WO1999014204A1 - Substituted 1,2,4-triazoles useful for inhibiting cholesteryl ester transfer protein activity - Google Patents

Abstract

A class of substitued 1,2,4-triazole compounds are described as useful for inhibiting the activity of cholesteryl ester transfer protein. Compounds of particular interest are defined by Formula (I), wherein R1 is selected from higher alkyl, higher alkenyl, higher alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, and cycloalkylalkyl; wherein R2 is selected from aryl, heteroaryl, cycloalkyl, and cycloalkenyl, wherein R2 is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, haloalkyl, alkylthio, alkylsulfinyl, hydroxy, alkylsulfonyl, alkoxy, halo, aryloxy, aralkyloxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylamino and dialkylamino; and wherein R3 is selected from hydrido, -SH and halo; provided R2 cannot be phenyl or 4-methylphenyl when R1 is higher alkyl and when R3 is -SH; or a pharmaceutically-acceptable salt or tautomer thereof.

Description

Substituted 1, 2 , -Triazoles Useful for Inhibiting Cholesteryl Ester Transfer Protein

Activity

Field of the Invention

This invention is in the field of treating cardiovascular disease, and specifically relates to compounds, compositions and methods for treating atherosclerosis and other coronary artery disease. More particularly, the invention relates to substituted 1, 2 , 4-triazole compounds that inhibit cholesteryl ester transfer protein (CETP) , also known as plasma lipid transfer protein-I.

Background of the Invention

Numerous studies have demonstrated that a low plasma concentration of high density lipoprotein (HDL) cholesterol is a powerful risk factor for the development of atherosclerosis (Barter and Rye, Atherosclerosis, 121, 1-12 (1996) ) . HDL is one of the major classes of lipoproteins that function in the transport of lipids through the blood. The major lipids found associated with HDL include cholesterol, cholesteryl ester, triglycerides, phospholipids and fatty acids . The other classes of lipoproteins found in the blood are low density lipoprotein (LDL) and very low density lipoprotein (VLDL) . Since low levels of HDL cholesterol increase the risk of atherosclerosis, methods for elevating plasma HDL cholesterol would be therapeutically beneficial for the treatment of atherosclerosis and other diseases associated with accumulation of lipid in the blood vessels . These diseases include, but are not limited to, coronary heart disease, peripheral vascular disease, and stroke.

Atherosclerosis underlies most coronary artery disease (CAD) , a major cause of morbidity and mortality in modern society. High LDL cholesterol (above 180 mg/dl) and low HDL cholesterol (below 35 mg/dl) have been shown to be important contributors to the development of atherosclerosis. Other diseases, such as peripheral vascular disease, stroke, and hypercholesterolaemia are negatively affected by adverse HDH/LDL ratios . Inhibition of CETP by the subject compounds are shown to effectively modify plasma HDH/LDL ratios, and to check the progress and/or formation of these diseases.

CETP is a plasma protein that facilitates the movement of cholesteryl esters and triglycerides between the various lipoproteins in the blood (Tall, J. Lipid Res . , 34, 1255-74

(1993)). The movement of cholesteryl ester from HDL to LDL by CETP has the effect of lowering HDL cholesterol. It therefore follows that inhibition of CETP should lead to elevation of plasma HDL cholesterol and lowering of plasma LDL cholesterol, thereby providing a therapeutically beneficial plasma lipid profile (McCarthy, Medicinal Res . Revs . , 13, 139-59 (1993); Sitori, Pharmac . Ther . , 67,443-47 (1995)) . This exact phenomenon was first demonstrated by Swenson et al . , (J^". Biol . Chem. , 264, 14318 (1989)) with the use of a monoclonal antibody that specifically inhibited CETP. In rabbits, the antibody caused an elevation of the plasma HDL cholesterol and a decrease in LDL cholesterol. Son et al . (Biochim . Biophys . Acta 795, 743-480 (1984)), Morton et al . (J^". Lipid Res . 35, 836-847 (1994)) and Tollefson et al . (Am. J. Physiol . , 255, (Endocrinol. Metab. 18, E894-E902 (1988))) describe proteins from human plasma that inhibit CETP. U.S. Patent 5,519,001, issued to Kushwaha et al . , describes a 36 amino acid peptide derived from baboon apo C-l that inhibits CETP activity.

There have been several reports of compounds that act as CETP inhibitors. Barrett et al. (J. Am . Chem . Soc , 188, 7863-63 (1996)) and Kuo et al . ( J. Am . Chem . Soc , 111 , 10629-34 (1995) ) describe cyclopropane-containing CETP inhibitors. Pietzonka et al . (Bioorg. Med. Chem. Lett, 6 , 1951-54 (1996)) describe phosphonate-containing analogs of cholesteryl ester as CETP inhibitors. Coval et al . (Bioorg. Med. Chem. Lett . , 5, 605-610 (1995)) describe Wiedendiol-A and -B, and related sesquiterpene compounds as CETP inhibitors. Lee et al . (J. Antibiotics, 49, 693-96 (1996)) describe CETP inhibitors derived from an insect fungus. Busch et al. (Lipids, 25, 216-220, (1990)) describe cholesteryl acetyl bromide as a CETP inhibitor. Morton and Zilversmit (J. Lipid Res . , 35, 836-47 (1982)) describe that p-chloromercuriphenyl sulfonate, p-hydroxymercuribenzoate and ethyl mercurithiosalicylate inhibit CETP. Connolly et al. (Biochem . Biophys . Res . Comm . 223, 42-47 (1996) ) describe other cysteine modification reagents as CETP inhibitors . Xia et al . describe 1, 3 , 5-triazines as CETP inhibitors (Bioorg. Med. Chem. Lett., 6, 919-22 (1996)). Triazole compounds are known. Kittur et al. (J^". Oil Techno 1 . Assoc . India (Bombay) , 18, 49-52 (1986)) describe 3-tridecyl-4-p- methylphenyl-5-mercapto-4-l, 2, 4-triazole compounds as antifungal and antibacterial agents. In U.S. Patents 3,701,784 and 3,769,411, Seidel et al. describe 1,2,4-4H- triazole compounds with fungicidal properties for controlling cereal rusts in plants . No pharmacologic properties are recited in either patent .

Bisgaier et al . (Lipids, 29, 811-8 (1994)) describe 4-phenyl-5-tridecyl-4H-l , 2 , 4-triazole- thiol as a CETP inhibitor. However, the 1, 2 , 4-triazole derivatives of the present invention have not been described as inhibitors of CETP.

DESCRIPTION OF THE INVENTION The present invention relates to a class of compounds comprising substituted 1, 2, 4-triazoles which are beneficial in the therapeutic and prophylactic treatment of coronary artery disease as given in Formula I :

wherein R¹ is selected from higher alkyl, higher alkenyl, higher alkynyl, aryl, aralkyl, aryloxyalkyl , alkoxyalkyl, alkylthioalkyl, arylthioalkyl, and cycloalkylalkyl; wherein R² is selected from aryl, heteroaryl, cycloalkyi, and cycloalkenyl, wherein R is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halo, aryloxy, aralkyloxy, aryl, aralkyl, hydroxy, aminosulfonyl, amino, monoalkylamino and dialkylamino ; and wherein R³ is selected from hydrido, -SH and halo; provided R² cannot be phenyl or 4- methylphenyl when R is higher alkyl and when R is -SH; or a pharmaceutically-acceptable salt or tautomer thereof .

The compounds of this invention can be used to inhibit cholesteryl ester transfer protein (CETP) activity, thereby decreasing the concentrations of low density lipoprotein (LDL) and raising the level of high density lipoprotein (HDL) , resulting in a therapeutically beneficial plasma lipid profile. The compounds also can be used to treat dyslipidemia (hypoalphalipoproteinemia) , hyperlipoproteinaemia (chylomicronemia and hyperapobetalipoproteinemia) , peripheral vascular disease, hypercholesterolaemia, atherosclerosis, coronary artery disease and other CETP-mediated disorders . The compounds can also be used in prophylactic treatment of subjects who are at risk of developing such disorders . The compounds can be used to lower the risk of atherosclerosis. The compounds of Formula I would be also useful in prevention of cerebral vascular accident (CVA) or stroke. Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals , exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.

A class of compounds of particular interest consists of those compounds of Formula I wherein R is selected from Cio-is alkyl, C₁0-15 alkenyl, C10- 15 alkynyl, aryl, aryl-Cι-₁₂.alkyl, aryloxy-Cι_- alkyl, arylthio-Cι_₄-alkyl, higher alkoxyalkyl, higher alkylthioalkyl, and cycloalkyl-Cι-ι₂-alkyl; wherein R² is selected from aryl, 5-6 membered heteroaryl, lower cycloalkyi and lower

2 cycloalkenyl, wherein R is optionally substituted at a substitutable position with one or more radicals independently selected from lower alkyl, lower alkoxy, halo, lower haloalkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, aryloxy, lower aralkoxy, aryl, lower aralkyl, aminosulfonyl, amino, lower monoalkylamino and lower dialkylamino; and wherein R³ is selected from -SH, chloro and hydrido; or a pharmaceutically-acceptable salt or tautomer thereof .

A class of compounds of more particular interest consists of those compounds of Formula I wherein R¹ is selected from tridecyl, undecyl, dodecyl, tetradecyl, pentadecyl,

(heptylthio) pentyl, methoxyundecyl , dodecynyl, tridecynyl, tetradecynyl , (heptylphenyl) methyl, (octylphenyl) methyl , (nonylphenyl ) methyl , (decylphenyl) methyl, (hexylphenoxy) methyl, (octylphenoxy) methyl, (heptylphenyoxy)methyl, (hexylphenyl ) propyl , (octylphenyl) propyl , (heptylphenyl) propyl , decylthiomethyl, undecylthiomethy1, ethylthiodecyl, and (undecyloxy) methyl; wherein R is selected from cyclohexyl, naphthyl, pyridyl, and phenyl, wherein R² is optionally substituted at a substitutable position with one or more radicals independently selected from lower alkyl, lower alkoxy, halo, lower haloalkyl, phenoxy, methylenedioxy, benzyloxy, lower alkylthio, and lower dialkylamino; and wherein

3 ,

R is SH; or a pharmaceutically acceptable salt or tautomer thereof .

A class of compounds of even more particular interest consists of those compounds of Formula I wherein R¹ is selected from undecyl , dodecyl , tridecyl , tetradecyl , pentadecyl , tridecynyl , (heptylphenyl ) methyl , ( octylphenyl ) methyl , ( onylphenyl ) methyl , (decylphenyl ) methyl , (heptylphenyl) propyl and

(octylphenyl) propyl; wherein R² is selected from cyclohexyl, naphthyl, and phenyl, wherein R² is substituted by one or more radicals independently selected from methyl, fluoro, chloro, methylthio, benzyloxy, phenoxy, methoxy, ethoxy, methylenedioxy, and trifluoromethyl; and wherein R³ is SH; or a pharmaceutically acceptable salt or tautomer thereof .

Another class of compounds of more particular interest consists of those compounds of Formula I wherein R¹ is selected from (heptylthio) pentyl, tridecynyl, (undecyloxy)methyl, ethylthiodecyl, (heptylphenyl) methyl , (octylphenyl) methyl , ( onylphenyl)methyl, (decylphenyl)methyl, (heptylphenyl) propyl, (octylphenyl) propyl, and undecylthiomethyl; wherein R² is methoxyphenyl; and wherein R³ is -SH; or a pharmaceutically acceptable salt or tautomer thereof.

Another class of compounds of more particular interest consists of those compounds of Formula I wherein R¹ is tridecyl; wherein R² is selected from naphthyl, methylphenyl, methoxyphenyl, and benzodioxolyl; and wherein R³ is hydrido; or a pharmaceutically acceptable salt or tautomer thereof.

A subclass of compounds of Formula I of particular interest consists of compounds of the Formula II:

2 wherein R is selected from lower cycloalkyi, naphthyl and phenyl substituted with one or more radicals independently selected from halo, lower alkoxy, lower haloalkyl, lower alkyl, lower alkylthio and lower aralkyloxy; provided that R cannot be 4-methylphenyl; or a pharmaceutically acceptable salt or tautomer thereof .

A preferred class of compounds of Formula

2 II comprises those compounds wherein R is selected from naphthyl and phenyl substituted with one or more radicals independently selected from lower alkoxy, halo and lower haloalkyl.

A family of specific compounds of particular interest within Formula I consists of compounds, pharmaceutically-acceptable salts and derivatives thereof as follows:

2,4-dihydro-4-(3-methoxyphenyl)-5-tridecyl-3H-l,2,4- triazole-3-thione; 2 , 4-dihydro-4- (2-fluorophenyl) -5-tridecyl-3H-l, 2 , 4- triazole-3-thione; 2 , 4-dihydro-4- (2-methylphenyl) -5-tridecyl-3H-l, 2, 4- triazole-3-thione; 4- (3-chlorophenyl) -2, 4-dihydro-5-tridecyl-3H-l, 2, 4- triazole-3-thione;

2 , 4-dihydro-4- (2-methoxyphenyl) -5-tridecyl-3H-l, 2 , 4- triazole-3-thione; 2, 4-dihydro-4- (3-methylphenyl) -5-tridecyl-3H-l, 2 , 4- triazole-3-thione; 4-cyclohexyl-2, 4-dihydro-5-tridecyl-3H-l, 2, 4-triazole.-3- thione; 2, 4-dihydro-4- (3-pyridyl) -5-tridecyl-3H-l, 2, 4-triazole- 3-thione; , 4-dihydro-4- (2-ethoxyphenyl) -5-tridecyl-3H-l, 2 , 4- triazole-3-thione ; , 4-dihydro-4- (2 , 6-dimethylphenyl) -5-tridecyl-3H-l , 2,4- triazole-3-thione ; , 4-dihydro-4- (4-phenoxyphenyl) -5-tridecyl-3H-l, 2, 4- triazole-3-thione; - (l,3-benzodioxol-5-yl) -2 , 4-dihydro-5-tridecyl-3H-

1,2, 4-triazole-3 -thione; -(2-chlorophenyl) -2 , 4-dihydro-5-tridecyl-3H-l, 2 , 4- triazole-3-thione; , 4-dihydro-4- (4-methoxyphenyl) -5-tridecyl-3H-l,2 , 4- triazole-3-thione; , 4-dihydro-5-tridecyl-4- (3-trifluoromethylphenyl) -3H-

1,2, 4-triazole-3 -thione; , 4-dihydro-4-( 3-fluorophenyl) -5-tridecyl-3H-l, 2 , 4- triazole-3-thione; - (3-chloro-4-methylphenyl) -2, 4-dihydro-5-tridecyl-3H-

1,2, 4-triazole-3-thione; , 4-dihydro-4- (2-methylthiophenyl) -5-tridecyl-3H-l, 2, 4- triazole-3-thione; - (4-benzyloxyphenyl) -2, 4-dihydro-5-tridecyl-3H-l, 2 , 4- triazole-3-thione; ,4-dihydro-4-(2-naphthyl)-5-tridecyl-3H-l,2,4-triazole-

3-thione; , 4-dihydro-5-tridecyl-4- (4-trifluoromethylphenyl) -3H-

1,2, 4-triazole-3-thione; , 4-dihydro-4- ( 1-naphthyl) -5-tridecyl-3H-l, 2 , 4-triazole-

3-thione; , 4-dihydro-4- (3-methylthiophenyl) -5-tridecyl-3H-l, 2 , 4- triazole-3-thione; ,4, -dihydro-4- (4-methylthiophenyl) -5-tridecyl-3H-l, 2, 4- triazole-3-thione; ,4-dihydro-4- (3, 4-dimethoxyphenyl) -5-tridecyl-3H-l, 2 , 4- triazole-3-thione; ,4-dihydro-4- (2, 5-dimethoxyphenyl) -5-tridecyl-3H-l, 2 , 4- triazole-3-thione; , 4-dihydro-4- (2-methoxy-5-chlorophenyl) -5-tridecyl-3H-

1,2, 4-triazole-3-thione; - (4-aminosulfonylphenyl) -2 , 4-dihydro-5-tridecyl-3H-

1,2, 4-triazole-3 -thione; , 4-dihydro-5-dodecyl-4- (3-methoxyphenyl) -3H-1,2,4- triazole-3-thione ,^• ,4-dihydro-4- (3 -methoxyphenyl) -5-tetradecyl-3H-l, 2, 4- triazole-3-thione; , 4-dihydro-4- (3 -methoxyphenyl) -5-undecyl-3H-1, 2, 4- triazole-3-thione; , 4-dihydro-4- (3 -methoxyphenyl) -5-pentadecyl-3H-1, 2 , 4- triazole-3-thione; ,4-dihydro-5-[5-(heptylthio)pentyl] -4- (3- methoxyphenyl) -3H-1, 2 , 4-triazole-3-thione; , 4-dihydro-4- (3-methoxyphenyl) -5- (tridec-12-ynyl) -3H-

1,2, 4-triazole-3-thione; , 4-dihydro-4- (3-methoxyphenyl) -5- (tridec-6-ynyl] -3H- 1, 2, 4-triazole-3-thione; , 4-dihydro-4- (3-methoxyphenyl) -5- (undecyloxy)methyl-3H-

1,2, 4-triazole-3 -thione; , 4-dihydro-5- (ethylthio) decyl-4- (3-methoxyphenyl) -3H-

1,2, 4-triazole-3 -thione; , 4-dihydro-4- (3-methoxyphenyl) -5- (4-octylphenyl) ethy1-

3H-1, 2, 4-triazole-3-thione; , 4-dihydro-5- (4-heptylphenyl)methyl-4- (3- methoxyphenyl) -3H-1, 2, 4-triazole-3-thione; , 4-dihydro-5- (4-nonylphenyl)methyl-4- (3-methoxyphenyl) - 3H-1, 2, 4-triazole-3-thione; - (4-decylphenyl) methyl-2 , 4-dihydro-4- (3-methoxyphenyl) -

3H-1,2, 4-triazole-3-thione; , 4-dihydro-5- (4-hexylphenoxy)methyl-4- (3- methoxyphenyl) -3H-1, 2, 4-triazole-3-thione; 2, 4-dihydro-5- (4-heptylphenoxy)methyl-4- (3- methoxyphenyl ) -3H-1, 2, 4-triazole-3 -thione; 2, 4-dihydro-5- (4-octylphenoxy)methyl-4- (3- methoxyphenyl ) -3H-1, 2 , 4-triazole-3-thione; 2, 4-dihydro-5- (4-hexylphenyl) propyl-4- (3-methoxyphenyl) - 3H-1, 2, 4-triazole-3 -thione; 2, 4-dihydro-5- (4-heptylphenyl) propyl-4- (3- methoxyphenyl ) -3H-1, 2 , 4-triazole-3-thione; 2, 4-dihydro-5- (4-τoctylphenyl)propyl-4- (3-methoxyphenyl) - 3H-1, 2,4-triazole-3-thione;

4- (2-naphthyl) -3-tridecyl-4H-l, 2 , 4-triazole, nitrate; 4- (3-methoxyphenyl) -3-tridecyl-4H-l, 2 , 4-triazole, nitrate; 4- (4-methoxyphenyl) -3-tridecyl-4H-l, 2 , 4-triazole, nitrate;

4- (2-methoxyphenyl) -3-tridecyl-4H-l, 2 , 4-triazole, nitrate; and 4- (1, 3-benzodioxol-5-yl) -3-tridecyl-4H-l, 2, 4-triazole, nitrate.

The use of generic terms in the description of the compounds are herein defined for clarity. Where the term "alkyl" is used, either alone or within other terms such as "haloalkyl" and "alkylthio", it embraces linear or branched radicals having one to about 10 carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and the like. The term "higher alkyl" denotes linear or branched radicals having eleven to about twenty carbon atoms . Examples of such radicals include undecyl, dodecyl, tridecyl, tetradecyl, and pentadecyl. The term "higher alkenyl" denotes linear or branched radicals having from 11 to about 20 carbon atoms and having one or more double bonds . Examples of such radicals include undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl . The term "higher alkynyl" denotes linear or branched radicals having from 11 to about 20 carbon atoms having one or more triple bonds. Examples of such radicals include undecynyl, dodecynyl, tridecynyl, tetradecynyl, and pentadecynyl . The term "hydrido" denotes a single hydrogen atom (H) . This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (-CH₂-) radical. The term "halo" means halogens such as fluorine, chlorine, bromine or iodine atoms. The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkyl radicals are "lower haloalkyl" radicals having one to about six carbon atoms . Examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl , trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl , dichlorofluoromethyl , difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl . The terms "alkoxy" and "alkoxyalkyl" embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. The term "alkoxyalkyl" also embraces alkyl radicals having two or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals . More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms . Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Preferred alkoxyalkyl radicals are "higher alkoxyalkyl" radicals having alkoxy radicals of six to fifteen carbon atoms. Examples of such radicals include octyloxypropyl and undecyloxymethyl . The "alkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy. 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. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl , indane and biphenyl . Said "aryl" group may have 1 to 3 substituents such as lower alkyl, alkoxy, halo, hydroxy, oxo, amino and lower alkylamino. The term "heterocyclyl" embraces saturated, partially saturated and unsaturated heteroatom-containing ring- shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, i idazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole . Examples of unsaturated heterocyclic radicals, also termed "heteroaryl" radicals, include unsaturated 5 to 6 me bered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, 1H-1, 2 , 3-triazolyl, 2H-1,2,3- triazolyl, etc.] tetrazolyl [e.g. lH-tetrazolyl, 2H- tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1, 5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6- membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3- thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1, 2 , 4-oxadiazolyl, 1,3,4- alkylthio" is methylthio (CH₃-S-) . Also preferred alkylthio radicals are "higher alkylthio" radicals having seven to fifteen carbon atoms. An example of "higher alkylthio" is dodecyl hio. The term "alkylsulfinyl" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent -S(=0)- atom. Also preferred alkylsulfinyl radicals are "higher alkylsulfinyl" radicals having seven to fifteen carbon atoms . An example of "higher alkylsulfinyl" is dodecylsulfinyl . The term "aminosulfonyl" denotes an amino radical attached to a sulfonyl radical. The terms alkylamino denotes "monoalkylamino" and "dialkylamino" containing one or two alkyl radicals, respectively, attached to an amino radical. The term "aryloxy" embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy. The aryl in said aryloxy may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term "aralkoxy" embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy" radicals having phenyl radicals attached to lower alkoxy radical as described above. The aryl in said aralkoxy radicals may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term "aryloxyalkyl" embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl . The aryl in said aryloxyalkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term "arylthio" embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio. The aryl in said arylthio may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term " arylthioalkyl " embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl . The aryl in said arylthioalkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term

"alkylthioalkyl" embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methylthiomethyl . Also preferred alkylthioalkyl radicals are "higher alkylthioalkyl" radicals having seven to fifteen carbon atoms. An example of "higher alkylthioalkyl" is undecylthiomethyl . The term "alkoxyalkyl" embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl . Also preferred alkoxyalkyl radicals are "higher alkoxyalkyl" radicals having seven to fifteen carbon atoms. An example of "higher alkoxyalkyl" is undecyloxymethy1.

The terms "cis" and "trans" denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond ("cis") or on opposite sides of the double bond ("trans") .

When R³ is SH in Formula I, the compounds can be represented as either of the two tautomers shown below:

I^a I^b

Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or "E" and "Z" geometric forms. one to six carbon atoms. An example of "lower alkylthio" is methylthio (CH₃-S-) . Also preferred alkylthio radicals are "higher alkylthio" radicals having seven to fifteen carbon atoms . An example of "higher alkylthio" is dodecylthio. The term

"alkylsulfinyl" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent -S(=0)- atom. Also preferred alkylsulfinyl radicals are "higher alkylsulfinyl" radicals having seven to fifteen carbon atoms. An example of "higher alkylsulfinyl" is dodecylsulfinyl. The term "aminosulfonyl" denotes an amino radical attached to a sulfonyl radical. The terms alkylamino denotes "monoalkylamino" and "dialkylamino" containing one or two alkyl radicals, respectively, attached to an amino radical. The term "aryloxy" embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy. The aryl in said aryloxy may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term "aralkoxy" embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy" radicals having phenyl radicals attached to lower alkoxy radical as described above. The aryl in said aralkoxy radicals may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term "aryloxyalkyl" embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl . The aryl in said aryloxyalkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term "arylthio" embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio. The aryl in said arylthio may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term "arylthioalkyl" embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl . The aryl in said arylthioalkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term "alkylthioalkyl" embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methylthiomethyl . Also preferred alkylthioalkyl radicals are "higher alkylthioalkyl" radicals having seven to fifteen carbon atoms. An example of "higher alkylthioalkyl" is undecylthiomethyl . The term "alkoxyalkyl" embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl . Also preferred alkoxyalkyl radicals are "higher alkoxyalkyl" radicals having seven to fifteen carbon atoms . An example of "higher alkoxyalkyl" is undecyloxymethy1.

The terms "cis" and "trans" denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond ("cis") or on opposite sides of the double bond ( "trans" ) . When R³ is SH in Formula I, the compounds can be represented as either of the two tautomers shown below:

r ι^b

Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or "E" and "Z" geometric forms. The present invention comprises a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formula I in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent .

The present invention also comprises a treatment and prophylaxis of coronary artery disease in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of a compound of Formula I'

wherein R¹ is selected from higher alkyl, higher alkenyl, higher alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, and cycloalkylalkyl; wherein R² is selected from aryl, heteroaryl, cycloalkyi, and cycloalkenyl, wherein R is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, halo, alkoxy, aryloxy, aralkyloxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylamino and dialkylamino; and wherein R³ is selected from hydrido, -SH and halo; provided R² cannot be phenyl when R is tridecyl and when R is SH; or a pharmaceutically-acceptable salt or tautomer thereof .

Compounds of Formula I ' are capable of inhibiting activity of cholesteryl ester transfer protein (CETP) , and thus could be used in the manufacture of a medicament or a method for the prophylactic or therapeutic treatment of diseases mediated by CETP, such as peripheral vascular disease, hyperlipidaemia, hypercholesterolemia, and other diseases attributable to either high LDL and low HDL or a combination of both. The compounds of Formula I' would be also useful in prevention of cerebral vascular accident (CVA) or stroke. Also included in the family of compounds of Formula I are 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 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, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic) , methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'- dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procain. 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

The compounds of the present invention can be synthesized according to the following

1 2 procedures of Schemes I-II, wherein the R and R substituents of the triazole ring are as defined for Formula I, above, except where further noted.

SCHEME I

o o* R²NCS

II N₂H₄ 0 s

R¹-C—OR" 1 " 3 n II

R¹-C— HNH₂ „__„, ^► R¹-C— NHNH-C— HR²

P CH₃

2 4

L MeONa, MeOH

2. HOAc

♦ / H

N — N N— N cone. HNO3 . II

R I I _« ^R -*- ,

N H₂0, NaN0₂ N

• HN0₃ |

R² if

S0₂CI₂

Synthetic Scheme I shows the preparation of 1,2, 4-triazole-5-thione derivatives 5. A suitable carboxylic acid ester 1 is converted to the corresponding carboxylic acid hydrazide 2 by heating with hydrazine in a suitable solvent such as methanol or ethanoi. The resulting hydrazide 2 is then heated with an appropriate organic isothiocyanate 3 in a suitable aprotic solvent such as toluene. The resulting urea product 4 usually crystallizes from this solution upon cooling. Subsequent treatment of the isolated urea 4 with methanolic sodium methoxide produces the desired 1, 2 , 4-triazole-5- thione 5, which usually forms as a solid precipitate after acidification with acetic acid. Further reaction of the 1, 2 , 4-triazole, such as with warm aqueous nitric acid and a catalytic amount of sodium nitrite produces the 1, 2, 4-triazole 6 as a solid nitrate salt.

Alternatively, treating 1, 2 , 4-triazole with neat sulfuryl chloride produces the 3-chloro-l, 2 , 4- triazole 7, after purification, such as by chromatography.

SCHEME II

R = C₃H -CsH₁₇

HPNNH_P

H NNH_?

Synthetic Scheme II shows the preparation of 1 , 2 , 4-triazole-5-thione derivatives 14 and 17 embraced by Formula I wherein a phenyl or phenoxy group containing a saturated or unsaturated alkyl substituent has been inserted

1 into the R sidechain. In step 1, an appropriate p-iodophenyl- or p-iodophenoxy-alkyl carboxylic acid 8 is converted to its corresponding alkyl carboxylate ester 9 by heating in acidic alcohol. The resulting ester 9 is then coupled with an appropriate acetylene in the presence of a base, such as triethylamine and a suitable catalyst, such as bis- (triphenylphosphine) - palladium dichloride and cuprous iodide under an inert atmosphere and anhydrous conditions in an appropriate aprotic solvent, such as acetonitrile. The resulting coupled p-acetylene ester 10 may then be reduced by hydrogenolysis in the presence of a suitable catalyst, such as 10% palladium on carbon in a suitable solvent, such as methanol or ethyl acetate to give the corresponding saturated p-alkylphenyl or p- alkylphenoxy ester 11. Ester 11 may then be converted to the corresponding hydrazide 12, which can be treated with an appropriate organic isothiocyante, as described for Scheme I above, to give the urea 13. Subsequent cyclization of urea 13 is achieved, such as with methanolic sodium methoxide which then gives the desired 3- (p-alkylphenyl) alkyl- or 3-(p- alkylphenoxy)alkyl-l, 2, 4-triazole-5-thione 14, after acidification with acetic acid and subsequent purification, such as by chromatography.

Alternatively, ester 10 may be reacted directly with hydrazine to give the corresponding hydrazide 15, which can be treated with an appropriate organic isothiocyante, as described for Scheme I above, to give the urea product 16. Subsequent cyclization of 16 is achieved with methanolic sodium methoxide which then gives the desired 3- (p-alkynylphenyl) alkyl- or 3- (p-alkynylphenoxy) alkyl-1, 2, 4-triazole-5- thione 17, after acidification with acetic acid and subsequent purification by chromatography. One skilled in the art may use these generic methods to prepare the following specific examples, which have been properly characterized by H NMR and mass spectrometry. These compounds also may be formed in vivo. The following examples contain detailed descriptions of the methods of preparation of compound of Formula I. These detailed descriptions fall within the scope and are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are Degrees centigrade unless otherwise indicated.

EXAMPLE 1

2,4-Dihydro-4- (3-methoxyphenyl) -5-tridecyl-3H- l,2,4-triazole-3-thione

Step 1. Preparation of tetradecanoic acid hydrazide

As described in J^". Oil Technol . Assoc . India, 11, 78-79 (1979), ethyl myristate (102.6 g, 0.4 mol) was combined with 25 mL of hydrazine monohydrate in 100 mL of ethanoi. The resulting clear, homogeneous solution was stirred at room temperature for 30 minutes, then heated at reflux overnight. Upon cooling the clear homogeneous solution to room temperature, a voluminous white precipitate was produced which was collected by vacuum filtration, washed with cold ethanoi and air-dried to give a white solid (72 g) : m.p. 101-106 °C. Recrystallization from about 500 mL of hot ethyl acetate gave 56 g (58%) of the desired tetradecanoic acid hydrazide as white needles: m.p. 106.5-108 °C (lit. m.p. 114-115 °C) . H NMR (d₆-DMSO) δ 0.83 (t, J = 6.5 Hz, 3H) , 1.22 (br s, 20H) , 1.44 (m, 2H) , 1.96 (t, J = 7.5 Hz, 2H) , 4.11 (br s, 2H) , 8.87 (br s, 1H) . FABMS m/z = 243.4(M+H).

Step 2. Preparation of tetradecanoic acid 2- r r (3-methoxyphenyl ) amino1 thioxomethyl1 hydrazide

Tetradecanoic acid hydrazide (Step 1)(1.6 g, 6.6 mmol) was combined with toluene (20 mL) and 3-methoxyphenyl isothiocyanate (1.2 g, 7.3 mmol) . This mixture was heated to 60 °C and stirred for five hours . The heating was stopped, and the solution was cooled to room temperature. A white precipitate formed which was collected by vacuum filtration. The resulting solid was washed with cold diethyl ether and air-dried to give 2.4 g (89%) of the desired tetradecanoic acid, 2-[[(3- methoxyphenyl) amino] thioxomethyl] hydrazide as a white solid: m.p. 109.4-111.4 °C. ^XH NMR CD₃CN δ 8.54 (s, 1H) , 8.17 (s, 1H) , 7.87 (s, 1H) , 7.26 (t, J = 8.2 Hz, 1H) , 7.16 (m, 1H) , 7.02 (m, 1H) , 6.78 (m, 1H) , 3.78 (s, 3H) , 2.24 (t, J = 7.5 Hz, 2H) , 1.60 (m, 2H) , 1.27 (m, 20H) , 0.89 (t, J = 6.6 Hz, 3H) . FABMS m/z = 408 (M+H) . Calc'd for C₂₂H₃₇N₃0₂S: C, 64.83; H, 9.15; N, 10.31; S, 7.87. Found: C, 64.72; H, 9.20; N, 10.37; S, 7.79.

Step 3. Preparation of 2 , 4-dihvdro-4- (3- methoxyphenyl) -5-tridecyl-3H-l , 2 , 4-triazole-3- thione. Tetradecanoic acid, 2-[[(3- methoxyphenyl) amino] thioxomethyl] hydrazide (Step 2) (2.15 g, 5.28 mmol) was combined with methanol (10 L) and a methanolic solution of sodium methoxide (1.6 mL of 25% sodium methoxide in methanol, 6.9 mL) . This solution was stirred at room temperature while the progress of the reaction was monitored by HPLC. After three days at room temperature, the reaction was complete. The solution was filtered and acidified (pH 5) with acetic acid. Upon standing, a white solid formed, which was collected by vacuum filtration, washed with cold methanol and cold diethyl ether, and air-dried to give 5-tridecyl-2 , 4-dihydro-4- (3- methoxyphenyl) -3H-1, 2, 4-triazole-3-thione as a white solid (1.34g, 65%): m.p. 91.5-93.7 °C. H NMR (d₆-DMSO) δ 13.63 (s, 1H) , 7.45 (t, J = 8.1 Hz, 1H) , 7.08 (m, 1H) , 6.99 (m, 1H) , 6.93 (m, 1H) , 3.77 (s, 3H) , 2.40 (t, J = 7.5 Hz, 2H) , 1.40 (m, 2H) , 1.20 ( , 20H) , 0.83 (t, J = 6.2 Hz, 3H) . FABMS m/z = 390 (M+H) . Calc'd for C₂₂H₃₅N₃0S: C, 67.82; H, 9.05; N, 10.79; S, 8.23. Found: C, 67.71; H, 9.10; N, 10.80; S, 8.31.

Additional examples of 2 , 4-dihydro-4- substituted-5-tridecyl-3H-l, 2 , 4-triazole-3- thiones are prepared by one skilled in the art using similar methods from tetradecanoic acid hydrazide. These examples are summarized in Table 1.

Additional examples of 5-substituted-2 , 4- dihydro-4-(3-methoxyphenyl) -3H-1,2, 4-triazole-3- thiones can be prepared by one skilled in the art using similar methods from the appropriate fatty acids, fatty acid esters, or fatty acid hydrazides known in the literature, e.g., J. Oil Technol . Assoc . India, 11, 78-79 (1979); J. Biol . Chem. , 266, 8835-8855 (1991). These examples are summarized in Tables 2 and 3 , where Z represents an acetylenic linkage, and Y represents either a cis or trans -CH=CH- linkage. C-₃036

TABLE 1

2 2-F-C₆H₄- 119.8-121.7 FABMS: m/z = 378 (M+H) co HRMS: Calcd 378.2379 Found: 378.2391 c 3 cyclohexyl- 84-86 Calcd. C, 68.99; H, 10.75; N, 11.49; S,8.77

CD (Λ Obs. C, 68.97; H, 10.79; N, 11.45; S,8.71

H 4

H 2-CH₃-C₆H₄- 105.4-106.7 Calcd. C, 70.71; H,9.46; N, 11.25

C Obs. C,70.67; H,9.45; N, 11.30 H rπ 5 3-Cl-C₆H - FABMS: m/z = 394 (M+H) cn x m 10 6 2-CH₃0-C₆H₄- 139.6-140.8 Calcd. C, 67.81; N, 10.79 m Obs. C, 67.74 ; N,10.59 7

31 3-CH₃-C₆H - 139.0-140.8 Calcd. C70.71; H,9.46 N, 11.25 c r Obs. C70.74; H,9.62 N, 10.95 m 8 4-F-C₆H₄- 88.7-90.6 Calcd. C, 66.79; H,8.59 N, 11.13 to Obs. C, 66.44; H,8.51 N, 11.21 9 4-C₆H₅0-C₆H₄- 106.4-107.5 Calcd. C,71.80; H,8.26 N,9.32

Obs. C71.62; H,8.09 N,9.24 10 3-F-C₆H - 105.3-108.9 Calcd. C, 66.79; H,8.59 N, 11.13

Obs. C, 66.75; H,8.53 N,10.87

15 11 3,4-(OCH₂0)-C₆H₃- 95.1-96.9 Calcd. C, 65.47; H,8.24 N, 10.41

Obs. C, 65.42; H,8.11 N, 10.40 12 4-CH₃-C₆H₄- 107.5-108.5 Calcd. C,70.71; H,9.46 N, 11.25

Obs. C70.60; H,9.32 N, 11.26 13 2-Cl-C₆H - 153.7-154.9 FABMS: m/z = 394 (M+H)

HRMS: Calcd 394.2084 Found: 394.2084

C-3036

TABLE 1 (continued)

14 4-CH₃0-C₆H - 84.1-86.3 Calcd. C,67.81; H,9.07; N, 10.79

CO c Obs. C, 68.15; H,9.12; N, 10.91

OD 15 3 -CF₃ -C₆H₄- 92.5-93.7 Calcd. C, 61.79; H,7.56; N,9.83 CO Obs. C, 61.97; H,7.61; N,9.83

H 16 4-Cl-2-CH₃-C₆H₃- 86-87 FABMS : m/z = 408 (M+H)

C H HRMS: Calcd 408.2240 Found: 408. .2215 m 17 2 -CH₃S-C6H - 122.0-123.0 Calcd. C65.14; H,8.70; N,10.36; co s, ,15.81 x Obs. C, 64.87; H,8.77; N, 10.25; s, 16.01 rπ 1

10 18 C₆H₅ 95.5-96.5 FABMS : m/z = 360 (M+H)

H 30 19 4-C₆H₅CH₂0-C₆H - 123.7-124.8 Calcd. C72.20; H,8.46; N,9.02 c r Obs. C72.14; H,8.40; N,8.90 rπ ro 20 2 -naphthyl - 118.5-120.7 Calcd. C73.29; H,8.63; N, 10.26 cn Obs. C73.29; H,8.61; N, 10.34 21 4-Cl-C₆H - 61.7-64.3 Calcd. C, 64.00; H,8.20; N,10.66 Obs. C, 64.08; H,8.00; N, 10.49 22 4-CH₃-3 -Cl-C₆H₃ - 99-102 FABMS : m/z = 408 (M+H)

HRMS: Calcd 408.2240 Found: 408, .2214

15 23 4-CF₃ -C₆H₄- 59.7-63.8 Calcd. C, 61.79; H,7.56; N,9.82

Obs. C, 61.82; H,7.45; N,9.80 24 3-C₆H₅CH₂OC₆H - 107.6-109.9 FABMS : m/z = 466 (M+H)

HRMS: Calcd 466.2892 Found: 466. .2897 25 3,5-(CH₃0)₂-C₆H₃- 120.2-122.4 Calcd. C, 65.83; H,8.89; N, 10.01 ; s, ,7.64

Obs. C65.71; H,8.94; N, 10.00; s, ,7.60

C-3036

TABLE 1 (continued)

26 3- -pyridyl- 135 .4-137.0 Calcd. C, 66 62 ^• H,8.95 N, 15.54 ; S,8.89

CO Obs. C,66 64 ^• H,8.86 ^■ N,15.56; S,8.80 c

CD 27 2- -CH₃CH₂0-C₆H₄- 116 .8-118.4 Calcd. C,68 44 H,9.24 N,10.41; S,7.94 O

H Obs. C,68 60 H,9.32 N,10.38; S,7.91

H 28 2 6-(CH₃)2-C₆H₃- 106 5-109.0 Calcd. C,71 27 H,9.62 N, 10.84 ; S,8.27 C H Obs. C,71 15 H,9.91 N, 10.67 ; S,7.96 29 1- -naphthyl- 161 0-162.5 Calcd. C,73 29 H,8.63 N, 10.26 o x Obs. C,73 41 H,8.57 N, 10.10 m 10 30 m 3 4-(CH₃)₂-C₆H₃- 126 .1-128.1 Calcd. C,71 27 H,9.62 N, 10.84 ; S,8.27

H Obs. C, 71 11 ^■ H,9.67 ^• N,10.91; S,8.19 31 4- -CH₃S-C₆H - 68 .8-69.9 Calcd. C,65 14 H,8.70 N,10.36; S, 15.81 c r- Obs. C,65 19 H,8.61 N, 10.38; S, 15.90 m 32 3- -CH₃S-CeH - 80 .8-83.4 Calcd. C,65 14 H,8.70 N, 10.36; S, 15.81 ro co Obs. C,65 09 ^■ H,8.69 ^• N, 10.39; S, 15.74 33 2 5-(CH₃0)₂-C₆H₃- 131. 6-133.4 Calcd. C,65 83 H,8.89 ^• N, 10.01. ; S,7.64

Obs. C,65 88 H,8.87 ^• N, 10.11 ; S,7.58 34 2- -CH₃0-5-Cl-C₆H₃- 161 .1-162.4 Calcd. C,62 32 ^■ H,8.08 ^• N,9.91; S,7.56

Obs. C,62 20 ^• H,8.11 ^• N,9.98; S,7.47

15 35 4- -(H₂NS0₂)-C₆H₄- 188 .4-191.4 Calcd. C,57 50 H,7.81 N, 12.77;; S, 14.62

Obs. C,57 30 H,7.76 N, 12.75 ; S, 14.46 36 4- -(CH₃)₂N-C₆H₄- 145 .2-146.3 Calcd. C,68 61 H,9.51 ^• N, 13.91; S,7.96

Obs. C, 68 52 H,9.53 ^• N, 13.84 ; S,7.89 37 2- -CH₃O-5-NO₂-C₆H₃- 148. 5-149.9 Calcd. C,60 80 H,7.89 ^• N, 12.89 ; S,7.38

Obs. C,60 90 H,7.83 ^• N, 12.92 ; S,7.29

TABLE 1 (continued)

38 3-N0₂-C₆H₄- 115.5-117.4 Calcd. C62.35 H,7.97 N,13.85 S,7.92

CO c Obs. C, 62.49 H,8.02 N.13.92 S,7.84

CD 39 4-CH₃CH₂0-C6H - 106.0-107.1 Calcd. C, 68.44 H,9.24 N, 10.41 S,7.94

CO

H Obs. C, 68.17 H,9.32, N, 10.37 S.7.81

H 40 3,5-(CH₃)₂-C₆H₃- 145.7-147.1 Calcd. C, 71.27 H,9.62 N, 10.84 S,8.27

C

H Obs. C71.18 H,9.64 N, 10.79 S,8.22 rπ 41 2,5-(CH₃)₂-C₆H₃- 107.6-108.9 Calcd. C, 71.27 H,9.62, N, 10.84 S,8.27

CO

X 10 Obs. C, 71.22 H,9.62 N,10.84 S, 8.19 rπ _ m 42 2-CH₃0-5-CH₃-C₆H₃- 126.5-127.5 Calcd. C, 68.44 H,9.24 N, 10.41 S,7.94

H Obs. C, 68.24 H, 9.18 N, 10.37 S,7.86

43 2 -CH₃ -4 -CH₃0-C₆H₃ - 89.1-91.5 Calcd. C, 68.44 H,9.24 N, 10.41 S,7.94 c Obs. C, 68.27 H,9.27 N, 10.51 S,7.85 m r

44 2,4-(CH₃0)₂-C₆H₃- 74.0-75.1 Calcd. to C, 65.83 H,8.89 N, 10.01 S,7.64 σ> Obs. C, 65.94 H,8.90 N, 10.04 ^• S,7.56

45 2,4-(CH₃)₂-C₆H₃- 90.4-93.0 Calcd. C, 71.27 H,9.62 N.10.84 ^■ S,8.27

Obs. C71.13 H,9.99 ^• N, 10.94 ^• S,7.97

46 3,4-(CH₃0)2-C₆H₃- 111.4-114.3 Calcd. C, 65.83 H,8.89 N,10.01 S,7.64

15 Obs. C, 65.82 H,8.95 N,10.03 S,7.58

47 3,4,5-(CH₃0)₃-C₆H2- 108.8-110.7 Calcd. C, 64.11 H,8.74 N,9.34; S,7.13

Obs. C, 64.31 H,8.73 N,9.36; S,7.03

48 2-CH₃0-4-N0₂-C₆H₃- 114.3-116.9 Calcd. C, 60.80 H,7.89 N, 12.89 S,7.38

Obs. C60.80, H, 7.91, N, 12.90 S,7.32

C-3036

TABLE 2

49 π-Cι₅H₃ι- 94.0-96.0 Calcd. C, 69.02 H,9.41 N, 10.06 S,7.68

Obs. C, 68.91 ^• H,9.46 N, 10.14 S,7.57 02.7-105.9 Calcd. C, 68.44 H,9.24 N, 10.41 S,7.94

Obs. C, 68.49 H,9.19 N, 10.47 S,8.08 00.0-101.9 Calcd. C67.16 H,8.86 N,11.19 S,8.54

Obs. C, 66.60 H,8.88 N,11.14 ^• S,8.44

90.1-93.2 Calcd. C,66.44 H,8.64 N, 11.62 S,8.87

CO Obs. C, 66.39 H,8.72 N, 11.65 S,8.78

X 10 53 CH3CH₂S(CH₂)ιo- 89.4-90.5 Calcd. C, 61.88 ^■ H,8.16 ^■ N, 10.31 ^• S, 15.73 m —1 Obs. C, 61.85 H,8.22 N, 10.38 S, 15.81

54 CH₃(CH₂)ιoSCH₂- 75.5-78.2 Calcd. C, 61.88 H.8.16 N,10.31

3) S, 15.73

C Obs. C, 61.95 ^• H,8.24 N, 10.36 S, 15.83 r" m 55 CH₃CH₂0(CH₂)ιo- 91.2-92.3 Calcd. C, 64.42 H,8.49 N, 10.73 S,8.19 ro Obs. C, 64.36 H,8.53 N, 10.76 S,8.12

56 CH₃0(CH₂)n- 82.7-83.7 Calcd. C, 64.42 H,8.49 ^• N, 10.73 ^• S,8.19

Obs. C, 64.32 ^• H,8.51 ^• N,10.81 ^• S,8.10

57 CH₃(CH₂)ιoOCH₂- oil Calcd. C, 64.42 H,8.49 N, 10.73 ^• S,8.19

Obs. C, 64.32 H,8.59 N, 10.72 ^■ S,8.09

15 58 CH₃(CH₂)₆S(CH₂)5- waxy solid Calcd. C61.88 H,8.16 N, 10.31 ^■ S, 15.73

Obs. C, 62.11 H,8.13 N, 10.33 S, 15.70

59 CH₃(CH₂)₅Z(CH₂)₅- waxy solid Calcd. C, 68.53, H,8.10 N, 10.90 S,8.31

Obs. C, 68.51 H,8.16 N, 10.83 S, 8.23

60 HZ(CH₂)n- 55.0-58.5 Calcd. C, 68.53 H,8.10 N, 10.90 S,8.31

Obs. C, 68.55, H,8.13 N,10.94 S,8.43

TABLE 3

No. No.

61 CH₃ ⁽CH2⁾6θ⁽CH₂ ⁾5- 80 CH₃ ⁽CH2⁾5θ⁽CH₂ ⁾6-

62 CH3(CH₂)6Z(CH₂) - 81 CH₃ ⁽CH₂ ⁾ ₅S⁽CH₂ ⁾6-

63 CH₃(CH₂)₄Z(CH₂)₆- 82 CH₃ ⁽CH₂ ⁾4θ⁽CH₂ ⁾7-

64 CH₃(CH₂)₃Z(CH₂)₇- 83 CH₃ ⁽CH₂ ⁾4S⁽CH₂ ⁾7-

65 CH3⁽CH₂ ⁾ ₂Z⁽CH₂ ⁾8- 84 CH₃ ⁽CH₂ ⁾3θ⁽CH₂ ⁾ ₈-

66 CH₃CH₂Z(CH₂)g- 85 CH₃ ⁽CH₂ ⁾ ₃S⁽CH₂ ⁾8-

67 CH₃Z⁽CH₂)ιo- 86 CH₃(CH₂)₈0(CH₂)₃-

68 CH₃(CH₂)₅Y⁽CH₂)₅- 87 CH₃ ⁽CH₂ ⁾8S⁽CH₂ ⁾3-

69 CH₂=CH(CH₂)n- 88 4-CH₃-C₆H₄ ⁽CH₂ ⁾9-

70 CH₃(CH₂)₆Y(CH₂) - 89 4-C₂H5-C₆H₄ ⁽CH2⁾7-

71 CH₃(CH₂)₄Y(CH₂)₆- 90 4-C₂H₅-C₆H₄ ⁽CH2⁾8-

72 CH₃ ⁽CH₂ ⁾ ₃Y⁽CH₂ ⁾7- 91 C₆H₅(CH₂)₈-

73 CH₃ ⁽CH2⁾2Y⁽CH₂)8- 92 C₆H₅(CH₂)₉-

74 CH₃CH₂Y(CH₂)₉- 93 C₆H₅ ⁽CH₂)ιo-

75 CH₃Y⁽CH₂)ιo- 94 C₆H₅(CH₂)ιι-

76 C₆H₅S(CH₂)9- 95 cyclohexyl (CH₂) ₈ ^_

77 C₆H₅0⁽CH₂ ⁾9- 96 cyclohexyl (CH₂) ₉-

78 CH₃(CH2)7θ(CH₂) - 97 cyclohexyl (CH ) ₁₀-

TABLE 3 (continued)

R ,1

Example R^l Example R¹ No. No.

99 CH₃(CH₂)₅Z(CH₂)₅- 119 CH₃(CH₂)₆S(CH₂)₅-

100 CH₃(CH₂)₄Z(CH₂)₆- 120 CH₃(CH₂)₅0(CH₂)₆-

101 CH₃(CH₂)₃Z(CH₂)7- 121 CH₃(CH₂)5S(CH₂)₆-

102 CH₃(CH₂)₂Z(CH₂)₈- 122 CH₃(CH₂)₄0(CH₂)₇-

103 CH₃CH₂Z(CH₂)9- 123 CH₃(CH₂)₄S(CH₂)₇-

104 CH₃Z(CH₂)ιo- 124 CH₃(CH₂)₈0(CH₂)₃-

105 HZ(CH₂)u- 125 CH₃(CH₂)₈S(CH₂)3-

106 CH₃(CH₂)₅Y(CH2)5- 126 4-CH₃-C₆H₄(CH₂)9-

107 CH₂=CH(CH₂)n- 127 4-C₂H5-C₆H4(CH₂)7-

108 CH₃(CH₂)₆Y(CH₂)4- 128 4-(n-C₃H7)C₆H₄(CH₂)6-

109 CH₃(CH₂)₄Y(CH₂)₆- 129 4-(n-C₄H9)C₆H₄(CH₂)₅-

110 CH₃(CH₂)₃Y(CH₂)7- 130 4-C₂H₅-C₆H₄(CH₂)8-

111 CH₃(CH2)2Y(CH₂)8- . 131 cyclo-C₆Hιι(CH₂)₈-

112 CH₃CH₂Y(CH₂)9- 132 cyclo-C₆Hn(CH₂)9-

113 CH₃Y(CH₂)ιo- 133 cyclo-C₆Hn(CH₂)ιo-

114 C₆H₅0(CH₂)9- 134 C₆H₅(CH₂)₈-

115 C₆H₅S(CH₂)9- 135 C₆H₅(CH₂)9-

116 CH₃(CH2)7θ(CH₂)₄- 136 C₆H₅(CH₂)ιo-

117 CH₃(CH₂)₇S(CH2)₄- 137 C₆H₅(CH₂)ιι- TABLE 3 (continued)

R ^,1 _c

Example R¹ Example R¹ No. No.

139 CH₃ ⁽CH₂ ⁾ ₅Z⁽CH₂ ⁾5- 159 CH₃ ⁽CH₂ ⁾6S⁽CH₂ ⁾5-

140 CH₃(CH₂)₄Z⁽CH₂)₆- 160 CH₃(CH₂)₅0(CH₂)₆-

141 CH₃(CH₂ ⁾ ₃Z⁽CH₂ ⁾7- 161 CH₃(CH₂)₅S(CH₂)₆-

142 CH₃(CH₂)₂Z(CH₂)₈- 162 CH₃ ⁽CH₂ ⁾ 0⁽CH₂ ⁾7-

143 CH₃CH₂Z(CH₂)₉- 163 CH₃(CH₂)₄S(CH₂)₇-

144 CH₃Z⁽CH₂ ⁾ιo- 164 CH₃(CH₂)₈0(CH₂)₃-

145 HZ(CH₂)n- 165 CH₃ ⁽CH₂ ⁾ ₈S⁽CH₂ ⁾3-

146 CH₃(CH₂)₅Y(CH₂)₅- 166 4-CH₃-C₆H₄ ⁽CH₂ ⁾ ₉-

147 CH₂=CH(CH₂)n- 167 4-C₂H5-C₆H₄ ⁽CH₂ ⁾7-

148 CH₃ ⁽CH₂)6Y⁽CH₂ ⁾4- 168 4-⁽n-C₃H₇ ⁾C₆H₄ ⁽CH2)6-

149 CH₃(CH₂)₄Y(CH₂)₆- 169 4-(n-C₄H₉)C₆H₄(CH₂)₅-

150 CH₃(CH₂)₃Y(CH₂)₇- 170 4-C₂H₅-C₆H₄(CH₂)₈-

151 CH₃(CH2)2Y⁽CH₂)8- . 171 cyclo-C₆Hn(CH₂)₈-

152 CH₃CH₂Y(CH₂ ⁾ ₉- 172 cyclo-C₆Hn(CH₂)₉-

153 CH₃Y(CH₂)ι₀- 173 cyclo-C₆Hιι⁽CH₂ ⁾ιo-

154 C₆H₅0(CH₂)₉- 174 C₆H₅ ⁽CH₂)8-

155 C₆H₅S(CH₂)9- 175 C₆H₅(CH₂)₉-

156 CH₃(CH₂)7θ(CH₂) - 176 C₆H₅(CH₂)ιo-

157 CH₃ ⁽CH₂)7S⁽CH2)4- 177 C₆H₅(CH₂)ιι- TABLE 3 (continued)

N-NH

R ^κ1^ N Η ^b rv^CH_ ¹

Example R¹ Example R^l No. No.

178 CH₃(CH₂)₆Z(CH₂)₄- 198 CH₃(CH₂)₆0(CH₂)₅-

179 CH (CH₂)₅Z(CH₂)₅- 199 CH₃(CH₂)₆S(CH₂)₅-

180 CH₃(CH₂)₄Z(CH₂)6- 200 CH₃(CH₂)₅0(CH₂)6-

181 CH₃(CH₂)₃Z(CH₂)7- 201 CH₃(CH₂)₅S(CH₂)₆-

182 CH₃(CH₂)₂Z(CH₂)₈- 202 CH₃(CH₂)₄0(CH₂)₇-

183 CH₃CH₂Z(CH₂)₉- 203 CH₃(CH₂)₄S(CH₂)₇-

184 CH₃Z(CH₂)ιo- 204 CH₃(CH₂)₈0(CH₂)₃-

185 HZ(CH₂)n- 205 CH₃(CH₂)₈S(CH₂)₃-

186 CH₃(CH₂)₅Y(CH₂)5- 206 4-CH₃-C₆H₄(CH₂)9-

187 CH₂=CH(CH₂)n- 207 4-C₂H₅-C₆H₄(CH₂)₇-

188 CH₃(CH₂)₆Y(CH₂)₄- 208 4-(n-C₃H₇)C₆H₄(CH₂)₆-

189 CH₃(CH₂)₄Y(CH₂)₆- 209 4-(n-C₄H₉)C₆H₄(CH₂)5-

190 CH₃(CH₂)₃Y(CH₂)7- 210 4-C₂H₅-C₆H₄(CH2)8-

191 CH₃(CH₂)₂Y(CH₂)₈- 211 cyclo-C₆Hn(CH₂)₈-

192 CH₃CH₂Y(CH₂)₉- 212 cyclo-C₆Hn(CH₂)₉-

193 CH₃Y(CH₂)ιo- 213 cyclo-C₆Hn (CH₂) ιo-

194 C₅H₅0(CH₂)9- 214 C₆H₅(CH₂)8-

195 C₆H₅S(CH₂)₉- 215 C₆H₅(CH₂)9-

196 CH₃(CH₂)₇0(CH₂)₄- 216 C₆H₅(CH₂)ιo- 197 CH₃ ( CH₂ ) ₇S ( CH₂ ) ₄- 217 C₆H₅ ( CH₂ ) ιι-

TABLE 3 (continued)

No. No.

218 CH₃(CH₂)₆Z(CH₂)₄- 238 CH₃(CH₂)₆0(CH₂)₅-

219 CH₃(CH₂)₅Z(CH₂)₅- 239 CH₃(CH₂)₆S(CH₂)₅-

220 CH₃(CH₂)₄Z(CH₂)₆- 240 CH₃(CH₂)₅0(CH₂)₅-

221 CH₃(CH₂)₃Z(CH₂)₇- 241 CH₃(CH₂)₅S(CH₂)₆-

222 CH₃(CH₂)₂Z(CH₂)₈- 242 CH₃(CH₂)₄0(CH₂)₇-

223 CH₃CH₂Z(CH₂)₉- 243 CH₃ ⁽CH₂)₄S⁽CH₂ ⁾ ₇-

224 CH₃Z(CH₂)ιo- 244 CH₃ ⁽CH₂)8θ⁽CH2⁾3-

225 HZ(CH₂)n- 245 CH₃ ⁽CH2)8S⁽CH₂ ⁾3-

226 CH₃(CH₂)₅Y(CH₂)₅- 246 4-CH₃-C₆H₄(CH₂)₉-

227 CH₂=CH(CH₂)n- 247 4-C₂H5-C₆H₄ ⁽CH2)7-

228 CH₃(CH₂)₆Y(CH₂)₄- 248 4-(n-C₃H₇)C₆H₄(CH₂)₆-

229 CH₃(CH₂)₄Y(CH₂)₆- 249 4-(n-C₄H₉ ⁾C₆H₄ ⁽CH₂ ⁾5-

230 CH₃(CH2)3Y(CH₂)7- 250 4-C₂H₅-C₅H₄ ⁽CH2)8-

231 CH₃(CH₂)₂Y(CH₂)₈- 251 cyclo-C₆Hn⁽CH₂)8-

232 CH₃CH₂Y(CH₂)₉- 252 cyclo-C₆Hn(CH₂)₉-

233 CH₃Y(CH₂)ι₀- 253 cyclo-C₆Hn(CH₂)ιo-

234 C₆H₅0(CH₂)₉- 254 C₆H₅ ⁽CH₂)8-

235 C₆H₅S(CH₂)₉- 255 C₆H₅ ⁽CH₂)9- 236 CH₃(CH₂)₇0(CH₂)₄- 256 C₆H₅(CH₂)ιo-

237 CH₃(CH₂)₇S(CH₂)₄- 257 C₆H₅(CH₂)n-

TABLE 3 (continued)

Example R^l Example R^l

No. No.

258 CH₃(CH₂)₆Z(CH₂)₄- 278 CH₃(CH₂)₆0(CH₂)₅-

259 CH₃(CH₂)₅Z(CH₂)₅- 279 CH₃(CH₂)₆S(CH₂)₅-

260 CH₃ ⁽CH₂ ⁾ ₄Z⁽CH₂ ⁾ ₆- 280 CH₃(CH₂)₅θ(CH₂)₆-

261 CH₃(CH₂)₃Z(CH₂)₇- 281 CH₃ ⁽CH₂)₅S⁽CH₂ ⁾6-

262 CH₃(CH₂)₂Z(CH₂)₈- 282 CH₃(CH₂)₄0(CH₂)₇-

263 CH₃CH₂Z(CH₂)₉- 283 CH₃ ⁽CH₂ ⁾ ₄S⁽CH₂ ⁾ ₇-

264 CH₃Z(CH₂)₁₀- 284 CH₃ ⁽CH₂)8θ⁽CH₂ ⁾3-

265 HZ(CH₂)n- 285 CH₃ ⁽CH₂)₈S⁽CH₂ ⁾3- 266 CH₃ ⁽CH₂)₅Y⁽CH2⁾5- 286 4-CH₃-C₆H (CH₂ ⁾9-

267 CH₂=CH(CH₂)n- 287 4-C₂H₅-C₆H₄(CH₂)₇-

268 CH₃(CH₂)₆Y(CH₂)₄- 288 4-(n-C₃H₇)C₆H₄(CH₂)₆-

269 CH₃(CH₂)₄Y(CH₂)₆- 289 4-(n-C₄H9)C₆H₄(CH₂)5-

270 CH₃ ⁽CH₂)3Y⁽CH2)7- 290 4-C₂H₅-C₆H₄(CH₂)₈-

271 CH₃(CH₂)₂Y(CH₂)₈- 291 cyclo-C₆Hn(CH₂)₈-

272 CH₃CH₂Y(CH₂)9- 292 cyclo-C₆Hn(CH₂)9-

273 CH₃Y⁽CH₂ ⁾ιo- 293 cyclo-C₆Hn (CH₂) ιo-

274 C₆H₅0(CH₂)9- 294 C₆H₅ ⁽CH₂)8- 275 C₆H₅S(CH₂)₉- 295 C₆H₅(CH₂)₉-

276 CH₃(CH₂)₇0(CH₂)₄- 296 C₆H₅(CH₂)₁₀-

277 CH₃(CH₂)₇S(CH₂)₄- 297 C₆H₅(CH₂)₁₁-

TABLE 3 (continued)

No. No.

298 CH₃ ⁽CH₂ ⁾6Z⁽CH₂ ⁾4- 318 CH₃(CH₂)₆0(CH₂)₅-

299 CH₃(CH₂)₅Z(CH₂)₅- 319 CH₃(CH₂)₆S(CH₂)₅-

300 CH₃ ^{CH₂ ⁾ ₄Z⁽CH₂ ⁾6- 320 CH₃(CH₂)₅0(CH₂)₆-

301 CH₃ ⁽CH₂ ⁾ ₃Z⁽CH₂ ⁾ ₇- 321 CH₃(CH₂)₅S(CH₂)₆-

302 CH₃(CH₂)₂Z(CH₂)₈- 322 CH₃(CH₂)₄0(CH₂)₇-

303 CH₃CH₂Z(CH₂)₉- 323 CH₃(CH₂) S(CH₂)₇-

304 CH₃Z(CH₂)ιo- 324 CH₃ ⁽CH₂ ⁾ ₈0⁽CH₂ ⁾3-

305 HZ(CH₂)n- 325 CH₃(CH₂)₈S(CH₂)₃-

306 CH₃ ⁽CH₂ ⁾5Y⁽CH₂ ⁾5- 326 4-CH₃-C₆H₄(CH₂)₉-

307 CH₂=CH(CH₂)n- 327 4-C₂H₅-C₆H₄ ⁽CH2⁾7-

308 CH₃(CH₂)6Y⁽CH₂)₄- 328 4-⁽n-C₃H7⁾C₆H4⁽CH2)6-

309 CH₃(CH2)₄Y(CH₂)6- 329 4-⁽n-C₄H₉ ⁾C₆H₄(CH2)5-

310 CH₃(CH₂)₃Y(CH₂)₇- 330 4-C₂H5-C₆H₄(CH₂)8-

311 CH₃(CH₂)₂Y⁽CH₂)8- 331 cyclo-C₆Hn(CH₂ ⁾8- 312 CH₃CH₂Y(CH₂)₉- 332 cyclo-C₆Hιι(CH₂)₉-

313 CH₃Y(CH₂)ιo- 333 cyclo-C₆Hιι(CH₂)ιo- 314 C₆H₅0(CH₂)₉- 334 C₆H₅(CH₂)₈-

315 C₆H₅S(CH₂)₉- 335 C₆H₅(CH₂)₉-

316 CH₃(CH₂)₇0(CH₂)₄- 336 C₆H₅(CH₂)ιo-

317 CH₃(CH₂)₇S(CH₂)₄- 337 C₆H₅(CH₂)ι

TABLE 3 (continued)

R ^R1

Example Example R> No. No.

338 CH₃(CH₂)₆Z(CH₂)₄- 358 CH₃(CH₂)₆0(CH₂)5-

339 CH₃(CH₂)₅Z(CH₂)₅- 359 CH₃(CH₂)₆S(CH₂)5-

340 CH₃(CH₂)₄Z(CH₂)₆- 360 CH₃(CH₂)5θ(CH₂)6-

341 CH₃(CH₂)₃Z(CH₂)₇- 361 CH₃(CH₂)₅S(CH₂)6-

342 CH₃ ⁽CH₂ ⁾2Z⁽CH₂ ⁾8- 362 CH₃(CH₂)₄0(CH₂)₇-

343 CH₃CH₂Z(CH₂)g- 363 CH₃(CH₂)₄S(CH₂)₇-

344 CH₃Z(CH₂)ιo- 364 CH₃(CH₂)8θ(CH₂)3-

345 HZ(CH₂)n- 365 CH₃(CH₂)₈S(CH₂)3-

346 CH₃ ⁽CH₂)5Y⁽CH2⁾5- 366 4-CH3-C₆H₄(CH₂)9-

347 CH₂=CH(CH₂)n- 367 4-C₂H5-C₆H₄(CH2)7-

348 CH₃(CH₂)₆Y(CH₂)₄- 368 4-(n-C₃H₇)C₆H4(CH₂)₆-

349 CH₃ ⁽CH₂) Y⁽CH₂ ⁾6- 369 4-(n-C₄H₉)C₆H₄(CH₂)5-

350 CH₃ ⁽CH₂ ⁾3Y⁽CH2)7- 370 4-C₂H₅-C₆H₄(CH₂)₈-

351 CH₃(CH )9.Y(CH )8- 371 cyclo-C₆Hn(CH₂)₈- 352 CH₃CH₂Y(CH )₉- 372 cyclo-C₆Hn(CH₂)₉-

353 CH₃Y(CH₂)ιo- 373 cyclo-C₆Hn(CH₂)ιo-

354 C₆H₅0(CH₂)9- 374 C₆H₅(CH₂)₈-

355 C₆H₅S(CH₂)9- 375 C₆H₅(CH₂)₉-

356 CH₃(CH )₇0(CH )₄- 376 C₆H₅(CH₂)₁₀-

357 CH₃(CH₂)₇S(CH₂)₄- 377 C₆H₅(CH₂)ιι- TABLE 3 (continued)

Example R¹ Example R¹ No. No.

378 CH₃(CH₂)₆Z(CH₂)₄- 398 CH₃(CH₂)₆0(CH₂)₅-

379 CH₃(CH₂)₅Z(CH₂)₅- 399 CH₃(CH₂)₆S(CH₂)₅-

380 CH₃ ⁽CH₂ ⁾ Z⁽CH₂ ⁾6- 400 CH₃ ⁽CH₂ ⁾5θ⁽CH₂ ⁾6-

381 CH₃(CH₂)₃Z(CH₂)7- 401 CH₃ ⁽CH₂ ⁾5S⁽CH₂ ⁾6-

382 CH₃(CH₂)₂Z(CH₂)₈- 402 CH₃ ⁽CH₂ ⁾ ₄0⁽CH₂ ⁾7-

383 CH₃CH₂Z(CH₂)₉- 403 CH₃(CH₂)₄S(CH₂)₇-

384 CH₃Z⁽CH₂ ⁾ιo- 404 CH₃(CH₂)8θ(CH₂)₃-

385 HZ(CH₂)n- 405 CH3⁽CH₂)8S⁽CH₂)3-

386 CH₃ ⁽CH₂)₅Y⁽CH2⁾5- 406 4-CH₃-C₆H₄(CH₂)₉-

387 CH₂=CH(CH₂)n- 407 4-C₂H₅-C₆H₄(CH₂)₇- 388 CH₃(CH₂)₆Y(CH₂)₄- 408 4-(n-C₃H₇)C₆H₄(CH₂).₆-

389 CH₃(CH₂)₄Y(CH₂)₆- 409 4-(n-C₄H₉)C₆H₄(CH₂)₅- 390 CH₃(CH₂)₃Y(CH₂)₇- 410 4-C₂H₅-C₆H₄(CH₂:

391 CH₃(CH₂)₂Y(CH₂)₈- 411 cyclo-C₆Hn(CH₂)₈-

392 CH₃CH₂Y(CH₂)₉- 412 cyclo-C₆Hn⁽CH₂ ⁾9-

393 CH₃Y(CH₂)ιo- 413 cyclo-C₆Hn(CH₂)ιo-

394 C₆H₅0(CH₂)₉- 414 C₆H₅(CH₂)₈-

395 C₆H₅S(CH₂)₉- 415 C₆H₅(CH₂)₉-

396 CH₃ ⁽CH₂ ⁾ ₇0⁽CH₂ ⁾ ₄- 416 C₆H₅(CH₂)ιo-

397 CH₃(CH₂)₇S(CH₂)₄- 417 C₆H₅(CH₂)ι TABLE 3 (continued)

Example R^l Example R¹ No. No.

418 CH₃(CH₂)₆Z(CH₂)₄- 438 CH₃(CH₂)₆0(CH₂)₅-

419 CH₃(CH₂)₅Z(CH₂)₅- 439 CH₃(CH₂ ⁾ ₆S⁽CH₂)5-

420 CH₃(CH₂)₄Z(CH₂)₆- 440 CH₃(CH₂)₅0(CH₂)₆-

421 CH₃(CH₂)₃Z(CH₂)₇- 441 CH₃(CH₂)₅S(CH₂)₆-

422 CH₃(CH₂)₂Z(CH₂)₈- 442 CH₃(CH₂)₄0(CH₂)₇-

423 CH₃CH₂Z(CH₂)₉- 443 CH₃(CH₂)₄S(CH₂)₇-

424 CH₃Z(CH₂)ιo- 444 CH₃(CH₂)₈0(CH₂)₃-

425 HZ(CH₂)u- 445 CH₃(CH₂)₈S(CH₂)₃-

426 CH₃(CH₂)₅Y(CH₂)₅- 446 4-CH₃-C₆H₄(CH₂)₉-

427 CH₂=CH(CH₂)n- 447 4-C₂H₅-C₆H₄ ⁽CH₂ ⁾7-

428 CH₃(CH₂)₆Y(CH₂)₄- 448 4-(n-C₃H₇)C₆H₄ ⁽CH₂ ⁾6- 429 CH₃(CH₂)₄Y(CH₂)₆- 449 4- (n-C₄H₉ ) C₆H₄ (CH₂ ) ₅-

430 CH₃(CH₂)₃Y(CH₂)₇- 450 4-C₂H₅-C₆H₄ (CH₂) ₈-

431 CH₃(CH₂)₂Y(CH₂)₈- 451 cyclo-C₆Hn (CH₂) ₈-

432 CH₃CH₂Y(CH₂)9- 452 cyclo-C₆Hn (CH₂) 9-

433 CH₃Y(CH₂)₁₀- 453 cyclo-C₆Hn (CH₂) _l0-

434 C₆H₅0(CH₂)₉- 454 C₆H₅(CH₂)₈-

435 C₆H₅S(CH₂)₉- 455 C₆H₅(CH₂)₉-

436 CH₃(CH₂)₇0(CH₂)₄- 456 C₆H₅(CH₂)ι₀-

437 CH₃(CH₂)₇S(CH₂)₄- 457 C₆H₅(CH₂)ιι-

TABLE 3 (continued)

No_. No^

458 CH₃(CH₂)₆Z(CH₂)₄- 478 CH₃ (CH₂) ₆0 (CH₂) 5-

45.9 CH₃(CH₂)₅Z(CH₂)₅- 479 CH₃ (CH₂ ) ₆S (CH₂) 5-

460 CH₃(CH₂) Z(CH₂)₆- 480 CH3 (CH₂) ₅0 (CH₂) ₆-

461 CH₃(CH₂)₃Z(CH₂)₇- 481 CH3 (CH₂) 5S (CH₂) ₆-

462 CH₃(CH₂)₂Z(CH₂)₈- 482 CH₃ (CH₂) 0 (CH₂) 7-

463 CH₃CH₂Z(CH₂)₉- 483 CH₃ (CH₂) ₄S (CH₂) 7-

464 CH₃Z(CH₂)ιo- 484 CH₃ (CH₂) ₈0 (CH₂) 3-

465 HZ(CH₂)n- 485 CH3 (CH₂) ₈S (CH₂) 3-

466 CH₃(CH₂)5Y(CH₂)5- 486 4-CH₃-C₆H (CH₂) 9- 467 CH₂=CH(CH₂)n- 487 4-C₂H₅-C₆H₄(CH₂)7-

468 CH₃(CH₂)₆Y(CH₂)₄- 488 4-(n-C₃H7)C₆H₄(CH₂)₆-

469 CH₃(CH₂)₄Y(CH₂)₆- 489 4-(n-C₄H₉)C₆H₄(CH2)5-

470 CH₃(CH₂)₃Y(CH₂)₇- 490 4-C₂H5-C₆H₄(CH₂)₈-

471 CH₃(CH₂)₂Y(CH₂)₈- 491 cyclo-C₆Hn(CH₂)₈-

472 CH₃CH₂Y(CH₂)₉- 492 cyclo-C6Hιι(CH₂)g-

473 CH₃Y(CH₂)ιo- 493 cyclo-C₆Hn(CH₂)ιo-

474 C₆H₅0(CH₂)₉- 494 C₆H₅(CH₂)₈-

475 C₆H₅S(CH₂)9- 495 C₆H₅(CH₂)g-

476 CH₃(CH₂)₇θ(CH₂) - 496 C₆H₅(CH₂)ιo-

477 CH₃(CH₂)₇S(CH₂)₄- 497 C₆H₅(CH₂)n-

TABLE 3 (continued)

Example R^l Example R¹ No. No.

498 CH₃(CH₂)₆Z(CH₂)₄- 518 CH₃(CH₂)₆0(CH₂)5-

499 CH₃(CH₂)₅Z(CH₂)₅- 519 CH₃(CH₂)6S(CH₂)5-

500 CH₃(CH₂)₄Z(CH₂)₆- 520 CH₃(CH2)5θ(CH₂)6- 501 CH₃(CH₂ ⁾3Z⁽CH2)7- 521 CH₃(CH₂)₅S(CH₂)6-

502 CH₃ ⁽CH₂)2Z⁽CH₂)8- 522 CH₃(CH₂) 0(CH₂)₇-

503 CH₃CH₂Z(CH₂)g- 523 CH₃(CH₂)4S(CH₂)7-

504 CH₃Z(CH₂)ιo- 524 CH₃(CH₂)8θ(CH2)3- 505 HZ(CH₂)n- 525 CH₃(CH₂)₈S(CH₂)₃-

506 CH₃(CH₂)₅Y(CH₂)₅- 526 4-CH₃-C₆H₄(CH₂)₉-

507 CH₂=CH(CH₂)n- 527 4-C₂H₅-C₆H₄(CH₂)₇-

508 CH₃(CH₂)₆Y(CH₂)₄- 528 4-(n-C₃H₇)C₆H₄(CH₂)₆-

509 CH₃(CH₂)₄Y(CH₂)₆- 529 4-(n-C₄Hg)C₆H₄(CH₂)₅-

510 CH₃(CH₂)3Y(CH₂ ⁾7- 530 4-C₂H₅-C₆H₄(CH₂)₈-

511 CH₃(CH₂)₂Y(CH₂)₈- 531 cyclo-C₆Hn⁽CH₂ ⁾8-

512 CH₃CH₂Y(CH₂)g- 532 cyclo-C₆Hn(CH₂)g-

513 CH₃Y(CH₂)ιo- 533 cyclo-C₆Hn(CH₂)₁₀-

514 C₆H₅0(CH₂)g- 534 C₆H₅(CH₂)8-

515 C₆H₅S(CH₂)9- 535 C₆H₅(CH₂)g-

516 CH₃(CH₂)7θ(CH₂) - 536 C₆H₅(CH₂)ιo-

517 CH₃(CH₂)₇S(CH₂)₄- 537 C₆H₅(CH₂)ιι-

TABLE 3 (continued)

N-NH

R- -_N— S

Example R^l Example R¹ No. No.

538 CH₃(CH₂)6Z(CH₂)₄- 558 CH₃(CH₂)6θ(CH2)5-

539 CH₃(CH₂)₅Z(CH₂)₅- 559 CH₃(CH₂)₆S(CH₂)₅-

540 CH₃(CH2) Z(CH₂)6- 560 CH₃(CH₂)₅0(CH₂)6-

541 CH₃(CH₂)3Z(CH2)7- 561 CH₃(CH₂)₅S(CH₂)₆-

542 CH₃(CH₂)₂Z(CH₂)₈- 562 CH₃(CH₂) 0(CH₂)₇-

543 CH₃CH₂Z(CH₂)g- 563 CH₃(CH₂) S(CH₂)₇- 544 CH₃Z(CH₂)ιo- 564 CH₃(CH₂)₈0(CH₂)₃-

545 HZ(CH₂)n- 565 CH₃(CH₂)₈S(CH₂)₃-

546 CH₃(CH₂)₅Y(CH₂)₅- 566 4-CH₃-C₆H (CH₂)g-

547 CH₂=CH(CH₂)n- 567 4-C₂H₅-C₆H₄(CH₂)₇- 548 CH₃(CH₂)₆Y(CH₂) - 568 4-(n-C₃H7)C₆H₄(CH₂)6-

549 CH₃(CH2) Y(CH₂)6- 569 4-(n-CH₉)C₅H₄(CH₂)₅-

550 CH₃(CH₂)₃Y(CH₂)₇- 570 4-C₂H₅-C₆H₄(CH₂)₈-

551 CH₃(CH₂)₂Y(CH₂)₈- 571 cyclo-C₆Hn(CH₂)₈-

552 CH₃CH₂Y(CH₂)9- 572 cyclo-C₆Hιι(CH₂)₉-

553 CH₃Y(CH₂)ιo- 573 cyclo-C₆Hn(CH₂)ιo-

554 C₆H₅0(CH₂)g- 574 C₆H₅(CH₂)₈-

555 C₆H₅S(CH₂)g- 575 C₆H₅(CH₂)g-

556 CH₃(CH₂)₇0(CH₂)₄- 576 C₆H₅ ⁽CH₂)ιo-

557 CH₃(CH₂)₇S(CH₂) - 577 C₆H5(CH₂)ιι- TABLE 3 (continued)

Example R¹ Example R¹ No. No.

578 CH₃(CH₂)6Z(CH₂) - 598 CH₃(CH₂)₆θ(CH₂)₅-

579 CH3⁽CH₂)5Z⁽CH₂)5- 599 CH₃(CH₂)₆S(CH₂)₅-

580 CH₃ ⁽CH₂)4Z(CH₂)6- 600 CH₃ ⁽CH₂)5θ⁽CH₂)6-

581 CH₃(CH₂)₃Z(CH₂)7- 601 CH3⁽CH₂)5S⁽CH₂)6- 582 CH₃(CH₂)₂Z(CH₂)₈- 602 CH₃(CH₂)₄0(CH₂)₇-

583 CH₃CH₂Z(CH₂)g- 603 CH₃(CH₂)₄S(CH₂)₇-

584 CH₃Z(CH₂)ιo- 604 CH₃(CH₂)₈0(CH₂)₃-

585 HZ(CH₂)n- 605 CH₃ ⁽CH₂ ⁾ ₈S⁽CH₂ ⁾ ₃-

586 CH3(CH₂ ⁾5Y⁽CH₂)5- 606 4-CH₃-C₆H₄(CH₂)g-

587 CH₂=CH(CH₂)n- 607 4-C₂H₅-C₆H₄(CH₂)₇-

588 CH₃(CH₂)₆Y(CH₂) - 608 4-(n-C₃H₇)C₅H₄ ⁽CH₂)₆-

589 CH₃(CH₂)₄Y(CH₂)₆- 609 4-(n-C₄Hg)C₆H₄(CH₂)₅-

590 CH₃(CH₂)₃Y(CH₂)₇- 610 4-C₂H₅-C₆H₄(CH₂)₈-

591 CH₃(CH₂)₂Y(CH₂)₈- 611 cyclo-C₅Hιι(CH₂)₈-

592 CH₃CH₂Y(CH₂)g- 612 cyclo-C₆Hn(CH₂)g-

593 CH₃Y(CH₂)ιo- 613 cyclo-C₆Hn(CH₂)₁₀-

594 C₆H₅0(CH₂)g- 614 C₆H₅(CH₂)₈-

595 C₆H₅S(CH₂)g- 615 C₆H₅(CH₂)g-

596 CH₃(CH₂)₇0(CH₂)₄- 616 C₆H₅(CH₂)ιo-

597 CH₃(CH₂)₇S(CH₂)₄- 617 C₆H₅(CH₂)n-

TABLE 3 (continued)

No. No.

618 CH₃(CH₂)₆Z(CH₂)₄- 638 CH₃(CH₂)₆0(CH₂)5-

619 CH₃(CH₂)₅Z(CH₂)₅- 639 CH₃(CH₂)6S(CH₂)5-

620 CH₃(CH₂)₄Z(CH₂)6- 640 CH₃(CH₂)₅0(CH₂)₆- 621 CH₃(CH₂)₃Z(CH₂)₇- 641 CH₃(CH₂)₅S(CH₂)₆-

622 CH₃(CH₂)₂Z(CH₂)₈- 642 CH₃(CH₂)₄0(CH₂)₇-

623 CH₃CH₂Z(CH₂)g- 643 CH₃(CH₂)₄S(CH₂)₇-

624 CH₃Z(CH₂)ιo- 644 CH₃(CH₂)₈0(CH₂)₃-

625 HZ(CH₂)n- 645 CH₃(CH₂)₈S(CH₂)₃-

626 CH₃(CH₂)₅Y(CH₂)₅- 646 4-CH₃-C₆H₄(CH₂)g-

627 CH₂=CH(CH₂)n- 647 4-C₂H₅-C₆H₄(CH₂)₇-

628 CH₃(CH₂)₆Y(CH₂)₄- 648 4-(n-C₃H7)C₆H₄(CH₂)6-

629 CH₃(CH₂)₄Y(CH₂)₆- 649 4-(n-C₄Hg)C₆H₄(CH₂)₅-

630 CH₃(CH₂)₃Y(CH₂)₇- 650 4-C₂H₅-C₆H₄(CH₂)₈-

631 CH₃(CH₂)₂Y(CH₂)₈- 651 cyclo-C₆Hn(CH₂)₈-

632 CH₃CH₂Y⁽CH₂ ⁾9- 652 cyclo-C₆Hn(CH₂)g-

633 CH₃Y(CH₂)ιo- 653 cyclo-C₆Hn(CH₂)ιo-

634 C₆H₅0(CH₂)g- 654 C₆H₅(CH₂)₈-

635 C₆H₅S(CH₂)g- 655 C₆H₅(CH₂)g-

636 CH₃(CH₂)₇0(CH₂)₄- 656 C₆H₅(CH₂)ιo-

637 CH₃(CH2)7S(CH₂)4- 657 C₆H (CH₂)ιι-

TABLE 3 (continued)

No . No .

658 CH₃ (CH₂ ) ₆Z (CH₂ ) - 678 CH3 ⁽CH₂ ⁾ 6θ ⁽CH₂ ⁾ 5- 659 CH₃(CH₂)₅Z(CH₂)₅- 679 CH₃ (CH₂ ) ₆S (CH₂ ) ₅-

660 CH₃(CH₂)₄Z(CH₂)6- 680 CH₃ (CH₂) ₅0 (CH₂) ₆-

661 CH₃(CH₂)3Z(CH₂)₇- 681 CH3 (CH₂) ₅S (CH₂) ₆-

662 CH₃(CH₂)₂Z(CH₂)₈- 682 CH3 (CH₂) ₄0 (CH₂) 7-

663 CH₃CH₂Z(CH₂)g- 683 CH3 (CH₂) ₄S (CH₂) 7-

664 CH₃Z(CH₂)ιo- 684 CH3 (CH₂) ₈0 (CH₂) 3-

665 HZ(CH₂)n- 685 CH₃ (CH₂) ₈S (CH₂) 3-

666 CH₃(CH₂)₅Y(CH₂)5- 686 4-CH₃-C₆H₄ (CH₂) 9-

667 CH₂=CH(CH₂)n- 687 4-C₂H₅-C₆H₄ (CH₂) 7-

668 CH₃(CH₂)6Y(CH₂) - 688 4- (n-C₃H₇) C₆H₄ (CH₂) ₆-

669 CH₃(CH₂)₄Y(CH₂)6- 689 4- (n-C₄Hg) C₆H₄ (CH₂) 5-

670 CH₃(CH₂)3Y(CH₂)₇- 690 4-C₂H₅-C₆H₄ (CH₂) ₈"

671 CH3(CH₂)2Y(CH₂)8- 691 cyclo-C₆Hn (CH₂) ₈-

672 CH₃CH₂Y(CH₂)g- 692 cyclo-C₆Hu (CH₂) 9-

673 CH₃Y(CH₂)ιo- 693 cyclo-C₆Hn (CH₂) _1Q-

674 C₆H₅0(CH₂)₉- 694 C₆H₅(CH₂)₈-

675 C₆H₅S(CH₂)9- 695 C₆H₅(CH₂)9-

676 CH₃(CH₂)₇0(CH₂)₄- 696 C₆H₅(CH₂)ιo-

677 CH₃(CH₂)₇S(CH₂)₄- 697 C₆H5(CH₂)ιι- TABLE 3 ( continued)

R

Example R¹ Example R¹ No. No.

698 CH₃ ⁽CH₂)6Z⁽CH2)4- 718 CH₃(CH₂)₆0(CH₂)₅-

699 CH₃(CH₂)₅Z(CH₂)₅- 719 CH₃(CH₂)₆S(CH₂)₅-

700 CH₃ ⁽CH₂)₄Z⁽CH₂)₆- 720 CH₃(CH₂)₅0(CH₂)₆-

701 CH₃ (CH₂)₃Z(CH₂)₇- 721 CH₃(CH₂)₅S(CH₂)₆-

702 CH₃ ⁽CH₂)2Z⁽CH2)8- 722 CH₃(CH₂)₄0(CH₂)₇-

703 CH₃CH₂Z(CH₂)₉- 723 CH₃(CH₂) S(CH₂)₇-

704 CH₃Z(CH₂)ι₀- 724 CH₃ ⁽CH₂ ⁾ ₈0⁽CH₂ ⁾3-

705 HZ(CH₂)n- 725 CH₃ ⁽CH₂ ⁾ ₈S⁽CH2)3- 706 CH₃(CH₂)₅Y(CH₂)₅- 726 4-CH3-C₆H₄ ⁽CH₂ ⁾9-

707 CH₂=CH(CH₂)n- 727 4-C₂H5-C6H₄ ⁽CH₂)7-

708 CH₃(CH₂)6Y(CH₂)4- 728 4-⁽n-C₃H7⁾C₆H₄ ⁽CH2⁾6-

709 CH₃(CH₂)₄Y(CH₂)₆- 729 4-⁽n-C₄Hg⁾C₆H₄ ⁽CH₂ ⁾5-

710 CH₃(CH₂)₃Y(CH₂)₇- 730 4-C₂H₅-C₆H₄(CH₂)₈-

711 CH₃(CH₂)2Y(CH2)8- 731 cyclo-C₆Hιι(CH₂)₈-

712 CH₃CH₂Y(CH₂)9- 732 cyclo-C₆Hn(CH₂)9-

713 CH₃Y(CH₂)ιo- 733 cyclo-C₆Hn (CH₂ ) ι₀-

714 C₆H₅0(CH₂)₉- 734 C₆H₅(CH₂)₈-

715 C₆H₅S(CH₂)9- 735 C₆H₅(CH₂)g- 716 CH₃(CH₂)₇0(CH₂)₄- 736 C₆H₅(CH₂)₁₀-

717 CH₃(CH₂)₇S(CH₂)₄- 737 C₆H₅(CH₂)_ι

TABLE 3 (continued)

Example R^l Example R¹ No. No.

738 CH₃(CH₂)₆Z(CH₂)₄- 758 CH₃(CH₂)₆0(CH₂)₅-

739 CH₃ ⁽CH₂ ⁾ ₅Z⁽CH₂)5- 759 CH₃(CH₂)₆S(CH₂)₅-

740 CH₃ ⁽CH₂ ⁾ ₄Z⁽CH₂ ⁾6- 760 CH₃(CH₂)₅0(CH₂)₆-

741 CH₃(CH₂)₃Z(CH₂)₇- 761 CH3⁽CH₂ ⁾5S⁽CH₂ ⁾6-

742 CH₃(CH₂)₂Z(CH₂)₈- 762 CH₃(CH₂)₄0(CH2)₇-

743 CH₃CH₂Z(CH₂)₉- 763 CH₃(CH₂)₄S(CH₂)₇-

744 CH₃Z(CH₂)ιo- 764 CH₃(CH₂)₈0(CH₂)₃-

745 HZ(CH₂)n- 765 CH₃(CH₂)₈S(CH₂)₃-

746 CH₃ ⁽CH₂ ⁾ ₅Y⁽CH₂ ⁾5- 766 4-CH₃-C₆H₄(CH₂)g-

747 CH₂=CH(CH₂)n- 767 4-C₂H₅-C₆H₄(CH₂)₇-

748 CH₃(CH₂)₆Y(CH₂)₄- 768 4-⁽n-C₃H₇ ⁾C₆H₄ ⁽CH₂)6-

749 CH₃ ⁽CH2⁾ Y⁽CH₂)6- 769 4-(n-C₄H₉)C₆H₄(CH₂)₅-

750 CH₃(CH₂)3Y(CH₂)₇- 770 4-C₂H₅-C₆H₄(CH₂)₈-

751 CH₃(CH₂ ⁾ ₂Y(CH₂)₈- 771 cyclo-C₆Hn⁽CH₂ ⁾8-

752 CH₃CH₂Y(CH₂)g- 772 cyclo-C₆Hn⁽CH₂)9-

753 CH₃Y(CH₂)ιo- 773 cyclo-C₆Hn (CH₂) ιo-

754 C₆H₅0(CH₂)g- 774 C₆H₅(CH₂)₈- 755 C₆H₅S(CH₂)g- 775 C₆H₅(CH₂)₉-

756 CH₃(CH₂)₇0(CH₂)₄- 776 C₆H₅(CH₂)ι₀-

757 CH₃(CH₂)₇S(CH₂)₄- 777

TABLE 4

R ^R1

No. No.

779 4- n-Cι₀H₂ι)C₆H - 797 4- n-Cι₀H₂ι)C₆H -

780 4- n-CgHi9_)C₆H₄- 798 4- n-C₉Hιg)C₆H -

781 3- n-CιoH₂ι)C₆H - 799 n-Cι₀H₂ι)C₆H -

0 782 3- n-C₉Hi9)C₆H₄- 800 3- n-CgHι₉)C₆H -

783 4- n-Cι₀H₂ι)C₆H₄CH₂- 801 4- n-Cι₀H₂ι)C₆H CH₂-

784 4- n-C₉Hi9)C₆H₄CH₂- 802 4- n-C₉Hιg)C₆H₄CH₂-

785 4- n-C₇Hι₅)C₆H₄CH₂- 803 4- n-C₈Hι₇)C₆H₄CH₂-

786 4- n-C₇Hι₅Z)C₅H₄CH₂- 804 4- n-C₇Hi5)C₆H₄CH2- 5 787 4- n-C₆H₁₃Z)C₆H₄CH₂- 805 4- n-C₇Hi5Z)C₆H₄CH2-

788 4- n-C₅HnZ)C₆H CH₂- 806 4- n-C₆Hi3Z)C₆H₄CH₂-

789 4- n-C₈Hι₇)C₆H₄OCH₂- 807 n-C₅HιιZ)C₆H₄CH2-

790 4- n-C₇Hι₅)C₆H₄OCH₂- 808 4- n-C₈Hi7)C₆H₄OCH2-

791 4- n-C₆Hi3)C₆H₄OCH2- 809 4- n-C₇Hi5)C₆H OCH2-

20 792 3- n-C₉Hi9)C₆H₄CH2- 810 4- n-C₆Hi3)C₆H₄OCH2-

793 3- n-C₈Hi7)C₆H₄CH₂- 811 3- n-C9Hi9)C₆H₄CH₂-

794 4- n-C8Hi7)C₆H₄(CH2)3- 812 3- n-C8Hi7)C₆H₄CH2-

795 4- (n-C₇Hi5)C₆H₄(CH₂)3- 813 4- n-C₈Hι₇)C₆H₄(CH₂)3-

796 4- (n-C₆Hi3)C₆H₄(CH2)3- 814 4- n-C₇Hι₅)C₆H₄(CH₂)3-

25 815 4- n-C₆Hi3)C₆H₄(CH2)3- TABLE 4 (con't)

No. No.

816 4- n-Cι₀H₂₁)C₆H₄- 835 4- n-Cι₀H₂ι)C₆H₄-

817 4- n-CgHιg)C₆H₄- 836 4- n-C₉Hιg)C₆H -

818 3- n-Cι₀H₂ι)C₆H₄- 837 3- n-Cι₀H₂ι)C₆H₄-

819 3-< n-C₉Hi9)C₆H - 838 3- n-CgHιg)C₆H₄-

820 4-< n-Cι₀H₂₁)C₆H₄CH₂- 839 4- n-Cι₀H₂ι)C₆H₄CH₂-

821 4- < n-C₉H₁₉)C₆H₄CH₂- 840 4- n-C₉Hi9)C₆H₄CH₂-

822 4- n-C₈Hι₇)C₆H₄CH₂- 841 4- n-C₈H₁₇)C₆H₄CH₂-

823 4- n-C₇Hι₅)C₆H₄CH₂- 842 4- n-C₇Hι₅)C₆H₄CH₂-

824 4- n-C₇Hι₅Z)C₆H₄CH₂- 843 4- n-C₇Hι₅Z)C₆H₄CH₂-

825 4- n-C₆Hι₃Z)C₆H₄CH2- 844 4- n-C₆Hι₃Z)C₆H₄CH₂-

826 4- n-C₅Hι₁Z)C6H₄CH2- 845 4- n-C₅HnZ)C₆H CH₂-

827 4- n-C₈Hι₇)C₆H₄OCH2- 846 4- n-C₈Hι₇)C₆H₄OCH₂-

828 4- n-C₇Hι₅)C₆H₄OCH₂- 847 4- n-C₇Hι₅)C₆H₄OCH₂-

829 4- n-C₆Hi3)C6H₄OCH2- 848 4- n-C₆Hι₃)C₆H₄OCH₂-

830 3- n-C9Hι₉)C₆H₄CH₂- 849 3- n-C₉Hιg)C₆H₄CH₂-

831 3- n-C₈Hι₇)C₆H₄CH₂- 850 3- n-C₈Hι₇)C₆H₄CH₂-

832 4- n-C₈Hι₇)C₆H₄(CH₂)₃- 851 4- n-C₈Hι₇)C₆H (CH₂)₃-

833 4- (n-C₇Hι₅)C₅H₄(CH₂)3- 852 4- (n-C₇Hi5)C₆H₄(CH₂)3-

834 4- (n-C₆Hi3)C₆H4(CH₂)3- 853 4- (n-C₆Hι₃)C₆H₄(CH₂)₃- Table 4 (con't)

No. No.

854 4- (n-Cι₀H₂ι)C₆H₄- 873 4- (n-C₁₀H₂ι)C₆H₄-

855 4- (n-C₉Hιg)C₆H₄- 874 4- n-CgH₁₉)C₆H₄-

856 3- n-Cι₀H₂ι)C₆H₄- 875 3- n-Cι₀H₂ι)C₆H₄-

857 3- (n-C₉H₁₉)C₆H₄- 876 3- n-C₉H₁₉)C₆H₄-

858 4- n-Cι₀H₂ι)C₆H₄CH₂- 877 4- n-Cι₀H₂ι)C₆H₄CH₂-

859 4- n-C₉Hιg)C₆H₄CH₂- 878 4- n-CgH₁₉)C₆H₄CH₂-

860 4- n-C₈Hι₇)C₆H₄CH₂- 879 4- n-C8H₁₇)C₆H₄CH₂-

861 4- n-C₇Hι₅)C₆H₄CH₂- 880 4- n-C7H₁₅)C₆H₄CH2-

862 4- n-C₇Hi5Z)C₆H₄CH₂- 881 4- n-C₇Hi5Z)C₆H₄CH₂-

863 4- n-C₅Hι₃Z)C₆H₄CH₂- 882 4- n-C₆Hι₃Z)C₆H₄CH₂-

864 4-, n-C₅HuZ)C₆H₄CH₂- 883 4-( n-C₅HιιZ)C₆H CH -

865 4- n-C₈Hι₇)C₆H₄OCH₂- 884 4- n-C₈H₁₇)C₆H₄OCH₂-

866 4- n-C₇Hι₅)C₆H₄OCH₂- 885 4-( n-C₇Hι₅)C₆H₄OCH₂-

867 4-1 n-C₆Hι₃)C₅H₄OCH₂- 886 4-< n-C₆Hi3)C₆H40CH₂-

868 3-( n-CgHι₉)C₆H₄CH₂- 887 3-( n-C₉Hι₉)C₆H₄CH₂-

869 3- n-C₈Hι₇)C₆H₄CH₂- 888 3- n-C₈Hι₇)C₆H₄CH₂-

870 4- n-C₈Hι₇)C₆H₄(CH₂)3- 889 4-( n-C₈Hι₇)C₆H₄(CH₂)₃-

871 4-( n-C₇Hι₅)C₆H₄(CH₂)3- 890 4-( n-C₇Hi5)C₆H₄(.CH₂)₃-

872 4-< n-C₆Hι₃)C₆H₄(CH₂)₃- 891 4-( n-C₆Hi3)C₆H₄(CH₂)₃- TABLE 4 (con't)

5

No. No.

892 4- n-C₁₀H₂ι)C₆H₄- 911 4- n-Cι₀H₂ι)C₆H₄-

893 4- (n-C₉Hιg)C₆H₄- 912 4- [n-CgHιg)C₆H₄-

894 3- [n-Cι₀H₂ι)C₆H₄- 913 3- n-Cι₀H₂ι)C₆H₄-

10 895 3- n-C₉Hιg)C₆H₄- 914 3- n-C₉Hi9)C₆H₄-

896 4- n-C₁₀H₂ι)C₆H₄CH₂- 915 4- n-Cι₀H₂ι)C₆H₄CH₂-

897 4- n-C₉Hι₉)C₆H₄CH₂- 916 4- n-C₉Hιg)C₆H₄CH₂-

898 4- n-C₈Hι₇)C₆H₄CH₂- 917 4- n-C₈Hι₇)C₆H CH₂-

899 4- n-C₇Hi5)C₆H₄CH2- 918 4- n-C₇Hι₅)C₆H₄CH₂-

15 900 4- n-C₇Hι₅Z)C₆H4CH₂- 919 4- n-C₇Hι₅Z)C₆H₄CH₂-

901 4- n-C₆Hi3Z)C₆H CH₂- 920 4- n-C₆Hi3Z)C₆H₄CH2-

902 4- n-C₅HnZ)C₆H₄CH₂- 921 4- n-C₅HιιZ)C₆H₄CH2-

903 4- n-C₈H₁₇)C₆H₄OCH₂- 922 4- n-C₈Hι₇)C₆H₄OCH₂-

904 4- n-C₇Hi5)C₆H40CH₂- 923 4- n-C₇Hι₅)C₆H₄OCH2-

20 905 4- n-C₆Hι₃)C₆H40CH₂- 924 4- n-C₆Hι₃)C₆H₄OCH2-

906 3- n-C₉Hι₉)C₆H₄CH2- 925 3- n-C₉Hi9)C₆H₄CH₂-

907 3- n-C₈Hi7)C₆H₄CH2- 926 3- n-C₈Hι₇)C₆H₄CH₂-

908 4- n-C₈Hi7)C₆H₄(CH₂)₃- 927 4- n-C₈Hi7)C₆H₄(CH2)3-

909 4- n-C₇Hi5)C₆H4(CH₂)3- 928 4- n-C₇Hi5)C₆H₄(CH₂)₃-

25 910 4- n-C₆Hι₃)C₆H₄(CH₂)₃- 929 4- n-C₆Hι₃)C₆H₄(CH₂)3- TABLE 4 (con't)

Example R¹ Example R¹ No. No.

930 4-(n-Cι₀H₂ι)C₆H₄- 949 4-(n-Cι₀H₂ι)C₆H₄-

931 4- n-CgHιg)C₆H₄- 950 4- n-CgHιg)C₆H₄-

932 3- n-Cι₀H₂ι)C₅H₄- 951 3- n-Cι₀H₂ι)C₆H₄-

933 3- n-C₉Hιg)C₆H₄- 952 3- n-CgHιg)C₆H₄-

934 4- n-Cι₀H₂ι)C₆H₄CH₂- 953 4- n-Cι₀H₂₁)C₆H₄CH₂-

935 4- n-C₉H₁₉)C₆H₄CH₂- 954 4- n-C₉Hi9)C₆H₄CH₂-

936 4- n-C₈Hι₇)C₆H₄CH₂- 955 4- n-C₈Hι₇)C₆H₄CH₂-

937 4- n-C₇Hι₅)C₆H₄CH₂- 956 4- n-C₇Hι₅)C₆H₄CH₂-

938 4- n-C₇Hι₅Z)C₆H CH₂- 957 4- n-C₇Hι₅Z)C₆H₄CH₂-

939 4- n-C₆Hι₃Z)C₆H₄CH₂- 958 4- n-C₆Hι₃Z)C₆H₄CH₂-

940 4- n-C₅HnZ)C₆H₄CH₂- 959 4- n-C₅HnZ)C₆H₄CH₂-

941 4- n-C₈Hι₇)C₆H₄OCH₂- 960 4- n-C₈Hι₇)C₆H₄OCH₂-

942 n-C₇Hι₅)C₆H OCH₂- 961 4- n-C₇Hι₅)C₆H₄OCH₂-

943 4- n-C₆Hι₃)C₆H₄OCH₂- 962 4- n-C₆Hι₃)C₆H₄OCH₂-

944 3- n-C₉Hi9)C₆H CH2- 963 3- n-C₉Hιg)C₆H₄CH₂-

945 3- n-C₈Hι₇)C₆H₄CH₂- 964 3- n-C₈Hι₇)C₆H₄CH₂-

946 4- n-C₈H₁₇)C₆H₄(CH₂)₃- 965 4- n-C₈Hι₇)C₆H₄(CH₂)₃-

947 4- n-C₇H₁₅)C₆H₄(CH₂)₃- 966 4- n-C₇Hi5)C₆H₄(CH₂)3-

948 4- n-C₆H₁₃)C₆H₄(CH₂)3- 967 4- n-C₆Hι₃)C₆H4(CH₂)3- TABLE 4 (con't)

No. No.

968 4-(n-Cι₀H₂ι)C₆H₄- 987 4-(n-Cι₀H₂ι)C₆H₄-

969 n-C₉Hι₉)C₆H - 988 4- n-CgHιg)C₆H₄-

970 3- n-Cι₀H₂ι)C₆H - 989 3- n-Cι₀H₂ι)C₆H₄-

971 3- n-CgHι₉)C₆H₄- 990 3- n-CgHιg)C₆H₄-

10 972 n-Cι₀H₂ι)C₆H₄CH₂- 991 4- n-Cι₀H₂ι)C₆H₄CH₂-

973 n-CgHι₉)C₆H₄CH₂- 992 4- n-CgHιg)C₆H₄CH2-

974 n-C₈Hι₇)C₆H₄CH₂- 993 4- n-C₈H₁₇)C₆H₄CH2-

975 n-C₇Hι₅)C₆H₄CH₂- 994 4- n-C₇H₁₅)C6H₄CH2-

976 4- n-C₇Hι₅Z)C₆H₄CH₂- 995 4- n-C₇Hι₅Z)C6H CH₂-

15 977 4- n-C₆Hι₃Z)C₆H4CH₂- 996 4- n-C₆Hi3Z)C₆H₄CH2-

978 4- n-C₅HιιZ)C6H₄CH₂- 997 4- n-C₅HnZ)C₆H₄CH₂-

979 4- n-C₈Hι₇)C₆H₄OCH₂- 998 4- n-C₈Hι₇)C₆H₄OCH₂-

980 4- n-C₇Hι₅)C₆H₄OCH₂- 999 4- n-C₇Hι₅)C₆H₄OCH₂-

981 4- n-C₆Hi3)C₆H₄OCH₂- 1000 4- n-C₆Hι₃)C₆H₄OCH₂-

20 982 3- n-C₉Hι₉)C₆H₄CH₂- 1001 3- n-C₉Hιg)C₆H4CH₂-

983 3- n-C₈Hι₇)C₆H₄CH₂- 1002 3- n-C₈H₁₇)C₆H4CH₂-

984 n-C₈Hi7)C₆H₄(CH₂)3- 1003 4- n-C₈Hi7)C6H₄(CH2)3-

985 4- n-C₇Hι₅)C₆H₄(CH₂)₃- 1004 4- n-C₇Hi5)C₆H4(CH₂)3-

25 986 4- n-C₆H₁₃)C₆H₄(CH₂)3- 1005 4- n-C₆Hi3)C₆H4(CH₂)₃- TABLE 4 (con't)

Example R^l Example R¹ No. No.

1006 4- n-Cι₀H₂ι)C₆H₄- 1025 4- n-Cι₀H₂₁)C₆H₄-

1007 4- n-C₉Hιg.)C₆H₄- 1026 4- n-CgHιg)C₆H₄-

1008 3- n-Cι₀H₂ι)C₆H₄- 1027 3- n-Cι₀H₂ι)C₆H₄-

1009 3- n-C₉Hι₉)C₆H₄- 1028 3- n-CgHιg)C₆H -

1010 4- n-CιoH₂ι)C₆H₄CH₂- 1029 4- n-Cι₀H₂ι)C₆H₄CH₂-

1011 4- n-CgHιg)C₆H₄CH₂- 1030 4- n-C₉Hιg)C₆H₄CH₂-

1012 4- n-C₈Hι₇)C₆H₄CH₂- 1031 4- n-C₈H₁₇)C6H₄CH2-

1013 4- n-C₇Hι₅)C₆H₄CH₂- 1032 4- n-C₇Hi5)C₆H₄CH2-

1014 4- n-C₇Hι₅Z)C₆H₄CH₂- 1033 4- n-C₇Hi5Z)C₆H CH2-

1015 4- n-C₆Hi3Z)C₅H₄CH₂- 1034 4- n-C₆Hi3Z)C₆H₄CH2-

1016 4- n-C₅HnZ)C₆H₄CH₂- 1035 4- n-C₅HnZ)C₆H₄CH₂-

1017 4- n-C₈Hι₇)C₆H₄OCH₂- 1036 4- n-C₈Hι₇)C₆H₄OCH₂-

1018 4- n-C₇Hι₅)C₆H₄OCH₂- 1037 4- n-C₇H ₅)C₆H40CH₂-

1019 4- n-C₆Hι₃)C₆H₄OCH₂- 1038 4- n-C₆Hi3)C6H₄OCH2-

1020 3- n-CgHιg)C₆H₄CH₂- 1039 3- n-C9Hi9)C₆H₄CH₂-

1021 3- n-C₈Hi7)C₆H₄CH₂- 1040 3- n-C₈Hi7)C₆H₄CH2-

1022 4- n-C₈Hι₇)C₆H₄(CH₂)3- 1041 4- n-C₈H₁₇)C₆H₄(CH₂)₃-

1023 4- (n-C₇Hi5)C₆H4(CH₂)3- 1042 4- n-C₇Hi5)C₆H₄(CH2)3-

1024 4- (n-C₆Hi3)C₅H4(CH₂)3- 1043 4- (n-C₆Hi3)C₆H₄(CH2)3- TABLE 4 (con't)

No. No.

1044 4-(n-Cι₀H₂ι)C₆H₄- 1063 4-(n-Cι₀H₂ι)C₆H₄-

1045 4- n-C₉Hi9.)C₆H - 1064 4- n-C₉Hιg)C₆H₄- 1046 3- n-Cι₀H₂ι)C₆H - 1065 3- n-Cι₀H₂ι)C6H₄-

10 1047 3- n-C₉Hιg)C₆H₄- 1066 3- n-C₉Hιg)C₆H₄- 1048 4- n-Cι₀H₂ι)C₆H₄CH₂- 1067 4- n-CιoH₂ι)C₆H₄CH₂-

1049 4- n-C₉Hιg)C₆H CH₂- 1068 4- n-C₉Hι₉)C₆H₄CH₂- 1050 4- n-C₈Hι₇)C₆H₄CH₂- 1069 4- n-C₈Hι₇)C₆H₄CH₂- 1051 n-C₇Hι₅)C₆H₄CH₂- 1070 4- n-C₇Hi5)C₆H CH2-

15 1052 n-C₇Hι₅Z)C6H₄CH₂- 1071 4- n-C₇Hi5Z)C6H₄CH2- 1053 n-C₆Hι₃Z)C₆H₄CH₂- 1072 4- n-C₆Hι₃Z)C₆H₄CH₂- 1054 4- n-C₅HnZ)C₆H₄CH₂- 1073 4- n-C₅HnZ)C6H4CH₂-

1055 n-C₈Hι₇)C₆H₄OCH₂- 1074 4- n-C₈H₁₇)C₆H₄OCH₂-

1056 n-C₇Hi5)C₆H40CH2- 1075 4- n-C₇Hι₅)C₆H₄OCH2-

20 1057 4- n-C₆Hi3)C6H₄OCH2- 1076 4- n-C₆Hi3)C₆H₄OCH2- 1058 3- n-C₉Hι₉)C₆H₄CH₂- 1077 3- n-CgHιg)C6H₄CH2-

1059 3- n-C₈Hι₇)C₆H₄CH₂- 1078 3- n-C₈Hι₇)C₆H₄CH₂-

1060 4- n-C₈Hi7)C₆H₄(CH₂)3- 1079 4- n-C₈Hι₇)C₆H₄(CH₂)3- 1061 4- n-C₇Hi5)C₆H₄(CH2)3- 1080 4- n-C₇Hι₅)C₆H₄(CH₂)3-

25 1062 4- n-C₆Hι₃)C₆H₄(CH2)3- 1081 4- n-C₆Hi3)C₆H₄(CH2)3- TABLE 4 (con't)

I y

Example R¹ Example R^l No. No.

1082 n-C₁₀H₂ι)C₆H₄- 1101 4- n-Cι₀H₂ι)C₆H₄-

1083 n-CgH!g)C₆H - 1102 4- n-CgHιg)C₆H₄-

1084 3- n-Cι₀H₂ι)C₆H₄- 1103 3- n-Cι₀H₂ι)C₆H₄-

1085 3- n-C₉Hi9)C₆H₄- 1104 3- n-C9H₁₉)C₆H4-

1086 n-Cι₀H₂ι)C₆H₄CH₂- 1105 4- n-Cι₀H₂ι)C₆H₄CH₂-

1087 4- n-C₉Hi9)C6H CH₂- 1106 4- n-C₉Hιg)C₆H₄CH₂-

1088 4- n-C₈H₁₇)C6H₄CH2- 1107 4- n-C₈Hi7)C₆H₄CH2-

1089 n-C₇Hι₅)C₆H4CH2- 1108 4- n-C₇Hi5)C₆H₄CH2-

1090 4- n-C₇Hι₅Z)C₆H₄CH₂- 1109 4- n-C₇Hι₅Z)C₆H₄CH₂-

1091 4- n-C₆H₁₃Z)C₆H CH₂- 1110 4- n-C₆Hι₃Z)C₆H₄CH₂-

1092 4- n-C₅HnZ)C₆H CH₂- 1111 n-C₅HnZ)C₆H₄CH₂-

1093 n-C₈Hι₇)C₆H₄OCH₂- 1112 4- n-C₈Hι₇)C₆H₄OCH₂-

1094 n-C₇Hι₅)C₆H₄OCH₂- 1113 4- n-C₇Hι₅)C₆H₄OCH -

1095 4- n-C₆Hι₃)C₆H OCH₂- 1114 4- n-C₆Hι₃)C₆H₄OCH₂-

1096 3- n-CgHιg)C₆H₄CH₂- 1115 3- n-C₉Hi9)C₆H₄CH₂-

1097 3- n-C₈Hi7)C₆H₄CH₂- 1116 3- n-C₈Hι₇)C₆H₄CH₂-

1098 n-C₈Hι₇)C₆H₄(CH₂)3- 1117 4- n-C₈H₁₇)C₆H₄(CH₂)3-

1099 n-C₇Hi5)C₆H₄(CH2)3- 1118 4- n-C₇Hi5)C₆H₄(CH₂)3-

1100 4- n-C₆Hi3)C₆H₄(CH₂)3- 1119 4- n-C₆H₁₃)C6H₄(CH₂)3- EXAMPLE 1120

3-Tridecyl-4- (3-methoxyphenyl) -4H-1, 2, 4-triazole, nitrate

Following the general procedure adapted from C . Ainsworth, Organic Synthesis Collective Volume 5, 1070 (1973), concentrated nitric acid (0.6 mL) was dissolved in cold water (5.0 mL) . Solid sodium nitrite (1 mg) was added, followed with solid 2,4- dihydro-4- (3 -methoxyphenyl) -5-tridecyl-3H-l, 2, 4- triazole-3 -thione (Example 1) (about 0.1 g) . The resulting slurry was gently warmed to about 45-50 °C. The reaction gas was monitored for the evolution of a brown gas. The remaining triazol-3-thione (0.68 g) was added as a solid in portions so as to maintain the reaction. When the addition was complete, the reaction mixture was stirred at 45-50 °C for one hour then cooled to room temperature. As the reaction completed, the evolution of gas ceased and foaming diminished. Water (about 5 mL) was added to facilitate stirring. The mixture was stirred overnight at room temperature to produce a flocculent off-white precipitate, which was collected by vacuum filtration, washed with cold water and dried in vacuo to give 3 -tridecyl-4- (3 -methoxyphenyl ) -4H-1, 2 , 4- triazole, nitrate as an off-white solid: M.P. 65.4- 68.9 °C. ^XH NMR (d₆-acetone) δ 0.85 (t, J = 6 Hz, 3H) , 1.28 (br s, 20H) , 1.72 (m, 2H) , 3.02 (t, J = 8 Hz, 2H) , 3.93 (s, 3H) , 7.45 ( , 4H) , 9.14 (s, 1H) . Calc'd for C₂₂H₃₆N₄0₄: C, 62.82; H, 8.64; N, 13.32. Found: C, 63.04; H, 8.59; N, 13.11.

Additional representative examples of substituted-1, 2, 4-triazoles can be prepared by one skilled in the art from the appropriate triazole thiones using similar methods as shown in Example 1120 and can be found in Table 5 below.

C-30 6

O TABLE 5

00 N-N

H C 1n U 3Hⁿ27 ΛP> •HNO,

N >2

5 Example No. R^J m.p. Analyses

1121 3-CH₃-C₆H₄- 53-56 Calcd. C63.21 H,9.04 N,13 40 •0.75H₂O Obs. C63.34 H,9.15 N,12 94

1122 4-CH₃0-C₆H₄- 62-64 Calcd. C62.82 H,8.64 N,13 32

Obs. C, 62.80 H,8.63 N,13 27 1123 2-CH₃0-C₆H - 75-77 Calcd. C, 62.82 H,8.64 N,13 32

Obs. C, 62.47 H,8.33 N,12 80 1124 2 -naphthyl - 65.2-66.2 Calcd. C, 68.14 H,8.25 N,12 72

Obs. C, 68.22 H,8.26 N,12 67 vo 10 1125 3,4-(OCH₂0)-C₆H₃- 103-105 Calcd. C, 60.84 H,7.89 N,12 92

Obs. C, 61.48 H,8.17 N,13 01 1126 2-Cl-C₆H - 75.5-79.6 FABMS: m/z = 362 (M+H)

HRMS: Calcd 362.2363 Found: 362.2345 1127 2-F-C₆H₄- 52.1-55.0 FABMS: m/z = 346 (M+H)

HRMS: Calcd 346.2659 Found: 346.2662 1128 3-Cl-C₆H - 61.5-63.2 FABMS: m/z = 362 (M+H)

HRMS: Calcd 362.2363 Found: 362.2336 1129 3-C₆H5CH₂0-C₆H₄- 51.7-52.9 FABMS: m/z = 434 (M+H)

HRMS: Calcd 434.3171 Found : 434.3193

15 1130 4-C₆H₅CH₂0-C₆H - 123.0-124.1 Calcd. C, 67.72; H,8.13; N, 11.28

Obs. C, 67.97 H,8.15 N,ll.23 o 1131 4-Cl-C₆H - 94.1-95.1 Calcd. C, 59.34 H,7.84 N,13.18

Obs. C, 59.29 H,7.93 N,13.10 1132 2-CH₃-C₆H - 57.8-61.7 Calcd. C65.30; H,8.99; N,13.85

O Obs. C65.37; H,8.77; N,13.96

EXAMPLE 1133

3-Chloro-4- (3-methoxyphenyl) -5-tridecyl-4H-l,2,4- triazole

Solid 2,4, -dihydro-4- (3 -methoxyphenyl) -5- tridecyl-3H-l,2,4-triazole-3-thione (Example 1) (0.20 g, 0.51 mmol) was dissolved in S0₂C1₂ (10 mL) and stirred at room temperature for 45 minutes at which time TLC analysis showed that the reaction was complete. The reaction mixture was poured over ice (100 g) , and ethyl acetate (400 mL) was used to extract the product. The organic layer was washed with water (25 mL) , saturated sodium bicarbonate (2 x 25 mL) , and brine (2 x 25 mL) , then dried (MgSO and concentrated to leave a clear oil. This oil was dissolved in hot hexane, and upon cooling, a white solid formed. This solid was collected by vacuum filtration, washed with n-pentane, and air-dried to give 70 mg (35%) of a white solid: m.p. 63.6-65.1 °C. Subsequent recrystallization from acetonitrile provided an analytical sample 2 mg (1%) of the desired 3-chloro-5-tridecyl-4- (3 -methoxyphenyl) -4H- 1,2,4-triazole product as a white solid: m.p. 65.3- 67.3 °C. ^XH NMR (d,-DMSO) 57.50 (m, 1H) , 7.15 (m, 2H) , 7.04 (m, 1H) , 3.78 (s, 3H) , 2.52 (t, J = 7.5 Hz, 2H) , 1.50 (m, 2H) , 1.21 (m, 20H) , 0.83 (t, J = 6.6 Hz, 3H) . ESMS m/z= 392 (M+H). HRMS: Calc'd 392.2469; Observed 392.2454.

Biological Evaluation

WHOLE SERUM CETP ACTIVITY ASSAY (Tritiated cholesterol ester) Blood was obtained from healthy volunteers recruited from the personnel of Monsanto Company, Saint Louis, MO.

Blood was either collected in tubes containing EDTA (EDTA plasma pool) or without (spun to form the serum pool) .

The EDTA human plasma pool or human serum pool, previously stored at -20 °C, was thawed at room temperature, and centrifuged for 5 minutes to remove any particulate matter. Tritiated HDL, radiolabeled in the cholesteryl ester moiety ([³H]CE-HDL) as described by Morton and Zilversmit (J. Biol. Chem., 256, 11992-95 (1981) ) , was added to the plasma or serum to a final concentration of (25 μg/ml cholesterol) . Inhibitor compounds were added to the plasma or serum as follows: Equal volumes of the plasma or serum containing the

[ H]CE-HDL (396 μl) were pipetted into micro tubes (Titertube^®, Bio-Rad Laboratories , Hercules , CA) .

Compounds, usually dissolved as 20-50 mM stock solutions in DMSO, were serially diluted in DMSO (or an alternative solvent in some cases, such as dimethylformamide or ethanoi) . Four μl of each of the serial dilutions of inhibitor compounds or DMSO alone were then added to each of the plasma or serum tubes . The tubes were immediately mixed. Triplicate aliquots (100 μl) from each plasma or serum tube were then transferred to wells of 96-well round-bottomed polystyrene microtiter plates (Corning, Corning, NY) . Plates were sealed with plastic film and incubated at 37 °C for 4 hours. Test wells contained plasma or serum with dilutions of inhibitor compounds. Control wells contained plasma or serum with DMSO alone. Blank wells contained plasma or serum with DMSO alone that were left in the micro tubes at 4 °C for the 4 hour incubation and were added to the microtiter wells at the end of the incubation period. VLDL and LDL were precipitated by the addition of 10 μl of precipitating reagent (1% (w/v) Dextran Sulfate (Dextralip50) /0.5M magnesium chloride, pH 7.4) to all wells. The wells were mixed on a plate mixer and then incubated at ambient temperature for 10 min. The plates were then centrifuged at 1000 x g for 30 mins at 10 °C . The supematants (50 μl) from each well were then transferred to Picoplate™ 96 plate wells (Packard, Meriden, CT) containing 250:1

Microscint™-40 (Packard, Meriden, CT) . The plates were heat-sealed (TopSeal™-P, Packard, Meriden, CT) according to the manufacturers directions and mixed for 30 min. Radioactivity was measured on a microplate scintillation counter (TopCount, Packard, Meriden, CT) . ICS_Q'S were determined as the concentration of inhibitor compound inhibiting transfer of [3H]CE from the supernatant

[³H]CE-HDL to the precipitated VLDL and LDL by 50% compared to the transfer obtained in the control wells. The maximum percent transfer (in the control wells) was determined using the following equation: t ^{d m}blan -^{d m}contro ^{X 10} °

% Transfer = dpm.blank

The percent of control transfer determined in the wells containing inhibitor compounds was determined as follows

^{d m}blank-^{d m}test J ^x 1° °

% Control = ^dP^mblank-^dP^mcontrol

IC50 values were then calculated from plots of % control versus concentration of inhibitor compound. Examples of IC50 values determined by this method are specified in Table 6.

CETP Activity In Vitro The ability of compounds to inhibit CETP were assessed using an in vitro assay that measured the rate of transfer of radiolabled cholesteryl ester ([³H]CE) from HDL donor particles to LDL acceptor particles. Details of the assay are provided by Glenn et al . ("Quantification of Cholesteryl Ester Transfer Protein (CETP) : A) CETP Activity and B) Immunochemical Assay of CETP Protein," Meth . Enzymol . , Glenn and Melton (Meth. Enzymol., 263, 339-351 (1996)). CETP was obtained from the serum-free conditioned medium of CHO cells transfected with a cDNA for CETP (Wang, S. et al . J. Biol Chem. 267, 17487-17490 1992) . To measure CETP activity,

[³H]CE-labeled HDL, LDL, CETP and assay buffer (50 mM tris (hydroxymethyl)aminomethane, pH 7.4; 150 mM sodium chloride; 2 mM ethylenediamine-tetraacetic acid; 1% bovine serum albumin) were incubated in a volume of 200 μl, for 2 hours at 37°C in 96 well plates. LDL was differentially precipitated by the addition of 50 μl of 1% (w/v) dextran sulfate/0.5 M magnesium chloride, mixed by vortex, and incubated at room temperature for 10 minutes The solution (200μl) was transferred to a filter plate (Millipore) . After filtration, the radioactivity present in the precipitated LDL was measured by liquid scintillation counting. Correction for non-specific transfer or precipitation was made by including samples that did not contain CETP. The rate of [³H]CE transfer using this assay was linear with respect to time and CETP concentration, up to 25-30% of [³H]CE transferred. The potency of test compounds was determined by performing the above described assay in the presence of varying concentrations of the test compounds and determining the concentration required for 50% inhibition of transfer of [³H]CE from HDL to LDL. This value was defined as the ICso- Examples of IC₅₀ values determined by this method are specified in Table 6.

Inhibition of CETP Activity In Vivo.

Inhibition of CETP by a test compound can be determined by administering the compound to an animal by intravenous injection, determining the rate of transfer of tritium-labeled cholesteryl ester (³H]CE) from HDL to VLDL and LDL particles, and comparing the rate of transfer with the rate of transfer observed in control animals. Male golden Syrian hamsters were maintained on a diet of chow containing 0.24% cholesterol for at least two weeks prior to the study. Immediately before the experiment, animals were anesthetized with pentobarbital . Anesthesia was maintained throughout the experiment. Indwelling catheters were inserted into the jugular vein and carotid artery. Test compound was dissolved as a 80 mM stock solution in vehicle (2% ethanoi: 98% PEG 400, Sigma Chemical Company, St. Louis, Missouri, USA). At the start of the experiment all animals received 0.2 ml of a solution containing [³H]CE-HDL into the jugular vein. [³H]CE-HDL is a preparation of human HDL containing tritium-labeled cholesteryl ester, and was prepared according to the method of Glenn et al . (Meth. Enzymol., 263, 339-351 (1996)). After 2 minutes, animals received 0.1 ml of the test solution injected into the jugular vein. Control animals received 0.1 ml of the vehicle solution without test compound. After 5 minutes, the first blood samples (0.5 ml) were taken from the carotid artery and collected in standard microtainer tubes containing ethylenediame tetraacetic acid. Saline (0.5 ml) was injected to flush the catheter and replace blood volume. Subsequent blood samples were taken at two hours and four hours by the same method. Blood samples were mixed well and kept on ice until the completion of the experiment. Plasma was obtained by centrifugation of the blood samples at 4° C. The plasma (50 μl) was treated with 5 μl of precipitating reagent (dextran sulfate, 10 g/1; 0.5 M magnesium chloride) to remove VLDL/LDL. After centrifugation, the resulting supernatant (25 μl) containing the HDL was analyzed for radioactivity using a liquid scintillation counter. The percentage [³H]CE transferred from HDL to LDL and VLDL (% transfer) was calculated based on the total radioactivity in equivalent serum samples before precipitation. Typically, the amount of transfer from HDL to LDL and VLDL in control animals was 20 to 35% after 4 hours. The polyethylene glycol vehicle was determined to have no effect on CETP activity in this model.

Table 6 shows the results of experiments utilizing compounds of the present invention. Student t tests were performed to determine if the means for control and treated animals were statistically different. Values of p < 0.01 for both sets of data indicate that the differences are highly significant. The term "ND" means not determined.

1036

TABLE 6

30 c 5 n-C₁₃H₂₇- 2-CH3θ-CgH₄- -SH 7 70 r m ι 6 π-Cι₃H₂₇- 3-CH3-C6H₄- -SH 7 150

7 n-C₁₃H₂₇- cyclohexyl- -SH 7 >500

8 n-Cι₃H₂7- 4-F-C6H - -SH 8 200

15 9 n-Cι₃H₂₇- 4-C6H5θ-C6H₄- -SH 8 500

10 n-C₆Hi₃CC(CH₂)5- 3-CH3θ-CδH₄- -SH 8 >200

11 π-Cι₃H₂₇- 3-F-CeH₄- -SH 9 90

036

TABLE 6 (cont.)

5 Example Ri R² R³ CETP Human Serum

No. IC50 (μM) IC₅₀(μM)

3 17 π-Ci3H₂₇- 4-Cl-2-CH₃-C6H₃- -SH 10 >500 c r- m 18 n-Cl3H₂7- 2-CH3S-C6H - -SH 10 >200 ro

B

19 n-Ci3H₂₇- 4-C₆H₅CH₂0-C₆H - -SH 15 >500

15 20 π-Cι₃H₂₇- 2 -naphthyl - -SH 15 ND

21 n-Cι₃H₂₇- 4-Cl-C6H₄- -SH 15 ND

22 CH₃(CH₂)₆S(CH₂)₅- 3-CH3θ-C6H₄- -SH 15 ND

036

ACTIVITY TABLE 6 (cont.)

Example R¹ R² R³ CETP Human Serum No. IC₅₀ (μM) IC₅₀(μM)

c CO 23 HCC(CH₂)n- 3-CH3θ-C6H₄- -SH 15 ND

00

CO

H 24 π-Ci3H₂7- 3-CH3-C6H₄- •HNO3 -H 20 >500

H

C H m 25 π-Cl3H 7- 4-CH3-3-CI-C6H3- -SH 20 500

Sfj 10 26 n-Ci3H₂₇- 4-CH3θ-C6H - •HNO3 -H 20 ND m m

27 n-Cι₃H₂7- 2-CH₃0-C6H₄- • HNO3 -H 20 ND

r c m- 28 n-Ci₃H₂7- 4-CF3-C6H₄- -SH 20 ND

CO 29 CH₃(CH₂)ι₀OCH₂- 3-CH3θ-C6H - -SH 20 ND

30 π-Cι₄H₂₉- 3-CH₃0-C6H₄- -SH 25 ND

15 31 «-Cl₂H₂₅- 3-CH₃0-C6H₄- -SH 25 ND

32 n-Cl3H₂7- C6H5- -SH 30 >500

33 n-Cι₃H₂₇- 2 -naphthyl - •HNO3 -H 30 ND

1036

TABLE 6 (cont.)

Example Rⁱ R² R³ CETP Human Serum No. IC₅₀ (μM) IC ₀(μM) c CO

34 4-(n-C₈Hι₇)C₆H CH2- 3-CH₃0-C6H₄- -SH 35 ND

00 CO

H

H 35 12-C11H23- 3-CH3θ-C6H₄- -SH 35 ND

C H m 36 "-C13H27- 3-C6H5CH₂OC6H₄- -SH 40 ND

CO rπ 10 37 CH₃CH₂S(CH₂)ιo- 3-CH3θ-C6H₄- -SH 40 ND m

H

38 CH₃(CH₂)ι₀SCH₂- 3-CH3O-C6H4- -SH 40 ND c r- rπ 39 π-Cι₃H₂7- 3,4-(OCH₂0)-C₆H₃- -H 45 ND

10 at • HNO3 40 π-Cι₃H₂₇- 3,5-(CH₃0)₂-C₆H3- -SH 50 ND

41 11-C13H27- 3-pyridyl- -SH 50 ND

15 42 n-Cι₃H₂₇- 2-CH3CH₂0-C6H₄- -SH 50 ND

43 n-Cι₃H₂7- 2,6-(CH₃)₂-C₆H3- -SH 50 ND

44 n-Cι₅H₃ι- 3-CH3θ-C6H₄- -SH 50 ND

J036

TABLE 6 (cont.)

5 Example R¹ R² R³ CETP Human Serum

No. IC₅₀ (μM) IC₅₀(μM)

CO c 783 4- (π-C oH₂ιbenzyl) - 3-CH₃0-C6H₄- -SH 4.5 ND

00 CO

H 784 4- (rj-CgH gbenzyl) - 3-CH₃0-C6H₄- -SH 6 ND

H C H 785 4- (π-C7H 5benzyl) - 3-CH₃0-C6H₄- -SH 6 ND m co 4-(n-C₈Hi7)C₆H₄OCH₂- 3-CH₃0-C6H - -SH 15 ND x 10 789 m m 790 4-(n-C₇Hi5)C₆H OCH₂-- 3-CH₃0-C6H₄- -SH 20 ND

30 4-(n-C₆Hι₃)C₆H OCH₂- 3-CH₃0-C6H₄- -SH 25 ND c 791 ι- rπ 794 4-(n-C₈Hi7)C6H (CH₂₎3- 3-CH₃0-C6H₄- -SH 4 ND

NJ 795 4-(n-C₇Hι₅)C6H (CH₂)3- 3-CH₃0-C6H - -SH 7.5 ND

15 796 4-(n-C₆Hi3)C₆H (CH₂)3- 3-CH₃0-C6H₄- -SH 20 ND

Also embraced within this invention is a class of pharmaceutical compositions comprising the active 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 active 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 active compounds and composition may, for example, be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically. The phrase "co-therapy" (or "combination-therapy"), in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co- administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent . The compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in co-therapy with one or more cardiovascular agents , such as compounds that lower serum cholesterol concentrations including inhibitors of cholesterol biosynthesis such as H G-CoA reductase inhibitors such as the statins (atorvastatin, cerivastatin, pravastatin, simvastatin, fluvastatin and lovastatin) , inhibitors of squalene synthase, oxido squalene cyclase or inhibitors of other enzymes involved with cholesterol biosynthesis; inhibitors of the ileal bile acid transport protein (IBAT) , cholesterol absorption antagonists, ACAT inhibitors, bile acid sequestrants such as Cholestyramine and Cholestagel, fibrates such as Gemfibrozil, niacins such as Niaspan, and omega-3 fatty acids such as O acor. Compounds of the present invention can also be used in co-therapy with cardiovascular drugs that reduce hypertension such as Enalopril and Captopril, or with anti-diabetes drugs such as troglitazone, or with antithrombotic agents such as aspirin, warfarin, and glycoprotein Ilbllla antagonists such as Reopro, Xemilofiban and Orbofiban. The compounds of this invention can also be used in co-therapy with agents which lower serum triglyceride concentrations, including inhibitors of cholesterol biosynthesis such as HMG-CoA reductase inhibitors such as the statins (atorvastatin) , fibrates such as Gemfibrozil, niacins such as Niaspan, and omega-3 fatty acids such as Omacor. The phrase "therapeutically-effective" is intended to qualify the amount of each agent which will achieve the goal of improvement in disease severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.

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 . 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 .

The amount of therapeutically active compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely.

The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 2000 mg, and preferably in the range of about 0.5 to 500 mg. A daily dose of about 0.01 to 100 mg/kg body weight, and preferably between about 0.5 and about 20 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day.

The compounds may be formulated in topical ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1, 3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof . The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas . Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane .

The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier (s) with or without stabilizer (s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so- called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also include .eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients . The antiinflammatory active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w.

For therapeutic purposes, the active compounds of this combination 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, ethanoi, 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 .

All mentioned references are incorporated by reference as if here written.

Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations .

Claims

What is claimed is

1. A compound of Formula I

wherein R¹ is selected from higher alkyl, higher alkenyl, higher alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl , arylthioalkyl , and cycloalkylalkyl ; wherein R² is selected from aryl, heteroaryl, cycloalkyi, and cycloalkenyl, wherein R is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halo, aryloxy, aralkyloxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylamino and dialkylamino; and wherein R³ is selected from hydrido, -SH and halo; provided R² cannot be phenyl or 4-methylphenyl when R is higher alkyl and when R is -SH; or a pharmaceutically-acceptable salt or tautomer thereof.

2. A compound of Claim 1 wherein R is selected from C╬╣o-i5 alkyl, C╬╣o-₁₅ alkenyl, C╬╣o-15 alkynyl, aryl, aryl-C╬╣-12-alkyl, aryloxy-C╬╣-C╬╣₂-alkyl, arylthio-C╬╣-C╬╣₂- alkyl, higher alkoxyalkyl, higher alkylthioalkyl, and eyeloalkyl-C╬╣-╬╣₂-alkyl; wherein R² is selected from aryl, 5-6 membered heteroaryl, lower cycloalkyi and lower cycloalkenyl, wherein R² is optionally substituted at a substitutable position with one or more radicals independently selected from lower alkyl, lower alkoxy, halo, lower haloalkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, aryloxy, lower aralkoxy, aryl, lower aralkyl, aminosulfonyl, amino, lower monoalkylamino and lower dialkylamino; and wherein R³ is selected from -SH, chloro and hydrido; or a pharmaceutically-acceptable salt or tautomer thereof.

3. A compound of Claim 2 wherein R¹ is selected from tridecyl, undecyl, dodecyl, tetradecyl, pentadecyl, (heptylthio) pentyl , methoxyundecyl, dodecynyl, tridecynyl, tetradecynyl, (heptylphenyl ) methyl , (octylphenyl) ethyl , (nonylphenyl ) methyl , (decylphenyl) methyl , (hexylphenoxy) methyl , ( octylphenoxy) methyl , he tylphenyoxy) methyl, (hexylphenyl) propyl, (octylphenyl ) propyl , (heptylphenyl ) propyl , decylthiomethyl, undecylthiomethyl, ethylthiodecyl, and (undecyloxy) methyl; wherein R is selected from cyclohexyl, naphthyl, pyridyl, and phenyl, wherein R² is optionally substituted at a substitutable position with one or more radicals independently selected from lower alkyl, lower alkoxy, halo, lower haloalkyl, phenoxy, methylenedioxy, benzyloxy, lower alkylthio, and lower dialkylamino; and wherein R is SH; or a pharmaceutically acceptable salt or tautomer thereof.

4. A compound of Claim 3 wherein R¹ is selected from undecyl, dodecyl, tridecyl, tetradecyl , pentadecyl , tridecynyl , (heptylphenyl) methyl, (octylphenyl) ethyl,

(nonylphenyl ) methyl , (decylphenyl) methyl ,

(heptylphenyl) propyl and (octylphenyl) propyl; wherein R² is selected from cyclohexyl, naphthyl, and phenyl, wherein R² is substituted by one or more radicals independently selected from methyl, fluoro, chloro, methylthio, benzyloxy, phenoxy, methoxy, ethoxy, methylenedioxy, and trifluoromethyl; and wherein R³ is SH; or a pharmaceutically acceptable salt or tautomer thereof .

5. A compound of Claim 1 selected from compounds and their pharmaceutically acceptable salts and tautomer of the group consisting of:

2 , 4-dihydro-4- (3-methoxyphenyl) -5-tridecyl-3H-l, 2 , 4-triazole- 3-thione;

2, 4-dihydro-4- (2-fluorophenyl) -5-tridecyl-3H-l, 2 , 4-triazole-3- thione; 2, 4-dihydro-4- (2-methylphenyl) -5-tridecyl-3H-l, 2, 4-triazole-3- thione; 2,4-dihydro-4-(3-chlorophenyl) -5-tridecyl-3H-l, 2 , 4-triazole-3- thione; 2, 4-dihydro-4- (2-methoxyphenyl) -5-tridecyl-3H-l, 2 , 4-triazole-

3-thione; 2,4-dihydro-4-(3-methylphenyl)-5-tridecyl-3H-l,2,4-triazole-3- thione;

4-cyclohexyl-2 , 4-dihydro-5-tridecyl-3H-l , 2 , 4-triazole-3- t ione; 2,4-dihydro-4-(3-pyridyl) -5-tridecyl-3H-l, 2 , 4-triazole-3- thione; 2,4-dihydro-4-(2-ethoxyphenyl)-5-tridecyl-3H-l,2,4-triazole-3- thione; 2 , 4-dihydro-4- (2 , 6-dimethylphenyl) -5-tridecyl-3H-l ,2,4- triazole-3-thione; 2,4-dihydro-4- (4-phenoxyphenyl) -5-tridecyl-3H-l, 2, 4-triazole- 3-thione;

4- (1, 3-benzodioxol-5-yl) -2 , 4-dihydro-5-tridecyl-3H-l, 2, 4- triazole-3 -thione ; 4- (2-chlorophenyl) -2 , 4-dihydro-5-tridecyl-3H-l , 2 , 4-triazole-3- thione; 2 , 4-dihydro-4- (4 -methoxyphenyl) -5-tridecyl-3H-l , 2 , 4-triazole- 3 -thione; , 4-dihydro-5-tridecyl-4- (3-trifluoromethylphenyl) -3H-1,2, 4- triazole-3- hione; , 4-dihydro-5-tridecyl-4-(3-fluorophenyl) -3H-1, 2 , 4-triazole-3- thione; - (3-chloro-4-methylphenyl) -2 , 4-dihydro-5-tridecyl-3H-1, 2 , 4- triazole-3-thione; , 4-dihydro-4- (2-methylthiophenyl) -5-tridecyl-3H-l, 2 , 4- triazole-3-thione; -(4-benzyloxyphenyl) -2, 4-dihydro-5-tridecyl-3H-l, 2,4- triazole-3-thione,^Γûá ,4-dihydro-4-(2-naphthyl)-5-tridecyl-3H-l,2,4-triazole-3- thione; , 4-dihydro-5-tridecyl-4- (4-trifluoromethylphenyl) -3H-1, 2 , 4- triazole-3-thione; ,4-dihydro-4-(l-naphthyl) -5-tridecyl-3H-l, 2 , 4-triazole-3- thione; ,4-dihydro-4-(3-methylthiophenyl) -5-tridecyl-3H-l, 2 , 4- triazole-3-thione; , 4-dihydro-4- (4-methylthiophenyl) -5-tridecyl-3H-l , 2 , 4- triazole-3-thione; , 4-dihydro-4- (3 , 4-dimethoxyphenyl) -5-tridecyl-3H-l, 2 , 4- triazole-3-thione; ,4-dihydro-4-(2,5-dimethoxyphenyl) -5-tridecyl-3H-l, 2 , 4- triazole-3-thione; ,4-dihydro-4-(2-methoxy-5-chlorophenyl) -5-tridecyl-3H-l, 2 , 4- triazole-3-thione; - (4-aminosulfonylphenyl) -2 , 4-dihydro-5-tridecyl-3H-l, 2 , 4- triazole-3-thione; ,4-dihydro-5-dodecyl-4-(3-methoxyphenyl)-3H-l, 2,4-triazole-3- thione; , 4-dihydro-4- (3-methoxyphenyl) -5-tetradecyl-3H-l, 2 , 4- triazole-3-thione; , 4-dihydro-4-(3-methoxyphenyl) -5-undecyl-3H-1, 2 , 4-triazole-3- thione; and ,4-dihydro-(4-methoxyphenyl) -5-pentadecyl-3H-l, 2 , 4-triazole- 3-thione.

6. A compound of Claim 3 wherein R¹ is selected from (heptylthio) pentyl, tridecynyl, (undecyloxy) methyl , ethylthiodecyl, (heptylphenyl ) methyl , (octylphenyl) methyl, ( onylphenyl ) methyl , (decylphenyl ) methyl , (heptylphenyl) propyl, (octylphenyl) propyl, and undecylthiomethyl; wherein R² is methoxyphenyl; and wherein R³ is -SH; or a pharmaceutically acceptable salt or tautomer thereof.

7. A compound of Claim 6 selected from compounds and pharmaceutically acceptable salts thereof of the group consisting of:

2, 4-dihydro-5- (heptylthio)pentyl-4- (3-methoxyphenyl) -3H-1,2, 4- triazole-3-thione; 2, 4-dihydro-4- (3 -methoxyphenyl) -5- ( tridecyn-12-yl) -3H-1, 2, 4- triazole-3 -thione;

2 , 4-dihydro-4- (3 -methoxyphenyl) -5- ( tridec-6-ynyl] -3H-1, 2 , 4- triazole-3-thione; 2, 4-dihydro-4- (3-methoxyphenyl) -5- (undecyloxy) methyl-3H-l, 2 , 4- triazole-3 -thione; 2 , 4-dihydro-5- (ethylthio) decyl-4- (3 -methoxyphenyl) -3H-1, 2 , 4- triazole-3-thione; 2, 4-dihydro-4- (3-methoxyphenyl) -5- (4-octylphenyl)methyl-3H-

1,2, 4-triazole-3-thione; 2, 4-dihydro-5- (4-heptylphenyl) ethyl-4- ( 3 -methoxyphenyl ) -3H- 1, 2, 4-triazole-3-thione;

2, 4-dihydro-5- (4-nonylphenyl ) methyl-4- (3 -methoxyphenyl) -3H-

1,2, 4-triazole-3-thione; 5- (4-decylphenyl)methyl-2, 4-dihydro-4- (3 -methoxyphenyl) -3H-

1,2, 4-triazole-3 -thione; 2, 4-dihydro-5- (4-hexylphenoxy)methyl-4- ( 3 -methoxyphenyl ) -3H-

1,2, 4-triazole-3-thione; 2 , 4-dihydro-5- (4-heptylphenoxy)methyl-4- ( 3 -methoxyphenyl ) -3H-

1,2, 4-triazole-3-thione; 2 , 4-dihydro-5- (4-octylphenoxy)methyl-4- (3 -methoxyphenyl) -3H- 1, 2, 4-triazole-3-thione; 2, 4-dihydro-5- (4-hexylphenyl) ropyl-4- (3 -methoxyphenyl) -3H-

1,2, 4-triazole-3-thione; 2, 4-dihydro-5- (4-heptylphenyl) propyl-4- (3 -methoxyphenyl) -3H-

1, 2, 4-triazole-3 -thione; and 2, 4-dihydro-5- ( 4-octylphenyl ) propyl-4- (3 -methoxyphenyl) -3H-

1,2, 4-triazole-3 -thione.

8. A compound of Claim 3 wherein R¹ is tridecyl; wherein R² is selected from naphthyl, methylphenyl, methoxyphenyl, and benzodioxolyl; and wherein R³ is hydrido; or a pharmaceutically acceptable salt or tautomer thereof.

9. A compound of Claim 8 selected from compounds, and tautomers of the group consisting of:

4- (2-naphthyl) -3-tridecyl-4H-l, 2 , 4-triazole, nitrate; 4- (3 -methylphenyl) -3-tridecyl-4H-l, 2 , 4-triazole, nitrate; 4- (3-methoxyphenyl) -3-tridecyl-4H-l, 2, 4-triazole, nitrate; 4- (4-methoxyphenyl) -3-tridecyl-4H-l, 2 , 4-triazole, nitrate; 4- (2-methoxyphenyl) -3-tridecyl-4H-1, 2, 4-triazole, nitrate; and 4- ( 1 , 3 -benzodioxol-5-yl ) -3 -tridecyl-4H-l , 2 , 4-triazole, nitrate.

10. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compounds selected from a family of compounds of Claim 1.

11. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compounds selected from a family of compounds of Claim 2.

12. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compounds selected from a family of compounds of Claim 3.

13. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compounds selected from a family of compounds of Claim 4.

14. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compounds selected from a family of compounds of Claim 5.

15. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compounds selected from a family of compounds of Claim 6.

16. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compounds selected from a family of compounds of Claim 7.

17. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compounds selected from a family of compounds of Claim 8.

18. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compounds selected from a family of compounds of Claim 9.

19. A method for treatment and prophylaxis of coronary artery disease comprising administering to the subject a therapeutically-effective amount of a compound of Formula I'

wherein R¹ is selected from higher alkyl, higher alkenyl, higher alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, and cycloalkylalkyl ; wherein R² is selected from aryl, heteroaryl, cycloalkyi, and cycloalkenyl, wherein R is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halo, aryloxy, aralkyloxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylamino and dialkylamino; and wherein R³ is selected from hydrido, -SH and halo; provided R² cannot be phenyl when R is tridecyl and when R is SH; or a pharmaceutically-acceptable salt or tautomer thereof .

20 A method for increasing plasma levels of low density lipoproteins and decreasing plasma levels of high density lipoproteins by administering to the subject a therapeutically effective amount of a compound of Formula I'

wherein R¹ is selected from higher alkyl, higher alkenyl, higher alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, and cycloalkylalkyl ; wherein R² is selected from aryl, heteroaryl, cycloalkyi, and cycloalkenyl, wherein R is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halo, aryloxy, aralkyloxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylamino and dialkylamino; and wherein R³ is selected from hydrido, -SH and halo; provided R² cannot be phenyl when R is tridecyl and when R³ is SH; or a pharmaceutically-acceptable salt or tautomer thereof .

21. A method for inhibiting the activity of cholesteryl ester transfer protein in vivo by administering to the subject a therapeutically effective amount of a compound of Formula I'

wherein R¹ is selected from higher alkyl, higher alkenyl, higher alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, and cycloalkylalkyl ; wherein R² is selected from aryl, heteroaryl, cycloalkyi, and cycloalkenyl, wherein R is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halo, aryloxy, aralkyloxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylamino and dialkylamino; and wherein R³ is selected from hydrido, -SH and halo; provided R² cannot be phenyl when R is tridecyl and when R³ is SH; or a pharmaceutically-acceptable salt or tautomer thereof .