 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.51859 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 C.sub.6 H.sub.51860 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H1861 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H1862 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.31863 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51864 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.51865 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.51866 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1867 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H1868 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.31869 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.51870 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.51871 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H1872 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 H1873 C.sub.4 H.sub.9 (n) H CH.sub.31874 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.51875 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.51876 C.sub.4 H.sub.9 (n) H CH.sub.2 C.sub.6 H.sub.51877 C.sub.4 H.sub.9 (n) H CH.sub.2 CO.sub.2 H1878 C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H1879 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.31880 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.51881 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.51882 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 C.sub.6 H.sub.51883 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CO.sub.2 H1884 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H1885 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.31886 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.51887 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.51888 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 C.sub.6 H.sub.51889 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H1890 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H1891 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.31892 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51893 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.51894 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.51895 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1896 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H1897 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.31898 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.51899 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.51900 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H1901 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______________________________________1902 C.sub.3 H.sub.7 (n) O1903 C.sub.3 H.sub.7 (n) H,H1904 C.sub.3 H.sub.7 (n) H,CH.sub.31905 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.51906 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1907 C.sub.3 H.sub.7 (n) H,CO.sub.2 H1908 C.sub.4 H.sub.9 (n) O1909 C.sub.4 H.sub.9 (n) H,H1910 C.sub.4 H.sub.9 (n) H,CH.sub.31911 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51912 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1913 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______________________________________1914 C.sub.3 H.sub.7 (n) O1915 C.sub.3 H.sub.7 (n) H,H1916 C.sub.3 H.sub.7 (n) H,CH.sub.31917 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.51918 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH1919 C.sub.3 H.sub.7 (n) H,CO.sub.2 H1920 C.sub.4 H.sub.9 (n) O1921 C.sub.4 H.sub.9 (n) H,H1922 C.sub.4 H.sub.9 (n) H,CH.sub.31923 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.51924 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH1925 C.sub.4 H.sub.9 (n) H,CO.sub.2 OH______________________________________
TABLE XLVIII______________________________________ ##STR112##EX. # R.sup.137 R.sup.136______________________________________1926 C.sub.3 H.sub.7 (n) CH.sub.21927 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)1928 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1929 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.21930 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.21931 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.21932 C.sub.4 H.sub.9 (n) CH.sub.21933 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)1934 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)1935 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.21936 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.21937 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 pyrrole 66 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 alcohol 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 72 may 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 74may be hydrogenated to its saturated analogue 75. Alternatively, olefin 74 can be prepared from ketone 71 by treatment with an appropriate organometallic reagent, such as a Grignard reagent. ##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 1938 ##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 1938.
EXAMPLE 1939 ##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 1938), 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 1938 and purified to give the title compound of Example 1939.
EXAMPLE 1940 ##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 1938) 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 1940.
EXAMPLE 1941 ##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 1938) 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 1943).
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 1938 and purified to give the title compound of Example 1941.
EXAMPLE 1942 ##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 1941) 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 1942.
EXAMPLE 1943 ##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 1941) 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 1942), 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 temperture 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 1943.
EXAMPLE 1944 ##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 1938, 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 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 1942 or 1943), 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 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 1938 and purified to give the title compound of Example 1944.
EXAMPLE 1945 ##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 1944) 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 1945.
EXAMPLE 1946 ##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 1938) 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 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 1938 and purified to give the title compound of Example 1946.
EXAMPLE 1947 ##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 1940) 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 1938 and purified to give the title compound of Example 1947.
EXAMPLE 1948 ##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 1947) 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 1948.
EXAMPLE 1949 ##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 1947) 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 1938. The crude product is purified to give the title compound of Example 1949.
EXAMPLE 1950 ##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 1949) 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 1950.
EXAMPLE 1951 ##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 1949) 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 1951.
EXAMPLE 1952 ##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 1951) 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 1952.
EXAMPLE 1953 ##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 1941), 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 1953.
EXAMPLE 1954 ##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 1942 or 1943), 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 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 1938 and purified give the title compound of Example 1954.
EXAMPLE 1955 ##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 1954) 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 1955.
Alternatively, the title compound of Example 1955 can be prepared from the corresponding oxime. A suspension of the biphenyl imidazolyl oxime (0.059 mmol, the title compound of Example 1953) 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 1955.
Examples 1956-3256 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______________________________________1956 H C.sub.3 H.sub.7 (n) H1957 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51958 H C.sub.3 H.sub.7 (n) CH.sub.2 OH1959 H C.sub.3 H.sub.7 (n) CO.sub.2 H1960 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1961 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31962 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H1963 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.31964 H C.sub.3 H.sub.7 (n) phenyl1965 H C.sub.3 H.sub.7 (n) benzyl1966 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51967 H C.sub.4 H.sub.9 (n) CH.sub.2 OH1968 H C.sub.4 H.sub.9 (n) CO.sub.2 H1969 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H1970 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C (CH.sub.3).sub.31971 H C.sub.4 H.sub.9 (n) phenyl1972 H C.sub.4 H.sub.9 (n) benzyl1973 Cl C.sub.3 H.sub.7 (n) H1974 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51975 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH1976 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H1977 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1978 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31979 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H1980 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.31981 Cl C.sub.4 H.sub.9 (n) H1982 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51983 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH1984 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H1985 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H1986 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31987 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H1988 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.31989 ethyl C.sub.3 H.sub.7 (n) H1990 ethyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.51991 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 OH1992 ethyl C.sub.3 H.sub.7 (n) CO.sub.2 H1993 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H1994 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.31995 ethyl C.sub.4 H.sub.9 (n) H1996 ethyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.51997 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 OH1998 ethyl C.sub.4 H.sub.9 (n) CO.sub.2 H1999 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2000 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32001 n-butyl C.sub.3 H.sub.7 (n) H2002 n-butyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52003 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 OH2004 n-butyl C.sub.3 H.sub.7 (n) CO.sub.2 H2005 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2006 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32007 n-butyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52008 n-butyl C.sub.4 H.sub.9 (n) H2009 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 OH2010 n-butyl C.sub.4 H.sub.9 (n) CO.sub.2 H2011 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2012 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32013 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H2014 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52015 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH2016 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H2017 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2018 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32019 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H2020 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52021 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH2022 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H2023 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2024 (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______________________________________2025 H C.sub.3 H.sub.7 (n) O2026 H C.sub.3 H.sub.7 (n) S2027 H C.sub.3 H.sub.7 (n) CHCO.sub.2 H2028 H C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32029 H C.sub.3 H.sub.7 (n) NOH2030 H C.sub.4 H.sub.9 (n) S2031 Cl C.sub.3 H.sub.7 (n) O2032 Cl C.sub.3 H.sub.7 (n) S2033 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 H2034 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32035 Cl C.sub.3 H.sub.7 (n) NOH2036 Cl C.sub.4 H.sub.9 (n) O2037 Cl C.sub.4 H.sub.9 (n) S2038 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 H2039 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32040 Cl C.sub.4 H.sub.9 (n) NOH2041 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O2042 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) S2043 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 H2044 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32045 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NOH2046 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O2047 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) S2048 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 H2049 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32050 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NOH2051 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O2052 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) S2053 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 H2054 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32055 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NOH2056 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O2057 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) S2058 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 H2059 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32060 C.sub.4 H.sub.9 (n C.sub.4 H.sub.9 (n) NOH2061 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O2062 (2-ethylphenyl) C.sub.3 H.sub.7 (n) S2063 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 H2064 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NOH2065 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O2066 (2-ethylphenyl) C.sub.4 H.sub.9 (n) S2067 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H2068 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NOH______________________________________
TABLE LI______________________________________ ##STR137##EX. # R.sup.145 R.sup.146 R.sup.147______________________________________2069 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52070 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2071 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52072 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2073 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52074 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2075 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52076 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2077 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52078 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2079 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52080 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2081 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52082 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52083 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52084 (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______________________________________2085 H C.sub.3 H.sub.7 (n) H2086 H C.sub.3 H.sub.7 (n) NH.sub.22087 H C.sub.3 H.sub.7 (n) OH2088 H C.sub.3 H.sub.7 (n) CH.sub.2 OH2089 H C.sub.3 H.sub.7 (n) CO.sub.2 H2090 H C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32091 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52092 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2093 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.52094 H C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.52095 H C.sub.3 H.sub.7 (n) (2-ethylphenyl)2096 H C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H2097 H C.sub.4 H.sub.9 (n) CH.sub.2 OH2098 H C.sub.4 H.sub.9 (n) CO.sub.2 H2099 H C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32100 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52101 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2102 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.52103 H C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.52104 H C.sub.4 H.sub.9 (n) (2-ethylphenyl)2105 H C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H2106 Cl C.sub.3 H.sub.7 (n) H2107 Cl C.sub.3 H.sub.7 (n) NH.sub.22108 Cl C.sub.3 H.sub.7 (n) OH2109 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH2110 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H2111 Cl C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32112 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52113 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2114 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.52115 Cl C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.52116 Cl C.sub.3 H.sub.7 (n) (2-ethylphenyl)2117 Cl C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H2118 Cl C.sub.4 H.sub.9 (n) H2119 Cl C.sub.4 H.sub.9 (n) NH.sub.22120 Cl C.sub.4 H.sub.9 (n) OH2121 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH2122 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H2123 Cl C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32124 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52125 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2126 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.52127 Cl C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.52128 Cl C.sub.4 H.sub.9 (n) (2-ethylphenyl)2129 Cl C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H2130 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H2131 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NH.sub.22132 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) OH2133 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 OH2134 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CO.sub.2 H2135 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32136 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52137 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H2138 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H2139 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NH.sub.22140 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) OH2141 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 OH2142 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CO.sub.2 H2143 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32144 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52145 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H2146 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H2147 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NH.sub.22148 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) OH2149 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 OH2150 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CO.sub.2 H2151 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32152 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52153 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H2154 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H2155 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NH.sub.22156 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) OH2157 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 OH2158 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CO.sub.2 H2159 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32160 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52161 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H2162 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.22163 (2-ethylphenyl) C.sub.3 H.sub.7 (n) OH2164 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH2165 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H2166 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32167 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52168 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H2169 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.22170 (2-ethylphenyl) C.sub.4 H.sub.9 (n) OH2171 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH2172 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H2173 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32174 (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______________________________________2175 H C.sub.3 H.sub.7 (n) H CH.sub.32176 H C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32177 H C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.32178 H C.sub.4 H.sub.9 (n) H CH.sub.32179 H C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32180 H C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.32181 Cl C.sub.3 H.sub.7 (n) H CH.sub.32182 Cl C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32183 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.5 CH.sub.2 CH.sub.32184 Cl C.sub.4 H.sub.9 (n) H CH.sub.32185 Cl C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32186 Cl C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.32187 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H CH.sub.32188 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32189 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H CH.sub.32190 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32191 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H CH.sub.32192 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32193 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.32194 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32195 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.32196 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32197 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.32198 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32199 H C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.52200 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.52201 H C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.52202 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.52203 Cl C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.52204 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.52205 Cl C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.52206 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.52207 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.52208 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.52209 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.52210 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.52211 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.52212 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.52213 H C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.52214 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.52215 H C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.52216 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.52217 Cl C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.52218 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.52219 Cl C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.52220 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.52221 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.52222 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.52223 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.52224 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.52225 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.52226 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.52227 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.52228 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.52229 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H2230 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 H2231 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H2232 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H2233 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H2234 (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______________________________________2235 H C.sub.3 H.sub.7 (n) O2236 H C.sub.3 H.sub.7 (n) H,H2237 H C.sub.3 H.sub.7 (n) H,CH.sub.32238 H C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.52239 H C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2240 H C.sub.3 H.sub.7 (n) H,CO.sub.2 H2241 H C.sub.4 H.sub.9 (n) H,H2242 H C.sub.4 H.sub.9 (n) H,CH.sub.32243 H C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.52244 H C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2245 H C.sub.4 H.sub.9 (n) H,CO.sub.2 H2246 Cl C.sub.3 H.sub.7 (n) O2247 Cl C.sub.3 H.sub.7 (n) H,H2248 Cl C.sub.3 H.sub.7 (n) H,CH.sub.32249 Cl C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.52250 Cl C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2251 Cl C.sub.3 H.sub.7 (n) H,CO.sub.2 H2252 Cl C.sub.4 H.sub.9 (n) O2253 Cl C.sub.4 H.sub.9 (n) H,H2254 Cl C.sub.4 H.sub.9 (n) H,CH.sub.32255 Cl C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.52256 Cl C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2257 Cl C.sub.4 H.sub.9 (n) H,CO.sub.2 H2258 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O2259 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,H2260 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.32261 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.52262 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2263 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CO.sub.2 H2264 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O2265 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,H2266 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.32267 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.52268 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2269 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CO.sub.2 H2270 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O2271 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,H2272 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.32273 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2274 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CO.sub.2 H2275 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O2276 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,H2277 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.32278 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2279 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CO.sub.2 H2280 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O2281 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,H2282 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.32283 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.32284 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2285 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CO.sub.2 H2286 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O2287 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,H2288 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.32289 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3,CH.sub.32290 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2291 (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______________________________________2292 H C.sub.3 H.sub.7 (n) O2293 H C.sub.3 H.sub.7 (n) H,H2294 H C.sub.3 H.sub.7 (n) H,CH.sub.32295 H C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.52296 H C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2297 H C.sub.3 H.sub.7 (n) H,CO.sub.2 H2298 H C.sub.4 H.sub.9 (n) O2299 H C.sub.4 H.sub.9 (n) H,H2300 H C.sub.4 H.sub.9 (n) H,CH.sub.32301 H C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.52302 H C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2303 H C.sub.4 H.sub.9 (n) H,CO.sub.2 H2304 Cl C.sub.3 H.sub.7 (n) O2305 Cl C.sub.3 H.sub.7 (n) H,H2306 Cl C.sub.3 H.sub.7 (n) H,CH.sub.32307 Cl C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.52308 Cl C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2309 Cl C.sub.3 H.sub.7 (n) H,CO.sub.2 H2310 Cl C.sub.4 H.sub.9 (n) O2311 Cl C.sub.4 H.sub.9 (n) H,H2312 Cl C.sub.4 H.sub.9 (n) H,CH.sub.32313 Cl C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.52314 Cl C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2315 Cl C.sub.4 H.sub.9 (n) H,CO.sub.2 H2316 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O2317 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,H2318 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.32319 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.52320 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2321 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CO.sub.2 H2322 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O2323 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,H2324 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.32325 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.52326 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2327 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CO.sub.2 H2328 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O2329 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,H2330 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.32331 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2332 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CO.sub.2 H2333 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O2334 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,H2335 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.32336 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2337 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CO.sub.2 H2338 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O2339 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,H2340 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.32341 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.32342 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2343 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CO.sub.2 H2344 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O2345 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,H2346 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.3______________________________________
TABLE LVI______________________________________ ##STR142##EX. # R.sup.163 R.sup.164 R.sup.165______________________________________2347 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3,CH.sub.32348 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2349 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CO.sub.2 H2350 H C.sub.3 H.sub.7 (n) CH.sub.22351 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)2352 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)2353 H C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22354 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.22355 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.22356 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)2357 H C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.22358 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.22359 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.22360 Cl C.sub.3 H.sub.7 (n) CH.sub.22361 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)2362 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)2363 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22364 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.22365 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.22366 Cl C.sub.4 H.sub.9 (n) CH.sub.22367 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)2368 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)2369 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.22370 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.22371 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.22372 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.22373 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22374 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.22375 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.22376 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.22377 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22378 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.22379 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.22380 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.22381 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22382 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.22383 (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______________________________________2384 H C.sub.3 H.sub.7 (n) H2385 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52386 H C.sub.3 H.sub.7 (n) CH.sub.2 OH2387 H C.sub.3 H.sub.7 (n) CO.sub.2 H2388 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2389 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32390 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H2391 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.32392 H C.sub.3 H.sub.7 (n) phenyl2393 H C.sub.3 H.sub.7 (n) benzyl2394 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52395 H C.sub.4 H.sub.9 (n) CH.sub.2 OH2396 H C.sub.4 H.sub.9 (n) CO.sub.2 H2397 H C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2398 H C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32399 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H2400 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.32401 H C.sub.4 H.sub.9 (n) phenyl2402 H C.sub.4 H.sub.9 (n) benzyl2403 Cl C.sub.3 H.sub.7 (n) H2404 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52405 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH2406 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H2407 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2408 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32409 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H2410 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.32411 Cl C.sub.4 H.sub.9 (n) H2412 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52413 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH2414 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H2415 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2416 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32417 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H2418 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.32419 ethyl C.sub.3 H.sub.7 (n) H2420 ethyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52421 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 OH2422 ethyl C.sub.3 H.sub.7 (n) CO.sub.2 H2423 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2424 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32425 ethyl C.sub.4 H.sub.9 (n) H2426 ethyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52427 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 OH2428 ethyl C.sub.4 H.sub.9 (n) CO.sub.2 H2429 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2430 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32431 n-butyl C.sub.3 H.sub.7 (n) H2432 n-butyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52433 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 OH2434 n-butyl C.sub.3 H.sub.7 (n) CO.sub.2 H2435 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2436 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32437 n-butyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52438 n-butyl C.sub.4 H.sub.9 (n) H2439 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 OH2440 n-butyl C.sub.4 H.sub.9 (n) CO.sub.2 H2441 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2442 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32443 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H2444 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52445 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH2446 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H2447 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2448 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32449 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H2450 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52451 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH2452 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H2453 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2454 (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______________________________________2455 H C.sub.3 H.sub.7 (n) O2456 H C.sub.3 H.sub.7 (n) S2457 H C.sub.3 H.sub.7 (n) CHCO.sub.2 H2458 H C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32459 H C.sub.3 H.sub.7 (n) NOH2460 H C.sub.4 H.sub.9 (n) O2461 H C.sub.4 H.sub.9 (n) S2462 H C.sub.4 H.sub.9 (n) CHCO.sub.2 H2463 H C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32464 Cl C.sub.3 H.sub.7 (n) O2465 Cl C.sub.3 H.sub.7 (n) S2466 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 H2467 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32468 Cl C.sub.3 H.sub.7 (n) NOH2469 Cl C.sub.4 H.sub.9 (n) O2470 Cl C.sub.4 H.sub.9 (n) S2471 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 H2472 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32473 Cl C.sub.4 H.sub.9 (n) NOH2474 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O2475 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) S2476 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 H2477 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32478 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NOH2479 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O2480 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) S2481 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 H2482 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32483 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NOH2484 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O2485 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) S2486 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 H2487 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32488 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NOH2489 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O2490 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) S2491 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 H2492 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32493 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NOH2494 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O2495 (2-ethylphenyl) C.sub.3 H.sub.7 (n) S2496 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 H2497 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NOH2498 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O2499 (2-ethylphenyl) C.sub.4 H.sub.9 (n) S2500 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H2501 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NOH______________________________________
TABLE LIX______________________________________ ##STR145##EX. # R.sup.172 R.sup.173 R.sup.174______________________________________2502 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52503 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2504 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52505 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2506 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52507 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2508 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52509 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2510 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52511 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2512 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52513 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2514 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52515 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n)2516 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52517 (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______________________________________2518 H C.sub.3 H.sub.7 (n) H2519 H C.sub.3 H.sub.7 (n) NH.sub.22520 H C.sub.3 H.sub.7 (n) OH2521 H C.sub.3 H.sub.7 (n) CH.sub.2 OH2522 H C.sub.3 H.sub.7 (n) CO.sub.2 H2523 H C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32524 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52525 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2526 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.52527 H C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.52528 H C.sub.3 H.sub.7 (n) (2-ethylphenyl)2529 H C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H2530 H C.sub.3 H.sub.7 (n) H2531 H C.sub.3 H.sub.7 (n) NH.sub.22532 H C.sub.3 H.sub.7 (n) OH2533 H C.sub.4 H.sub.9 (n) CH.sub.2 OH2534 H C.sub.4 H.sub.9 (n) CO.sub.2 H2535 H C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32536 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52537 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2538 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.52539 H C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.52540 H C.sub.4 H.sub.9 (n) (2-ethylphenyl)2541 H C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H2542 Cl C.sub.4 H.sub.9 (n) H2543 Cl C.sub.4 H.sub.9 (n) NH.sub.22544 Cl C.sub.3 H.sub.7 (n) OH2545 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH2546 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H2547 Cl C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32548 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52549 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2550 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.52551 Cl C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.52552 Cl C.sub.3 H.sub.7 (n) (2-ethylphenyl)2553 Cl C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H2554 Cl C.sub.4 H.sub.9 (n) H2555 Cl C.sub.4 H.sub.9 (n) NH.sub.22556 Cl C.sub.4 H.sub.9 (n) OH2557 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH2558 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H2559 Cl C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32560 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52561 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2562 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.52563 Cl C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.52564 Cl C.sub.4 H.sub.9 (n) (2-ethylphenyl)2565 Cl C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H2566 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H2567 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NH.sub.22568 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) OH2569 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 OH2570 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CO.sub.2 H2571 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32572 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52573 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H2574 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NH.sub.22575 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) OH2576 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 OH2577 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CO.sub.2 H2578 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32579 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52580 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H2581 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NH.sub.22582 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) OH2583 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 OH2584 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CO.sub.2 H2585 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32586 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52587 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.52588 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H2589 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NH.sub.22590 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) OH2591 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 OH2592 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CO.sub.2 H2593 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32594 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52595 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H2596 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.22597 (2-ethylphenyl) C.sub.3 H.sub.7 (n) OH2598 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH2599 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H2600 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32601 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52602 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H2603 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.22604 (2-ethylphenyl) C.sub.4 H.sub.9 (n) OH2605 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH2606 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H2607 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32608 (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______________________________________2609 H C.sub.3 H.sub.7 (n) H CH.sub.32610 H C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32611 H C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.32612 H C.sub.4 H.sub.9 (n) H CH.sub.32613 H C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32614 H C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.32615 Cl C.sub.3 H.sub.7 (n) H CH.sub.32616 Cl C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32617 Cl C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.32618 Cl C.sub.4 H.sub.9 (n) H CH.sub.32619 Cl C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32620 Cl C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.32621 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H CH.sub.32622 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32623 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H CH.sub.32624 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32625 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H CH.sub.32626 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32627 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.32628 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32629 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.32630 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.32631 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.32632 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.32633 H C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.52634 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.52635 H C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.52636 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.52637 Cl C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.52638 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.52639 Cl C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.52640 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.52641 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.52642 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.52643 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.52644 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.52645 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.52646 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.52647 H C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.52648 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.52649 H C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.52650 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.52651 Cl C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.52652 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.52653 Cl C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.52654 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.52655 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.52656 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.52657 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.52658 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.52659 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.52660 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.52661 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.52662 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.52663 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H2664 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 H2665 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H2666 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H2667 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H2668 (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______________________________________2669 H C.sub.3 H.sub.7 (n) O2670 H C.sub.3 H.sub.7 (n) H,H2671 H C.sub.3 H.sub.7 (n) H,CH.sub.32672 H C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.52673 H C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2674 H C.sub.3 H.sub.7 (n) H,CO.sub.2 H2675 H C.sub.4 H.sub.9 (n) O2676 H C.sub.4 H.sub.9 (n) H,H2677 H C.sub.4 H.sub.9 (n) H,CH.sub.32678 H C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.52679 H C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2680 H C.sub.4 H.sub.9 (n) H,CO.sub.2 H2681 Cl C.sub.3 H.sub.7 (n) O2682 Cl C.sub.3 H.sub.7 (n) H,H2683 Cl C.sub.3 H.sub.7 (n) H,CH.sub.32684 Cl C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.52685 Cl C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2686 Cl C.sub.3 H.sub.7 (n) H,CO.sub.2 H2687 Cl C.sub.4 H.sub.9 (n) O2688 Cl C.sub.4 H.sub.9 (n) H,H2689 Cl C.sub.4 H.sub.9 (n) H,CH.sub.32690 Cl C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.52691 Cl C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2692 Cl C.sub.4 H.sub.9 (n) H,CO.sub.2 H2693 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O2694 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,H2695 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.32696 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.52697 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2698 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CO.sub.2 H2699 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O2700 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,H2701 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.32702 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.52703 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2704 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CO.sub.2 H2705 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O2706 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,H2707 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.32708 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2709 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CO.sub.2 H2710 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O2711 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,H2712 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.32713 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2714 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CO.sub.2 H2715 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O2716 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,H2717 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.32718 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.32719 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2720 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CO.sub.2 H2721 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O2722 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,H2723 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.32724 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3,CH.sub.32725 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2726 (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______________________________________2727 H C.sub.3 H.sub.7 (n) O2728 H C.sub.3 H.sub.7 (n) H,H2729 H C.sub.3 H.sub.7 (n) H,CH.sub.32730 H C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.52731 H C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2732 H C.sub.3 H.sub.7 (n) H,CO.sub.2 H2733 H C.sub.4 H.sub.9 (n) O2734 H C.sub.4 H.sub.9 (n) H,H2735 H C.sub.4 H.sub.9 (n) H,CH.sub.32736 H C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.52737 H C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2738 H C.sub.4 H.sub.9 (n) H,CO.sub.2 H2739 Cl C.sub.3 H.sub.7 (n) O2740 Cl C.sub.3 H.sub.7 (n) H,H2741 Cl C.sub.3 H.sub.7 (n) H,CH.sub.32742 Cl C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.32743 Cl C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2744 Cl C.sub.3 H.sub.7 (n) H,CO.sub.2 H2745 Cl C.sub.4 H.sub.9 (n) O2746 Cl C.sub.4 H.sub.9 (n) H,H2747 Cl C.sub.4 H.sub.9 (n) H,CH.sub.32748 Cl C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.52749 Cl C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2750 Cl C.sub.4 H.sub.9 (n) H,CO.sub.2 H2751 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O2752 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,H2753 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.32754 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.52755 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2756 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CO.sub.2 H2757 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O2758 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,H2759 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.32760 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.52761 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2762 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CO.sub.2 H2763 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O2764 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,H2765 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.32766 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2767 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CO.sub.2 H2768 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O2769 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,H2770 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.32771 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2772 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CO.sub.2 H2773 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O2774 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,H2775 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.32776 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.32777 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH2778 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CO.sub.2 H2779 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O2780 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,H2781 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.32782 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3,CH.sub.32783 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH2784 (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______________________________________2785 H C.sub.3 H.sub.7 (n) CH.sub.22786 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)2787 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)2788 H C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22789 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.22790 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.22791 H C.sub.4 H.sub.9 (n) CH.sub.22792 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)2793 H C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.22794 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.22795 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.22796 Cl C.sub.3 H.sub.7 (n) CH.sub.22797 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)2798 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)2799 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22800 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.22801 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.22802 Cl C.sub.4 H.sub.9 (n) CH.sub.22803 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)2804 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)2805 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.22806 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.22807 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.22808 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.22809 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22810 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.22811 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.22812 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.22813 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22814 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.22815 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.22816 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.22817 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.22818 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.22819 (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______________________________________2820 H C.sub.3 H.sub.7 (n) H2821 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52822 H C.sub.3 H.sub.7 (n) CH.sub.2 OH2823 H C.sub.3 H.sub.7 (n) CO.sub.2 H2824 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2825 H C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32826 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H2827 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.32828 H C.sub.3 H.sub.7 (n) phenyl2829 H C.sub.3 H.sub.7 (n) benzyl2830 H C.sub.4 H.sub.9 (n) H2831 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52832 H C.sub.4 H.sub.9 (n) CH.sub.2 OH2833 H C.sub.4 H.sub.9 (n) CO.sub.2 H2834 H C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2835 H C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32836 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H2837 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.32838 H C.sub.4 H.sub.9 (n) phenyl2839 H C.sub.4 H.sub.9 (n) benzyl2840 Cl C.sub.3 H.sub.7 (n) H2841 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52842 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH2843 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H2844 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2845 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32846 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H2847 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.32848 Cl C.sub.4 H.sub.9 (n) H2849 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52850 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH2851 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H2852 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2853 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32854 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 H2855 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CO.sub.2 C(CH.sub.3).sub.32856 ethyl C.sub.3 H.sub.7 (n) H2857 ethyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52858 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 OH2859 ethyl C.sub.3 H.sub.7 (n) CO.sub.2 H2860 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2861 ethyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32862 ethyl C.sub.4 H.sub.9 (n) H2863 ethyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52864 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 OH2865 ethyl C.sub.4 H.sub.9 (n) CO.sub.2 H2866 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2867 ethyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32868 n-butyl C.sub.3 H.sub.7 (n) H2869 n-butyl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52870 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 OH2871 n-butyl C.sub.3 H.sub.7 (n) CO.sub.2 H2872 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2873 n-butyl C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32874 n-butyl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52875 n-butyl C.sub.4 H.sub.9 (n) H2876 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 OH2877 n-butyl C.sub.4 H.sub.9 (n) CO.sub.2 H2878 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2879 n-butyl C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32880 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H2881 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52882 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH2883 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H2884 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H2885 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 C(CH.sub.3).sub.32886 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H2887 (2-ethylphenyl) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52888 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH2889 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H2890 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H2891 (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______________________________________2892 H C.sub.3 H.sub.7 (n) O2893 H C.sub.3 H.sub.7 (n) S2894 H C.sub.3 H.sub.7 (n) CHCO.sub.2 H2895 H C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32896 H C.sub.3 H.sub.7 (n) NOH2897 H C.sub.4 H.sub.9 (n) O2898 H C.sub.4 H.sub.9 (n) S2899 H C.sub.4 H.sub.9 (n) CHCO.sub.2 H2900 H C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32901 Cl C.sub.3 H.sub.7 (n) O2902 Cl C.sub.3 H.sub.7 (n) S2903 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 H2904 Cl C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32905 Cl C.sub.3 H.sub.7 (n) NOH2906 Cl C.sub.4 H.sub.9 (n) O2907 Cl C.sub.4 H.sub.9 (n) S2908 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 H2909 Cl C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32910 Cl C.sub.4 H.sub.9 (n) NOH2911 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O2912 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) S2913 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 H2914 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32915 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NOH2916 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O2917 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) S2918 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 H2919 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32920 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NOH2921 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O2922 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) S2923 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 H2924 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CHCO.sub.2 C(CH.sub.3).sub.32925 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NOH2926 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O2927 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) S2928 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 H2929 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CHCO.sub.2 C(CH.sub.3).sub.32930 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NOH2931 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O2932 (2-ethylphenyl) C.sub.3 H.sub.7 (n) S2933 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CHCO.sub.2 H2934 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NOH2935 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O2936 (2-ethylphenyl) C.sub.4 H.sub.9 (n) S2937 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CHCO.sub.2 H2938 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NOH______________________________________
TABLE LXVII______________________________________ ##STR153##EX. # R.sup.199 R.sup.200 R.sup.201______________________________________2939 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52940 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2941 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52942 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2943 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52944 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2945 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52946 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2947 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52948 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2949 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52950 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2951 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52952 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52953 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52954 (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______________________________________2955 H C.sub.3 H.sub.7 (n) H2956 H C.sub.3 H.sub.7 (n) NH.sub.22957 H C.sub.3 H.sub.7 (n) OH2958 H C.sub.3 H.sub.7 (n) CH.sub.2 OH2959 H C.sub.3 H.sub.7 (n) CO.sub.2 H2960 H C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32961 H C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52962 H C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2963 H C.sub.3 H.sub.7 (n) C.sub.6 H.sub.52964 H C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.52965 H C.sub.3 H.sub.7 (n) (2-ethylphenyl)2966 H C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H2967 H C.sub.3 H.sub.7 (n) H2968 H C.sub.3 H.sub.7 (n) NH.sub.22969 H C.sub.3 H.sub.7 (n) OH2970 H C.sub.4 H.sub.9 (n) CH.sub.2 OH2971 H C.sub.4 H.sub.9 (n) CO.sub.2 H2972 H C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32973 H C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52974 H C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2975 H C.sub.4 H.sub.9 (n) C.sub.6 H.sub.52976 H C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.52977 H C.sub.4 H.sub.9 (n) (2-ethylphenyl)2978 H C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H2979 Cl C.sub.4 H.sub.9 (n) H2980 Cl C.sub.4 H.sub.9 (n) NH.sub.22981 Cl C.sub.3 H.sub.7 (n) OH2982 Cl C.sub.3 H.sub.7 (n) CH.sub.2 OH2983 Cl C.sub.3 H.sub.7 (n) CO.sub.2 H2984 Cl C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.32985 Cl C.sub.3 H.sub.7 (n) C.sub.2 H.sub.52986 Cl C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)2987 Cl C.sub.3 H.sub.7 (n) C.sub.6 H.sub.52988 Cl C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.52989 Cl C.sub.3 H.sub.7 (n) (2-ethylphenyl)2990 Cl C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H2991 Cl C.sub.4 H.sub.9 (n) H2992 Cl C.sub.4 H.sub.9 (n) NH.sub.22993 Cl C.sub.4 H.sub.9 (n) OH2994 Cl C.sub.4 H.sub.9 (n) CH.sub.2 OH2995 Cl C.sub.4 H.sub.9 (n) CO.sub.2 H2996 Cl C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.32997 Cl C.sub.4 H.sub.9 (n) C.sub.2 H.sub.52998 Cl C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)2999 Cl C.sub.4 H.sub.9 (n) C.sub.6 H.sub.53000 Cl C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.53001 Cl C.sub.4 H.sub.9 (n) (2-ethylphenyl)3002 Cl C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H3003 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H3004 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) NH.sub.23005 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) OH3006 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 OH3007 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CO.sub.2 H3008 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.33009 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53010 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H3011 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) NH.sub.23012 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) OH3013 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 OH3014 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CO.sub.2 H3015 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.33016 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53017 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H3018 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) NH.sub.23019 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) OH3020 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 OH3021 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CO.sub.2 H3022 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.33023 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53024 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.53025 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H3026 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) NH.sub.23027 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) OH3028 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.2 OH3029 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CO.sub.2 H3030 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.33031 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53032 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H3033 (2-ethylphenyl) C.sub.3 H.sub.7 (n) NH.sub.23034 (2-ethylphenyl) C.sub.3 H.sub.7 (n) OH3035 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 OH3036 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 H3037 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CO.sub.2 C(CH.sub.3).sub.33038 (2-ethylphenyl) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53039 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H3040 (2-ethylphenyl) C.sub.4 H.sub.9 (n) NH.sub.23041 (2-ethylphenyl) C.sub.4 H.sub.9 (n) OH3042 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.2 OH3043 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 H3044 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CO.sub.2 C(CH.sub.3).sub.33045 (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______________________________________3046 H C.sub.3 H.sub.7 (n) H CH.sub.33047 H C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.33048 H C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.33049 H C.sub.4 H.sub.9 (n) H CH.sub.33050 H C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.33051 H C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.33052 Cl C.sub.3 H.sub.7 (n) H CH.sub.33053 Cl C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.33054 Cl C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.33055 Cl C.sub.4 H.sub.9 (n) H CH.sub.33056 Cl C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.33057 Cl C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.33058 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H CH.sub.33059 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.33060 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H CH.sub.33061 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.33062 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H CH.sub.33063 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.33064 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.33065 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.33066 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.33067 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.33068 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.33069 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.33070 H C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.53071 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.53072 H C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.53073 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.53074 Cl C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.53075 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.53076 Cl C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.53077 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.53078 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.53079 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.53080 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.53081 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.53082 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.53083 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.53084 H C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.53085 H C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.53086 H C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.53087 H C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.53088 Cl C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.53089 Cl C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.53090 Cl C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.53091 Cl C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.53092 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.53093 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.53094 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.53095 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.53096 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.53097 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.53098 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.53099 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.53100 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3101 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 H3102 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3103 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H3104 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3105 (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______________________________________3106 H C.sub.3 H.sub.7 (n) O3107 H C.sub.3 H.sub.7 (n) H,H3108 H C.sub.3 H.sub.7 (n) H,CH.sub.33109 H C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.53110 H C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3111 H C.sub.3 H.sub.7 (n) H,CO.sub.2 H3112 H C.sub.4 H.sub.9 (n) O3113 H C.sub.4 H.sub.9 (n) H,H3114 H C.sub.4 H.sub.9 (n) H,CH.sub.33115 H C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53116 H C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3117 H C.sub.4 H.sub.9 (n) H,CO.sub.2 H3118 Cl C.sub.3 H.sub.7 (n) O3119 Cl C.sub.3 H.sub.7 (n) H,H3120 Cl C.sub.3 H.sub.7 (n) H,CH.sub.33121 Cl C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.53122 Cl C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3123 Cl C.sub.3 H.sub.7 (n) H,CO.sub.2 H3124 Cl C.sub.4 H.sub.9 (n) O3125 Cl C.sub.4 H.sub.9 (n) H,H3126 Cl C.sub.4 H.sub.9 (n) H,CH.sub.33127 Cl C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53128 Cl C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3129 Cl C.sub.4 H.sub.9 (n) H,CO.sub.2 H3130 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O3131 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,H3132 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.33133 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.53134 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3135 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CO.sub.2 H3136 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O3137 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,H3138 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.33139 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53140 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3141 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CO.sub.2 H3142 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O3143 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,H3144 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.33145 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3146 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CO.sub.2 H3147 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O3148 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,H3149 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.33150 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3151 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CO.sub.2 H3152 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O3153 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,H3154 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.33155 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.33156 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3157 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CO.sub.2 H3158 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O3159 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,H3160 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.33161 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3,CH.sub.33162 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3163 (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______________________________________3164 H C.sub.3 H.sub.7 (n) O3165 H C.sub.3 H.sub.7 (n) H,H3166 H C.sub.3 H.sub.7 (n) H,CH.sub.33167 H C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.53168 H C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3169 H C.sub.3 H.sub.7 (n) H,CO.sub.2 H3170 H C.sub.4 H.sub.9 (n) O3171 H C.sub.4 H.sub.9 (n) H,H3172 H C.sub.4 H.sub.9 (n) H,CH.sub.33173 H C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53174 H C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3175 H C.sub.4 H.sub.9 (n) H,CO.sub.2 H3176 Cl C.sub.3 H.sub.7 (n) O3177 Cl C.sub.3 H.sub.7 (n) H,H3178 Cl C.sub.3 H.sub.7 (n) H,CH.sub.33179 Cl C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.33180 Cl C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3181 Cl C.sub.3 H.sub.7 (n) H,CO.sub.2 H3182 Cl C.sub.4 H.sub.9 (n) O3183 Cl C.sub.4 H.sub.9 (n) H,H3184 Cl C.sub.4 H.sub.9 (n) H,CH.sub.33185 Cl C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53186 Cl C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3187 Cl C.sub.4 H.sub.9 (n) H,CO.sub.2 H3188 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) O3189 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,H3190 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.33191 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.53192 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3193 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) H,CO.sub.2 H3194 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) O3195 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,H3196 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.33197 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53198 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3199 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) H,CO.sub.2 H3200 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) O3201 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,H3202 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.33203 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3204 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) H,CO.sub.2 H3205 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) O3206 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,H3207 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.33208 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3209 C.sub.4 H.sub.9 (n) C.sub.4 H.sub.9 (n) H,CO.sub.2 H3210 (2-ethylphenyl) C.sub.3 H.sub.7 (n) O3211 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,H3212 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.33213 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.3,CH.sub.33214 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3215 (2-ethylphenyl) C.sub.3 H.sub.7 (n) H,CO.sub.2 H3216 (2-ethylphenyl) C.sub.4 H.sub.9 (n) O3217 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,H3218 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.33219 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.3,CH.sub.33220 (2-ethylphenyl) C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3221 (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______________________________________3222 H C.sub.3 H.sub.7 (n) CH.sub.23223 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)3224 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3225 H C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.23226 H C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.23227 H C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.23228 H C.sub.4 H.sub.9 (n) CH.sub.23229 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)3230 H C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.23231 H C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.23232 H C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.23233 Cl C.sub.3 H.sub.7 (n) CH.sub.23234 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)3235 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3236 Cl C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.23237 Cl C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.23238 Cl C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.23239 Cl C.sub.4 H.sub.9 (n) CH.sub.23240 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2l H.sub.5)3241 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3242 Cl C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.23243 Cl C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.23244 Cl C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.23245 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.23246 C.sub.2 H.sub.5 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.23247 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.23248 C.sub.2 H.sub.5 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.23249 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CH.sub.23250 C.sub.4 H.sub.9 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.23251 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CH.sub.23252 C.sub.4 H.sub.9 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.23253 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.23254 (2-ethylphenyl) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.23255 (2-ethylphenyl) C.sub.4 H.sub.9 (n) CH.sub.23256 (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 triazole 96 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 alcohol 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.
The ketone 101 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. Mita; Y. Hatanaka; M. Yokoyama, J. Org. Chem., 49, 3904-3912 (1984). b) D. Bonneville, J. Org. Chem., 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 103. The olefin 103 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 104. The olefins 103 or 104 may be hydrogenated to its saturated analogue 105. Alternatively, olefin 104 can be prepared from ketone 101 by treatment with an appropriate organometallic reagent, such as a Grignard reagent. ##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 �Mitsunobu, 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 DMF (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 3257 ##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 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 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 (1.45M 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 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 3236.
EXAMPLE 3258 ##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 3257), 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 3257 and purified to give the title compound of Example 3258.
EXAMPLE 3259 ##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 3257) 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 3259.
EXAMPLE 3260 ##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 3257) 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 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 3262).
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 3257 and purified to give the title compound of Example 3260.
EXAMPLE 3261 ##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 3260) 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 3261.
EXAMPLE 3262 ##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 3260) 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 3261), 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 temperture 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 3262.
EXAMPLE 3263 ##STR169##
�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 3257, 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 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 1 of Example 3261 or 3262), 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 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 3257 and purified to give the title compound of Example 3263.
EXAMPLE 3264 ##STR170##
�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 3263) 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 3264.
EXAMPLE 3265 ##STR171##
3-Butyl-6,7-dihydro-5-�2'-(1H-tetrazol-5-yl)�1,1'-biphenyl!-4-yl!-5H, 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 3257) 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 3257 and purified to give the title compound of Example 3265.
EXAMPLE 3266 ##STR172##
1,1-Dimethylethyl �3-butyl-6,7-dihydro-5-�2.degree. -(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 3260) 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 3257 and purified to give the title compound of Example 3266.
EXAMPLE 3267 ##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 3266) 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 32367.
EXAMPLE 3268 ##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 3266) 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 3257. The crude product is purified to give the title compound of Example 3268.
EXAMPLE 3269 ##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 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 3269.
EXAMPLE 3270 ##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 3268) 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 3270.
EXAMPLE 3271 ##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 3270) 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 3271.
EXAMPLE 3272 ##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 3260), 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 3272.
EXAMPLE 3273 ##STR179##
�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 3261 or 3262), 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 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 3257 and purified give the title compound of Example 3273.
EXAMPLE 3274 ##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 3273) 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 3274.
Alternatively, the title compound of Example 3274 can be prepared from the corresponding oxime. A suspension of the biphenyl imidazolyl oxime (0.059 mmol, the title compound of Example 3273) 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 3274.
Further examples of conformationally restricted angiotensin II antagonists (3275-3739) embraced by Formula V above are located in Tables LXXIII-XCVI.
TABLE LXXIII______________________________________ ##STR181##EX. # R.sup.220 R.sup.221______________________________________3275. C.sub.3 H.sub.7 (n) H3276. C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53277. C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3278. C.sub.3 H.sub.7 (n) (2-ethylphenyl)3279. C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)3280. C.sub.3 H.sub.7 (n) phenyl3281. C.sub.3 H.sub.7 (n) benzyl3282. C.sub.3 H.sub.7 (n) phenylethyl3283. C.sub.3 H.sub.7 (n) CH.sub.2 OH3284. C.sub.3 H.sub.7 (n) CO.sub.2 H3285. C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3286. C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53287. C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)3288. C.sub.4 H.sub.9 (n) (2-ethylphenyl)3289. C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)3290. C.sub.4 H.sub.9 (n) phenyl3291. C.sub.4 H.sub.9 (n) benzyl3292. C.sub.4 H.sub.9 (n) phenylethyl3293. C.sub.4 H.sub.9 (n) CH.sub.2 OH3294. C.sub.4 H.sub.9 (n) CO.sub.2 H______________________________________
TABLE LXXIV______________________________________ ##STR182##EX. # R.sup.222 R.sup.223______________________________________3295. C.sub.3 H.sub.7 (n) O3296. C.sub.3 H.sub.7 (n) S3297. C.sub.3 H.sub.7 (n) NOH3298. C.sub.3 H.sub.7 (n) CHCO.sub.2 H3299. C.sub.3 H.sub.7 (n) C(C.sub.2 H.sub.5)CO.sub.2 H3300. C.sub.3 H.sub.7 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H3301. C.sub.3 H.sub.7 (n) CHC.sub.2 H.sub.53302. C.sub.4 H.sub.9 (n) S3303. C.sub.4 H.sub.9 (n) C(C.sub.2 H.sub.5)CO.sub.2 H3304. C.sub.4 H.sub.9 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H3305. C.sub.4 H.sub.9 (n) CHC.sub.2 H.sub.5______________________________________
TABLE LXXV______________________________________ ##STR183##EX. # R.sup.224 R.sup.225______________________________________3306. C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53307. C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3308. C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53309. C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)______________________________________
TABLE LXXVI______________________________________ ##STR184##EX. # R.sup.226 R.sup.227______________________________________3310. C.sub.3 H.sub.7 (n) H3311. C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53312. C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3313. C.sub.3 H.sub.7 (n) (2-ethylphenyl)3314. C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)3315. C.sub.3 H.sub.7 (n) phenyl3316. C.sub.3 H.sub.7 (n) benzyl3317. C.sub.3 H.sub.7 (n) phenylethyl3318. C.sub.3 H.sub.7 (n) NH.sub.23319. C.sub.3 H.sub.7 (n) OH3320. C.sub.3 H.sub.7 (n) CH.sub.2 OH3321. C.sub.3 H.sub.7 (n) CO.sub.2 H3322. C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53323. C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)3324. C.sub.4 H.sub.9 (n) (2-ethylphenyl)3325. C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)3326. C.sub.4 H.sub.9 (n) phenyl3327. C.sub.4 H.sub.9 (n) benzyl3328. C.sub.4 H.sub.9 (n) phenylethyl3329. C.sub.4 H.sub.9 (n) CH.sub.2 OH3330. C.sub.4 H.sub.9 (n) CO.sub.2 H______________________________________
TABLE LXXVII______________________________________ ##STR185##EX. # R.sup.228 R.sup.229 R.sup.230______________________________________3331. CH.sub.3 H.sub.7 (n) H CH.sub.33332. C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.53333. C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.53334. C.sub.3 H.sub.7 (n) H CH.sub.2 C.sub.6 H.sub.53335. C.sub.3 H.sub.7 (n) H CH.sub.2 CO.sub.2 H3336. C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3337. C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.33338. C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.53339. C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.53340. C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 C.sub.6 H.sub.53341. C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CO.sub.2 H3342. C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H3343. C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.33344. C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.53345. C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.53346. C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 C.sub.6 H.sub.53347. C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H3348. C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H3349. C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.33350. C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53351. C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.53352. C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.53353. C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3354. C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H3355. C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.33356. C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.53357. C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.53358. C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H3359. 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 H3360. C.sub.4 H.sub.9 (n) H C.sub.33361. C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.53362. C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.53363. C.sub.4 H.sub.9 (n) H CH.sub.2 C.sub.6 H.sub.53364. C.sub.4 H.sub.9 (n) H CH.sub.2 CO.sub.2 H3365. C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3366. C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.33367. C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.53368. C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.53369. C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 C.sub.6 H.sub.53370. C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CO.sub.2 H3371. C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H3372. C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.33373. C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.53374. C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.53375. C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 C.sub.6 H.sub.53376. C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H3377. C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H3378. C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.33379. C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53380. C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.53381. C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.53382. C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3383. C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H3384. C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.33385. C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.53386. C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.53387. C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H3388. 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______________________________________3389. C.sub.3 H.sub.7 (n) O3390. C.sub.3 H.sub.7 (n) H, H3391. C.sub.3 H.sub.7 (n) H, CH.sub.33392. C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.53393. C.sub.3 H.sub.7 (n) H, CH.sub.2 OH3394. C.sub.3 H.sub.7 (n) H, CO.sub.2 H3395. C.sub.4 H.sub.9 (n) H, H3396. C.sub.4 H.sub.9 (n) H, CH.sub.33397. C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.53398. C.sub.4 H.sub.9 (n) H, CH.sub.2 OH3399. C.sub.4 H.sub.9 (n) H, CO.sub.2 H______________________________________
TABLE LXXVIX______________________________________ ##STR187##EX. # R.sup.234 R.sup.235, R.sup.236______________________________________3400. C.sub.3 H.sub.7 (n) O3401. C.sub.3 H.sub.7 (n) H, H3402. C.sub.3 H.sub.7 (n) H, CH.sub.33403. C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.53404. C.sub.3 H.sub.7 (n) H, CH.sub.2 OH3405. C.sub.3 H.sub.7 (n) H, CO.sub.2 H3406. C.sub.4 H.sub.9 (n) O3407. C.sub.4 H.sub.9 (n) H, H3408. C.sub.4 H.sub.9 (n) H, CH.sub.33409. C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.53410. C.sub.4 H.sub.9 (n) H, CH.sub.2 OH3411. C.sub.4 H.sub.9 (n) H, CO.sub.2 H______________________________________
TABLE LXXX______________________________________ ##STR188##EX. # R.sup.237 R.sup.238______________________________________3412. C.sub.3 H.sub.7 (n) CH.sub.23413. C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)3414. C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3415. C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.23416. C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.23417. C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.23418. C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)3419. C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3420. C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.23421. C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.23422. 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______________________________________3423. C.sub.3 H.sub.7 (n) H3424. C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53425. C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3426. C.sub.3 H.sub.7 (n) (2-ethylphenyl)3427. C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)3428. C.sub.3 H.sub.7 (n) phenyl3429. C.sub.3 H.sub.7 (n) benzyl3430. C.sub.3 H.sub.7 (n) phenylethyl3431. C.sub.3 H.sub.7 (n) CH.sub.2 OH3432. C.sub.3 H.sub.7 (n) CO.sub.2 H3433. C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3434. C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53435. C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)3436. C.sub.4 H.sub.9 (n) (2-ethylphenyl)3437. C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)3438. C.sub.4 H.sub.9 (n) phenyl3439. C.sub.4 H.sub.9 (n) benzyl3440. C.sub.4 H.sub.9 (n) phenylethyl3441. C.sub.4 H.sub.9 (n) CH.sub.2 OH3442. C.sub.4 H.sub.9 (n) CO.sub.2 H3443. C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H______________________________________
TABLE LXXXII______________________________________ ##STR190##EX. # R.sup.241 R.sup.242______________________________________3444. C.sub.3 H.sub.7 (n) O3445. C.sub.3 H.sub.7 (n) S3446. C.sub.3 H.sub.7 (n) NOH3447. C.sub.3 H.sub.7 (n) CHCO.sub.2 H3448. C.sub.3 H.sub.7 (n) C(C.sub.2 H.sub.5)CO.sub.2 H3449. C.sub.3 H.sub.7 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H3450. C.sub.3 H.sub.7 (n) CHC.sub.2 H.sub.53451. C.sub.4 H.sub.9 (n) O3452. C.sub.4 H.sub.9 (n) S3453. C.sub.4 H.sub.9 (n) NOH3454. C.sub.4 H.sub.9 (n) CHCO.sub.2 H3455. C.sub.4 H.sub.9 (n) C(C.sub.2 H.sub.5)CO.sub.2 H3456. C.sub.4 H.sub.9 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H3457. C.sub.4 H.sub.9 (n) CHC.sub.2 H.sub.5______________________________________
TABLE LXXXIII______________________________________ ##STR191##EX. # R.sup.243 R.sup.244______________________________________3458. C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53459. C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3460. C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53461. C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)______________________________________
TABLE LXXXIV______________________________________ ##STR192##EX. # R.sup.245 R.sup.246______________________________________3462 C.sub.3 H.sub.7 (n) H3463 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53464 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3465 C.sub.3 H.sub.7 (n) (2-ethylphenyl)3466 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)3467 C.sub.3 H.sub.7 (n) phenyl3468 C.sub.3 H.sub.7 (n) benzyl3469 C.sub.3 H.sub.7 (n) phenylethyl3470 C.sub.3 H.sub.7 (n) NH.sub.23471 C.sub.3 H.sub.7 (n) OH3472 C.sub.3 H.sub.7 (n) CH.sub.2 OH3473 C.sub.3 H.sub.7 (n) CO.sub.2 H3474 C.sub.4 H.sub.9 (n) H3475 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53476 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)3477 C.sub.4 H.sub.9 (n) (2-ethylphenyl)3478 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)3479 C.sub.4 H.sub.9 (n) phenyl3480 C.sub.4 H.sub.9 (n) benzyl3481 C.sub.4 H.sub.9 (n) phenylethyl3482 C.sub.4 H.sub.9 (n) NH.sub.23483 C.sub.4 H.sub.9 (n) OH3484 C.sub.4 H.sub.9 (n) CH.sub.2 OH3485 C.sub.4 H.sub.9 (n) CO.sub.2 H______________________________________
TABLE LXXXV______________________________________ ##STR193##EX. # R.sup.247 R.sup.248 R.sup.249______________________________________3486 CH.sub.3 H.sub.7 (n) H CH.sub.33487 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.53488 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.53489 C.sub.3 H.sub.7 (n) H CH.sub.2 C.sub.6 H.sub.53490 C.sub.3 H.sub.7 (n) H CH.sub.2 CO.sub.2 H3491 C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3492 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.33493 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.53494 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.53495 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 C.sub.6 H.sub.53496 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CO.sub.2 H3497 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H3498 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.33499 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.53500 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.53501 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 C.sub.6 H.sub.53502 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H3503 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H3504 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.33505 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53506 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.53507 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.53508 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3509 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H3510 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.33511 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.53512 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.53513 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H3514 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 H3515 C.sub.4 H.sub.9 (n) H C.sub.33516 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.53517 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.53518 C.sub.4 H.sub.9 (n) H CH.sub.2 C.sub.6 H.sub.53519 C.sub.4 H.sub.9 (n) H CH.sub.2 CO.sub.2 H3520 C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3521 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.33522 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.53523 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.53524 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 C.sub.6 H.sub.53525 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CO.sub.2 H3526 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H3527 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.33528 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.53529 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.53530 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 C.sub.6 H.sub.53531 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H3532 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H3533 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.33534 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53535 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.53536 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.53537 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3538 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H3539 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.33540 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.53541 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.53542 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H3543 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______________________________________3544. C.sub.3 H.sub.7 (n) O3545 C.sub.3 H.sub.7 (n) H, H3546 C.sub.3 H.sub.7 (n) H, CH.sub.33547 C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.53548 C.sub.3 H.sub.7 (n) H, CH.sub.2 OH3549 C.sub.3 H.sub.7 (n) H, CO.sub.2 H3550 C.sub.4 H.sub.9 (n) O3551 C.sub.4 H.sub.9 (n) H, H3552 C.sub.4 H.sub.9 (n) H, CH.sub.33553 C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.53554 C.sub.4 H.sub.9 (n) H, CH.sub.2 OH3555 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______________________________________3556 C.sub.3 H.sub.7 (n) O3557 C.sub.3 H.sub.7 (n) H, H3558 C.sub.3 H.sub.7 (n) H, CH.sub.33559 C.sub.3 H.sub.7 (n) H, C.sub.2 H.sub.53560 C.sub.3 H.sub.7 (n) H, CH.sub.2 OH3561 C.sub.3 H.sub.7 (n) H, CO.sub.2 H3562 C.sub.4 H.sub.9 (n) O3563 C.sub.4 H.sub.9 (n) H, H3564 C.sub.4 H.sub.9 (n) H, CH.sub.33565 C.sub.4 H.sub.9 (n) H, C.sub.2 H.sub.53566 C.sub.4 H.sub.9 (n) H, CH.sub.2 OH3567 C.sub.4 H.sub.9 (n) H, CO.sub.2 H______________________________________
TABLE LXXXVIII______________________________________ ##STR196##EX. # R.sup.256 R.sup.257______________________________________3568 C.sub.3 H.sub.7 (n) CH.sub.23569 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)3570 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3571 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.23572 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.23573 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.23574 C.sub.4 H.sub.9 (n) CH.sub.23575 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)3576 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3577 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.23578 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.23579 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______________________________________3580 C.sub.3 H.sub.7 (n) H3581 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53582 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3583 C.sub.3 H.sub.7 (n) (2-ethylphenyl)3584 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)3585 C.sub.3 H.sub.7 (n) phenyl3586 C.sub.3 H.sub.7 (n) benzyl3587 C.sub.3 H.sub.7 (n) phenylethyl3588 C.sub.3 H.sub.7 (n) CH.sub.2 OH3589 C.sub.3 H.sub.7 (n) CO.sub.2 H3590 C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3591 C.sub.4 H.sub.9 (n) H3592 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53593 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)3594 C.sub.4 H.sub.9 (n) (2-ethylphenyl)3595 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)3596 C.sub.4 H.sub.9 (n) phenyl3597 C.sub.4 H.sub.9 (n) benzyl3598 C.sub.4 H.sub.9 (n) phenylethyl3599 C.sub.4 H.sub.9 (n) CH.sub.2 OH3600 C.sub.4 H.sub.9 (n) CO.sub.2 H3601 C.sub.4 H.sub.9 (n) CH.sub.2 CO.sub.2 H______________________________________
TABLE XC______________________________________ ##STR198##EX. # R.sup.260 R.sup.261______________________________________3602 C.sub.3 H.sub.7 (n) O3603 C.sub.3 H.sub.7 (n) S3604 C.sub.3 H.sub.7 (n) NOH3605 C.sub.3 H.sub.7 (n) CHCO.sub.2 H3606 C.sub.3 H.sub.7 (n) C(C.sub.2 H.sub.5)CO.sub.2 H3607 C.sub.3 H.sub.7 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H3608 C.sub.3 H.sub.7 (n) CHC.sub.2 H.sub.53609 C.sub.4 H.sub.9 (n) O3610 C.sub.4 H.sub.9 (n) S3611 C.sub.4 H.sub.9 (n) NOH3612 C.sub.4 H.sub.9 (n) CHCO.sub.2 H3613 C.sub.4 H.sub.9 (n) C(C.sub.2 H.sub.5)CO.sub.2 H3614 C.sub.4 H.sub.9 (n) C(CH.sub.2 C.sub.6 H.sub.5)CO.sub.2 H3615 C.sub.4 H.sub.9 (n) CHC.sub.2 H.sub.5______________________________________
TABLE XCI______________________________________ ##STR199##EX. # R.sup.262 R.sup.263______________________________________3616 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53617 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3618 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53619 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)______________________________________
TABLE XCII______________________________________ ##STR200##EX. # R.sup.264 R.sup.265______________________________________3620 C.sub.3 H.sub.7 (n) H3621 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53622 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n)3623 C.sub.3 H.sub.7 (n) (2-ethylphenyl)3624 C.sub.3 H.sub.7 (n) (2,6-dimethylphenyl)3625 C.sub.3 H.sub.7 (n) phenyl3626 C.sub.3 H.sub.7 (n) benzyl3627 C.sub.3 H.sub.7 (n) phenylethyl3628 C.sub.3 H.sub.7 (n) NH.sub.23629 C.sub.3 H.sub.7 (n) OH3630 C.sub.3 H.sub.7 (n) CH.sub.2 OH3631 C.sub.3 H.sub.7 (n) CO.sub.2 H3632 C.sub.3 H.sub.7 (n) OCH.sub.2 C.sub.6 H3633 C.sub.4 H.sub.9 (n) H3634 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.53635 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n)3636 C.sub.4 H.sub.9 (n) (2-ethylphenyl)3637 C.sub.4 H.sub.9 (n) (2,6-dimethylphenyl)3638 C.sub.4 H.sub.9 (n) phenyl3639 C.sub.4 H.sub.9 (n) benzyl3640 C.sub.4 H.sub.9 (n) phenylethyl3641 C.sub.4 H.sub.9 (n) NH.sub.23642 C.sub.4 H.sub.9 (n) OH3643 C.sub.4 H.sub.9 (n) CH.sub.2 OH3644 C.sub.4 H.sub.9 (n) CO.sub.2 H3645 C.sub.4 H.sub.9 (n) OCH.sub.2 C.sub.6 H______________________________________
TABLE XCIII______________________________________ ##STR201##EX. # R.sup.266 R.sup.267 R.sup.268______________________________________3646 C.sub.3 H.sub.7 (n) H CH.sub.33647 C.sub.3 H.sub.7 (n) H C.sub.2 H.sub.53648 C.sub.3 H.sub.7 (n) H C.sub.6 H.sub.53649 C.sub.3 H.sub.7 (n) H CH.sub.2 C.sub.6 H.sub.53650 C.sub.3 H.sub.7 (n) H CH.sub.2 CO.sub.2 H3651 C.sub.3 H.sub.7 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3652 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.33653 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.2 H.sub.53654 C.sub.3 H.sub.7 (n) CH.sub.3 C.sub.6 H.sub.53655 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 C.sub.6 H.sub.53656 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CO.sub.2 H3657 C.sub.3 H.sub.7 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H3658 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.33659 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.53660 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.53661 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 C.sub.6 H.sub.53662 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H3663 C.sub.3 H.sub.7 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H3664 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.33665 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53666 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.53667 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.53668 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3669 C.sub.3 H.sub.7 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H3670 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.33671 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.53672 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.53673 C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H3674 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 H3675 C.sub.4 H.sub.9 (n) H CH.sub.33676 C.sub.4 H.sub.9 (n) H C.sub.2 H.sub.53677 C.sub.4 H.sub.9 (n) H C.sub.6 H.sub.53678 C.sub.4 H.sub.9 (n) H CH.sub.2 C.sub.6 H.sub.53679 C.sub.4 H.sub.9 (n) H CH.sub.2 CO.sub.2 H3680 C.sub.4 H.sub.9 (n) H CH.sub.2 CH.sub.2 CO.sub.2 H3681 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.33682 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.2 H.sub.53683 C.sub.4 H.sub.9 (n) CH.sub.3 C.sub.6 H.sub.53684 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 C.sub.6 H.sub.53685 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CO.sub.2 H3686 C.sub.4 H.sub.9 (n) CH.sub.3 CH.sub.2 CH.sub.2 CO.sub.2 H3687 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.33688 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.2 H.sub.53689 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 C.sub.6 H.sub.53690 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 C.sub.6 H.sub.53691 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CO.sub.2 H3692 C.sub.4 H.sub.9 (n) C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 CO.sub.2 H3693 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.33694 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.2 H.sub.53695 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) C.sub.6 H.sub.53696 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 C.sub.6 H.sub.53697 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CO.sub.2 H3698 C.sub.4 H.sub.9 (n) C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.2 CO.sub.2 H3699 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.33700 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.2 H.sub.53701 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 C.sub.6 H.sub.53702 C.sub.4 H.sub.9 (n) CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 CO.sub.2 H3703 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______________________________________3704 C.sub.3 H.sub.7 (n) O3705 C.sub.3 H.sub.7 (n) H,H3706 C.sub.3 H.sub.7 (n) H,CH.sub.33707 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.53708 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3709 C.sub.3 H.sub.7 (n) H,CO.sub.2 H3710 C.sub.4 H.sub.9 (n) O3711 C.sub.4 H.sub.9 (n) H,H3712 C.sub.4 H.sub.9 (n) H,CH.sub.33713 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53714 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3715 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______________________________________3716 C.sub.3 H.sub.7 (n) O3717 C.sub.3 H.sub.7 (n) H,H3718 C.sub.3 H.sub.7 (n) H,CH.sub.33719 C.sub.3 H.sub.7 (n) H,C.sub.2 H.sub.53720 C.sub.3 H.sub.7 (n) H,CH.sub.2 OH3721 C.sub.3 H.sub.7 (n) H,CO.sub.2 H3722 C.sub.4 H.sub.9 (n) O3723 C.sub.4 H.sub.9 (n) H,H3724 C.sub.4 H.sub.9 (n) H,CH.sub.33725 C.sub.4 H.sub.9 (n) H,C.sub.2 H.sub.53726 C.sub.4 H.sub.9 (n) H,CH.sub.2 OH3727 C.sub.4 H.sub.9 (n) H,CO.sub.2 H______________________________________
TABLE XCVI______________________________________ ##STR204##EX. # R.sup.275 R.sup.276______________________________________3728 C.sub.3 H.sub.7 (n) CH.sub.23729 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)3730 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3731 C.sub.3 H.sub.7 (n) CH.sub.2 CH.sub.23732 C.sub.3 H.sub.7 (n) CH(C.sub.2 H.sub.5)CH.sub.23733 C.sub.3 H.sub.7 (n) CH(CH.sub.2 C.sub.6 H.sub.5)CH.sub.23734 C.sub.4 H.sub.9 (n) CH.sub.23735 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)3736 C.sub.4 H.sub.9 (n) CH(CH.sub.2 C.sub.6 H.sub.5)3737 C.sub.4 H.sub.9 (n) CH.sub.2 CH.sub.23738 C.sub.4 H.sub.9 (n) CH(C.sub.2 H.sub.5)CH.sub.23739 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 mM 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 moveable and fixed ends of a stainless steel wire with the moveable end attached to an FT03 Grass transducer coupled to a Model 7D Grass Polygraph for recording isometric force responses. The bath was filled with 20 ml of oxygenated (95% oxygen/5% carbon dioxide) Krebs solution of the following composition (mM): 130 NaCl, 15 NaHCO.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 AII. Aorta rings were exposed to the test antagonist at 10.sup.-5 M for 5 minutes before challenging with AII. Adjacent segments of the same aorta ring were used for all concentration-response curves in the presence or absence of the test antagonist. The effectiveness of the test compound was expressed in terms of pA.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 IC.sub.50 value for AII by a factor of two. Each test antagonist was evaluated in aorta rings from two rabbits. Results are reported in Table 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 7.15/7.24 10 330 NA 11 120 NA 12 110 6.66/7.05 13 23 7.00/6.86 14 120 6.48/6.26 15 160 6.46/6.73 16 440 8.11/7.79 17 41 7.79/7.27 18 200 NA 19 67 7.15/6.85 20 240 6.89/6.85 21 66 6.98/6.13 24 36 NA351 (cis) 15 8.63/8.43351 (trans) 110 7.11/7.06363 (cis) 11 8.77/-363 (trans) 41 7.19/7.73______________________________________ .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.

Compositions including and methods of using conformationally restricted angiotensin II antagonist

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