[go: up one dir, main page]

GB2062622A - Aniline Derivatives - Google Patents

Aniline Derivatives Download PDF

Info

Publication number
GB2062622A
GB2062622A GB7938541A GB7938541A GB2062622A GB 2062622 A GB2062622 A GB 2062622A GB 7938541 A GB7938541 A GB 7938541A GB 7938541 A GB7938541 A GB 7938541A GB 2062622 A GB2062622 A GB 2062622A
Authority
GB
United Kingdom
Prior art keywords
acid
compound according
amino
loweralkyl
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
GB7938541A
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth Holdings LLC
Original Assignee
American Cyanamid Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Priority to GB7938541A priority Critical patent/GB2062622A/en
Publication of GB2062622A publication Critical patent/GB2062622A/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
    • C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Hypolipidemic and atherosclerotic compounds have the formulae <IMAGE> wherein R' is a branched or unbranched mono- or polyunsaturated or cyclopropylated C3-C22 alkyl group; R is H or a group convertible thereto in vivo; Z is a> <IMAGE> wherein D is H, OH or a substituted or unsubstituted loweralkyl, loweralkoxy, benzyloxy, phenoxy or 3-pyridyloxy (substituents defined in the specification) b> <IMAGE> wherein B is a saturated or unsaturated lower alkylene group and E is selected from hydrogen, loweralkyl, loweralkoxyethyl, diloweralkylaminoethyl, (mono- or polyhydroxy) loweralkyl, (mono- or polycarboxy) loweralkyl, (mono- or polycarboxy) hydroxyloweralkyl, allyl, 2,3-epoxypropyl, substituted or unsubstituted (phenyl, benzyl or 3- pyridyl), pyridylmethyl, and tetrahydropyranyl; or c> <IMAGE> wherein R4 and R5 are selected from H or certain specified hydrocarbon, oxygen-, sulphur- or nitrogen- containing groups or may together form specified rings; and R6 and R7 are the same or different and are selected from loweralkyl, (mono- and polyhydroxy) loweralkyl, carboxyloweralkyl, sulfo loweralkyl, sodium sulfo loweralkyl, and, when taken together, loweralkylene; and include the pharmaceutically acceptable salts thereof.

Description

SPECIFICATION Anti-atherosclerotic Agents Brief Summary of the Invention This invention relates to new organic compounds and more particularly, is concerned with novel 2- or 3-(alkenylamino, cyclopropylalkylamino, and alkynylamino)phenyl compounds and derivatives which may be represented by the following structural formula:
wherein R' is a branched or unbranched mono- or poly-unsaturated or cyclopropylated C3-C22 alkyl group and can be represented by the formula::
wherein R2 and R3 are the same or different and are hydrogen or a saturated or unsaturated C, to C9 alkyl group; Z is
wherein D is selected from the group consisting of hydrogen, hydroxy, loweralkyl, a loweralkoxy group unsubstituted or substituted with one or more moieties selected from the group consisting of hydroxy, carboxyl, carboloweralkoxy, carboxamido, N,N-dilowera Ikylcarboxamido, cyano, diloweralkylamino, piperazino or polymethyleneimino (ring size 58) group; a benzyloxy group unsubstituted or substituted with at least one halogen or carboxy group; a phenoxy moiety unsubstituted or substituted with at least one halogen, carboxy, carboloweralkoxy loweralkyl, carboxamido, loweralkoxy or cyano group; or a 3-pyridyloxy group unsubstituted or substituted with a loweralkyl group, halogen, cyano, carboxyl, carboloweralkoxy, loweralkoxy or hydroxy group; and loweralkyl bearing one or more carboxy, carboloweralkoxy, carbamoyl, acyl, sulfinyl or sulfonyl groups;
wherein B is a saturated or unsaturated lower alkylene group and E is selected from the group consisting of hydrogen, loweralkyl, loweralkoxyethyl, diloweralkylaminoethyl, (mono- or polyhydroxy)lowera Ikyl, (mono- or polycarboxy) loweralkyl, (mono- or polycarboxy)hydroxyloweralkyl, allyl, 2,3-epoxypropyl, substituted or unsubstituted (phenyl, benzyl, or 3-pyridyl), pyridylmethyl, and tetrahydropyranyl; or
wherein R4 is selected from the group consisting of hydrogen, carboxyloweralkyl, carboalkoxyloweralkyl, lowerallkanoyl, loweralknesulfonyl, arylsulfonyl, sodium sulfo loweralkyl, sulfo loweralkyl, loweralkenyl, loweralkynyl, phenylloweralkyl and -hydroxyloweralkyl; R5 is selected from the group consisting of hydrogen, lowerakyl, hydroxy, loweralkoxy, haloloweralkyl, phenyl, carboxyphenyl, chlorophenyl, sodium sulfophenyl, pyridyl, pyridyl loweralkyl, (mono- and polyhydroxy)lower alkyl, c9- loweralkoxyloweralkyl, cl)-di(loweralkyl)aminoloweralkyl, -piperidinoloweralkyl, a)- pyrrolidinohydroxylower alkyl, amino, loweralkanoylamino, loweralkanesulfonylamino, N-piperidyl, arylsulfonylamino, and 4-loweralkyl-1 -piperazino;R4 and R5 taken together with the associated nitrogen is selected from the group consisting of pyrrolidino, piperidino, morpholino, hexamethyleneimino, 4-(loweralkyl)piperidino, 4-loweralkyl-1 -piperazino, 4-phenylpiperazino, 3pyrrolinyl, A3-piperidino, 4-(carboethoxy or carboxy)-3-thiazolidinyl and 4-(ca rboethoxy)-3-oxazolidinyl; R6 and R7 are the same or different and are selected from the group consisting of loweralkyl, (monoand polyhydroxy)loweralkyl, carboxyloweralkyl, sulfo loweralkyl, sodium sulfo loweralkyl, and, when taken together, loweralkylene;R is selected from the group consisting of hydrogen, or a group convertible in vivo thereinto, such as methyl, carboxymethyl, acetyl, succinyl, 1 -(sodium sulfo)loweralkyl, 1 sodium sulfo)polyhydroxyalkyl and 1 ,3-bis-(sodium sulfo)-aralkyl; and wherein R1 is a:: Formula I-A) C2 to C21 E- orZ-alkenyl group unsubstituted or substituted with at least one lower alkyl group; Formula I-B) C2 to C20 alkynyl group unsubstituted or substituted with at least one methyl or ethyl group; Formula I-C) C4 to C20 alkyl group containing at least 2 non-cumulative double bonds, said group being unsubstituted or substituted with at least one methyl or ethyl group; Formula I-D) C3 to C,2 allenyl group unsubstituted or substituted with at least one methyl or ethyl group; Formula l-E) vinyl or C3 to C8 E- orZ-alkenyl group said vinyl or alkenyl group being unsubstituted or substituted with at least one methyl group, and in this Formula l-E, R2 is a vinyl or C3 to C9 E- orZ-alkenyl group unsubstituted or substituted with at least one methyl group;; Formula I-F) allyl or C4 to C8E-orZ-alkenyl group said allyl oralkenyl group being substituted with at least one exo-(methylene, ethylidene, or isopropylidene), and either further unsubstituted or substituted with at least one methyl group; Formula I-G) vinyl or C3 to C9 E- orZ-alkenyl group substituted between the nitrogen and the double bond with at least one loweralkenyl said vinyl or alkenyl group being unsubstituted or substituted with at least one methyl group; Formula I-H) vinyl C3 to C9 E- orZ-alkenyl group said vinyl or alkenyl group being unsubstituted or substituted with at least one methyl and in this case, R2 is a C2 to C9 alkynyl group unsubstituted or substituted with at least one methyl group;; Formula I-I) C4 to C20 alkyl group containing at least one carbon-carbon double bond and at least one carbon-carbon triple bond said group being unsubstituted or substituted with at least one loweralkyl group; or wherein R' is a: Formula l-J) group of the formula
wherein R1, is hydrogen or a C, to C15 alkyl group unsubstituted or substituted with at least one methyl group, P10 is hydrogen or methyl and X is a bond or a C, to C15 branched or unbranched alkylene group unsubstituted or substituted with at least one methyl group; and the pharmaceutically acceptable non-toxic acid addition and cationic salts thereof.
The loweralkyl, loweralkenyl, loweralkynyl, loweralkoxy, loweralkanoyl, and loweralkanesulfonyl groups referred to herein contain 1 to 6 carbon atoms and are optionally unbranched or branched. The polyhydroxy and polycarboxy groups referred to above contain 2 to 4 hydroxy or carboxy groups, respectively.
Preferred compounds of Formula I, including preferred compounds of Formulas I-A through l-J are described below.
Preferred compounds of Formula I are those wherein Z is:
wherein R4 is a loweralkyl group substituted with at least one hydroxyl group, allyl, propargyl, 2 sulfoethyl, (CH2)rnC00P9 wherein m is 2-4 and P9 is hydrogen or a loweralkyl, group,
wherein Rl2 is a loweralkyl or aryl group, -S02P12,
or a -NHS02-P12 group; n is one of the integers 4, 5 and 6 and R,3 is hydrogen or at least one methyl group.
Also preferred are compounds of Formula I wherein Z is the moiety
wherein R6 and R7 are as previously defined.
Additionally preferred compounds of Formula I are those where D is hydroxy; a ioweralkoxy group unsubstituted or substituted with one or more carboxyl, hydroxyl, diloweralkylamino or polymethyleneimino (ring size 5-8) groups; a benzyloxy or phenoxy group which is unsubstituted or substituted with at least one halogen or carboxyl group; or 3-pyridyloxy.
Preferred compounds of Formula I are those wherein Ris hydrogen, R2 and R3 are hydrogen or methyl.
Preferred compounds of Formula I-A are those wherein P1 is a vinyl or C3 to C21 E- orZ-alkenyl group said vinyl or alkenyl group being unsubstituted or substituted with at least one methyl group; the most preferred compounds of Formula I-A are those wherein P1 is a C7 to C15E- orZ-alkenyl group; and the most preferred of these are those in which R, R2 and R3 are hydrogen.
Preferred compounds of Formula I-B are those wherein R2 and R3 are methyl; even more preferred compounds of Formula I-B are those wherein P1 is C2 to C,8 alkynyl and most preferred are those wherein P1 is C7 to C,8 alkynyl; and the most preferred of these are those wherein R, R2 and R3 are hydrogen.
Preferred compounds of formula I-C are those wherein R2 and R3 are hydrogen or a loweralkyl group and those compounds of Formula I-C wherein P1 is C4 to C19 alkyl group containing at least two non-cumulative double bonds; and most preferred of these are those wherein R, R2 and R3 are hydrogen.
Preferred compounds of Formula l-D are those wherein R2 is methyl; more preferred compounds are those of Formula l-D wherein P1 is a C3 to C,2 allenyl group and the other groups are as defined above; and the most preferred of these are those wherein R, R2 and R3 are hydrogen.
Preferred compounds of Formula l-E are those wherein P1 is a C2 or C3 alkenyl group; and the most preferred of these are those wherein R, R2 and R3 are hydrogen.
Particularly preferred compounds of Formula I-F are those wherein R, R2 and R3 are hydrogen.
Particularly preferred compounds of Formula l-G are those wherein R, R2 and R3 are hydrogen.
Particularly preferred compounds of Formula I-H are those wherein R, R2 and R3 are hydrogen; more preferred compounds are those wherein P1 is a loweralkenyl or lower alkynyl group.
Particularly preferred compounds of Formula I-I are those wherein R2 and R3 are the same or different and each is hydrogen or methyl. More preferred compounds of Formula I-I are those wherein R3 and/or R2 is hydrogen; and other preferred compounds of Formula I-I are those wherein P1 is a C4 to C13 alkyl group containing at least one carbon-carbon double bond and at least one carbon-carbon triple bond. Most preferred compounds of Formula I-I are those wherein P1 is a C9 to C,8 alkyl group containing at least one carbon-carbon double bond and at least one carbon-carbon triple bond.
Particularly preferred compounds of Formula l-J are those wherein R,Ois hydrogen. Most preferred compounds of Formula l-J are those wherein R, and Rro are hydrogen.
Suitable keto-acids and keto-esters contemplated by the present invention are those in which the group D is selected from the group consisting of carboxymethyl; carboxyethyl; 2-carboethoxy-2-propyl; dicarboethoxymethyl; carboethoxyvinyl and the like. Suitable alkanoic, alkenoic and alkynoic acids and esters are those in which the radical Z is selected from the group consisting of 4-carboxybutyl; 2carboethoxyethyl; 2-carboxyvinyl, 2-carboethoxyethynyl, and the like.
The invention also pertains to novel compositions of matter useful as antiatherosclerotic agents and to methods of ameliorating atherosclerosis by counteracting hyperlipemia and arterial plaque formation in mammals therewith; the active ingredients of said compositions of matter being the novel 2-or 3-[(unsaturated or cyclopropylated alkyl)amino]phenyl compounds of the present invention.
These compounds may be utilized either as such or in the form of a pharmaceutically acceptable sa!t with an organic or inorganic acid or base. The invention also contemplates a method for lowering serum lipids and for ameliorating atherosclerosis in mammals by the administration of said compounds.
Background of the Invention Considerable effort has been directed in recent years to obtain substances useful in counteracting the consequences of hyperlipidemia, a condition involving elevated cholesterol, phospholipid and/or triglyceride levels in the blood, and of hyperlipoproteinemia, involving an imbalance of the lipoproteins. The most serious condition associated with hyperlipidemia and hyperlipoproteinimia is atherosclerosis, a form of arteriosclerosis characterized by lipid accumulation and thickening of the walls of both medium-sized and large arteries such as the aorta. Their walls are thereby weakened and the elasticity and effective internal size of the arteries decreased.Atherosclerosis, the most common cause of coronary artery disease, is of great medical importance since it tends to occlude those arteries supplying blood to the heart muscles and brain, thereby producing permanent damage to these organs.
Such damage may lead to ischemic heart disease, congestive heart failure, lifethreatening arrhythmias, senility, or stroke. Involvement of leg arteries may lead to gangrene and loss of the limb. It has been known for more than 100 years that cholesterol is a major component of atherosclerotic lesions or plaques. Investigators have been trying to determine the role of cholesterol in iesion initiation and development and also, more importantly, whether lesion formation can be prevented or reversed and enlargement of lesions be slowed or stopped. The earliest lesions are now known to be fatty streaks, largely of cholesterol, which often progress in stages to plaques containing cellular, fibrous and calcified material in addition to the lipids.
The evidence that hyperlipidemia is one of the factors involved in coronary heart disease is very impressive. A most important study carried out in Framingham, Mass. (Gordon and Verter, 1969) in over 5,000 persons for more than 12 years established a correlation between high concentrations of blood cholesterol and increased risk of heart attack. Although the causes of coronary artery disease are multiple, one of the most constant factors has been the elevated concentration of lipids in the blood plasma. A combined elevation of cholesterol and triglycerides have been shown (Carlson and Bottiger, 1972) to carry the highest risk of coronary heart disease. The majority of patients with ischemic heart disease or peripheral vascular disease were found to have hyperlipoproteinemia, involving very lowdensity and/or low-density lipoproteins (Lewis et al. 1974).
The reason for most treatment of hyperlipidemia or hyperlipoproteinemia is for arresting, reversing or preventing atherosclerosis. In the past, attempts have been made to lower the levels of cholesterol, phospholipids, and triglycerides in the blood by the oral feeding of various substances which have been generally referred to in the art as hypolipidemic agents or hypocholesteremic adjuvants. Typical of such substances are lecithin, pectin, cottonseed oil, and the mucilaginous substances listed in U.S. Patent No.3,148,114. In addition, several synthetic hypolipidemic agents are now available, namely clofibrate, D-thyroxine, cholestyramine, and nicotinic acid [Levy and Frederickson, Postgraduate Medicine 47, 130 (1 970)]. Clofibrate has the undesirable side-effect of causing hypertrophy of the liver in some patients.
The development of agents capable of reducing elevated blood lipids and of favorably altering blood-lipoprotein patterns is considered by medical authorities to be extremely important for the treatment and prevention of atherosclerosis.
Related compounds are the subject of my copending applications Serial No. 884,673, filed March 8, 1978 and Serial No. 8,641, filed February 1, 1979.
Detailed Description of the Invention The compounds of this invention are new and novel 2- or 3-[(unsaturated or cyclopropylated alkyl)amino]phenyl compounds and derivatives of Formula I (including Formulas I-A to l-J) which have useful biological and pharmacological properties. No hypolipidemic activity has been reported in the literature for these compounds and they are different in structure from other hypolipidemic agents. The compounds of this invention lower serum-lipid concentrations and also minimize atheroma formation in the aorta. These substances also provide the oral administration required for hypolipidemic agents, which patients usually take for many years. The novel compounds of this invention are adequately absorbed from the gastrointestinal tract.
We have now found that the compounds of the present invention can safely and effectively lower both serum sterols and triglycerides in warm-blooded mammals. Such actions on serum-lipid components are considered to be very useful in the treatment of atherosclerosis, especially in contrast to available drugs whose action is much more limited. For some time it has been considered desirable to lower serum-lipid levels and to correct lipoprotein imbalance in mammals as a preventive measure against atherosclerosis. The compounds of the present invention do not act by blocking late stages of cholesterol biosynthesis and thus do not produce accumulation of intermediates such as desmosterol, as equally undesirable as cholesterol itself.Compounds with the combination of therapeutically favorable characteristics possessed by those of the present invention can be safely administered to warm-blooded mammals for the treatment of hyperlipidemic and atherosclerotic states found in patients with or prone to heart attacks, to peripheral or cerebral vascular disease, and to stroke.
The novel compounds of the present invention are, in general, white crystalline solids having characteristic melting points and absorption spectra. They are soluble in organic solvents such as lower alkanol, cholorform, benzene, dimethylformamide, and the like, but are generally not very soluble in water. The novel compounds of the present invention, which are organic bases may be converted to their non-toxic acid-addition or cationic salts with a variety of pharmaceutically acceptable organic and inorganic salt-forming reagents. Thus, acid-addition salts may be formed by admixture of the organic free base in a neutral solvent with one or two equivalents of an acid such as sulfuric, phosphoric, hydrochloric, hydrobromic, trifluoroacetic, citric, ascorbic, and the like.Compounds which contain acidic groups form pharmaceutically acceptable cationic salts with organic or inorganic bases such as the alkali metal hydroxides, the alkaline earth metal hydroxides, and the like. The sodium or potassium salts which are formed in solution in the course of hydrolysis of their esters can be isolated as the solid alkali metal salts by cooling. Where it is desirable to purify a compound in the form of the acid, the salt is conveniently formed by treating its solution with exactly one equivalent of base and evaporation or lyophilization. Alkaline earth salts are prepared similarly, often using their acetate salts as a conveniently soluble form. Organic base salts such as those of N-methylglucamine are prepared by dissolving equimolar mounts of the acid and the base in hot ethanol or aqueous alcohols and cooling to crystallization.
The 2-or 3-[(unsaturated or cyclopropylated alkyl)amino]phenyl compounds of this invention are prepared by reaction of the corresponding 2- or 3-aminophenyl compounds with suitable alkylating agents, such as (unsaturated or cyclopropylated alkyl) halides, sulfates, tosylates, mesylates or trifluoromethylsulfonates, with or without a solvent at 25-1 500 C. Suitable solvents are lower alkanols, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, diglyme, dimethylsulfoxide, acetonitrile, toluene, benzene, hexamethylphosphoramide and like solvents.The reaction may be carried out with 2 equivalents of the unsubstituted amine compound or with only one equivalent and one equivalent of an unreactive organic base such as diisopropylethylamine or an alkali carbonate or bicarbonate, or with a catalytic amount of copper powder when an appropriate halide is used as the alkylating agent.
The N-acetyl-2- or 3-(substituted-amino)phenyl compounds are prepared by reaction of a corresponding 2- or 3-(acetylamino)phenyl compound with an appropriate (unsaturated or cyclopropylated alkyl) halide in the presence of an equivalent of sodium hydride in an inert solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or diglyme at 50-1 500 C. The N-acetyl compounds are readily hydrolyzed to the acids in boiling aqueous ethanolic dilute alkali or acid.
Alternative methods of preparation are by reductive alkylation of a 2- or 3-aminophenyl compound which may also be generated in situ by reduction of 2- or 3-amino precursors such as a 2or 3-nitro group and the like, or by a borohydride reduction of a 2- or 3-(acylamino)phenyl compound.
For example, a carbonylalkene such as an unsaturated ketone or aldehyde and ethyl 2aminophenyiacetate or methyl 2-amlnobenzoate and the like are reduced under 1-10 atmospheres of hydrogen using a suitable metal catalyst or with a metal hydride such as sodium borohydride forming the corresponding phenylacetic or benzoic acid and the like. Diborane reduction of 2- or 3 (cyclopropylalkanoylamino)phenyl compounds such as ethyl 2-or 3-(1 1 - cyclohexylundecanoylamino)phenylacetate at room temperature or above for 1-6 hours yields the corresponding 2- or 3-(cyclopropylalkylamino)phenyl compounds such as ethyl 3-( 11 - cyclopropylundecylamino)phenylacetate.The 2- or 3-(cyclopropylalkanoylamino)phenyl compounds used in these reductions are prepared by acylation of the appropriate 2- or 3-aminophenyl compounds with suitable acylating agents, such as cyclopropylalkanoyl halides. To prepare the 2- or 3 (substituted-amino)phenyl alkenoic and alkynoic acids it is advantageous to form the corresponding alkylchloromide from the 2- or 3-(acylamino)phenyl compounds using phosphorous oxychloride and base, and then reduce the alkylchloromide moiety to an alkylamino group with sodium borohydride.
The 2- or 3-(substituted amino)phenyl compounds of this invention are often prepared from the corresponding 2- or 3-aminophenyl compounds by the sequence involving esterification of any carboxyl group present with ethanol or methanol in the presence of boron trifluoride etherate, followed by alkylation of the amino function as described above. The free acids are then liberated by hydrolysis of the ester with aqueous alcoholic sodium hydroxide at 800 C. for 2-1 0 hours followed by acidification. The acids obtained by this procedure may be converted to the corresponding cationic salts. For example, the sodium salt may be prepared by reaction of the benzoic acid with sodium hydroxide in a mixture of ethanol and water.Alternatively, the free acids may be prepared by hydrolysis of the corresponding nitriles or various amides, imidates or oxazolines.
The 2- or 3-[(unsaturated or cyclopropylated alkyl)amino]phenyl compounds and derivatives are prepared by deacylation of the corresponding 2- or 3-[(N-trifluoroacetyl)-(unsaturated or cyclopropylated alkyl)amino]phenyl compounds by reacting with an alkali hydroxide such as sodium or potassium hydroxide in a lower alkanol, water or an aqueous lower alkanol at 50C. to 500C.
Alternatively, these compounds may be prepared by deacylation of the 2- or 3-(N-carbo-tbutoxyalkenylamino)phenyl compounds with mineral acids such as hydrochloric or hydrobromic acid, preferably in glacial acetic acid at OOC. to 500C. Also, they are prepared by removal of the carbobenzyloxy protecting group from the anilino nitrogen atom by means of mild catalytic hydrogenation or by treatment with a mineral acid such as hydrobromic acid in glacial acetic acid.
With certain kinds of substrates for amide formation, it is necessary to form the alkali metal or strong organic base salts of these substrates in order to react them with the various aforementioned acylating forms of the 2- or 3-[(unsaturated or cyclopropylated alkyl)amino]benzoic acids. The aminoalkanecarboxylic and aminoalkanesulfonic acids are zwitterionic and must be converted to their cationic salts, suitably in situ. They may also be used in the form of their esters and then hydrolyzed after amide formation. Certain substrates, which are neutral like the carboxamides or slightly acidic like the alkane or arene sulfonamides, are converted to reactive salts by reaction with sodium hydride or other basic reagents.
Alternatively the free acids may be prepared by hydrolysis of the corresponding nitriles or various amides, imidates or oxazolines. The carboxylic acid moiety may also be generated by oxidation of the corresponding aldehydes, acetophenones, benzyl alcohols, toluenes, most often with the use of an amine-protecting group such as trifluoroacetyl or t-butyloxycarbonyl.
The imidates of the present invention are preferably prepared either by addition of hydroxy compounds to the corresponding nitriles or by alkylation of the corresponding amides, suitably bearing a protecting group on the aromatic amino nitrogen atom in many cases. The addition of alcohols and other hydroxy compounds is carried out under acid catalysis without additional solvent, if possible.
Alkylation of the protonated substituted aminoamide may be carried out or the aforementioned amino protecting groups can be employed. In some cases, simultaneous O-alkylation of the amide and Nalkylation of the aromatic amino moiety can be used to obtain a desired imidate. Intramolecular formation of imidates results from 2-haloethyl and 3-halopropyl amides as well as from 2-hydroxyethyl and 3-hydroxypropyl amides when treated with a condensing agent.
Certain derivatives
of the aminophenyl nitrogen atom are useful for providing greater solubility, more uniform and reliable intestinal absorption, and for a certain degree of modification of the pharmacology of the compounds of the present invention. Some of these derivatives can be converted to the corresponding N-H forms by the acidity of the stomach or the alkalinity of the small intestine. Others are converted by metabolic processes. The methyl and carboxymethyl derivatives and the like are prepared by the alkylation, reductive alkylation, and acylamino reduction methods above. Derivatives such as the acetyl and succinyl compounds may be prepared using acetyl chloride, acetic anhydride, succinic anhydride, etc., in the presence of pyridine, triethylamine or the like at temperatures moderate enough to avoid acylation of the amide moiety.The 1sodium sulfo)alkyl derivatives are obtained by reaction of the 2or 3-[(unsaturated or cyclopropylated alkyl)amino]phenyl compound with sodium bisulfite and an aliphatic aldehyde, a polyhydroxyaldehyde such as glyceraldehyde or glucose, or cinnamaldehyde in a mixed organic aqueous medium. In the case of cinnamaldehyde, the di-sulfonate salts result from addition of the bisulfite to the carbon-nitrogen double bond of the anil intermediate as well as to the carbon-carbon double bond of cinnamaldehyde itself.
In certain cases, the unsaturation is introduced at a late stage of the preparation, of the 2- or 3 (unsaturated alkylamino)phenyl compounds. For example, a 2- or 3-(m-haloalkylamino)phenyl compound is dehydrohalogenated to the corresponding olefinic compound or, alternatively, it is converted to a Wittig trialkyiphosphonium reagent and reacted with an aldehyde to yield a product with an internal double bond. This w-halo substrate can also be reacted with an alkylacetylene sodium or lithium salt to form the corresponding 2- or 3-alkynylamino derivatives.
The carboxaldehydes of this invention may be prepared by several methods among which is alkylation of the corresponding acetals as described above followed by hydrolysis of the resulting 2- or 3-(substituted-amino)phenyl compound to the desired aldehyde. Aldehydes may also be prepared by reduction of the appropriate nitriles. For example, treatment of 2-(hex-3enylamino)hydrocinnamonitrile with stannic chloride and anhydrous hydrogen chloride gas, followed by hydrolysis in hot water provides 2-(hex-3-enylamino)hydrocinnamaldehyde. These reductions are also conveniently carried out with hydrides such as diisobutylaluminum hydride.
The a-substituted 2- or 3-(substituted-amino)-acetophenones of the invention are prepared by reaction of a derivative of the appropriate benzoic acid, such as 2- or pentadecenylamino)phenylacetyl chloride hydrochloride, with two or more equivalents of the reactive salt of an acidic methylene compound, for example the sodium salt of diethyl malonate. Other benzoic acid derivatives are also suitable for this reaction, such as an N-trifluoroacetyl or N-tert-butyloxycarbonyl acid chloride, or a methyl ester of the acid. In some cases the final step in the preparation of the a-substituted 2-or 3-(substituted-amino)acetophenone is the removal of the nitrogenprotecting group.In other cases, hydrolysis of one or more of the ester groups in the acylation product affords an unstable polycarboxylic acid which undergoes decarboxylation to aliow the preparation of another acetophenone derivative. For example, the reaction of tert-butyl ethyl [3-(4pentadecenylamino)benzoyl]malonate with trifluoroacetic acid affords ethyl [3-(4pentadecenylamino)benzoyl]acetate. In other cases, hydrolysis of one or more of the ester groups allows the preparation of the corresponding acid derivative. For example, the hydrolysis of ethyl [2 (hept-3-enylamino)benzoyl]acetate yields 2-(hept-3-enylamino)benzoylacetic acid.
An alternative procedure for preparing certain 2- or 3-(substituted-amino)acetophenones is alkylation of the corresponding 2- or 3-aminoacetophenone by the methods above. For example, alkylation of methyl 3-(3-aminobenzoyl)propionate with undec-10-enyl bromide yields methyl 3-[3 (undec-i 0-enylamino)benzoyljpropionate. The related carboxylic acids are then obtained by hydrolysis.
Certain of these acids are particularly useful for the preparation or 2- or 3-(substituted amino)phenylalkanoic acids by reduction. For example, the Clemmensen or Wolff-Kishner reduction of 3-[3-(hex-3-enylamino)benzoyl]propionic acid yields 4-[3-(hex-3-enylamino)phenyl]butyric acid.
The 2-or 3-(substituted-amino)phenylalkenoic acids may be prepared by condensation of the appropriate aldehydes or by dehydration of the corresponding substituted phenylhydroxyalkanoic acids.
For example, ethyl 5-[3-(undec-1 0-enylamino)phenyl]-2,4-pentadienoate is obtained by the Wittig reaction of 3-(undec-1 O-enylamino)benzaldehyde with the Wittig reagent, triethyl 4phosphonocrotonate. Alternatively, these alkenoic acids are obtained by heating a 2- or 3-[N,Ndisubstituted-amino]benzaldehyde and the like with the sodium salt of the carbanion of ethyl acetate or with a mixture of ethyl acetate, acetic anhydride and potassium acetate. The second method is illustrated by dehydration of ethyl 3-[2-(undec-10-enylamino)phenyl]-3-hydroxypropionate to the corresponding cinnamate.
The acetylenic analogs are prepared by dehydrobromination of the side-chain vic-dibrominated alkanoic acid. For example, dehydrobromination of ethyl 3-[3-(allylamino)phenyl]-2,3dibromopropionate, its isomers or N-acyl analogs or of ethyl 3-[3-(allylamino)phenyl]-3-bromoacrylate yields ethyl 3-(allylamino)phenylpropiolate. The acetylenic acids are also formed from (2- or 3substituted-amino)phenylacetylene metal salts by carboxylation with carbon dioxide.The 2- or 3 (substituted-amino)phenylacetylenes are also prepared by N-acylating with t-butyl azidoformate followed by conversion to the lithium acetylide salt and the subsequent reaction of the lithium salt with boron trifluoride etherate in tetrahydrofuran at -2O0C to form tris-[(2- or 3-substituted amino)phenylethynyl]boranes. The tetrahydrofuran solution of the borane is in turn reacted with ethyl diazoacetate, followed by water to yield ethyl 4-[(2- or 3-substituted-amino)phenyl]butynoate.
The 2- or 3-(substituted-amino)phenylalkanoic acids, or esters are also prepared by catalytic reduction at 1 to 10 atmospheres of hydrogen of the corresponding alkenoic or alkynoic acid derivatives. The 2- or 3-(substituted-amino)phenylalkenoic acids and derivatives are prepared by Friedel-Crafts acylation of the N-acyl-N-alkylanilines with the appropriate dicarboxylic acid anhydride or half acid chloride. The 2- or 3-(substituted-amino)-benzoylalkanoic acids or esters, obtained by this and by other syntheses, may be converted to the corresponding 2- or 3-(substitutedamino)phenylalkanoic acids by reduction with (a) hydrazine and alkali in diethylene glycol at 1400 for 3 hours, (b) zinc amalgam and ethanolic hydrochloric acid at 600 for 5 hours, (c) red phosphorus and hydriodic acid, or (d) ketalization with 1,2-ethanedithiol followed by Raney nickel desulfurization.The amides of these 2- or 3-(substitutedamino)phenylalkanoic acids are prepared by heating the corresponding 2- or 3-(substituted-amino)phenylalkyl ketones with aqueous alcoholic ammonium polysulfide followed by hydrolysis to yield the acids with the same number of carbon atoms as the ketone. These acids are also prepared by reacting a 2- or 3-(N-t-butyloxycarbonyl-N-substituted- amino)phenylmagnesium halide with 2-(3-halopropyl)-2-oxazolines, followed by mild acid removal of 2-oxazolinyl and t-butoxycarbonyl protecting groups. Similarly, the above Grignard reagent can be reacted with 3-bromotriethyl-orthopropionate in the presence of dilithium-tetrachlorocuprate to yield the desired acids after removal of the protecting groups from the amino and carboxyl groups.
The novel 2-or 3-(substituted-amino)phenyl compounds of the present invention are not only potent hypolipidemic agents but also prevent or diminish the formation or enlargement of arterial plaques in mammals when administered in amounts ranging from about one mg. to about 250 mg. per kilogram of body weight per day. A preferred dosage regimen for optimum results would be from about 5 mg. to about 100 mg. per kilogram of body weight per day, and such dosage units are employed that a total of from about 0.35 grams to about 7.0 grams of the active compound, for a subject of about 70 kg. of body weight, are administered in a 24 hour period. This dosage regimen may be adjusted to provide the optimum therapeutic response.For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A decided practical advantage of this invention is that the active compound may be administered in a convenient manner by the oral route. The compounds of the present invention exert a more powerful hypocholesteremic and antiatherosclerotic effect than the aforementioned adjuvants and synthetic medicaments. It is not known how these novel compounds operate in the blood serum and no theory of why these compounds so operate is advanced. It is not intended that the present invention should be limited to any particular mechanism of action of lowering serum lipids or of ameliorating atherosclerosis, or be limited to compounds acting by only one mechanism.
The active compounds of the present invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelaUn capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of the unit. The amount of active ingredient in such therapeutically useful compositions is such that a suitable dosage will be obtained.
Preferred compositions or preparations according to the present invention are prepared so that an oral dosage-unit form contains between about 50 and 250 milligrams of active compound.
The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate, a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage-unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills or capsules may be coated with shellac, sugar or both.A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye, and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage-unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active ingredients may be incorporated into sustained-release preparations and formulations.
The invention will be described in greater detail in conjunction with the following specific Examples.
Example 1 Preparation of 3-(allylamino)phenylacetic acid; (Method A) To a solution of 1 8.2 g. of ethyl 3-aminophenylacetate in 100 ml. of dimethylformamide is added a solution of 4.7 ml. of allyl bromide in 60 ml. of dimethylformamide. The solution is heated at 600 C.
for 5 hours and then cooled and partitioned between diethyl ether and water. The combined ether phases are washed with water, dried over magnesium sulfate, and concentrated in vacuo to provide 16.5 g. of a semi-solid. A portion (6 g.) is absorbed onto 30 g. of silica gel and chromatographed on 475 g. of silica gel to provide ester.
A mixture of the ester, 22.0 g. of potassium hydroxide and 200 ml. of ethanol-water (8:1) is stirred under reflux for 6 hours. Concentrated hydrochloric acid (about 80 ml.) is added to the warm mixture and cooling and dilution with water affords a white solid which is collected by filtration and recrystallized from ethanol to yield the product as a white solid.
Example 2 Preparation of 3-(1-pentadeca-4,14-dienylamino)benzoic acid; (Method B) To a solution of 4,1 4-pentadecadien-1 -ol (1 5.0 g.) and triethylamine (14 ml.) in dry methylene chloride (320 ml.) at -80C. is added methanesulfonylchloride (5.73 ml.), dropwise. The reaction mixture is stirred at --100C. for 30 minutes and then diluted with methylene chloride, extracted with ice-water (250 ml.);followed by cold 10% hydrochloric acid (200 m); cold saturated sodium bicarbonate (200 ml.) and cold brine (200 ml.). The organic phase is dried over magnesium sulfate and the solvent removed in vacuo to provide the crude mesylate.
A solution of 1 8.1 g. of the above mesylate and 1 9.8 g. of ethyl 3-aminobenzoate in hexamethylphosphoramide is heated at 1 200C. for 20 hours. After cooling, the reaction mixture is diluted with 30 ml. of ethanol:water (1 :1) (30 ml.) and chilled. More ethanol is added and the solid material is collected. This solid is recrystallized twice from ethanol to provide the ester.
A mixture of the ester, 22.0 g. of potassium hydroxide and 200 ml. of ethanol-water (8:1) is stirred under reflux for 6 hours. Concentrated hydrochloric acid (about 80 ml.) is added to the warm mixture and cooling and dilution with water affords a white solid which is collected by filtration and recystallized from ethanol to yield the product as a white solid.
Examples 3-317 Treatment of the indicated halide or carbinol starting material set forth in Table I below by the indicated method is productive of the product listed in the table. Reference B in Tables I and II is J.
Med. Chem. t 11, 1190 (1968).
Table I Example Starting Material Method Product 3 E-4-tetradecenol B 2-(E-1-tetradec- 4-enylamino) phenylacetic acid 4 Z-9-octadecen-1-ol B 3-(Z-1-octadec-9 enylamino)benzoic acid 5 E-4-pentadecen-1-ol B 2-(E-1-pentadec-4- enylamino)phenyl acetic acid Table I (cont.) Example Starting Material Method Product 6 3-chloro-2,4,4-tri- A 3-13-(2,4,4-tri methyl-1-pentene methyl)-pent- 1 - Chem. Abst. 72, enylamino]benzoic 111081h acid 7 3-bromo-3-isopropyl- A 2-[3-(3-isopropyl 4-methyl-1-pentene 4-methyl)pent-1- Chem. Abst. 54, enyl-amino]phenyl 4355a acetic acid 8 4-bromo-2-heptene A 3-(4-hept-2-enyl Chem.Abst. 70, amino)benzoic acid 67482x 9 4-bromo-2,4-dimethyl- A 2-[4-(2,4-dimethyl- 2-hexene hex-2-enyl)amine] phenylacetic acid 10 5-chloro-3,5-dimethyl- A 3-[5-(3,5-dimethyl 3-heptene Chem. hept-3-enyl)amino] Abst. 54, 1256e benzoic acid 11 Z-1-hydroxy-2-hexa- B 2-(Z-1-hexadec-2- decene Ref. B enylamino)phenyl acetic acid 12 #-1-hydroxy-2-hexa B 3-(E-1-hexadec-2- decene Ref. B enylamino)phenyl acetic acid 13 1 -bromo-4-methyl- A 2-[1 -(4-methylhept- 3-heptene Chem. 3-enyl)amino]benzoic Abst. 71, 102020q acid 14 1 -bromo-4-methyl-3- A 3-[1-(4-methynon-3 none Chem. Abst. enyl)amino]phenyl 71, 101399h acetic acid 15 E-7-bromo-3-hept- A 2-(1-hept-4-enyl ene Chem.Abst. 74, amino)benzoic acid 99419f 16 1-bromo-5,9-dimethyl- A 3-[1 -(5,9-dimethyl- 4-decene Chem. dec-4-enyl)amino] Abst. 51, 8699g phenylacetic acid 17 1-methanesulfonyl- B 2-(1 -tetradec- oxy-4-tetradecene 4-enylamino)phenyl Ref. B. acetic acid 18 1-methanesulfonyl- B 3-(1-hexadec oxy-4-hexadecene 4-enylamino)benzoic Ref. B. acid 19 6-bromo-1-hexene A 2-(1-hex-5-enyl Chem. Abst. 66, amino)phenylacetic 2142j acid 20 6-bromo-2-methyl- A 3-[1-(5-methylhex 1 -hexene Chem. 5-enyl)amino]benzoic Abst. 75, 1 09624f acid 21 6-chloro-1-heptene- A 2-(2-hept-6-enyl Chem. Abst. 72, amino)phenylacetic 31877g acid 22 6-bromo-2-methyl-2- A 3-[2-(2,6-dimethyl heptene Chem. Abst. hept-5-enyl)amino] 54, 13166f benzoic acid 23 7-chloro-2-octene A 2-(2-oct-6-enyl Chem. Abst. 75, amino)phenylacetic 129245m acid 24 E-1-chloro-4-nonene A 2-(E- 1 -non-5-enyl- Chem. Abst. 67, amino)benzoic acid 322949 25 7-bromo- 1 -heptene A 3-( 1 -hept-6-enyl- amino)phenylacetic acid Table I (cont.) Starting Material Method Product 26 7-chloro-1-octene A 2-(2-oct-7-enyl Chem.Abst. 75, amino)benzoic acid 29245m 27 6-bromo-6-methyl- A 3-[1-(2-methylhept 1-heptene Chem. 6-enyl)amino]phenyl Abst. 66, 94482w acetic acid 28 6-chloro-6-methyl- A 2-[1 -(6-methylhept- 1 -heptene Chem. 6-enyl)aminojbenzoic Abst. 75, 129245 acid 29 E-8-bromo-2-octene A 3-(1-oct-6-enyl Chem. Abst. 74, 9941 9f amino)phenylacetic acid 30 8-bromo-2,6-dimethyl- A 2-[1-(3,7-dimethyl- 2-octene Chem. oct-6-enyl)amino] Abst. 72, 90573c benzoic acid 31 1 1-bromo-5-undecene- A 3-(1-undec-6-enyl Chem. Abst. 67, 73101 b amino)phenylacetic acid 32 8-bromo- 1 -octene A 2-( 1 -oct-7-enyl- Chem.Abst. 70, amino)benzoic acid 109909 33 R-8-iodo-7-methyl- A 3-[R-(2-methyloct 1-octene Chem. 7-enyl)amino]phenyl Abst. 74, 12573e acetic acid 34 1-chloro-7-tetra- A 2-(1-tetradec-7 decene Chem. Abst. enylamino)benzoic 54,22461 h acid 35 9-chloro-1-nonene A 3-(1-non-8-enyl Chem. Abst. 70, amino)phenylacetic 114490k acid 36 1 -bromo-8-hepta- A 2-( 1 -heptadec-8- decene Chem. Abst. enylamino)benzoic 52, 249d acid 37 E-1 -bromo-9-octa- A 2-(E-1 -octadec-9- decene Chem. Abst. enylamino)phenyl 70,46779j acetic acid 38 Z-1-bromo-9-octa- A 3-(Z-1-octadec-9- decene Chem.Abst. enylamino)benzoic 70, 46779j acid 39 1 1-chloro-1-undec- A 2-(1-undec-1O-enyl- ene Chem. Abst. 66, amino)phenylacetic P19046d acid 40 12-iodo-3,7,11-tri- A 3-[1-(2,6,10-tri methyl 1 -dodecene methyldodec- 11 enyl)amino]benzoic acid 41 13-bromo-1-tridec- A 2-(1-tridec-12 ene Chem. Abst. 67, enylamino)phenyl 43348v acetic acid 42 22-bromo-9-docos- A 3-[1-(2-methyl- ene Chem. Abst. hept-6-enyl)amino]- 73, 44976j benzoic acid 43 16-methanesulfonyloxy- B 2-(1 -hexadec-1 5- 1-hexadecene enylamino)phenyl Ref.B. acetic acid 44 propargyl alcohol B 3-(1-prop-2-ynyl amino)benzoic acid 45 3-chloro-1-butyne A 2-(2-but-3-ynyl amino)phenylacetic acid 46 3-chloro-3-methyl- A 3-[3-(3-methylnon nonyne Chem. Abst. 1-ynyl)amino]benzoic 55, 22090i acid Table I (cont.) Example Starting Material Method Product 47 3-bromo-1-penta- A 2-(3-pentadec-1 decyne Chem. Abst. nylamino)phenyl 53, 21 638c acetic acid 48 1-octyn-3-ol Chem.B 3-(3-oct-1-ynyl Abst. 66, 8541 On amino)benzoic acid 49 3,7,11,15-tetra- B 2-[3-(3,7,11,15- methyl-i -hexadecyn- tetramethyl hexadec 3-ol 1-ynyl)amino]- benzoic acid 50 2-butyn-1-ol B 3-(1-but-2-ynyl amino)phenylacetic acid 51 4-hexyn-3-ol B 2-(3-hex-4-ynyl amino)benzoic acid 52 2-methyl-3-pentyn- B 3-[2-(2-methylpent 2-ol Chem. Abst. 3-ynyl)amino]phenyl 69, 10496e acetic acid 53 2-octyn-1-ol B 2-(1-oct-3-ynyl amino)benzoic acid 54 4-decyn-3-ol B 3-(3-dec-4-ynyl Chem. Abst. 69, amino)phenylacetic P4630s acid 55 1-bromo-2-dodecyne A 2-[1-dodec-2-ynyl Chem. Abst. 28, amino)benzoic acid 40345 56 1-methanesulfonyl- B 3-(1-pentadec oxy-2-pentadecyne 2-ynylamino)phenyl J. Med.Chem. 19, acetic acid 946 (1977) 57 3-butyne-1-ol B 2-(1-but-3-ynyl Chem. Abst. amino)benzoic acid 66, P2319a 58 1-undecyn-4-ol B 3-(4-undec-1-ynyl Chem. Abst. 70, amino)phenylacetic 3219j acid 59 2-methyl-4-pentyn- B 2-[2-(2-methylpent 2-ol Chem. Abst. 4-ynyl)amino] 68, 12200g benzoic acid 60 4-pentyn-2-ol B 3-(2-pent-4-ynyl Chem. Abst. 64, amino)phenylacetic 13537e acid 61 3-pentyl-1-ol B 2-(1-hex-3-ynyl amino)phenylacetic acid 62 4-hexyn-2-ol B 3-(2-hex-4-ynyl amino)benzoic acid 63 2-methyl-3-pentyn- B 2-[1-(2-methyl- 1-ol Chem.Abst. 3-pent-3-ynyl) 66, 115242k amino]phenylacetic acid 64 2-(1-propynyl)-1- B 3-[2-(1-propynyl heptanol Chem. heptyl)amino] 66, 115242k benzoic acid 65 2-methyl-4-nonyn- B 2-[2-(2-methyl non- 2-ol Chem. Abst. 4-ynyl)amino] 68, 104593r phenylacetic acid 66 2-methyl-3-nonyn- B 3-[1 -(2-methylnon-3- 1-ol Chem. Abst. ynyl)amino]benzoic 66, 115242k acid 67 3-nonyn-1-ol B 2-(1-non-3-ynyk Chem. Abst. 75 amino)phenylacetic 5165r acid Table I (cont.) Example Starting Material Method Product 68 2-methyl-3-decyn- B 3-[1-(2-methyldec- 1 -ol Chem.Abst. 3-ynyl)amino] 66, 115242k benzoic acid 69 5-chloro-1-pentyne A 2-(1-pent-4-ynyi amino)phenylacetic acid 70 4-hexyn-1 -ol B 3-(1 -hex-4-ynyl- Chem. Abst. 74, amino)benzoic acid 9800w 71 1-chloro-4-nonyne A 2-(1-non-4-ynyl amino)phenylacetic acid 72 1 -chloro-4-tri- A 3-(1-pentadec decyne Chem. 2-ynylamino)benzoic Abst. 32, 7426 acid 73 1-chloro-4-hexa- A 2-(1-hexadec-4-ynyl decyne amino)benzoic acid 74 5-hexyn-1 -ol B 3-( 1 -hex-5-ynyl Chem. Abst. 74, amino)phenylacetic 9800w acid 75 6-octyn-2-ol B 2-[2-(2-methyloct Chem.Abst. 71, 6-ynyl)amino]benzoic 60300y acid 76 1 -iodo-5-decyne A 3-( 1 -dec-5-ynyl- Chem. Abst. 51, amino)phenylacetic 12817f acid 77 5-tetradecyn- 1 -ol B 2-( 1 -tetradec Chem. Abst. 71, 5-ynylamino)benzoic 12053k acid 78 5-octadecyn- 1 -ol B 3-(1 -octadec-5-ynyl- Chem. Abst. 72, amino)phenylacetic 42686v acid 79 6-octadecyn-1 -ol B 2-(1 -octadec-6-ynyl Chem. Abst. 72, amino)benzoic acid 42686v 80 10-chloro-3-decyne A 3-(1-dec-7-ynylamino)- Chem. Abst. 67, phenylacetic acid 108147a 81 1-chloro-7-tetra- A 2-(1-tetradec- decyne Chem. 7-ynylamino)benzoic Abst. 54, 2461 e acid 82 7-hexadecyn-1-ol B 3-(1-hexadec-7-ynyl Chem.Abst. 71, amino)phenylacetic 19554w acid 83 7-octadecyn-1-ol B 2-(1 -octadec-7-ynyl Chem. Abst. 67, amino)benzoic acid 81784w 84 8-octadecyn- 1 -ol B 3-(1 -octadec-8-ynyl Chem. Abst. 72, amino)phenylacetic acid 85 9-decyn-1-ol B 2-(1-octadec-9-ynyl Chem. Abst. 67, amino)benzoic acid 81787s 86 10-octadecyn-1-ol B 2-(1-octadec-10- Chem. Abst. 67, ynylamino)phenyl 81787s acetic acid 87 4-nonyn-1-ol B 3-(1-non-4-ynylamino) Chem. Abst. 67, benzoic acid 88 11-dodecyn-1-ol B 2-(1-dodec-1 1-ynyl- Chem. Abst. 68, amino)phenylacetic 3901 5n acid 89 11 -tetradecyn-1 -ol B 3-(1-tetradec-11-ynyl- Chem. Abst. 75, amino)benzoic acid 16792u Table I (cont.) Example Starting Material Method Product 90 11-tridecyn-1-ol B 2-(1-tridec-1 1-ynyl- Chem. Abst. 75, amino)phenylacetic 1679u acid 91 16-bromo-5-hexa- A 3-(1-hexadec-1 1-ynyl- decyne Chem. Abst. amino)benzoic acid 68,39015n 92 12-octadecyn-1-ol B 2-(1-octadec-12 Chem, Abst. 68, ynylamino) 39015n phenylacetic acid 93 12-octadecyn-1-ol B 3-(1 -octadec- Chem.Abst. 12-ynylamino) 72, 42686v benzoic acid 94 13-tetradecyn-1-ol B 2-(1 -tetradec- 13- Chem. Abst. 68, ynylamino)phenyl 39015n acetic acid 95 1 4-pentadecyn-1 -ol B 3-( 1 -pentadec-1 4- Chem. Abst. 68, ynylamino)benzoic 39015n acid 96 5,7-octadien-4-ol B 2-(4-octa-5,7-di Chem. Abst. 72, enylamino)phenyl 42686v acetic acid 97 4-ethyl-3,5-hexa- B 3-[2-(4-ethylhexa decadien-2-ol 3,5-dienyl)amino]-.
Chem. Abst. 70, benzoic acid 20116r 98 2-methyl-4,6-hepta- B 2-[3-(2-methylhepta dien-3-ol Chem. 4,6-dienyl)amino Abst. 71, 1 12534z phenylacetic acid 99 E-2,4,6-trimethyl- B 2-[E-2(2,4,6-hepta 3,5-heptadien-2-ol 3,5-dienyl)amino]- benzoic acid 100 4,6-octadien-3-ol B 3-(1-hexa-2,4-di- Chem. Abst. 69, enylamino)phenyl 58770s acetic acid 101 2,4-hexadien-1 -ol B 2-[1 -hexa-2,4-di Chem. Abst. 67, enylamino)benzoic 81787s acid 102 6-isopropyl-7,7- B 3-[2-6-isopropyl-7,7 dimethyl-3,5-octa- dimethylocta-3,5 dien-2-ol Chem. dienyl)amino]phenyl Abst. 75,36362g acetic acid 103 3,5,7-trimethyl- B 2-[3-(3,5,7-tri- 4,6-nonadien-3-ol methylnona-4, Chem.Abst. 74, 6-dienyl)amino] benzoic acid 104 2,6-dimethyl-3,5- B 3-[2-(2,6-dimethyl octadien-2-ol octa-3,5-dienyl) Chem. Abst. 68, amino]phenylacetic 1 14750d acid 105 E,E-6-ethyl-4,6- B 2-[E,E-3-(6-ethyl decadien-3-ol Chem. deca-4,6-dienyl) Abst. 73, 130585n amino]benzoic acid 106 5-ethyl-3,5-nona- B 3-[2-(5-ethylnona- dien-2-ol 3,5-dienyl)amino]- phenylacetic acid 107 E,E-2,4-octadien- B 2-(E,E-1 -octa-2 1 -ol Chem. Abst. 4-dienylamino) 67, 104946n benzoic acid 108 E,Z-2,4-nonadien- B 3-(E,Z-1-nona-2- 1-ol Chem.Abst. 4-dienylamino) 67, 99692w phenylacetic acid Table I (cont.) Example Starting Material Method Product 109 E,E-2,4-decadien- B 2-(E,E-1 -deca-2 1-ol Chem. Abst. 4-dienylamino) 67, 104946n benzoic acid 110 E3-2,4-decadien- B 3-E,Z-1-deca-2- 1-ol Chem. Abst. 4-dienyiamino) 67, 99692v phenylacetic acid 111 E-2,5-hexadien-1-ol B 2-(E-1-hexa-2,5-dienyl Chem. Abst. 73, amino)phenylacetic P 55709a acid 112 Z-2,5-hexadienyl- B 3-(Z-1-hexa-2,5-dienyl- 1 -ol Chem. Abst. amino)benzoic acid 73, PS5709a 113 E(+)-4-ethyl-2,5-di- B 2-(E(+)-1 -(2,5-dimeth methyl-2 ,5-hexadien- ylhexa-2,5-dienyl)- 1 -ol Chem.Abst. amino]phenylacetic 71,70152m acid 114 E-2,5,5-trimethyl- B 3-[E-2-(2,5,5-trimethyl 3,6-heptadien-1 -ol hepta-3,6-dienyl Chem. Abst. 74, amino]benzoic acid 52962n 115 Z-2,5,5-trimethyl- B 2-[Z-2-(2,5,5-trimethyl 3,6-heptadien-1 - hepta-3,6-dienyl) ol Chem. Abst. 74, amino]phenylacetic 52962n acid 116 Z,E-3,7-dimethyl- B 3-[Z,E-1 -(3,7-dimethyl- 2,5-octadien-1-ol octa-2,5-dienyi)amino] Chem. Abst. 71, benzoic acid 6156a 117 E-2,6-dimethyl-2,6- B 2-[E-1-(2,6-dimethyl heptadien-1 -ol hept-2,6-dienyl)amino] Chem.Abst. 72, phenylacetic acid 32036u 118 E,E-2,6-octadien- B 3-(E,E-1 -octa-2,6-dienyl 1-ol amino)benzoic acid 119 E,E-2,6-dimethyl- B 2-[E,E-1-(2,6-dimethyl- 2,6-octadien- octa-2,6-dienyl)amino]- 1-ol Chem. Abst. phenylacetic acid 71,22204n 120 Z,E-2,6-dimethyl- B 3-(Z,E-1 -(2,6-dimethyl octadien-1 -ol octa-2,6-dienylamino) Chem. Abst. 71, benzoic acid 22204n 121 E,Z-2,6-nonadien- B 2-(E,Z-1-nona-2,6-di 1-ol Chem. Abst. enylamino)phenylacetic 72, 24504e acid 122 E2-3,ethyl-7- B 2-[E,Z-1-(3-ethyl-7 methyl-2,6-nonadien- methylnona-2,6-dienyl) 1-ol Chem.Abst. amino]benzoic acid 75,63019g 123 3,7,11,1 1-tetramethyl- B 3-[1-(3,7,11,11-tetra- 2,6-dodecadien- methyldodeca-2,6-di 1-ol Chern. Abst. 75, enyl)amino]phenyl P117969n acetic acid 124 E,E-3,7,1 1-trimethyl- B 2-[E,E-1-(3,7,11-tri- 2,6-dodecadien- methyldodeca-2,6-di 1-ol Chem. Abst. enyl)amino]benzoic 69, 978z acid 125 E-Z-3,7,1 1-trimethyl- B 3-(E,Z-1-(3,7,11-tri- 2,6-dodecadien-1 -ol methyldodeca-2,6-di Chem. Abst. 69, enyl)amino]phenyl 9789 acetic acid Table I (cont.) Example Starting Material Method Product 126 2,7-octadien-1 -ol B 2-(1 -octa-2,7-dienyl- Chem.Abst. 74, amino)benzoic acid P41 892p 127 E-3,7-dimethyl-2,7- B 3-[E-1-(3,7-di- octadien-1 -ol methylocta-2,7-di Chem. Abst. 68, enyl)amino]phenyl 1 14750d acetic acid 128 Z,3,7-dimethyl- B 2-[Z-1-(3,7-di 2,7-octadien-1 -ol methylocta-2,7-di Chem. Abst. 68, enyl)amino]benzoic 1 14750d acid 129 3,4,8-trimethyl- B 3-[1-(3,4,8-tri- 2,7-nonadien-1 -ol methylnona-2,7-di Chem. Abst. 68, enyl)amino]phenyl 9184c acetic acid 130 3,4,8-trimethyi- B 2-[1 -(3,4,8-tri 2,8-nonadien- methylnona-2,8-di 1-ol Chem.Abst. enyl)amino]benzoic 68,291 84c acid 131 2,9-decadien-1 -ol B 3-(1-deca-2,9-di Chem. Abst. 68, enylamino)phenyl 68373h acetic acid 132 E,3,7,11-trimethyl- B 2-[E-1-(3,7,11-tri 2,10-dodecadien-1 -ol methyldodeca-2,10- Chem. Abst. 69, dienylamino]phenyl 978z acetic acid 133 Z-3,7,1 1-trimethyl- B 3-[Z-1-(3,7,1 1-tri- 2,1 0-dodecadien-1 -ol methyldodeca-2,1 0 dienyl)amino] benzoic acid 134 E,E-4-methyl-3,5- B 2-[E,E-1 -(4-methyl heptadien-1 -ol hepta-3,5-dienyl) Chem. Abst. 66, amino]phenylacetic 104730s acid 135 E,Z-4-methyl-3,5- B 3-[E,Z-1 -(4-methyl heptadien-1 -ol hepta-3,5-dienyl) Chem.Abst. 66, amino]benzoic acid 1 04730s 136 Z-E-4-methyl-3,5- B 2-[Z,E-1 -(4-methyl heptadien-1 -ol hepta-3,5-dienyl) Chem. Abst. 66, amino]phenylacetic 104730s acid 137 Z,Z-4-methyl-3,5- B 3-[Z,Z-1 -(4-methyl heptadien-1 -ol hepta-3,5-dienyl) Chem. Abst. 66, amino]benzoic acid 1 04730s 138 E-4,6-dimethyl-3,5- B 2-[E- 1 -(4,6-di- heptadien-1 -ol methylhepta-3,5 Chem. Abst. 66, dienyl)amino] 1 04730s phenylacetic acid 139 Z-4,6-dimethyl-3,5- B 3-[Z-1-(4,6-di heptadien-1 -ol methylhepta-3,5 Chem. Abst. 66, dienylamino] 1 04730s benzoic acid 140 E,Z-2,6-dimethyl-4,6- B 2-[E,Z-2-(2,6-di- octadien-2-ol Chem. methylocta-4,6-di Abst. 68, 1 14750d enyl)amino]phenyl acetic acid 141 1-hydroxy-3,7,11- B 3-[1-(3,7,11-tri trimethyl-2,6,10- methyldodeca-2,6,10- dodecatriene trienyl)amino]- benzoic acid Example Starting Material Method Product 142 5-methyl-3,5- B 2-[1 -(5-methylocta octadien-1 -ol, 3,5-dienyl)amino] Chem. Abst. 69, benzoic acid 18519k 143 E-4-methyl-3,6- B 3-[E-1 -(4-methylhepta heptadien-1 -ol 3,6-dienyl)-amino] Chem. Abst. 66, phenylacetic acid 1 04730s 144 Z-4-methyl-3,6- B 2-[Z-1 -(4-methyl heptadien-1 -ol hepta-3-6-dienyl) Chem. Abst. 66, amino-benzoic 104730s acid 145 E-(+)-2,6-dimethyl- B 3-[E-(+)-2-(2,6- 4,7-octadien-2-ol dimethylocta-4,7 Chem. Abst. 75, dienyl)-amino]- 49345d phenylacetic acid 146 Z(+)-2,6-dimethyl- B 2-[Z(+)-2-(2,6-di 4,7-octadien-2-ol methyl-octa-4,7-di Chem.Abst. 75, enyl)amino]benzoic 49345d acid 147 E-(3,7-dimethyl-3,6- B 3-[E-1 -(3,7-dimethyl octadien-1 -ol octa-3,6-dienyl) Chem. Abst. 67, amino]phenylacetic 64554z acid 148 E-3,7-dimethyl-3,6- B 2-[Z-1-(3,7-dimethyl- octadien-1 -ol octa-3,6-dienyl) amino]benzoic acid 149 Z-3-methyl-3,7- B 3-[E-1-(3-methyl- octadien-1 -ol octa-3,7-dienyl) Chem. Abst. 69, amino]phenylacetic 65681x acid 150 Z-3-methyl-3,7- B 2-[Z-1 -(3-methyl octadien-1 -ol octa-3,7-dienyl) Chem. Abst. 69, amino]benzoic acid 26681 x 151 E-2-methyl-4,8- B 3-[Z-1 -(4,6-dimethyl nonadien-1 -ol hepta-3,5-dienyl) Chem.Abst. 73, amino]phenylacetic 87253p acid 152 E-3,7-dimethyl-3,7- B 2-[E-1 -(3,7-di octadien-1 -ol Chem. methylocta-3,7 Abst. 69, 26681 x dienylamino]phenyl acetic acid 153 E-8-methyl-7- B 3-[E-1 -(8-methyl-7 methylene-3-nonen- methylenenon-3-enyl) 1-ol Chem. Abst. amino]benzoic acid 70, 29098u 154 2,4,9-trimethyl- B 2-[2-(2,4,9-tri 4,8-decadien-1 -ol methyldeca-4,8 Chem. Abst. 74, dienyl)amino]phenyl 99342s acetic acid 155 E-2-methyl-4,9- B 3-[E-2-(2-methyldeca decadien-1 -ol 4,9-dienyl)amino] Chem. Abst. 73, benzoic acid 872549 156 2,6-dimethyl-5,7- B 2-[2-(2,6-dimethyl octadien-2-ol octa-5,7-dienyl) Chem. Abst. 72, amino] phenylacetic 37616t acid 157 E-3,7-dimethyl- B 3-[E-1-(3,7-dimethyl 4,6-octadien-1 -ol octa-4,6-dienyl) Chem.Abst. 72, amino]benzoic acid 121291r Table I (cont.) Example Starting Material Method Product 158 Z-3,7-dimethyl- B 2-[Z-1 -(3,7-dimethyl- 4,6-octadien-1 -ol octa-4,6-dienyl) Chem. Abst. 72, amino]phenylacetic acid 121291r 159 E-4,7-octadien-1 -ol B 3-[E-1 -(octa-4,7-di- Chem. Abst. 66, enyl)aminobenzoic 2861 or acid 160 5,8-nonadien-2-ol B 2-[2-(nona-5,8- Chem. Abst. 68, dienyl)amino]phenyl 28610k acetic acid 161 E-7-methyl-4,7- B 3-[E-1-(7-methyl octadien-1 -ol octa-4,7-dienyl Chem. Abst. 66, amino]benzoic acid 28610k 162 E-8-methyl-5,8- B 2-[E-2-(8-methyl nonadien-2-ol nona-5,8-dienyl) Chem.Abst. 66, amino]benzoic acid 2861 or 163 E-6,10-dimethyl- B 3-[E-2-(6,10-di 5,9-undecadien- methylundeca-5,9 2-ol Chem. Abst. dienyl)amino]phenyl 73, 1331152f acetic acid 164 5,9,1 3-trimethyl- B 2-[6-(5,9,13-tri- 8,13-tetradecadien- methyltetradeca-8, 12- 2-ol Chem. Abst. dienyl)amino] 70, 28303v benzoic acid 165 E-3,7,11-trimethyl B 3-[E-3-(3,7,11-tri 6,10-dodecadien- methyldodeca-6,10- 3-ol Chem. Abst. dienyl-amino] 69, 8333f phenylacetic acid 166 Z-3,7,1 1-trimethyl- B 2-[Z-3-(3,7,1 1-tri- 6,10-dodecadien- methyldodeca-6,1 0- 3-ol Chem. Abst. dienyl)amino] 69, 8333f benzoic acid 167 5,9-dimethyl-4,8- B 3-[1-(5,9-dimethyl- decadien-1 -ol deca-4,8-dienyl) Chem.Abst. 74, amino]phenylacetic 112233n acid 168 15-methanesulfonyl- B 2-[1 -pentadeca-4, 14- oxy-1,11-pentadeca- dienylamino)benzoic diene Ref. B acid 169 5,7-octadien-1 -ol B 3-[1 -octa-5,7-dienyl- Chem. Abst. 68, amino)phenylacetic 68503a acid 170 E-3,7-dimethyl- B 2-[E-1 -(3,7-dimeth- 5,7-octadien- octa-5,7-dienyl) 1-ol Chem. Abst. amino]benzoic acid 72, P90672j 171 6,10-dimethyl- B 3-[1 -(6,1 0-dimethyl- 5,9-undecadien- undeca-5,9-dienyl) 1-ol Chem. Abst. amino]phenylacetic 71,50248y acid 172 2,6,10-trimethyl- B 2-[ 1 -(2,6,1 0-tri- 5,9-undecadien- methylundeca-5,9 1-ol Chem.Abst. dienyl)amino]phenyl 71, 50243t acetic acid 173 10-propyl-5,9-tri- B 3-[1-(10-propyl decadien-1 -ol trideca-5,9-dienyl)- Chem. Abst. 68, amino]benzoic acid 39028u 174 5,13-tetradecadien- B 2-[1-tetradeca-5,13- 2-ol Chem. Abst. dienylamino]phenyl 66, 35672k acetic acid Table I (cont.) Example Starting Material Method Product 175 E-3,7,1 1-trimethyl- B 3-[1-(3,7,1 1-tri- 6,10-dedecadien- methyldodeca-6,10- 1 -ol Chem. Abst. dienyl)amino] 69, 978z benzoic acid 176 E-6,10,1 4-trimethyl- B 2-[E-2-(6,10,14-tri- 9,13-pendadecadien- methylylpentadeca 2-ol Chem.Abst. 9,13-dienyl)amino]- 74, 53992j phenylacetic acid 177 Z-6, 10,1 4-trimethyl- B 3-[Z-2-(6, 10,1 4-tri- 9.13-pentadecadien- methylylpentadeca 2-ol Chem. Abst. 9,1 3-dienyl-amino]- 74,53992j benzoic acid 178 Z,Z-9,12-octadecadien- B 2-( 1 -octadeca-9,1 2- 2-ol Chem. Abst. dienylamino)phenyl 68, 92804v acetic acid 179 E,2'-10,12-hexadeca- B 3-[E,Z-1 -hexadeca- dien-1 -ol Chem. Abst. 10,12-dienylamino)- 66, 106133y benzoic acid 180 Z,E-1 0,1 2-hexadeca- B 2-[Z,E-1 -hexadeca- dien-1 -ol Chem.Abst. 10,12-dienylamino) 66, P7956f phenylacetic acid 181 2-methyl-2,3-buta- B 3-[1 -(2-methylbuta dien-1 -ol Chem. Abst. 2,3-dienyl)amino] 71, 30229n benzoic acid 182 2-ethyl-2,3-buta- B 2-[1 -(2-ethylbuta 2,4-hexadien-2-ol 2,3-dienyl)amino] Chem. Abst. 67, phenylacetic acid 535673e 183 2,3,5-trimethyl- B 2-[2-(2,3,5-tri- 3,4-hexadien-2-ol methylhexa-3,4-di- Chem. Abst. 72, enyl)amino]benzoic 131953x acid 184 3-isopropyl-2,4-di- B 3-[3-(2,4-dimethyl methyl-4,5-hexadien- hexa-4,5-dienyl) 3-ol amino]phenylacetic acid 185 2,5-dimethyl-3,4- B 2-[2-(2,5-dimethyl hexadien-2-ol hexa-3,4-dienyl) Chem.Abst. 68, amino]benzoic acid 39152e 186 3,5-dimethyl-3,4- B 3-[2-(3,5-dimethyl heptadien-2-ol hepta-3,4-dienyl) Chem. Abst. 72, amino]phenylacetic 131953x acid 187 2-methyl-3,4- B 2-[2-(2-methylhepta heptadien-2-ol 3,4-dienyl)amino] Chem. Abst. 71, benzoic acid 382199 188 2,3,5-trimethyl- B 3-[2-(2,3,5-tri 3,4-heptadien-2-ol methylhepta-3,4 Chem. Abst. 72, dienyl)amino]phenyl 131953x acetic acid 189 3-t-butyl-2-rnethyl- B 2-[2-(3-t-butyl 3,4-octadien-2-ol 2-methylocta-3 4- Chem. Abst. 66, dientyl)amino]benzoic 75593s acid 190 2-ethyl-2,3- B 3-[1 -(2-ethyihepta- heptadien-1 -ol 2,3-dienyl)amino] Chem. Abst. 75, phenylacetic acid 63063s 191 2-methyl-3,4- B 2-[1-(2-methylocta octadien-2-ol 3,4-dienyl)amino] Chem. Abst. 75, benzoic acid 140175g Table I (cont.) Example Starting Material Method Product 192 3-methyl-3,4- B 3-[2-3-(3-methyl octadien-2-ol octa-3,4-dienyl) Chem. Abst. amino]phenylacetic 66,75593s acid 193 5,6-decadien-4-ol B 2-(4-deca-5,6 Chem.Abst. 75, dienylamino)phenyl 76898t acetic acid 1 94 2,3-dimethyl-3,4- B 3-[2-(2,3-dimethyl octadien-2-ol octa-3,4-dienyl) Chem. Abst. 66, amino]benzoic acid 75593s 195 4-ethyl-4,5- B 2-[3-(4-ethylnona nonadien-3-ol 4,5-dienyl)amino] Chem. Abst. 75, phenylacetic acid 63063s 196 2-methyl-3-propyl- B 3-[2-(2-methyl 3,4-octadien-2-ol 3-propylocta-3,4 Chem. Abst. 66, dienyl)amino]benzoic 65592v acid 197 2-methyl-3,4- B 2-[2-(2-methyinona- nonadien-2-ol 3,4-dienyl)amino] Chem. Abst. 75, phenylacetic acid 1401739 198 2,8-dimethyl-3,4- B 3-[2-(2,8-dimethyl nonadien-2-ol nona-3,4-dienyl) Chem.Abst. amino]benzoic acid 71, 3821 99 199 2-methyl-3,4-deca- B 2-[2-(2-methyldeca dien-2-ol Chem. 3,4-dienyl)amino] Abst. 75, 1401739 phenylaceticacid 200 2,9-dimethyl-3,4- B 3-[2-(2,9-dimethyl decadien-2-ol deca-3,4-dienyl)- aminojbenzoic acid 201 2-methyl-3,4-dodeca- B 2-[2-(2-methyl dien-2-ol Chem. dodeca-3 ,4-dienyl)- Abst. 71,38219g amino]phenylacetic acid 202 2-methyl-3,4-tri- B 3-[2-(2-methyltri decadien-1 -ol Chem. deca-3,4-dienyl) Abst. 71,38219g amino]benzoic acid 203 4,5-hexadien-2-ol B 2-(2-hexa-4,5-dienyl Chem.Abst. 75, amino)benzoic 5152j acid 204 2-methyl-5,6- B 3-[2-(2-methyl hepta- heptadien-3-ol 5,6-dienyl)amino] Chem. Abst.
75,5152j phenylacetic acid 205 3,3-dimethyl-4,5- B 2-[2-(3,3-dimethyl hexadien-2-ol hexa-4,5-dienyl) Chem. Abst. amino]benzoic acid 69, 86256x 206 2,5-dimethyl-5,6- B 3-[2-(2,5,dimethyl heptadien-3-ol hepta-5,6-dienyl) Chem. Abst. amino]phenylacetic 68, 86855w acid 207 2,2,5-trimethyl- B 2-[1-(2,2,5-tri 3,4-hexadien-1 -ol methylhexa-3,4 Chem. Abst. dienyl)amino]benzoic 71,297679 acid 208 (+) 2,2-dimethyl- B 3-[1-(2,2-dimethyl- 3,4-hexadien-1 -ol hexa-3,4-dienyl) Chem. Abst. amino]phenylacetic 68, 58831s acid Table I (cont.) Example Starting Material Method Product 209 3,4-hexadien-1-ol B 2-[1-hexa-3,4 Chem.Abst. dienylamino)benzoic 66, 54943r acid 210 2,2,3,5-tetramethyl- B 3-[1 -(2,2,3,5-tetra 3,4-hexadien-1 -ol methylhexa-3,4-di Chem. Abst. enyl)amino]phenyl 71, 297679 acetic acid 211 3,3,6-trimethyl- B 2-[2-(3,3,6-trimethyl- 4,5-octadien-2-ol octa-4,5-dienyl) Chem.Abst. 69, amino]benzoic acid 86256x 212 2,5-dimethyl-5,6- B 3-[2-(2,5-dimethyl- heptadien-2-ol Chem. hepta-5,6-dienyl) Abst. 69, 86256x amino]phenylacetic acid 213 4-methyl-4-penten- B 2-[ 1 -(4-methyl pent- 2-yn-1 -ol 4-en-2-ynyl)amino] phenylacetic acid 214 2-methyl-2-penten- B 3-[1 -(2-methylpent 2-yn-1 -ol 2-en-4-ynyl)amino] benzoic acid 215 5-hexen-3-yn-2-ol B 2-[2-hex-5-en-3 ynylamino)phenyl acetic acid 216 7-octen-5-yn-4-ol B 3-[4-oct-7-en-5-ynyl Chem. Abst. 67, amino)benzoic acid 1135449 217 S-methyl-5-hexen- B 2-[2-(5-methylhex 3-yn-2-ol 5-en-3-ynyl)amino] phenylacetic acid 218 2,5-dimethyl-1-nonen- B 3-[5-(2,5-dimethyl- 3-yn-5-ol Chem. non-1 -en-3-ynyl) Abst. 69, 2433s amino]benzoic acid 219 E-3-decen-1 -yn-5-ol B 2-(5-dec-3-en-1 -ynyl Chem. Abst. 75, amino]phenylacetic 35042r acid 220 E-3-dodecen-l -yn-5-ol B 3-(5-dodec-3-en Chem. Abst. 75, 1 -ynylamino)benzoic 35042r acid 221 2-methyl-5-hexen-3- B 2-[2-(2-methylhex-5 yn-2-ol Chem. Abst. en-3-ynyl)amino] 66, 75760v phenylacetic acid 222 3-methyl-6-hepten-4- B 3-[3-(3-methyl hept- yn-3-ol Chem.Abst. 6-en-4-ynyl)amino] 67, 1 135449 benzoic acid 223 5-methyl-1-nonen-3- B 2-[5-(5-methyinon-1- yn-5-ol Chem. Abst. en-3-ynyl)amino] 67, 43345s phenylacetic acid 224 3-ethyl-6-hepten-4- B 3-[3-(3-ethylhept yn-3-ol Chem. Abst. 6-en-4-ynyl)a mi no]- 71, 1122029 benzoic acid 225 5-ethyl-1-nonen-3- B 2-[5-(5-ethylnon-l- yn-5-ol Chem. Abst. en-3-ynyl)amino] 72, 31 124j benzoic acid 226 2,5-dimethyl-5-hexen- B 3-[2-(2,5-dimethyl- 3-yn-2-ol Chem. Abst. hex-S-en-3-ynyl)- 71,1122029 amino]phenylacetic acid 227 3,6-dimethyl-6-hepten- B 2-[2-(2,5-dimethyl 4-yn-3-ol Chem.Abst. hex-S-en-3-ynyl)- 69, 96881 m amino]benzoic acid Table I (cont.) Example Starting Material Method Product 228 3-ethyl-6-methyl- B 3-[3-(3-ethyl 6-hepten-4-yn-3-ol 6-methylhept-6-en Chem. Abst. 71, 4-ynylamino]phenyl 1122026 acetic acid 229 5-ethyl-2-methyl- B 2-[5-(5-ethyl 3-yn-5-ol Chem. Abst. 2-methyl-n-l-en- 69, 2433s 3-ynyl)amino]benzoic acid 230 2-hexen-4-yn-1 -ol B 3-( 1 -hex-2-en- Chem. Abst. 4-ynylamino)phenyl 68, 77868a acetic acid 231 4-methyl-4-hexen-2- B 2-[ 1 -(4-methyl hex-4- yn-1 -ol Chem. Abst. en-2-ynyl)amino] 66, 11524r benzoic acid 232 5-hexen-2-yn-1-ol B 3-(1-hex-5-en-2-ynyl Chem.Abst. 71, amino)phenylacetic 80580t acid 233 5-methyl-5-hexen-2- B 2-[1-(5-methylhex yn-1 -ol Chem. Abst. 5-en-2-ynyl)amino] 70, 281 52v benzoic acid 234 5-hexen-3-yn-l-ol B 3-(1-hex-5-en Chem. Abst. 73, 3-ynylamino)phenyl 109833g acetic acid 235 E-4-methyl-5-yn-1 -ol B 2-[E-1-(4-methyl- Chem. Abst. 66, hept-3-en-5-ynyl)- 1 04730s amino]benzoic acid 236 Z-4-methyl-5-yn-1-ol B 2-[Z-1-(4-methyl Chem. Abst. 66, hept-3-en-5-ynyl) 1 04730s amino]phenylacetic acid 237 3-hexen-5-yn-2-ol B 3-(2-hex-3-en Chem.Abst. 75, 5-ynylamino)benzoic 5152j acid 238 6-methyl-6-hepten- B 2-[2-(6-methylhept 4-yn-2-ol 6-en-4-ynyl)amino] phenylacetic acid 239 7-methyl-7-octen- B 3-[3-(7-methyloct 5-yn-3-ol 7-en-5-ynyl)amino] benzoic acid 240 2,5-dimethyl-5-hex- B 2-[2-(2-dimethylhex en-3-yn-2-ol 5-en-3-ynyl)amino] phenylacetic acid 241 3-methyl-6-octen- B 3-[3-(3-methyloct 4-yn-3-ol Chem. 6-en-4-ynyl)amino] Abst. 74, 41 795j benzoic acid 242 S-methyl-9-decen- B 2-[5-(5-methyldec- 6-yn-5-ol Chem. 9-en-6-ynyl)amino] Abst. 73, 1 25271 c phenylacetic acid 243 2,5,5,6-tetramethyl- B 3-[2-(2,5,5,6-tetra- 6-hepten-3-yn- methylhept-6-en-3 2-ol Chem. Abst. ynyl)amino] 70, 10801w benzoic acid 244 3-ethyl-7-octen- B 2-[3-(3-ethyloct 4-yn-3-ol Chem. 7-en-4-ynyl)amino] Abst. 73, 3762t phenylacetic acid 245 3-methyl-7-octen- B 3-[3-(3-methyloct 4-yn-3-ol Chem. 7-en-4-ynyl)amino] Abst. 73, 3762t benzoic acid 246 2,6-dimethyl-6- B 2-[2-(2,6-dimethyl hepten-3-yn-2-ol hept-6-en-3-ynyl) Chem.Abst. 73, amino]phenylacetic 55677p acid Table I (cont.) Example Starting Material Method Product 247 3,6-diethyl-6- B 3-[3-(3,6-diethyl- octen-4-yn-3-ol oct-6-en-4-ynyl) Chem. Abst. 68, amino]benzoic acid 1 04850x 248 6-ethyl-6-octen- B 2-[2-(6-ethyloct 4-yn-2-ol Chem. 6-en-4-ynyl)amino] Abst. 73, 19632z benzoic acid 249 6-methyl-6-hepten- B 3-[1-6-methylhept 2-yn-1-ol Chem. 6-en-2-ynyl)amino] Abst. 72, 3587u phenylacetic acid 250 E-4-methyl-3-hept- B 2-[E-1-(4-methyl- en-6-yn-1 -ol Chem. hept-3-en-4-ynyl) Abst. 66, 1 04730s amino]benzoic acid 251 Z-4-methyl-3-hept- B 3-[Z- 1 -(4-methyl- en-5-yn-1-ol Chem. hept-3-en-6-ynyl) Abst. 66, 104730s amino]phenylacetic acid 252 E-2-octen-6-yn- B 2-(E-1-oct-2-en-6 1-ol Chem. Abst. ynylamino) 75, 630199 benzoic acid 253 Z-7-methyl-6-non- B 3-[Z-1-(7-methyl en-2-yn-1-ol Chem. non-6-en-2-ynyl) Abst. 70, 7871 8j amino]phenylacetic acid 254 8-methyl-7-methyl- B 2-[1-(8-methyl-1- ene-3-nonyn-1 -ol methylenenon Chem. Abst. 66, 3-ynyl)amino]benzoic 29098u acid 255 E-2-decen-4-yn- B 3-( 1 -dec-2-en- 1-ol Chem. Abst. 4-ynylamino)phenyl 67, 99692v acetic acid 256 4-methyl-4-decen- B 2-[1-(4-methyldec- 8-yn-1-ol Chem. 4-en-8-ynyl)amino] Abst. 75, 1 10510x benzoic acid 257 E-2-undecen-4-yn- B 3-( 1 -undec-2-en- 1-ol Chem.Abst. 4-ynylamino)phenyl 66, 28594h acetic acid 258 6-methyl-5-undecen- B 2-[ 1 -(6-methyl undec- 2-yn-1 -ol Chem. 5-en-2-ynyl)amino] Abst. 71, P101399h benzoic acid 259 E-5-tetradecen-3- B 3-(E-1-tetradec yn-1-ol Chem. 5-en-3-ynylamino) Abst. 73, 87370z phenylacetic acid 260 Z-5-tetradecen-3- B 2-(Z-1-tetradec- yn-l-ol Chem. 5-en-3-ynylamino) Abst. 73, 87370z phenylacetic acid 261 10-propyl-9-tridec- B 3-[1 -(1 0-propyltri- en-5-yn-1-ol dec-9-en-5-ynyl) Chem. Abst. 72, amino]benzoic acid 12017k 262 17-octadecen-14-yn- B 2-(1-octadec-17-en- 1 -ol Chem.Abst. 14-ynylamino)phenyl 68, 3901 Sn acetic acid 263 2,4-dimethyl-1 ,4- B 3-[3-(2,4-dimethyl hexadien-3-ol hexa-1,4-dienyl) Chem. Abst. 74, amino]benzoic acid 87269u 264 1 ,5-hexadien-3-ol B 2-(3-hexa-1,5-di Chem. Abst. 73, enylamino)phenyl 44822f acetic acid 265 3,5-dimethyl-1,5- B 3-[3-(3,5-dimethyl- hexadien-3-ol hexa-1,5-dienyl) Chem. Abst. 67, amino]benzoic acid 5341 sod Table I (cont.) Example Starting Material Method Product 266 2,6-dimethyl- 1,6- B 2-[3-(2,6-dimethyl heptadien-3-ol hepta-1 ,6-dienyl)- Chem.Abst. 73, amino]phenylacetic 87490p acid 267 E-2,6-dimethyl-1,6- B 3-[E-3-(2,6-di octadien-3-ol Chem. methylocta-1 ,6- Abst. 7?,61565a dienyl)amino]benzoic acid 268 Z-2,6-dimethyl-1,6- B 2-[Z-3-(2,6-di octadien-3-ol Chem. methylocta-1 ,6- Abst. 7?,61565a dienyl)amino]phenyl acetic acid 269 3-ethyl-7-methyl- B 3-[3-(3-ethyl 1,6-octadien-3-ol 7-methylocta-1 ,6- Chem. Abst. 66, dienyl)amino]benzoic P761 92x acid 270 3-t-butyl-7-methyl- B 2-[3-(3-/-butyl- 1,6-octadien-3-ol 7-methylocta-1 ,6- Chem.Abst. 66, dienyl)amino]phenyl P761 92x acetic acid 271 7,9-dimethyl-1 ,6- B 2-[3-(7,9-dimethyl decadien-3-ol deca-1,6-dienyl) Chem. Abst. 71, amino]benzoic acid P60078c 272 3,7-dimethyl-1,6- B 3-[3-(3,7-dimethyl decadien-3-ol deca-1 ,6-dienyl)- Chem. Abst. 67, amino]phenylacetic 2688n acid 273 2-methyl-1,5- B 2-[4-(2-methylhepta heptadien-4-ol 1,5-dienyl)amino] Chem. Abst. 67, benzoic acid 53415d 274 4,6-dimethyl- 1,5- B 3-[4-(4,6-dimethyl heptadien-4-ol hepta-1,5-dienyl) Chem. Abst. 67, amino]phenylacetic 5341 5d acid 275 E,E-3,4,5-trimethyl- B 2-[E,E-4-(3,4,5-tri 2,5-heptadien-4-ol methylhepta-2,5-di Chem. Abst. 72, enyl)amino]benzoic 2823f acid 276 E,Z-3,4,5-trimethyl- B 3-[E,Z-4-(3,4,5-tri 2,5-heptadien-4-ol methylhepta-2,5 Chem.Abst. 72, dienyl)amino]phenyl 2823f acetic acid 277 Z,Z-3 ,4,5-trimethyl- B 2-jZ,Z-4-(3,4,5-tri- 2,5-heptadien-4-ol methylhepta-2,5 Chem. Abst. 72, dienyl)amino]benzoic 2823f acid 278 2-methyl-2,9- B 3-[5-(2-methyldeca decadien-5-ol 2,9-dienyl)amino]- Chem. Abst. 73, phenylacetic acid 87254q 279 8-methyl-1,7-nona- B 2-[S-(8-methylnona- dien-5-ol Chem. 1,7-dienyl)amino]- Abst. 73, 87253p benzoic acid 280 3,4,7,7-tetramethyl- B 3-[5-(3,4,7,7-tetra 1,5-octadien-4-ol methylocta-1 ,5-dienyl) Chem. Abst. 67, enyl)amino]phenyl 63514z acetic acid 281 3,4-dimethylene-2- B 2-[2-(3,4-dimethylene hexanol Chem.Abst. hexyl)amino]benzoic 69,106850s acid Table I (cont.) Example Starting Material Method Product 282 3-methyl-2-methyl- B 2-[1 -(3-methyl- ene-3-butene-1 -ol 2-methylenebut Chem. Abst. 74, 3-enyl)amino]phenyl 42503z acetic acid 283 2-methylene-3- B 3-[1-(2-methylene buten-1 -ol Chem. but-3-enyl-amino] Abst. 73, P67478n benzoic acid 284 3,3-dimethyl-2- B 2-[1-(3,3-demethyl methylene-4-penten- 2-methylenepent 1-ol Chem. Abst. 4-enyl)amino]phenyl- 74, 52962n acetic acid 285 2-methylene-3-methyl- B 3-[1-(2-methylene 4-hexen-1-ol 3-methvlhex-4-enyl)- Chem. Abst. 68 amino]benzoic acid 59021q 286 2,4-dimethyi-3- B 2-[2-(2,4-dimethyl methylene-5-hexen- 3-methylenehex 2-ol Chem.Abst. 5-enyl)amino] 72, 66299x phenylacetic acid 287 2,4,4-trimethyl-3- B 3-[2-(2,4,4-tri methylene-5-hexen- methyl-3-methylene 2-ol Chem. Abst. hex-5-enyl)amino] 74, 52962n benzoic acid 288 E-2-methyl-3-methyl- B 2-[E-2-(2-methyl ene-5-hepten-2-ol 3-methylenehept Chem. Abst. 72, 5-enyl)amino]phenyl 1 32999d acetic acid 289 Z-2-methyl-3-methyl- B 3-[Z-2-(2-methyl-3 ene-5-hepten-2-ol methylenehept-5 Chem. Abst. 72, enyl)amino]benzoic 132999d acid 290 2-dimethyl-1,3- B 2-[2-(2,6-dimethyl- methylene-5-hepten- 3-methylenehept-5 2-ol Chem. Abst. enyl)amino] phenyl 72, 132999d acetic acid 291 3,7-dimethyl-2- B 3-[1-(3,7-dimethyl methylene-6-octen- 2-methyleneoct 1 -ol Chem.Abst. 6-enyl)amino] 68, 11 14750d benzoic acid 292 3,7-dimethyl-2- B 2-[1 -(3,7-dimethyl- methylene-7-octen- 2-methyleneoct 1-ol Chem. Abst. 7-enyl)amino]- 70, P37191j benzoic acid 293 3-isopropylidene- B 3-[2-(3-isopropyl 2,5-dimethyl-4-hex- idene-2,5-dimethyl en-2-ol Chem. Abst. hex-4-enyl)amino] 74, 53105x phenylacetic acid 294 2-methyl-6-methyl- B 2-[4-(2-methyl ene-7-octen-4-ol 6-methyleneoct Chem. Abst. 69, 7-enyl)amino]benzoic 10548y acid 295 2-isopropylidene- B 3-[1 -(2-isopropyl- 5-methyl-4-hexene- idene-5-methylhex 1-ol Chem. Abst. 4-enyl)amino]phenyl 72, 132999d acetic acid 296 7-methyl-3-methyl- B 2-[1-(7-methyl- ene-6-octen-1 -ol 3-methyleneoct Chem. Abst. 73, 6-enyl)amino]- 131140a benzoic acid 297 2-methyl-6-methyl- B 3-[2-(2-methyl ene-7-octen-2-ol 6-methyleneoct Chem.Abst. 6-enyl)amino]- P61 600h phenylacetic acid Table I (cont.) Example Starting Material Method Product 298 E-2-ethylidene-6- B 2-[E-1-(2-ethyl methyl-5-hepten-l-ol idene-6-methylhept Chem.Abst. 68, 5-enyl)amino]benzoic 114750d acid 299 Z-2-ethylidene-6- B 3-[Z-1 -(2-ethyl- methyl-5-hepten- 1 -ol idene-6-methyl hept Chem. Abst. 68, 5-enyl)amino]phenyl 1 14750d acetic acid 300 2,5-dimethyl-3- B 2-[2-(2,5-dimethyl vinyl-4-hexen-2-ol 3-vinylhex-4-enyl) Chem. Abst. 69, amino]benzoic acid 45983p 301 2-isopropenyi-5- B 3-[1-(2-isopropenyl- methyl-4-hexen- 1 -ol S-methyl hex-4-enyl)- Chem. Abst. 68, amino]phenylacetic 111190k acid 302 2-vinyl-5-hepten- B 2-[1-(2-vinylhept 1 -ol Chem. Abst. 5-enyl)amino]phenyl 75, P151673w acetic acid 303 2-vinyl-6-hepten- B 3-[1-(2-vinylhept 1-ol Chem.Abst. 6-enyl)amino]benzoic 75,P15167w acid 304 2-(2-methylpropen- B 2-[1 -(2-methyipro- yl)-5-hexen-l-ol penylhex-5-enyl) Chem. Abst. 68, amino]phenylacetic 1 14750d acid 305 7-methyl-3-vinyl- B 3-[1-(7-methyl 6-octen-1 -ol Chem. 3-vinyloct-6-enyl) Abst. 66, P 11 5838j aminojbenzoic acid 306 2-allyl-4-methyl-4- B 2-[1-2-allyl penten-1-ol Chem. 4-methylpent Abst. 72,21731r 4-enyl)amino]phenyl acetic acid 307 3-methyl-5-undecen- B 3-[3-(3-methylundec 1 -yn-3-ol Chem. 5-en-1 -ynyl)amino]- Abst. 71, P101399h benzoic acid 308 3,4,8-trimethyl-8- B 2-[3-(3,4,8-tri nonen-1-yn-3-ol methylnon-8-en Chem.Abst. 68, 1 -ynylamino]phenyl 29184r acetic acid 309 1-dodecen-4-yn-3-ol B 3-(3-dodec-1-en Chem. Abst. 66, 4-ynylamino)benzoic 75603v acid 310 11 -dedecen-1 -yn-3-ol B 2-(3-dodec-1 1-en- Chem. Abst. 73, 1 -ynylamino)phenyl- 120015n acetic acid 311 1-undecen-5-yn-4-ol B 3-(4-undec-1-en Chem. Abst. 69, 5-ynylamino)benzoic 2432r acid 312 3,7-dimethyl-6- B 2-[3-(3,7-dimethyl nonen- 1 -yn-3-ol non-6-en- 1 -ynyl) Chem.Abst. 71, amino]phenylacetic P91265v acid 313 7,7-dimethyl- 1-non- B 2-[5-(7,7-dimethyl- en-8-yn-5-ol Chem. non-1 -en-8-ynyl) Abst. 74, 22939t amino]benzoic acid 314 2,3-dimethyl-1 -non- B 3-[3-(2,5-dimethyl- en-4-yn-3-ol Chem. non-1-en-4-ynyl) Abst. 68,39161g amino]phenylacetic acid 315 3,7-dimethyl-7- B 2-[3-(3,7-dimethyl octen-1 -yn-3-ol Chem. oct-7-en-1 -ynyl)- Abst. 73, P7095a amino]benzoic acid Table I (cont.) Example Starting Material Method Product 316 4,6-dimethyl-5-hept- B 3-[3-(4,6-dimethyl- en-1-yn-4-ol Chem. hept-5-en-l-ynyl)- Abst. 66, 95156e amino]phenylacetic acid 317 1-penten-4-yn-3-oí B 2-(3-pent-1-en Chem. Abst. 74, 4-ynylamino)benzoic P140935m acid Preparation of Esters Treatment of the acids of Examples 1-317 and 321-358 with trifluoroacetic anhydride to provide the N-COCF3 derivative, followed by treatment with thionyl chloride to provide the N-COCF3 acid chloride, followed by treatment with one of the following alcohols, followed by removal of the N COCF3 group with 1 N sodium hydroxide solution at 200C. provides the corresponding ester of the starting acid.
Alcohols: methanol, ethanol, 2-methoxyethanol, butanol, pentanol, cyclopentanol, cyclohexanol, 1,2-propanediol, 1,3-propanedioi, ethylene glycol, glycerol, glycidol, methyl glycolate, ethyl glycolate, glycolic acid, 2-hydroxypropionic acid, 3-hydroxybutyric acid, 4-hydroxybutyric acid, glyceric acid, 3 diethylamino- 1 -propanol, 1 -diethylamino-2-propanol, 3-dimethylamino-1 -propanol, 2 diisopropylaminoethanol, 3-(4-methyl-1 -piperazino)-1 2-propanediol, 3-methoxy-1 2-propanediol, Npiperidineethanol, N,N-diethylethanolamine.
Example 319 Preparation of 2-[1 -(2,3-methano)octylamino] phenylacetic Acid To a stirred mixture of 5 g. of zinc-copper couple prepared by the Shank-shechter Method [R. S.
Shank and H. Schehter, J. Org. Chem., 24, 1825 (1959)], 0.02 g. of iodine, and 100 ml. of anhydrous ether is added 8.7 g. of (0.05 mol) of methylene iodide. The mixture is heated in the absence of atmospheric moisture until a spontaneous reaction begins as evidenced by continued refiuxing of the ether when the heat source is removed. Upon completion of the exothermic reaction, the mixture is refluxed for 30 minutes, the heat is removed and to this mixture is added a solution of 5.4 g. (0.04 mol) of cis-2-octenol [L. P. Paquette and R. F. Eizember, J. Am. Chem. Soc., 91, 7110(1969)] in 10 ml. of anhydrous ether at a rate sufficient to maintain constant reflux. When the addition is complete, the mixture is refluxed for 3 hours.The flask is cooled and the mixture is filtered and the filtrate is washed with cold dilute hydrochloric acid and saturated sodium bicarbonate, dried and evaporated to give Z-1hydroxymethyl-2-n-pentylcyclopropane.
Preparation of the tosylate by the method of Example 2, followed by condensation with ethyl 2aminophenylacetate by the method of Example 2, followed by saponification by the method of Example 2 provides 2-[1 -(2,3-methanol)octylamino]phenylacetic acid.
Example 320 Treatment of the indicated olefin of the Table II with zinc and diiodomethane by the method of Example 319 to produce the corresponding cyclopropyl compound followed by treatment of the halide with, for example, ethyl 2- or 3-aminophenylacetate or methyl 2- or 3-aminobenzoate by the method of Example 1, followed by saponification of the resulting ester by the method of Example 1, is productive, respectively, of a 2- or 3-(methanoalkyl)aminophenylacetic acid or a 2- or 3 (methanoalkyl)aminobenzoic acid of Table II (Method C).
Treatment of the oiefinic alcohols of Table II with zinc and diiodomethane by the method of Example 31 9 will produce the corresponding cyclopropyl alkanols which upon treatment with methanesulfonic anhydride (Method of Example 2) will produce the corresponding methanesulfonate ester which upon treatment with, for example, ethyl 2- or 3-aminophenylacetate or methyl 2- or 3aminobenzoate by the procedure of Example 2 followed by saponification will produce the 2- or 3 (methanoalkyl)aminophenylacetic acids or the 2-or 3-(methanoalkyl)aminobenzoic acids of Table Il (Method D).
Table II Example Starting Material Method Product 321 3-bromo-3-isopropyl- C 2-[3-(3-isopropyl 4-methyl-1 -pentene 4-methyl- 1 ,2-methano Chem. Abst. 54, pentyl)amino]phenyl 4355a acetic acid 322 4-bromo-2-heptene C 3-[4-(2,3-methano Chem. Abst. 70, heptyl)amino]benzoic 67482x acid Table II (cont.) Example Starting Material Method Product 323 4-bromo-2,4-dimethyl- C 2-[4-(2,4-dimethyl 2-hexene Chem. 2,3-methanohexyl) Abst. 70, 31 69t amino]phenylacetic acid 324 5-chloro-3,5-dimethyl- C 3-[5-(3,5-dimethyl- 3-heptene Chem. 3,4-methanoheptyl) Abst.54, 1256e amino]benzoic acid 325 Z-1 -hydroxy-2-hexa- D 2-[Z-1 -(2,3-methano- decene Ref.B hexadecyl)amino] phenylacetic acid 326 E-1-hydroxy-2-hexa- D 2-[E-1-(2,3-methano decene Ref. B hexadecyl)amino] benzoic acid 327 1-bromo-4-methyl-3- C 3-[1-(4-methyl-3,4 heptene Chem. Abst. methanoheptyl) 71, 102020q amino]phenylacetic acid 328 1-bromo-4-methyl-3- C 2-[1-(4-methyl-3,4 heptene Chem. Abst. methanononyl)amino] 71, P101399h benzoic acid 329 E-7-bromo-3-heptene C 3-[E-1-(4,5-methano Chem. Abst. 74, heptyl)amino]phenyl 99419f acetic acid 330 l-bromo-5,9-dimethyl- C 2-[l-(5,9-dimethyl- 4-decene Chem. 4,5-methanodecyl) Abst. 5?, 8699g amino]benzoic acid 331 1-methanesulfonyloxy- C 3-[1 -(4,5-methano- 4-tetradecene Ref.B tetradecyl)amino] phenylacetic acid 332 1-methanesulfonyloxy- C 2-[l-(4,5-methanol- 4-hexadecene Ref. B. hexadecyl)amino] benzoic acid 333 6-bromo-1 -hexene C 3-[1 -(5,6-methano- Chem. Abst. 66, hexyl)amino]phenyl 2142j acetic acid 334 6-bromo-2-methyl- C 2-[1-(5,6-methanol- 1-hexene Chem. 5-methylhexyl)amino] Abst. 75, 1 09624f benzoic acid 335 6-chloro-1-heptene C 3-[2-(6,7-methano Chem. Abst. 72, heptyl)amino]phenyl 318779 acetic acid 336 6-bromo-2-methyl-2- C 2-[2-(5,6-methano- heptene Chem. Abst. 6-methylheptyl) 54, 13166f amino]benzoic acid 337 7-chloro-2-octene C 3-[2-(6,7-methano Chem.Abst. 75, octyl)amino]phenyl 1 29245m acetic acid 338 E-1-chloro-4-nonene C 2-[E-1 -(4,5-methano Chem. Abst. 67, nonyl)amino]phenyl 32294y acetic acid 339 7-bromo-1-heptene C 3-[1-(6,7-methano heptyl)amino]benzoic acid 340 7-chloro-1-octene C 2-[2-(7,8-methano Chem. Abst. 75, octyl)amino]phenyl- 1 29245m acetic acid 341 6-bromo-6-methyl- C 3-[1-(2-methyl-6,7 1-heptene Chem. methanoheptyl)amino] Abst. 66, 94482w benzoic acid 342 6-chloro-2-methyl- C 2-[1-(6-methyl-6,7 1-heptene Chem. methanoheptyl)amino] Abst. 75, 129245 phenylacetic acid Table II (cont.) Example Starting Material Method Product 343 E-8-bromo-2-octene C 3-[1-(6,7-methano- Chem.Abst. 74, octyl)benzoic acid 99419f 344 8-bromo-2,6-dimethyl- C 2-[1-(3,7-demethyl 2-octene Chem. 6,7-methanooctyl) Abst. 72, 90573c amino]phenylacetic acid 345 1 1-bromo-5-undecene C 3-[1-(6,7-methano Chem. Abst. 67, undecyl)amino]benzoic 73101b acid 346 8-bromo-1-octene C 2-[1-(7,8-methano Chem. Abst. 70, octyl)amino]phenyl 109909 acetic acid 347 R-8-iodo-7-methyl- C 3-[1-(2-methyl-7,8 1 -octene Chem. methanooctyl)amino] Abst. 74, 1 2573e benzoic acid 348 1-chloro-7-tetra- C 2-[1-(7,8-methano decene Chem. Abst. tetradecyl)amino] 54, 22461h phenylacetic acid 349 9-chloro-1-nonene C 3-[1-(8,9-methano Chem.Abst. 70, nonyl)amino]benzoic 114490k acid 350 1-bromo-8-hepta- C 2-[1-(8,9-methano decene Chem. Abst. heptadecyl)amino] 52, 249d benzoic acid 351 E-1-bromo-9-octa- C 3-[E-1-(9,10-methano- decene Chem. Abst. octadecyl)amino] 70, 47799j phenylacetic acid 352 Z-1 -bromo-9-octa- C 2-[Z-1 -(9,1 0-methano- decene Chem. Abst. octadecyl)amino] 70, 46779j benzoic acid 353 1 1-chloro-1-undec- C 3-[1-(10,11-methano- ene Chem.Abst. undecyl)amino] 66, P19046d phenylacetic acid 354 1 2-iodo-3,7,1 1 -tri- C 2-[1 -(2,6,1 0-tri- methyl-1-dodecene methyl-i 1,12- methanododecyl) amino]benzoic acid 355 1 3-bromo-1 -tri- C 3-[1-(12,1 3-methano- decene Chem. Abst. tridecyl)amino] 67,43348v phenylacetic acid 356 22-bromo-9-docos- C 2-[ 1 -(13,1 4-methano- ene Chem. Abst. docosyl)amino] 73, 44976j benzoic acid 357 1 6-methanesulfonyl- C 3-[1 -(15,1 6-methano- oxy-1-hexadecene hexadecyl)amino] Ref.B phenylacetic acid 358 3-chloro-2,4,4-tri- C 1-[3-(2,4,4-tri methyl-i -pentene methyl]-1 2-methano Chem. Abst. 72, pentyl)amino]benzoic 1110811 acid Example 359 2,3-Dihydroxypropyl 2-(4-pentadecenyl)aminophenylacetate A solution of 7.35 g. of 2-(4-pentadecenyl)aminophenylacetic acid in 50 ml. of hexamethylphosphoramide is treated with 4.80 g. of 25% aqueous sodium hydroxide followed by 11.0 g. of 3-chloro-1 ,2-propanediol and then is heated at 1 400C. for 6 hours. The mixture is diluted with water and ether and filtered to yield a white solid. Recrystallization from acetonitrile and then from carbon tetrachloride affords the product as a white solid.
Example 360 2,3-Dihydroxypropyl 3-(4-tetradecenylamino)phenylbutyrate A mixture of 2.25 g. of methyl 3-(4-tetradecenylamino)phenylbutyrate, 280 mg. of glycerol, and 1.37 g. of p-toluenesulfonic acid is heated at 1 800C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield the product as a white solid.
Example 361 2,3-Dihydroxypropyl 2-(4-tetradecenylamino)phenylpropionate A solution of 11.8 g. of 2-(4-tetradecenylamino)phenylpropionic acid, 1.00 g. of glycerol, and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords the product as a white solid.
Example 362 Preparation of 3-(allylamino)hydrocinnamic acid A 4 g. sample of ethyl 3-(allylamino)hydrocinnamate is hydrolyzed with 1.6 g. 85% potassium hydroxide in 60 ml. 95% ethanol by refluxing the solution for 5 hours. The solution is cooled, diluted with 100 ml. water and acidified to pH 4.5 with 37% hydrochloric acid. The precipitate is collected, dried in vacuo and crystallized from acetone to yield the title compound as white powder.
Example 363 Preparation of 1 -methanesulfonyloxyoctadec-9-ene To a mixture of 250 ml. of dichloromethane, 25 g. 1 -hydroxyoctadec-9-ene and 16.7 g. of triethylamine cooled in an ice-salt bath to -100C. is added dropwise, over 15 minutes, 18.9 g. of methanesulfonyl chloride. The mixture is cooled at -100C to -1 50C. for 30 minutes and then washed with 300 ml. each of cold water, 109/0 hydrochloric acid, sodium carbonate solution and with saturated sodium chloride solution. The organic layer is dried with magnesium sulfate and concentrated in vacuo to give a pale yellow oil.
Example 364 Preparation of Ethyl 2-(1 -pentadec-4-enyla mino)phenylacetate To a cold (-20 0) stirred solution of 10.8 g. 1 -hydroxypentadec-4-ene prepared by lithium aluminum hydride reduction of methyl tetradec-3-encarboxylate and 1 3.4 ml. triethylamine in 300 ml.
ether is added dropwise 5.6 ml. methanesulfonyl chloride in 5 ml, of either. After addition is completed, the solution is warmed to room temperature, stirred for 30 minutes and filtered directly into a solution of 23.1 g. ethyl 2-aminophenyl acetate in 100 ml. ether. After 17 hours at room temperature, the precipitate is filtered and washed with several portions of methylene chloride. The organic solution is washed twice with 100 ml. water, 100 ml. brine, dried and evaporated. The tan residue is crystallized from ethanol and from acetonitrile to yield the title compound as white crystals.
Example 365 Preparation of Ethyl 3-( 1 -pentadeca-4,1 4-dienylamino)hydrocinnamate A solution of 8.6 ethyl 3-aminohydrocinnamate, 9.77 g. 3,1 3-tetradecadien-1 -carboxaldehde and a few crystals of 2,4-dinitrobenzenesulfonic acid in 250 ml. toluene is refluxed under a Dean-Stark trap for 1 7 hours, whereupon the theoretical amount (0.8 ml.) water has been collected. The toluene is evaporated to yield ethyl 3-[3-(1-pentadeca-4,14-dienylideneaminophenyl]propionate as a crystalline mass.
To a mixture of 17.8 g. of the above compound in 250 ml. ethanol is added 1.68 g. sodium borohydride and the mixture is stirred at room temperature for 18 hours. Excess reagent is decomposed by addition of 10 ml. acetic acid. The solution is concentrated in vacuo and the residue is partitioned between toluene and aqueous potassium carbonate. After drying, the toluene is evaporated to yield a solid. Crystallization from acetonitrile and from ethanol affords the title compound as white crystals.
Example 366 Preparation of Ethyl 3-[2-(3,7,11 -trimethyldodeca-2,6,I 0-trienylamino)phenyl]propionate A mixture of 5.0 g. of ethyl 2-aminohydrocinnamate, 10.0 g. of 1 -methanesulfonyloxy-3,7,1 1 - trimethyldodeca-2,6,1 0-triene (prepared by the method of Example 363), 4.2 g. of anhydrous powdered potassium carbonate and 40 ml. hexamethylphosphoramide is heated to 800C for 1 7 hours.
The mixture is then cooled, diluted with water and extracted with ethyl ether. The ether extracts are .
washed with water, dried and evaporated. The residue is recrystallized from ethanol yielding the title compound as white crystals.
Example 367 Preparation of Ethyl 2-ti (6-decylhept-6-enyl)amino]cinnamate A mixture of ethyl 2-aminocinnamate, 5.9 g. 6-decylhept-6-enylbromide and one equivalent of anhydrous powdered potassium carbonate in 50 ml. hexamethylphosphoramide is heated for 20 hours at 600C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated. Crystallization from acetonitrile provides the title compound as white crystals.
Table Ill The following 2- or 3-(substituted-amino)hydrocinnamates are prepared from the appropriate starting material by the method shown. Alcohols are converted to the corresponding mesylates by the method of Example 363.
Example Method of No. Example 2- or 3-fSubstituted-aminoJhydrocinnamate 368 364 Ethyl 2-(allylamino)hydrocinnamate 369 367 Ethyl 3-(1 -octadec-9-enylamino)hydrocinnamate 370 365 Ethyl 2-(1 -pentadec-4-enylamino)hydrocinnamate 371 366 Ethyl 3-(1-tetrndec-4-eylamino)hydrncinnamate 372 367 Ethyl 2-( 1 -pentadec-4, 1 4-dienylamino)hydrocinnamate 373 364 Ethyl 3-[1-(3,7,1 1-trimethyldodeca-2,6,10-trienyl)- amino]hydrocinnamate 374 366 Ethyl 2-[1 -(6-decylhept-6-enyl)amino] hydrocinnamate 375 364 Ethyl 3-[4-(2,3-methanoheptyl)amino] hydrocinnamate Table IV The following 2- or 3-(substituted-amino)hydrocinnamic acids are prepared from the esters of Table Ill by the method of Example 362.
Example No. 2- or 3-(Substftuted-amino)hydrocinnamic acid 376 2-(Allylamino)hydrocinnamic acid 377 3-(1 -Octadec-9-enylamino)hydrocinnamic acid 378 2-(1-Pentadec-4-enylamino)hydrocinnamic acid 379 3-( 1 -Tetradec-4-enylamino)hydrocinnamic acid 380 2-( 1 -Pentadec-4, 1 4-dienylamino)hydrocinnamic acid 381 3-[1 -(3,7,11 -Trimethyldodeca-2,6, 1 0-trienyl)amino]hydrocinnamic acid 382 2-[1 -(6-Decylhept-6-enyl)amino]hydrocinnamic acid 383 3-[4-(2,3-Methanoheptyl)amino]hydrocinnamic acid Table V The following 2- or 3-(substituted-amino)cinnamates are prepared from the appropriate starting materials by the methods shown.Alcohols are converted to their corresponding mesylates by the method of Example 363.
Example Method of No. Example 2- or 3-(Substftuted-amino)cinnamate 384 364 Ethyl 2-(allylamino)cinnamate 385 367 Ethyl 3-(1 -octadec-9-enylamino)cinnamate 386 365 Ethyl 2-( 1 -pentadec-4-enylamino)cinnamate 387 366 Ethyl 3-(1 -tetradec-4-enylamino)cinnamate 388 367 Ethyl 2-( 1 -pentadec-4,1 4-dienylamino)cinnamate 389 364 Ethyl 3-[1-(3,7,1 1-trimethyldodeca-2,6,10-trienyl)- amino]cinnamate 390 366 Ethyl 2-[1-(6-decylhept-6-enyl)amino]cinnamate 391 364 Ethyl 3-[4-(2,3-methanoheptyl)amino]cinnamate Table VI The following 2- or 3-(substituted-amino)cinnamic acids are prepared from the esters of Table V by the method of Example 362.
Example No. 2- or 3-ISubstituted-aminoIcinnamic acid 392 2-(Allylamino)cinnamic acid 393 3-(1-Octadec-9-enylamino)cinnamic acid 394 2-(1 -Pentadec-4-enylamino)cinnamic acid 395 3-(1 -Tetradec-4-enylamino)cinnamic acid 396 2-( 1 -Pentadec-4, 1 4-dienylamino)cinnamic acid 397 3-[1 -(3,7,11 -Trimethyldodeca-2,6,1 0-trienylamino]cinnamic acid 398 2-[1 -(6-Decylhept-6-enyl)amino]cinnamic acid 399 3-[4-(2,3-Methanoheptyl)amino]cinnamic acid Table VII The following 2- or 3-(substituted-amino)phenylpropiolates are prepared from the appropriate starting materials by the methods shown. Alcohols are converted to their corresponding mesylates by the method of Example 363.
Example Method of No. Example 2- or3-{Substituted-aminossphenylpropiolate esters 400 365 Ethyl 2-(allylamino)phenylprnpiolate 401 367 Ethyl 3-(1 -octadec-9-enylamino)phenylpropiolate 402 367 Ethyl 2-(1 -pentadec-4-enylamino)phenylpropiolate 403 366 Ethyl 3-(1 -tetradec-4-enylamino)-phenylpropiolate 404 366 Ethyl 2-( 1 -pentadec-4, 1 4-dienylamino)-phenyl- propiolate 405 364 Ethyl 3-[1 -(3,7,11 -trimethyldodeca-2,6, 1 0-trienyl)- amino] phenylpropiolate 406 364 Ethyl 2-[1 -(6-decylhept-6-enyl)amino]phenyl- propiolate 407 365 Ethyl 3-[4-(2,3-methanoheptyl)amino]phenyl- propiolate Table VIII The following 2- or 3-(substituted-amino)phenylpropiolic acids are prepared from the esters of Table VII by the method of Example 362.
Example No. 2- or 3-(Substituted-amino)phenylpropiollc acid 408 2-(Allylamino)phenylpropiolic acid 409 3-( 1 -Octadec-9-enylamino)phenylpropiolic acid 410 2-(1-Pentadec-4-enylamino)phenylpropiolic acid 411 3-( 1 -Tetradec-4-enylamino)phenylpropiolic acid 412 2-( 1 -Pentadeca-4,1 4-dienylamino)phenylpropiolic acid 41 3 3-[1 -(3,7,11 -Trimethyldodeca-2,6, 1 0-trienyl)amino]phenylpropiolic acid 414 2-[1 -(6-Decylhept-6-enyl)amino]phenylpropiolic acid 41 5 3-[4-(2,3-Methanoheptyl)amino]phenylpropiolic acid Table IX The following 2- or 3-(substituted-amino)phenylbutyrates are prepared from the appropriate mesylates by the method of Example 366. The requisite mesylates are prepared by the method of Example 363.
Example No. 2- or 3-(Substituted-amino)phenyltutyrate esters 416 Ethyl 2-(allylamino)phenylbutyrate 417 Ethyl 3-(1 -octadec-9-enylamino)phenylbutyrate 418 Ethyl 2-(1 -pentadec-4-enylamino)phenylbutyrate 419 Ethyl 3-(1 -tetradec-4-enylamino)phenylbutyrate 420 Ethyl 2-(1-pentadeca-4,1 4-dienylamino)phenylbutyrate 421 Ethyl 3-[1 -(3,7,11 -trimethyldodeca-2,6, 1 0-trienyl)amino] phenylbutyrate 422 Ethyl 2-[1 -(6-decylhept-6-enyl)amino]phenylbutyrate 423 Ethyl 3-[4-(2,3-methanoheptyl)amino]phenylbutyrate Table X The following 2- or 3-(substituted-amino)phenylbutyric acids are prepared from the esters of Table IX by the method of Example 362.
Example No. 2- or 3-{Substituted-amino)phenylbutyric acid 424 2-(Allylamino)phenylbutyric acid 425 3-(1 -Octadec-9-enylamino)phenylbutyric acid 426 2-(1 -Pentadec-4-enylamino)phenylbutyric acid 427 3-(1 -Tetradec-4-enylamino)phenylbutyric acid 428 2-( 1 -Pentadeca-4,14-dienylamino)phenylbutyric acid 429 3-[1-(3,7,1 1 -Trimethyldodeca-2,6,1 O-trienyl)amino]phenylbutyric acid 430 2-[1 -(6-Decylhept-6-enyl)amino]phenylbutyric acid 431 3-[4-(2,3-Methanoheptyl)amino]phenylbutyric acid Example 432 Preparation of 2-[4-(2.3-methanoheptyl)amino]acetopheno 2-Aminoacetophenone is heated with 5 g. 1-methanesulfonyloxy-2,3-methanoheptane (prepared by the method of Example 363) in 50 ml. hexamethylphosphoramide containing anhydrous potassium carbonate (1.9 g.) for 1 6 hours a 100 C. The solution is cooled to room temperature, filtered to remove solids, and the filtrate is diluted with cold water (50 ml.). The amber solid so obtained is collected and washed with water. Recrystallization from ethanol followed by dichloromethane provides 2-[4-(2,3methanoheptyl)amino]acetophenone.
Table Xl The following 2- or 3-(substituted-amino)acetophenones are prepared by the method of Example 432. The requisite mesylates are prepared by the method of Example 363.
Example No. 2- or 3-(Suhstituted-amino)acetophenone 433 2-(Allylamino)acetophenone 434 3-(1 -Octadec-9-enylamino)acetophenone 435 2-(1 -Pentadec-4-enylamino)acetophenone 436 3-(1 -Tetradec-4-enylamino)acetophenone 437 3-( 1 -Pentadeca-4, 1 4-dienylamino)acetophenone 438 2-[1 --(3,7,11 -Trimethyldodeca-2,6, 1 0-trienyl)amino]acetophenone 439 3-[ 1 -(6-Decylhept-6-enyl)amino]acetophenone 440 2-[4-(2,3-Methanoheptyl)amino]acetophenone Example 441 Preparation of Sodium 3-(allylamino)phenylacetate A mixture of 3.62 g. of 3-(allylamino)phenylacetic acid and 25 ml. of ethanol water (9::1) containing 0.400 g. of sodium hydroxide is stirred for 4 hours. The mixture is filtered and the residue washed with 10 ml. of ethanol-water (9:1) and dried in vacuo for 24 hours to yield sodium 3 (allylamino)phenylacetate as a white solid.
Example 442 Preparation of 2-( 1 -octadec-9-enylamino)phenylacetyl Chloride A cold solution of 25 g. 2-(1-octadec-9-enylamino)phenylacetic acid in 500 ml. dimethoxyethane methylene chloride (4:1) is prepared and dry hydrochloric acid is bubbled through the solution until no more precipitate forms. The solution is treated with 25 ml. thionyl chloride and refluxed until all of the precipitate has dissolved. The solvents are evaporated to yield the acid chloride hydrochloride as an orange, semi-crystalline mass.
Example 443 Preparation of 2-(N-trifluoroacetyl-allylamino)phenylacetyl Chloride A stirred ice-cold suspension of 9 g. 2-(allylamino)phenylacetic acid in 100 ml. of dimethoxyethane and 1 6 ml. of pyridine is treated with 1 8 ml. of trifluoroacetic anhydride at OOC. The solution is stirred for 30 minutes at room temperature and then diluted with 300 ml. ether and 100 g.
ice. After stirring vigorously for 1 5 minutes, the phases are separated, the ether solution is washed with brine, dried and evaporated to a white, amorphous solid.
To a solution of 9.2 g. of the above solid in 30 ml. methylene chloride and 0.5 ml.
dimethylformamide is added 5.7 ml. thionyl chloride. After 20 hours at reflux, the solvents are evaporated to yield 2-(N-trifluoroacetylallylamino)phenylacetyl chloride as a light yellow, mobile oil.
Example 444 Preparation of 3-(N-carbobenzyloxy-allylamino)phenylacetyl Chloride To 1 5 g. 3-(allylamino)phenylacetic acid in 200 ml. warm chloroform is added a solution of 1 2 g.
sodium carbonate in 1 50 ml. water. To the vigorously stirred solution is added 10 g. carbobenzyloxy chloride. After 2 hours stirring at 400C., the layers are separated, washed three times with 1N hydrochloric acid, dried, and evaporated to an oil. The oil is dissolved in 300 ml. toluene, treated with 1 5 ml. thionyl chloride and the solution is refluxed for 5 hours. The solvents are evaporated and the residue is dissolved three times in toluene, evaporating each time ultimately to yield 3-(Ncarbobenzyloxy-allylamino)phenylacetyl chloride as a viscous, orange oil.
Example 445 Preparation of I -[3-(N-tert-butyloxycarbonyl)-1 -tetradec-4-enylamino]phenylacetyl Imidazole A solution of 10 g. 3-(1 -tetradec-4-enylamino)phenylacetic acid in 100 ml. dioxane is treated with 4.0 g. tert-butylazidoformate and 10 ml. pyridine. After stirring at room temperature for 18 hours, the protected amidoacid is precipitated from solution by the addition of 1 50 ml. water. The solid is collected, thoroughly dried, and dissolved in 200 ml of a mixture consisting of methylene chloride/dimethoxyethane/pyridine (1:4:1). This solution is stirred overnight at room temperature and the solvents are evaporated to yield 1 -[3-(N-tert-butyloxycarbonyl)tetradec-4-enyl-amino]phenylacetyl imidazole as an orange oil.
Example 446 Preparation of Diethyl 2-( I -tetradec-4-enylamino)benzoylmalonate A solution of 26.6 g. of diethyl malonate and 10 mt. of 1 ,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1 ,2-dimethoxyethane under argon. A solution of 17.3 g. of 2 (1 -tetradec-4-enylamino)benzoyl chloride hydrochloride in 1 ,2-dimethoxyethane is then added. The reaction mixture is refluxed for 4.5 hours, cooled, poured on ice, acidified, and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Addition of a small amount of ethanol to the residue gives a solid which is filtered and discarded.The ethanol filtrate is concentrated and the residue is recrystallized from ether to yield diethyl 2-(1 -tetradec-4-enylamino)benzoylmalonate.
Example 447 Preparation of tert-butyl Ethyl 3-( I -pentadeca-4,I 4-dienyla mino)benzoylmalonate A solution of 28.0 g. of tert-butyl ethyl malonate in 10 ml. of 1 ,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1 ,2-dimethoxyethane under argon. A solution of 1 7.3 g. of 3 (1-pentadeca-4,14-dienylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added.
The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. The residue is then recrystallized from ether to yield tert-butyl ethyl 4-(1 -pentadeca-4,1 4-dienylamino)benzoylmalonate.
Example 448 Preparation of Ethyl 2-i.3-(1-allylamino)benzoylacetoacetate A solution of 21.6 g. of ethyl acetoacetate and 10 ml. of 1 ,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1 ,2-dimethoxyethane under argon. A solution of 1 7.3 g. of 2 (1-aííylamino)benzoyl chloride hydrochloride in 1 ,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Recrystallization from ether affords ethyl 2-[2-( 1 - allylamino)benzoyl]acetoacetate as a white solid.
Example 449 Preparation of Ethyl 3-( I -tetradec-4-enylamino)benzoylacetate A solution of 3.0 g. of tert-butyl ethyl 3-(1 -tetradec-4-enylamino)benzoyl malonate 10 ml. of trifluoroacetic acid is warmed with stirring for 3 hours. The solution is poured onto ice and neutralized with potassium hydroxide. The resulting precipitate is collected by filtration, washed with water and dried. Recrystallization from chloroform affords ethyl 3-(1 -tetradec-4-enylamino)benzoylacetate.
Example 450 Preparation of 2-(I -tetradec-4-enylamino)benzoylacetic Acid Two grams of ethyl 2-(1 -tetradec-4-enylamino)benzoylacetate is added to a solution of potassium hydroxide in 50 ml. of 1:9 water-ethanol. The reaction mixture is stirred for 24 hours at room temperature. Careful neutralization with sulfuric acid gave a precipitate which is filtered, washed with water, and dried to yield 2-(1 -tetradec-4-enylamino)benzoylacetic acid.
Example 451 Preparation of 2'-(l-allylamino)- 2-( methylsulfinyl)acetophenone To a solution of 5.8 g. of dimethyl sulfoxide, dried over sieves, and 50 ml. of tetrahydrofuran is slowly added 28 ml. of n-butyllithium (2.4 M in hexane). To this mixture is added 10 g. of methyl 2-(1 allylamino)benzoate in 200 ml. of tetrahydrofuran. After two hours, the reaction mixture is poured onto ice, acidified with dilute hydrochloric acid and quickly extracted with chloroform. The chloroform extract is washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentration afford a solid which is washed with 500 ml. of hot hexane, filtered while hot and then washed with hexane. The white solid is dried in vacuo to yield 2'-(1 -allylamino)-2 (methylsulfinyl)acetophenone.
Example 452 Preparation of 3'-( I -allylamino)-2-(phenylsulfonyl)acetophenone A solution of 864 mg. of sodium hydride and 5.3 g. of methylphenylsulfone in 20 ml. of 1,2dimethoxyethane is stirred at 60C. for one hour under an atmosphere of argon. To this solution is added a solution of 5.0 g. of methyl 3-(1 -allylamino)benzoate in 50 ml. of tetrahydrofuran and the reaction mixture is stirred at 600 C. for 1.5 hours. The mixture is cooled, poured onto ice, acidified with dilute hydrochloric acid to pH 3 and then extracted with chloroform. The organic layer is separated, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated to dryness.The crude solid is chromatographed on silica gel, diluted with methylene chloride to yield 3'-(1 -allylamino)-2-(phenylsulfonyl)acetophenone.
Example 453 Preparation of 2'-( I -cyclopentylethylamino)-2-(phenylsulfinyl)acetophenone To a solution of 6.2 g. of methylphenylsulfoxide, dried over sieves, and 50 ml. of tetrahydrofuran is slowly added 28 ml. of n-butyllithium (2.4 M in hexane). To this mixture is added 10 g. of a solution of methyl 2-(1 -allylamino)benzoate in 200 ml. of tetrahydrofuran. After two hours, the reaction mixture is poured onto ice, acidified with diluted hydrochloric acid and quickly extracted with chloroform. The chloroform layer is washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. Concentration affords a solid which is washed with 500 ml. of hot hexane, filtered while hot, and then washed with 50 ml. of hexane.The white solid is dried in vacuo yielding 2' (1 -allylamino)-2-(phenylsulfinyl)acetophenone.
Example 454 Preparation of 3-[3'-(1-allylamino)benzoyl]-2,4-pentanedione A solution of 28.4 g. of 2,4-pentanedione and 20 ml. of 1 ,2-dimethoxyethane is added to a suspension of 13.6 g. of sodium hydride in 220 ml. of 1 ,2-dimethoxyethane under argon. A solution of 28.7 g. of 3-(1 -allylamino)benzoylchloride hydrochloride in 1 ,2-dimethoxyethane is then added. The reaction mixture is stirred at room temperature for 12 hours, cooled, poured onto ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution dried over anhydrous sodium sulfate and concentrated. The residue is then chromatographed over silica gel to yield 3-[3'-(1 -allylamino)benzoyl]-2,4-pentanedione.
Example 455 Preparation of Methyl 3-[2-( I -allyiamino)benzoyljpropionate A mixture of 35 g. of 3-(2-acetamidobenzoyl)propionic acid, 700 ml. of methanol and 1.4 ml. of concentrated sulfuric acid is refluxed for 76 hours. The solution is cooled to 35"C. and poured onto 7 g.
of anhydrous sodium acetate while stirring. The reaction mixture is stirred in an ice-bath. The solid is collected and washed with cold methanol to yield 3-(2-aminobenzoyl)propionate as a white solid. A mixture of this solid, 9.2 g. of 1 -allylbromide and 4.2 g. of potassium carbonate is stirred for 20 hours at 1 250C. under nitrogen. The mixture is then cooled to 250C. and 30 ml. of water is added. After stirring, the product is filtered and washed with water. Recrystallization from methanol affords methyl 3-[2-(1-allylamino)benzoyl]propionate as a white solid.
Example 456 Preparation of 3-[3-( I -allylamino)benzoyl]propionic acid A solution of 5.4 g. of methyl 3-[3-(1 -allylamino)benzoyl]propionate is stirred with 5.4 g. of potassium hydroxide in 100 ml. of 95% ethanol for 3 hours at reflux. The reaction mixture is cooled, diluted with 50 ml. of ethanol and 100 ml. of water, neutralized with hydrochloric acid. The solution is cooled to room temperature and filtered. The white solid is washed with 50% aqueous ethanol and dried. The product is recrystallized from ethanol to yield 3-[3-(1-allylamino)benzoyl]propionic acid.
Table XII The following acetophenones are prepared by the noted methods from the carboxylic acids of Tables I or II or appropriate derivatives thereof which are obtained by the methods of Examples 442445.
Example Method of No. Example 2- or 3-(Substituted-amino)acetophenones 457 446 Diethyl 2-[( 1 -tetradec-4-enyl)aminojbenzoylmalonate 458 447 tert-Butyl ethyl 3-(1-allylamino)benzoylmalonate 459 448 Ethyl 2-[2-(1-pentadec-4,14-dienylamino) benzoyl]acetoacetate 460 449 Ethyl 3-[1-(3,7,11 -trimethyidodeca-2,6,10-trienyl)- amino]benzoylacetate 461 450 2-(2,3-Methanoheptylaminojbenzoylacetic acid 462 451 3-[1 -(6-Decylhept-6-enyl)amino]-2-(methyl- sulfonyl)acetophenone 463 452 2'-(Allylamino)-2-(phenylsulfonyl)acetophenone 464 453 3'-(Propargylamino)-2-(phenylsulfinyl)- acetophenone Example Method of No.Example 2- or3-6Substituted-aminoJacetophenones 465 454 3'-[3-(2,3-Methanoheptylamino)benzoyl]-2,4- pentanedione 466 455 Methyl 3-[3-(allylamino)benzoyl]propionate 467 456 3-[2-( 1 -Pentadec-4-enylamino)benzoyl]propionic acid Example 468 Preparation of 2-[1-(2,3-methanoheptyl)aminolbenzonitrile 2-Aminobenzonitrile (11.8 g.) and 1 -iodo-2,3-methanoheptane (16.3 g.) are dissolved in hexamethylphosphoramide (100 ml.) and heated under nitrogen in an oil bath maintained at 1200C.
for 22 hours. The reaction mixture is cooled to room temperature and water (100 ml.) is added gradually. The mixture is then chilled in an ice bath. The precipitate separated is filtered, washed thoroughly with water, and dried. It is then washed repeatedly with hexane and dried. Recrystallization from ether-hexane affords 2-[1 -(2,3-methanoheptyl)amino]benzonitrile as pale yellow crystals.
Example 469 Preparation of 3-(allylamino)benzaldehyde Di-isobutylaluminum hydride (54 ml., 25% solution in toluene) is added with stirring to a solution of 12.1 g. of 3-(allylamino)benzonitrile under a nitrogen atmosphere. After addition is completed, the solution is stirred for one hour. A solution of methanol in toluene (50 ml., 1:1) is added over 30 minutes and the mixture is poured into 500 ml. vigorously stirred ice-cold 50% aqueous sulfuric acid. The mixture is filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid.The product is recrystallized from dichloromethane/hexane giving colorless needles.
Table XIII The following 2- or 3-(substituted-amino)benzonitriles are prepared by the method of Example 468.
Example No. 2- or 3-(Substituted-amino)benzonitrlle 470 2-(Allylamino)benzonitrile 471 3-(1 -Octadec-9-enylamino)benzonitrile 472 2-(1 -Pentadec-4-enylamino)benzonitrile 473 3-(1 -Tetradec-4-enylamino)benzonitrile 474 2-( 1 -Pentadeca-4, 1 4-dienylamino)benzonitrile 475 3-[ 1 -(3,7,11 -Trimethyldodeca-2,6, 1 0-trienyl)amino]benzonitrile 476 2-[1 -(6-Decylhept-6-enyl)amino]benzonitrile 477 3-[4-(2,3-Methanoheptyl)am ino]benzonitrile Table XIV The following 2- or 3-(substituted-amino)benzaldehydes are prepared from the corresponding benzonitriles of Table XIII by the method of Example 469.
Example No. 2- or 3-{Substituted-amino)benzaldehydes 478 2-(Allylamino)benzaldehyde 479 3-( 1 -Octadec-9-enylamino)benzaldehyde 480 2-(1 -Pentadec-4-enylamino)benzaldehyde 481 3-(1 -Tetradec-4-enylamino)benzaldehyde 482 2-( 1 -Pentadeca-4,1 4-dienylamino)benzaldehyde 483 3-[1 -(3,7,11 -Trimethyldodeca-2,6,1 O-trienyl)amino]benzaldehyde 484 2-[1 -(6-Decylhept-6-enyl)amino]benzaldehyde 485 3-[4-(2,3-Methanoheptyl)amino]benzaldehyde Example 486 Preparation of 2,3-dihydroxypropyl 2-(allylamino)phenylacetate A solution of 7.34 g. of 2-(allylamino)phenylacetic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1 ,2-propanediol in 50 ml. of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 2-(allylamino)phenylacetate.
Example 487 Preparation of Methyl 3-(allylamino)phenylacetate A solution of 20.7 g. of 3-(allylamino)phenylacetic acid in 25 ml. of hexamethylphosphoramide is added to a stirred mixture of 0.800 g. of sodium hydride (57% in mineral oil) and 25 ml. of hexamethylphosphoramide. The solution which forms after one hour is treated with 11.0 g. of methyl iodide and is then stirred at 250C. for 1 8 hours. Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield methyl 3-(allylamino)phenylacetate.
Example 488 Preparation of 3-hydroxypropyl 2-(allylamino)phenylacetate A mixture of 2.25 g. of methyl 2-(allylamino)phenylacetate, 280 mg. of 1,3-propanediol and 1.37 g. p-toluenesulfonic acid is heated at 1800 C. for 1 8 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield 3hydroxypropyl 2-(allylamino)phenylacetate.
Example 489 Preparation of 2-ethoxyethyl 3-(allylamino)phenylacetate A solution of 11.8 g. of 3-(allylamino)phenylacetic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml.
of boron trifluoride etherate in 200 ml. toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 mi. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2-ethoxyethyl 3 (allylamino)phenylacetate.
Example 490 Preparation of Methyl 2-(allylamino) hydrocinnamate A solution of 50.5 g. of 2-(allylamino)hydrocinnamic acid and 34.4 ml. of boron trifluoride etherate in 200 ml. of methanol is stirred under reflux for 44 hours, allowed to cool, and poured into 1.20 liters of ice-cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzene-ethanol to yield methyl 2-(ailylamino)hydrocinnamate.
Example 491 Preparation of 1-(methoxyearbonyl)propyl 3-(allylamino)hydrncinnamate To a solution of 10.0 g. 3-(allylamino)hydrocinnamoyl chloride hydrochloride in 200 ml.
methylene chloride is added dropwise a solution of 3 g. methyl 2-hydroxybutyrate and 5 g.
triethylamine in 100 ml. ether. After 1 7 hours stirring at room temperature, the precipitate is collected and washed with several portions of ether. The ether solution is washed with water, dried and evaporated to yield 1 -(methoxycarbonyl)propyl 3-(allylamino)hydrocinnamate as a white solid.
Example 492 Preparation of 1-(ethoxycarbonyl)ethyl 2-(allylamino)phenylacetate To a warm mixture of 7 g. sodium 2-(allylamino)phenylacetate in 100 ml. ethanol is added 4.7 g.
ethyl 2-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield 1 -(ethoxycarbonyl)ethyl-2-(allylamino)phenylacetate as colorless crystals.
Example 493 Preparation of 1-carboxyethyl 3-(allylamino)phenylacetate A flask containing 10.0 g. 3-(allylamino)phenylacetic acid, 3.3 g. lactic acid, 500 mg.
toluenesulfonic acid and 500 ml. toluene equipped with a Soxhlet extractor charged with activated 4A Linde molecular sieves. The solution is refluxed for 24 hours during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon 1 carboxyethyl 3-(allylamino)phenylacetate separates as off-white crystals.
Example 494 Preparation of Diethyl 0-[2-(allylamino)phenylacetyl]tartrate A mixture of 2-[N-trifluoroacetyl-(allylamino)]phenylacetyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 2.5 g. diethyl tartrate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields diethyl 0-[2-(allylamino)phenylacetyljtartrate as a white, crystalline solid.
Example 495 Preparation of O-[3-(allylamino)phenylacetyl] malic Acid A warm solution of 3-[N-carbobenzyloxy-(allylamino]phenylacetyl chloride and 1.3 g.
triethylamine in 100 ml. ether is treated with 2 g. malic acid. An immediate precipitate forms, but the mixture is refluxed for one hour and filtered while hot. The solid is washed several times with hot ether, then the ether is evaporated to yield a white solid. The product is dissolved in tetrahydrofuran (100 mi.) and hydrogenated over 600 mg. 10% palladium-on-carbon at 50 psi until hydrogen uptake stops. The catalyst is filtered, and the solution is evaporated. The residue is crystallized from acetic acid to yield 0 [3-(allylamino)phenylacetyl]malic acid.
Example 496 Preparation of 2-(ethoxycarbonyl)vinyl 2-(allylamino)phenylacetate To a mixture containing 4.3 g. 1 -[2-(N-t-butyloxycarbonyl-allylamino)phenylacetyl]imidazole 50 ml. 5N sodium hydroxide is added 3 g. ethyl 2-formyl acetate. The solution is vigorously stirred for 24 hours. The layers are separated, and the chloroform solution is washed once with 50 ml. 1N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 400C. in 50 ml.
anhydrous trifluroacetic acid. The solvent is again evaporated and the oil is crystallized from acetone to yield light yellow crystals of 2-(ethoxycarbonyl)vinyl 2-(allylamino)phenylacetate.
Table XV The following esters are prepared by the methods shown from the carboxylic acids of Tables I, II, IV, VI, VIII and X or appropriate derivatives thereof obtained by the methods of Examples 441-445.
Example Method of No. Example Ester 497 486 2,3-Dihydroxypropyl 2-(allylamino)phenylacetate 498 486 2,3-Dihydroxypropyl 3-(1 -octadec-9-enylamino)- hydrocinnamate 499 486 2,3-Dihydroxypropyl 2-(1 -pentadec-4-enylamino)- cinnamate 500 486 2,3-Dihydroxypropyl 3-( 1 -pentadec-4, 1 4-dienylamino)- phenylpropiolate 501 486 2,3-Dihydroxypropyl 2-[1-(3,7,1 1-trimethyldodeca- 2,6,1 O-trienylamino]butyrate 502 487 Methyl 3-[1-(6-decylhept-6-enyl)amino]- phenylacetate 503 487 Methyl 2-[4-(2,3-methanoheptyl)amino]- hydrocinnamate 504 487 Methyl 3-( 1 -pentadeca-4,1 4-dienylamino)cinnamate 505 487 Methyl 2-( 1 -octadec-9-enylamino)phenylpropiolate 506 487 Methyl 3-[4-(allylamino)phenyl]butyrate 507 488 2-Hydroxypropyl 2-(allylamino)phenylacetate 508 488 4-Hydroxybutyl 3-[1 -(6-decylhept-6-enyl)amino]- hydrocinnamate 509 488 2-Hydroxypropyl 2-[1-(3,7,11 -trimethyldodeca-2,6,1 0- trienyl-amino]cinnamate 510 488 3-Hydroxypropy! 3-[4-(2,3-methanoheptylamino] phenylpropiolate 511 488 2-Hydroxyethyl 2-11 -(6-decylhept-6-enyl)amino]- phenylbutyrate 512 489 2-Methoxyethyl 3-(propargylamino)phenylacetate 513 489 2-Ethoxyethyl 2-(1 -cyclopropylmethylamino) propiolate 514 490 Methyl 3-(allylamino)hydrocinnamate 515 490 Methyl 2-(3-cyclopropylpropylamino)cinnamate 51 6 491 1 -Methoxycarbonylpropyl 3-( 1 -pentadec-4, 14- dienylamino)hydrocinnamate 517 491 1 -Ethoxycarbonylpropyl 2-[1 -(6-decylhept-6 enyl)aminojphenylpropiolate 51 8 492 1 -Ethoxycarbonylethyl 3-( 1 -pentadec-4- enylamino)phenylpropiolate 519 493 1 -Carboxyethyl 2-(1 -octadec-9-enylamino) phenylacetate 520 493 1 -Carboxyethyl 3-[2-(2-methylcyclopropylethyl aminojcinnamate Example Method of No.Example Ester 521 493 1-Carboxybutyl 2-(allylamino)phenylpropiolate 522 493 1-Carboxyethyl 4-[3-(1 -pentadec-4-enylamino) phenylibutyrate 523 494 Diethyl 0-[2-(1 -pentadec-4,1 4-dienylamino)- phenylacetyl]tartrate 524 495 0-[3-(Allylamino)benzoyi]malic acid 525 495 0-[2-(cyclopropylmethylamino)benzoyl]malic acid 526 496 2-(Ethoxycarbonyl)vinyl 3-(but-2-enylamino) hydrocinnamate 527 496 2-(Ethoxycarbonyl)vinyl 2-(allylamino)cinnamate 528 496 2-(Ethoxycarbonyl)vinyl 3-(tetradec-4-amino) propiolate 529 496 2-(Ethoxycarbonyl)vinyl 4-[2-( 1 -octadec-9- enylamino)phenylbutyrate Example 530 Preparation of 2-(pentadec-4-enylaminobenzhydroxamic Acid To a suspension of 2-(pentadec-4-enylamino)benzoic acid (44 g.) in glyme (350 ml.) and pyridine (70 ml.) at OOC. is added trifluoroacetic anhydride (67 ml., 100 g.) at such a rate as to maintain the temperature at 20--300C. The resulting solution is stirred at 10-1 50C. for 2 hours, then diluted with ether (499 ml.), cooled in an ice-bath and ice (100 gm.) is added. The mixture is stirred viorously at ambient temperature for 1 hours. The aqueous layer is extracted with ether and the combined ether extracts are washed with water, brine, dried over sodium sulfate and concentrated in vacuo to provide 57 g. of 2-[N-trifluoroacetyl-N-Kpentadec-4-enyl)amino]benzoic acid as an oil that solidifies upon standing.
The N-trifluoracetyl derivative (57 g.) is dissolved in thionyl chloride (300 ml.) and refluxed for 3 hours. After cooling, the mixture is diluted with toluene and concentrated in vacuo. The residue is diluted again with hot toluene and filtered. The toluene is concentrated in vacuo to provide 61 g. of 2 [N-trifluoroacetyl-N-fpentadec-4-enyl)aminojbenzoyl chloride as an oil.
To a stirred solution of hydroxylamine hydrochloride (16 g.) in pyridine (75 ml.) and dichloromethane (35 ml.) is added dropwise the previously prepared benzoyl chloride derivative (11.5 g.) in dichloromethane (20 ml.). After 1 hour, the mixture is diluted with water and extracted with ether.
The combined organic extract is then washed with water, brine, dried with sodium sulfate and concentrated in vacuo to afford 2-[N-trifluoroacetyl-N-(pentadec-4-enyl)amino]henzhydroxamic acid as an oil.
A portion of this oil (0.9 g.) is dissolved in ethanol (20 ml.), 1 N sodium hydroxide solution is added, and the mixture is stirred at ambient temperature. The mixture is stirred at ambient temperature. The mixture is chilled and filtered to provide a white solid that is washed with ethanol.
The white solid is recrystallized from hot ethanol to provide 2-Kpentadec-4-enylamino)benzhydroxamic acid.
Example 531 Preparation of Esters Treatment of the acids of Examples 1-317 and 321-358 with trifluoroacetic anhydride to provide the NCOCF3 derivative, followed by treatment with thionyl chloride to provide the N--COCF, acid chloride, followed by treatment with one of the following alcohols, followed by removal of the N-COCF3 group with sodium hydroxide by the method of Example 530 provides the corresponding ester of the starting acid.
Alcohols: benzyl alcohol, p-fluorobenzyl alcohol, p-bromobenzyl alcohol, p-chlorobenzyl alcohol, pmethoxybenzyl alcohol, m-chlorobenzyl alcohol, p-carboxybenzyl alcohol, phenol, p-fluorophenol, pbromophenol, p-chlorophenol, p-methoxyphenol, p-carboxyphenol, 4-cyanophenol, 3-hydroxypyridine, 2-chloro-3-hydroxypyridine, 5-ca rboxy-3-hydroxypyridine.
Example 532 Preparation of Amides Treatment of the acids of Examples 1-317 and 321-358 with trifluoroacetic anhydride to provide the N-COCF3 derivative, followed by treatment with thionyi chloride to provide the N-COCF3 acid chloride, followed by treatment with one of the following amines, followed by removal of the N--COCF, group with sodium hydroxide by the method of Example 530 provides the corresponding amide of the starting acid.
Amines: p-alanine, allylamine, allylcyclohexylamine, aminoacetonitrile, a-aminoacetophenone, 2- amino-1-butanol, 3-aminobutyric acid, 4-aminobutyric acid, 1-amino-1-cyclopentanemethanol, 2- amino-5-diethylaminopentane, N-(2-aminoethyl)morpholine, N-(2-aminoethyl)piperazine, N-(2 aminoethyi)-piperidine, 2-amino-2-ethyi-a,3-propanediol, 2-(2-aminoethyl)pyridine, N-(2- aminoethyl)pyrrolidine, DL-4-amino-3-hydroxybutyric acid, 5-aminolevulinic acid, aminoethanesulfonic acid, p-aminoethylbenzenesulfonamide, 2-amino-3-methyl-l -butanol, aminomethylcyclobutane, 4 (aminomethyl)cyclohexanecarbonitrile, 1 -aminoethyl-1 -cyclohexanol, aminomethylcyclopropane, 4- (aminomethyl)piperidine, 2-amino-2-methyl- 1 ,3-propanediol, 2-amino-2-methyl-1 -propanol, 2- (aminomethyl)-2-propanol, 2-aminomethylpyridine, 3-aminomethylpyridine, 4-aminomethylpyridine.
2-amino-1 -phenyl-ethanol, 2-amino-3-phenyl-1 -propanol, 3-amino-3-phenylpropionic acid, 3-amino- 1 ,2-propanediol, 1 -amino-2-propanol, N-(3-aminopropyl)diethanolamine, N-(3-aminopropyl) morpholine, 1 -(3-aminopropyl)-2-pipecoline, N-(3-aminopropyl)-2-pyrrolidinone, 5-aminovaleric acid, bis-(2-ethanolethyl)amine, bis(2-methylallyl)amine, p-bromophenethylamine, 3-bromopropylamine hydrobromide, n-butylamine, sec-butylamine, tert-butylamine, 2-chlorobenzylamine, 3- chlorobenzylamine, 5-chlorobenzylamine, 2-chloroethylamine, 3-chloropropylamine, cyclobutylamine, cycloheptylamine, 1 ,3-cyclohexanebis(methylamine), cyclohexanemethylamine, cyclohexylamine, cyclopentylamine, cyclopropylamine, 3-(di-n-butylamino)propylamine, 1 5-dimethylhexylamine, a,4 dimethyl-3-hydroxyphenethylamine, 1 , 1 -dimethylpropargylamine, 1 ,2-dimethylpropylamine, 1 ,2- diphenylethylamine, ethylamine, ethyl-3-aminobutyrate, ethyl-4-aminobutyrate, 2 (ethylamino)ethanol, 1 -ethylpropylamine, 1 -ethynylcyclohexamine, m-fluorobenzylamine, pfluorobenzylamine, 2-fluoroethylamine, furfurylamine, n-heptylamine, isoamylamine, isopropylamine, m-methoxybenzylamine, p-methoxybenzylamine, 2-methoxyethylamine, o-methoxyphenthylamine, pmethoxyphenethylamine, N-methyl-p-alanine-nitrile,2-methylallylamine, methylamine, methylaminoacetonitrile, 2-(methyl)aminoethanol, 2-methylbenzylamine, 3-methylbenzylamine, 4- methylbenzylamine, 4-methylbenzylamine, 1 -methylbutylamine, 4-methylcyclohexylamine, 1 - norepinephrine, 4-phenylbutylamine, 1 -phenylcyclopropanemethylaine, trans-2phenylcyclopropylamine, D(-)---phenylglycinol, 2-phenylglycinonitrile, phenylpropanolamine, 3phenyl-a-propylamine, monopropargylamine, propylamine, taurine, tetrahydrofurfurylamine, 1 ,2,3,4- tetrahydro-1 -naphthylamine, 2-(p-tolyl)-ethylamine, m-aminobenzoic acid, p-aminobenzoic acid, o- aminobenzyl alcohol, p-aminobenzyl alcohol, 3,5-dimethylpiperidine, 2-ethylpiperidine, 3- hydroxypiperidine, 4-hydroxypiperidine, 2-iminopiperidine, isonipecotamide, isonipecotic acid, methyl 4-oxo-3-piperidinecarboxylate, 2-methylpiperidine, 3-methylpiperidine, 4-methylpiperidine, nipecotamide, 4-phenylpiperidine, 4-phenyl-1 ,2,3,S-tetrahydropyridine, pipecolinic acid, piperidine, 2 piperidine-ethanol, 2-piperidinemethanol, 3-piperidinemethanol, 4-piperidinopiperidine, 4-piperidine 1 ,2,3,6-tetrahydropyridine, 2,2,6,6-tetramethylpiperidine, 2,2,6,6-tetramethyl-4-piperidinol, 2,2,6,6- tetramethyl-4-piperidone, 4,4-trimethylenedipiperidine, 2-methylpiperidine, 3-methylpiperidine, 4- methylpiperidine, 4-phenylpiperidine, piperidine, morpholine, hexamethyleneimine, heptamethyleneimine, pentamethyleneimine, pyrrolidine, N-methylpiperazine, dl-alanine, hydrazine, N acetyihydrazine, dl-valine, A3-piperidine, dl-leucine, 2-aminoisobutyric acid.
Example 533 Preparation of N-[3-(9-Octadecenyla mino)benzoyl]benzamide Sodium hydride (1.0 g., 50% dispersion in mineral oil) is washed with hexane three times under nitrogen. To the dry sodium hydride is added 5 ml. of freshly distilled tetrahydrofuran. To this suspension is added a solution of 2.4 g. of benzamide in 5 ml. of tetrahydrofuran. After complete reaction (30 min.), a solution of 0.9 g. 3-[N-trifluoracetyl-N-(9-octadecenyl)amino]benzoyl chloride (Example 530) in 3 ml. of tetrahydrofuran is added. After stirring at ambient temperature for 1 hour, the reaction mixture is poured into water and extracted twice with ether. The ether extracts are washed with water, brine, dried with sodium sulfate, and concentrated in vacuo.The residue is recrystallized from ether-acetonitrile (1:1) to provide N-83-[N-trifluoracetyl-N-(9- octadecenyl)amino]benzoyl)benzamide.
The N-trifluoroacetyl compound is in turn treated with ethanol and 1 N sodium hydroxide and the mixture is stirred at ambient temperature for 6 hours. Chilling and filtration affords a white solid which is recrystallized from ethanol to yield N-[3-(9-octadecenylamino)benzoyl]benzamide.
Example 534 Preparation of N-[2- or 3-(substituted amino)benzoyl or phenylacetyl]benzamides Treatment of the N--COCF, acid halides (prepared by the method of Example 530 from the corresponding acids of Examples 1-317 and 321-358) with benzamide and sodium hydride followed by removal of the N-COCF3 group by the method of Example 533 is productive of the corresponding benzamides.
Example 535 Preparation of 2-(4-pentadecenylamino)-N-(phenylsulfonyl)benzamide A solution of 31.4 g. of benzenesulfonamide in 250 ml. of dry dimethylacetamide is added dropwise, with stirring and cooling, to a suspension of 5.5 g. of sodium hydride in 100 ml. of dry dimethylacetamide over 30 minutes at room temperature. Stirring is continued for a further 30 minutes. In the meantime, a mixture of 36.2 g. of 2-(4-pentadecenylamino)benzoic acid in 1200 ml. of methylene chloride, 300 ml. of dimethoxyethane, and 40 ml. of thionyl chloride is refluxed for 1 hour and 1 5 minutes. The solution is evaporated to an oil which is co-evaporated twice with added dioxane to remove excess thionyl chloride.To the resulting oily residue of 2-(4-pentadecenylamino)benzoyl chloride hydrochloride is added, in one portion, the previously prepared mixture of sodium benzenesulfonamide in dimethylacetamide. The mixture is stirred for 30 minutes, without cooling, and is then filtered through a bed of diatomaceous earth. The filtrate is poured into 2 1. of water, and 250 ml. of saturated sodium chloride solution is added to coagulate the precipitate. The mixture is filtered and the product is washed with water and partially air dried. The product is dissolved in methylene chloride, the mixture is filtered through diatomaceous earth, and brine is added to break the emulsion.
The layers are separated, the organic phase is dried over anhydrous sodium sulfate and filtered through a bed of 300 g. of hydrous magnesium silicate. The product is eluted with an additional 3 1. of methylene chloride. The first approximately 1 I. of filtrate is set aside and the remainder is evaporated to dryness. The residue is crystallized three times from toluene and the product is dried in the Abderhalden at 650C. to provide the title compound as colorless crystals.
Example 536 Preparation of 2- or 3-(substituted amino)-N-(sulfonyl)benzamides or phenylacetamides Treatment of the acid chloride hydrochloride (prepared from the corresponding carboxylic acids of Examples 1-317 and 321-358 by the procedure of Example 539 with the following sulfonamides by the procedure of Example 535 is productive of the corresponding 2- or 3-(substituted amino)-N (sulfonyl)benzamide or phenylacetamides. The sulfonamide starting materials are benzenesulfonamide, methanesulfonamide, p-methylphenylsulfonamide, p-nitrophenylsulfonamide, pchlorophenylsulfonamide.
Example 537 Preparation of N-trifluoroacetyl-2 or 3-(4-tetradecenylamino)benzoyl Chloride A stirred, ice-cold suspension of 9 g. (24.9 mmoles) 2- or 3-(4-tetradecenylamino)benzoic acid in 100 ml. dimethoxy ethane and 1 6 ml. pyridine is treated with 1 8 ml. trifluoroacetic anhydride. The solution is stirred at OOC. for 30 minutes at room temperature. The solution is diluted with 300 ml.
ether and 100 g. ice. After stirring vigorously for 1 5 minutes, the phases are separated, the ether solution is washed with brine, dried and evaporated to a white amorphous solid.
To 9.2 g. of the above product in 30 ml. methylene chloride and 0.5 ml. dimethylformamide is added 5.7 ml. thionyl chloride. After 20 hours at reflux, the solvents are evaporated to yield the product as a light yellow mobile oil.
Example 538 Preparation of N-carbobenzyloxy-2 or 3-(4,1 4-pentadecadienylamino)benzoyl Chloride To 15 g. of 2- or 3-(4,1 4-pentadecadienylamino)benzoic acid in 200 ml. warm chloroform is added 1 5 g. sodium carbonate in 1 50 ml. water. To the vigorously stirred mixture is added 10 g.
carbobenzoyl chloride. After 2 hours stirring at 400 C, the layers are separated, the chloroform layer is washed three times with 1 N hydrochloric acid, dried, and the solvent evaporated to yield an oil. The oil is dissolved in 300 ml. toluene, treated with 15 ml. of thionyl chloride, and the solution is refluxed for 5 hours. The solvents are evaporated and the residue is dissolved three times in toluene. evaporating each time to yield a viscous, orange oil.
Example 539 Preparation of 2- or 3-(4-tetradecenylamino)benzoyl Chloride A cold solution of 25 g. 2- or 3-(4-tetradecenylamino)benzoic acid in 500 ml. dimethoxyethane methylene chloride (4:1) is prepared and dry hydrochloric acid is bubbled through the solution until no more precipitate forms.
The solution is treated with 25 ml. thionyl chloride and refluxed until all of the precipitate has dissolved. The solvents are evaporated to yield an orange, semi-crystalline mass.
In an analogous manner, 2- or 3-(4-tetradecenylamino)phenylacetyl chloride is obtained from the corresponding phenylacetic acid.
Example 540 Preparation of N-[2-(4-tetradecenylamino)benzoyl]alanine A solution of 4.75 g. of N-trifluoroacetyl-2-(tetradecenylamino)benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solvent is evaporated from the combined filtrate and washings. After treatment of the residue with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered and dried. Crystallization from acetone yields the product as a white, crystalline solid.
Example 541 Preparation of 1 -3-[N-(t-butyloxycarbonyl)-N-(4-tetradecenylamino)benzoyl iimidazole A solution of 10 g. of 3-(4-tetradecenylamino)-benzoic acid in 100 ml. dioxane is treated with 4.0 g. of t-butylazidoformate and 10 ml. pyridine. After stirring at room temperature for 1 8 hours, the protected amido-acid is precipitated from solution by addition of 1 50 ml. of water. The product is collected and thoroughly dried. The crude product is dissolved in 200 ml. of a mixture consisting of methylene chloride/dimethoxy ethane/pyridine (1:4:1), and to this is added 5.4 g. of 1,1'- carbonyldiimidazole. The solution is stirred overnight at room temperature and the solvents are evaporated to yield the title compound as a thick orange oil.
Example 542 Preparation of 1 -[2- or 3-(4,14-pentadecadienylamino)benzoyl]piperidine To a warm solution of 2- or 3-[N-carbobenzoyloxy-4,1 4-pentadecadienylamino)benzoyl chloride and 1.3 g. of triethylamine in 100 ml. ether is added 1.2 g. of piperidine. An immediate precipitate forms, but the mixture is refluxed for one hour and filtered while hot. The solid is washed several times with hot ether, then the ether is evaporated from the combined filtrate and washings to yield a white solid. The product is dissolved in tetrahydrofuran (100 ml.) and hydrogenated over 600 mg. 10% palladium on carbon at 20 psi until hydrogen uptake stops. The catalyst is filtered. The solution is evaporated, and the residue is crystallized from acetic acid to yield the title compound as a crystalline mass.
Treatment of a corresponding 2- or 3-(substituted-amino)phenylacetyl chloride in an analogous manner yields the corresponding piperidide.
Example 543 Preparation of 1 -[2- or 3-(4,I 4-pentadecadienylamino)benzoylipyrrolidine A solution of 6.0 g. of 2- or 3-[N-carbobenzyloxy-N-(4,1 4-pentadecadienylamino)]benzoyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 1.1 g. of pyrrolidine. After 1 hour at reflux, the precipitate is filtered off and washed with warm ether. After evaporation of the combined filtrate and washings to dryness, the residue is dissolved in 50 ml. 30% hydrobromic acid in acetic acid and warmed at 500C. for 2 hours. The solvents are evaporated and the product is partitioned between methylene chloride and water. The layers are separated and the methylene chloride is evaporated. The residue is crystallized from acetone to yield colorless crystals.
Treatment of a corresponding 2- or 3-(substituted amino)phenylacetyl chloride in an analogous manner yields the corresponding pyrolidide.
Example 544 Preparation of O-[2-(4, I 4-pentadecadienylamino)benzoylj malic Acid A warm solution of N-carbobenzyloxy-2-(4,14-pentadecadienylamino)benzoyl chloride and 1.3 g.
triethylamine in 100 ml. ether is treated with 2 g. malic acid an immediate precipitate forms, but the mixture is refluxed for one hour and filtered while hot. The solid is washed several times with hot ether, then the ether is evaporated to yield a white solid. The product is dissolved in tetrahydrofuran (100 ml.) and hydrogenated over 600 mg. 10% palladium-on-carbon at 50 psi until hydrogen uptake stops. The catalyst is filtered. The solution is evaporated and the residue is crystallized from acetic acid to yield the title compound as white crystals.
Example 545 Preparation of N-[2- or 3-(4-tetradecenylamino)benzoyl]alanine A solution of 4.75 g. of N-trifluoroacetyl-2- or 3-(4-tetradecenylamino)benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the combined filtrate and washings are evaporated. After treatment of the residue with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered and dried. Crystallization from acetone yields the product a white, crystalline solid.
Treatment of a corresponding 2- or 3-(substituted amino)phenylacetyl chloride in an analogous manner yields the corresponding alanines.
Example 546 Preparation of 4-chlorophenyl 2-(4-tetradecenylamino)benzoate To a solution of 6.4 g. 4-chlorophenol and 7.6 g. triethylamine in 500 ml. methylene chloride is added 10.4 g. 2-(4-tetradecenylamino)benzoyl chloride hydrochloride in 250 ml. methylene chloride.
After four hours at reflux, the solution is cooled, washed with water and dilute phosphoric acid, and dried. After passing the solution through a column of alumina, the solvent is evaporated and the residue is crystallized from diisopropyl ether.
Example 547 Preparation of N-[2-(4-tetradecenylamino)benzoyl]-2-aminoethanesulfonic Acid To a stirred solution of 2.50 g. of taurine and 5.6 ml. of triethylamine in 22.5 ml. of water is added 5.55 g. of N-f2-[2,2,2-trifluoro-N-(4-tetradecenyl)acetamido]benzoyloxylsuccinimide as a solution in 45 ml. of ethanol. After 24 hours, the mixture is treated with 20 ml. of 2.OM sodium hydroxide and 25 ml. of water. After stirring for 10 minutes, the mixture is acidified with dilute hydrochloric acid, and the crude product is collected by filtration. Recrystallization affords the title compound as a white solid.
Example 548 Preparation of 3-[3-(4-pentadecenylamino)benzoyl]-4-carboethoxythiazolidine One-tenth mole of 3-(4-pentadecenylamino)benzoyl chloride hydrochloride in methylene chloride is added to a solution of 0.1 mole of ethyl thiazolidine-4-carboxylate in chloroform containing two equivalents of triethylamine. After 5 hours at 20 C. the solution is filtered and evaporated to a white solid which is recrystallized from acetonitrile.
Example 549 Preparation of 3-[3-(4-pentadecenylamino)benzoyl]-4-carboxythiazolidine By means of the alkaline hydrolysis method of Example 2 the ethyl ester of Example 548 is converted to the subject carboxylic acid. This acid is also prepared using the procedure of Example 548 except that the acylation of the thiazolidine-4-carboxylic acid is carried out in aqueous acetone sodium bicarbonate solution.
Example 550 Preparation of N-[2- or 3-(4-pentadecenylamino)benzoyljglycine A mixture of 26.4 g. of ethyl N-[2- or 3-(4-pentadecenylamino)benzoyl]glycinate, 110 ml. of 1 N sodium hydroxide solution, and 100 ml. of ethanol is stirred at ambient temperature for 2 hours and then partially evaporated. The gaseous solution is washed with diethyl ether, acidified with 6N hydrochloric acid, and filtered. The white solid is dried in vacuo and recrystallized from acetone.
Treatment of a corresponding 2- or 3-substituted-aminophenylacetyl chloride in an analogous manner yields the corresponding glycine.
Example 551 Preparation of N-[3-(4-pentadecenylamino)benzoyl]-2,3-dihydroxypropylamine To a mixture containing 4.3 g. of [N-(t-butyloxycarbonyl)-3-(4- pentadecenylamino)benzoyl]imidazole, 50 ml. of chloroform, and 50 ml. of 5N sodium hydroxide is added 1.1 g. of 3-amino-1 2-propanediol. The mixture is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 400 C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the resulting oil is crystallized from acetone to yield the product as light yellow crystals.
Example 552 Preparation of N-(3-bromopropyl)-2-(4-tetradecenylamino)benzamide To a slurry of 21.80 g. of 3-bromopropylamine hydrobromide in 200 ml. of glyme at 30C. is added a solution of 23.9 g. of 2-(4-tetradecenylamino)benzoyl chloride hydrochloride in 65 ml. of glyme, concurrently with 26 ml. of triethylamine diluted to 39 ml. with 1 ,2-dimethoxyethane. The solution is warmed to reflux and 0.2 g. of 4-dimethylaminopyridine is added. The solution is heated for four hours and cooled overnight. The solid is removed and the mother liquor diluted with 200 ml. of water to yield a solid which is crystallized from cyclohexane and recrystallized from acetonitrile to yield the product.
Example 553 Preparation of 2-[3-(4-tetradecenylamino)phenylj-5,6-dihydro-[4H]-I ,3-oxazine To 0.4 g. of sodium hydride in 100 ml. of 1,2-dimethoxyethane is added 2.14 g. of N-(3bromopropyl)-3-(4-tetradecenylamino)benzamide and 12 ml. of triethylamine. The turbid solution is heated to reflux for 20 hours. The solution is diluted with 100 ml. of water and cooled overnight. The solid is collected, washed with water, crystallized from cyclohexane, and recrystallized from acetonitrile to yield the product.
Example 554 Preparation of 2-[2-(4-tetradecenylamino)phenyl]oxazoline To a slurry of 15 g. of 2-bromoethylamine hydrobromide in 150 ml. of 1 ,2-dimethoxyethane are added simultaneously solutions of 31 g. of 2-(4-tetradecenylamino)benzoyl chloride hydrochloride in 60 ml. of 1,2-dimethoxyethane and 50 cc. of triethylamine (dropwise). Upon addition of 0.5 g. of 4 dimethylaminopyridine the mixture is stirred at room temperature overnight. The solution is refluxed for one hour and filtered. The solid is oven dried and partitioned between methylene chloride and water.
The layers are separated and the organic phase dried over magnesium sulfate. The organic layer is concentrated and the residue collected and crystallized from cyclohexane and recrystallized from acetonitrile to yield the product.
Example 555 Preparation of Tetrahydropyranyl 3-(4-tetradecenylamino)benzoate A mixture of 7 g. 3-(4-tetradecenylamino)benzoic acid, 2 g. dihydropyran and 100 mg. anhydrous p-toluenesulfonic acid in 50 ml. toluene is stirred at room temperature for 20 hours. The solution is washed with saturated sodium bicarbonate, dried, and evaporated. The residue is collected and crystallized from methylcyclohexane to yield the product as white crystals.
Example 556 Preparation of 3-Pyridyl 2-(4-tetradecenylamino)benzoate A 6 g. sample of 2-(4-tetradecenylamino)benzoic acid and 2.7 g. 1,1 '-carbonyldiimidazole in 50 ml. dry tetrahydrofuran is stirred for 2 hours. Then 1.58 g. 3-hydroxypyridine and a trace of sodium hydride catalyst is added and the reaction is refluxed for 3 hours. The solution cooled, filtered, and evaporated. The product is crystallized from isopropanol.

Claims (77)

Claims
1. A compound of the formula: wherein Z is
wherein D is selected from the group consisting of hydrogen, hydroxy, loweralkyl, a loweralkoxy group unsubstituted or substituted with one or more moieties selected from the group consisting of hydroxy, carboxyl, carbolowera I koxy, carboxamido, N,N-diloweralkylcarboxamido, cyano, diloweralkyla mino, piperazino or polymethyleneimino (ring size 5-8) group; a benzyloxy group unsubstituted or substituted with at least one halogen or carboxy group; a phenoxy moiety unsubstituted or substituted with at least one halogen, carboxy, carboloweralkoxy loweralkyl, carboxamide, loweralkoxy or cyano group; or a 3-pyridyloxy group unsubstituted or substituted with a loweralkyl group, halogen, cyano, carboxyl, carboloweralkoxy, loweralkoxy or hydroxy group; and loweralkyl bearing one or more carboxy, carboloweralkoxy, carbamoyl, acyl, sulfinyl or sulfonyl groups;
wherein B is a saturated or unsaturated lower alkylene group and E is selected from the group consisting of hydrogen, loweralkyl, loweralkoxyethyl, diloweralkylaminoethyl, (mono- or polyhydroxy)loweralkyl, (mono- or polycarboxy)loweralkyl, (mono- or polycarboxy)hydroxyloweralkyl, allyl, 2,3-epoxypropyl, substituted or unsubstituted (phenyl, benzyl or 3-pyridyl), pyridylmethyl, and tetrahydropyranyl; or
wherein R4 is selected from the group consisting of hydrogen, carboxyloweralkyl, carboalkoxyloweralkyl, loweralkanoyl, loweralkanesulfonyl, arylsulfonyl, sodium sulfo loweralkyl, sulfo loweralkyl, loweralkenyl, lower alkynyl, phenylloweralkyl and -hydroxyloweralkyl;R5 is selected from the group consisting of hydrogen, loweralkyl, hydroxy, loweralkoxy, haloloweralkyl, phenyl, carboxyphenyl, chlorophenyl, sodium sulfophenyl, pyridyl, pyridyl, loweralkyl, (mono- and polyhydroxy)lower alkyl, w-loweralkoxyloweralkyl, w-di(loweralkyl)aminoloweralkyl, a)- piperidinoloweralkyl, w-pyrrolidinohydroxyloweralkyl, amino, loweralkanoylamino, loweralkanesulfonylamino, N-piperidyl, arylsulfonylamino, and 4-loweralkyl-1-piperazino;R4 and P5 taken together with the associated nitrogen is selected from the group consisting of pyrrolidino, piperidino, morpholino, hexamethyleneimino, 4-(loweralkyl)piperidino, 4-loweralkyl-1 -piperazino, 4- phenylpiperazino, 3-pyrrolinyl, A3-piperidino, 4-(carboethoxy or carboxy)-3-thiazolidinyl and 4 (carboethoxy)-3-oxazolidinyl; R6 and R7 are the same or different and are selected from the group consisting of loweralkyl, (mono- and polyhydroxy)loweralkyl, carboxyloweralkyl, sulfo loweralkyl, sodium sulfo loweralkyl, and, when taken together, loweralkylene;R is selected from the group consisting of hydrogen, or a group convertible in vivo thereinto, such as methyl, carboxymethyl, acetyl, succinyl, 1 -(sodium sulfo)loweralkyl, 1 -(sodium sulfo)polyhydroxy alkyl and 13-bis-(sodium sulfo)aralkyl; and R' is a branched or unbranched mono- or poly-unsaturated or cyclopropylated C3-C22 alkyl group; and the pharmaceutically acceptable non-toxic acid-addition and cationic salts thereof.
2. The compounds as in claim 1, wherein R is H; Z is
wherein D is selected from the group consisting of hydrogen, hydroxy, loweralkyl, a loweralkoxy group unsubstituted or substituted with one or more moieties selected from the group consisting of hydroxy, carboxyl, carboloweralkoxy, carboxamido, N,N-diloweralkylcarboxamido, cyano, diloweralkylamino, piperazino or polymethyleneimino (ring size 5-8) group; a benzyloxy group unsubstituted or substituted with at least one halogen or carboxy group; a phenoxy moiety unsubstituted or substituted with at least one halogen, carboxy, carboloweralkoxy loweralkyl, carboxamide, loweralkoxy or cyano group; or a 3-pyridyloxy group unsubstituted or substituted with a loweralkyl group, halogen, cyano, carboxyl, carboloweralkoxy, loweralkoxy or hydroxy group; and loweralkylbearing one or more carboxy carboloweralkoxy, carbamoyl, acyl, sulfinyl or sulfonyl groups; and the pharmaceutically acceptable non-toxic acid addition and cationic salts thereof.
3. The compounds as in claim 1, wherein R is H; Z is
wherein B is a saturated or unsaturated lower alkylene group and E is selected from the group consisting of hydrogen, loweralkyl, loweralkoxyethyl, diloweralkylaminoethyl, (mono- or polyhydroxy)loweralkyl, (mono- or polycarboxy)loweralkyl, (mono- or polycarboxy)hydroxyloweraikyl, allyl, 2,3-epoxypropyl, substituted or unsubstituted (phenyl, benzyl or 3-pyridyl), pyridylmethyl, and tetrahydropyranyl; and the pharmaceutically acceptable non-toxic acid addition and cationic salts thereof.
4. The compounds as in claim 1, wherein R is H; Z is
wherein R4 is selected from the group consisting of hydrogen, carboxyloweralkyl, carboalkoxyloweralkyl, loweralkanoyl, loweralkanesulfonyl, arylsulfonyl, sodium sulfo loweralkyl, sulfo loweralkyl, loweralkenyl, loweralkynyl, phenylloweralkyl and -hydroxyloweralkyl;R5 is selected from the group consisting of hydrogen, loweralkyl, hydroxy, loweralkoxy, haloloweralkyl, phenyl, carboxyphenyl, chlorophenyl, sodium sulfophenyl, pyridyl, pyridyl loweralkyl, (mono- and polyhydroxy)lower alkyl, a)- loweralkoxyloweralkyl, w-di(loweralkyl)aminoloweralkyl, w-piperidinoloweral kyl, a)- pyrrolidinohydroxyloweralkyl, amino, loweralkanoylamino, loweralkanesulfonylamino, N-piperidyl, arylsulfonylamino, and 4-loweralkyl-1 -piperazino;; R4 and R5 taken together with the associated nitrogen is selected from the group consisting of pyrrolidino, piperidino, morpholino, hexamethyleneimino, 4-(loweralkyl)piperidino, 4-loweralkyl-1 -piperazino, 4-phenylpiperazino, 3- pyrrolinyl, A3-piperidino, 4-(carboethoxy or carboxy)-3-thiazolidinyl and 4-(carboethoxy)-3oxazolidinyl; Re and R, are the same or different and are selected from the group consisting of loweralkyl, (mono- and polyhydroxy) loweralkyl, carboxyloweralkyl, sulfo loweralkyl, sodium sulfo loweralkyl, and, when taken together, loweralkylene;R is selected from the group consisting of hydrogen, or a group convertible in vivo thereinto, such as methyl, carboxymethyl, acetyl, succinyl, 1 (sodium sulfo)loweralkyl,1 -(sodium sulfo)polyhydroxy alkyl and 13-bis-(sodium sulfo)-aralkyl; and R' is a branched or unbranched mono- or poly-unsaturated or cyclopropylated C3-C22 alkyl group and the pharmaceutically acceptable non-toxic acid-addition and cationic salts thereof.
5. The compounds as in claim 1 wherein R is H; Z is
and the pharmaceutically acceptable non-toxic cationic salts thereof.
6. The compounds as in claim 1 , wherein R is H; Z is
R' is a branched or unbranched mono- or polyunsaturated or cyclopropylated C8-C18 alkyl group; and the pharmaceutically acceptable non-toxic acid addition and cationic salts thereof.
7. The compound according to claim 1, 2-(allylamino)phenylacetic acid.
8. The compound according to claim 1,3-(1 -octadec-9-enylamino)phenylacetic acid.
9. The compound according to claim 1,2-(1-pentadec-4-enylamino)benzoic acid.
10. The compound according to claim 1,3-(1 -tetradec-4-enylamino)benzoic acid.
11. The compound according to claim 1,2-(1 -pentadeca-4,14-dienylamino)phenylacetic acid.
12. The compound according to claim 1, 3-[1-(3,7,1 -trimethyldodeca-2,6, 10- trienyl)amino]phenylacetic acid.
13. The compound according to claim 1, 2-[1 -(6-decylhept-6-enyl)amino]phenylacetic acid.
14. The compound according to claim 1, 3-(2,3-methanohept-4-ylamino)benzoic acid.
1 5. The compound according to claim 1, 3-[2-(allylamino)phenyl]propionic acid.
1 6. The compound according to claim 1,3-[3-(1 -octadec-9-enylamino)phenyl]propionic acid.
17. The compound according to claim 1,3-[2-(1-pentadec-4-enylamino)phenyl]propionic acid.
18. The compound according to claim 1,3-[3-(1-tetradec-4-enylamino)phenyl]propionic acid.
1 9. The compound according to claim 1,3-[2-(1 -pentadeca-4,1 4-dienylamino)phenyl]propionic acid.
20. The compound according to claim 1,3- 3-[1 -(3,7,11 -trimethyldodeca-2,6,1 0- trienyl)amino]phenylpropionic acid.
21. The compound according to claim 1,3- 2-[1-(6-decylhept-6-enyl)amino]phenyl propionic acid.
22. The compound according to claim 1, 3-[3-(2,3-methanohept-4-ylamino)phenyl]propionic acid.
23. The compound according to claim 1, 4-[2-(allylamino)phenyl]butyric acid.
24. The compound according to claim 1,4-[3-(1 -octadec-9-enylamino)phenyl]butyric acid.
25. The compound according to claim 1, 4-[2-(1 -pentadec-4-enylamino)phenyl]butyric acid.
26. The compound according to claim 1,4-[3-(1-tetradec-4-enylamino)phenyl]butyric acid.
27. The compound according to claim 1,4-12-(1 -pentadeca-4,1 4-dienylamino)phenyl]butyric acid.
28. The compound according to claim 1,4- 3-[1 -(3,7,11 -trimethyldodeca-2,6,1 0- trienyl)amino]phenylbutyric acid.
29. The compound according to claim 1, 4- 2-[1 -(6-decylhept-6-enyl)amino]phenyl butyric acid.
30. The compound according to claim 1, 4-[3-(2,3-methanohept-4-ylamino)phenyl]butyric acid.
31. The compound according to claim 1, 3-[2-(allylamino)phenyl]acrylic acid.
32. The compound according to claim 1,3-[3-(1-octadec-9-enylamino)phenyl]acrylic acid.
33. The compound according to claim 1,3-[2-(1 -pentadec-4-enylamino)phenyl]acrylic acid.
34. The compound according to claim 1,3-[3-(1 -tetradec-4-enylamino)phenyl]acrylic acid.
35. The compound according to claim 1,3-[2-(1 -pentadeca4,1 4-dienylamino)phenyl]acrylic acid.
36. The compound according to claim 1, 3-[1-(3,7,11 -trimethyldodeca-2,6, 10- trienyl)amino]phenylacrylic acid.
37. The compound according to claim 1,3- 2-[1 -(6-decylhept-6-enyl)amino]phenyl acrylic acid.
38. The compound according to claim 1, 3-[3-(2,3-methanohept-4-ylamino)phenyl]acrylic acjd.
39. The compound according to claim 1, 2-(allylamino)phenylpropiolic acid.
40. The compound according to claim 1, 3-(1 -octadec-9-enylamino)phenylpropiolic acid.
41. The compound according to claim 1,2-(1 -pentadec-4-enylamino)phenylpropiolic acid.
42. The compound according to claim 1, 3-(1-tetradec-4-enylamino)phenylpropiolic acid.
43. The compound according to claim 1,2-(1 -pentadeca-4,1 4-dienylamino)phenylpropiolic acid.
44. The compound according to claim 1, 3-fl -(3,7,11 -trimethyldodeca-2,6,1 0- trienyl)amino]phenylpropiolic acid.
45. The compound according to claim 1,2-[1 -(6-decylhept-6-enyl)amino]phenylpropiolic acid.
46. The compound according to claim 1, 3-(2,3-methanohept-4-ylamino)phenylpropiolic acid.
47. The compound according to claim 1, 2-(allylamino)benzaldehyde.
48. The compound according to claim 1,3-(1-octadec-9-enylamino)benzaldehyde.
49. The compound according to claim 1,2-(1-pentadec-4-enylamino)benzaldehyde.
50. The compound according to claim 1 ,3-( 1 -tetradec-4-enylamino)benzaldehyde.
51. The compound according to claim 1,2-(1 -pentadeca-4,1 4-dienylamino)benzaldehyde.
52. The compound according to claim 1, 3-[1 -(3,7,11 -trimethyldodeca-2,6,1 0- trienyl)amino]benzaldehyde.
53. The compound according to claim 1,2-[1 -(6-decylhept-6-enyl)amino]benzaldehyde.
54. The compound according to claim 1, 3-(2,3-methanohept-4-ylamino)benzaldehyde.
55. The compound according to claim 1, 2-(allylamino)acetophenone.
56. The compound according to claim 1, 3-(1-octadec-9-enylamino)acetophenone.
57. The compound according to claim 1,2-(1 -pentddec-4-enylamino)acetophenone.
58. The compound according to claim 1, 3-(1-tetradec-4-enylamino)acetophenone.
59. The compound according to claim 1,2-(1 2-(1-pentadeca-4,14-dienylamino)acetophenone.
60. The compound according to claim 1, 3-[1 -(3,7,11 -trimethyldodeca-2,6,l 0- trienyl)amino]acetophenone.
61. The compound according to claim 1,2-[1 -(6-decylhept-6-enyl)amino]acetophenone.
62. The compound according to claim 1, 3-(2,3-methanohept-4-ylamino)acetophenone.
63. The compound according to claim 1,2-(1-tetradec-4-enylamino)benzoylacetic acid.
64. The compound according to claim 1, ethyl 2-[3-(1-tetradec-4- enylamino)benzoyl]acetoacetate.
65. The compound according to claim 1, diethyl 3-(1-tetradec-4-enylamino)benzoylmalonate.
66. The compound according to claim 1, 3'-( 1 -tetradec-4-enylamino-2 (methylsulfonyl)acetophenone.
67. The compound according to claim 1, 3-i2-(1 -tetradec-4-enylamino)benzoyl]propionic acid.
68. The compound according to claim 1, 3-(2,3-methanohept-4-ylamino)benzoylacetic acid.
69. The compound according to claim 1, ethyl 2-[2-(2,3-methanohept-4ylamino)benzoyl]acetoacetate.
70. The compound according to claim 1, diethyl 3-(2,3-methanohept-4ylamino)benzoylmalonate.
71. The compound according to claim 1, 2'-(2,3-methanohept-4-ylamino)-2 (methylsulfonyl)acetophenone.
72. The compound according to claim 1, 3-f3-(2,3-methanohept-4-ylamino)benzoyljpropionic acid.
73. The compound according to claim 1, 2-(2,3-methanohept-4-ylamino)benzoylacetic acid.
74. A process for preparing a compound of formula I as defined in claim 1 characterized by reacting a compound of the formula: A--M II wherein A is R' as defined above or
in which R" is a branched or unbranched mono- or poly-unsaturated or cyclopropylated C2 to C2, alkyl group and M is selected from the group consisting of halogen, (alkyl or aryl)sulfonyloxy and, except when A is R', also from acyloxy, 1 -imidazolyl, and activated ester moiety and hydrogen; with a compound of the formula:
wherein G is HN or H2N or a group convertible in situ thereinto and X is Z or a precursor thereto; with the proviso that when ll is R'Br and Ill is
the bromine in II and the amino group in Ill may be interchanged; and when required; after said reaction of Il with Ill, converting the product to the desired I by oxidation and/or reduction of appropriate functional groups in said product; or in any order and at any desired time before or after said reaction of Il with Ill converting any group or groups R, R', R", or Z to any other defined group or groups R, R', R", or Z respectively; or converting I to the corresponding pharmaceutically acceptable non-toxic acid-addition or cationic salts thereof.
75. A pharmaceutical composition, comprising a compound according to any one of Claims 1 to 73, and a pharmaceutically acceptable carrier or diluent.
76. A pharmaceutical composition according to Claim 75, in dosage unit form.
77. A compound according to Claim 1 and substantially as described in any one of the Examples herein.
GB7938541A 1979-11-07 1979-11-07 Aniline Derivatives Withdrawn GB2062622A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
GB7938541A GB2062622A (en) 1979-11-07 1979-11-07 Aniline Derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB7938541A GB2062622A (en) 1979-11-07 1979-11-07 Aniline Derivatives

Publications (1)

Publication Number Publication Date
GB2062622A true GB2062622A (en) 1981-05-28

Family

ID=10509023

Family Applications (1)

Application Number Title Priority Date Filing Date
GB7938541A Withdrawn GB2062622A (en) 1979-11-07 1979-11-07 Aniline Derivatives

Country Status (1)

Country Link
GB (1) GB2062622A (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0615970A1 (en) * 1990-09-25 1994-09-21 Eisai Co., Ltd. Benzene, pyridine and pyrimidine derivative
US5462958A (en) * 1992-07-20 1995-10-31 Eisai Co., Ltd. Benzene derivatives and method of treating arteriosclerosis with benzene derivatives
US5741926A (en) * 1997-02-12 1998-04-21 Shaman Pharmaceuticals, Inc. Aniline derivatives having antihyperglycemic activity
WO2000000458A1 (en) * 1998-06-26 2000-01-06 Daiichi Pharmaceutical Co., Ltd. Substituted propionyl derivatives and intermediates thereof
EP1811129A2 (en) 2006-01-21 2007-07-25 Rolls-Royce plc Aerofoils for gas turbine engines
WO2008015240A1 (en) * 2006-08-01 2008-02-07 Noscira, S.A. N-phenyl-prenylamine derivatives for the treatment of cognitive, neurodegenerative or neuronal diseases or disorders
EP2213286A1 (en) * 2009-02-02 2010-08-04 Zeltia, S.A. N-(phenyl or pyridyl)prenylamine derivatives for the treatment of obesity, diabetes and cardiovascular diseases

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0615970A1 (en) * 1990-09-25 1994-09-21 Eisai Co., Ltd. Benzene, pyridine and pyrimidine derivative
US5668136A (en) * 1990-09-25 1997-09-16 Eisai Co., Ltd. Trisubstituted benzene derivatives, composition and methods of treatment
US5462958A (en) * 1992-07-20 1995-10-31 Eisai Co., Ltd. Benzene derivatives and method of treating arteriosclerosis with benzene derivatives
US5741926A (en) * 1997-02-12 1998-04-21 Shaman Pharmaceuticals, Inc. Aniline derivatives having antihyperglycemic activity
WO2000000458A1 (en) * 1998-06-26 2000-01-06 Daiichi Pharmaceutical Co., Ltd. Substituted propionyl derivatives and intermediates thereof
EP1811129A2 (en) 2006-01-21 2007-07-25 Rolls-Royce plc Aerofoils for gas turbine engines
WO2008015240A1 (en) * 2006-08-01 2008-02-07 Noscira, S.A. N-phenyl-prenylamine derivatives for the treatment of cognitive, neurodegenerative or neuronal diseases or disorders
EP2213286A1 (en) * 2009-02-02 2010-08-04 Zeltia, S.A. N-(phenyl or pyridyl)prenylamine derivatives for the treatment of obesity, diabetes and cardiovascular diseases
WO2010086454A1 (en) * 2009-02-02 2010-08-05 Zeltia, S.A. N-(phenyl or pyridyl)prenylamine derivatives for the treatment of obesity, diabetes, cardiovascular diseases and other adiponectin-related diseases

Similar Documents

Publication Publication Date Title
US4440940A (en) Anti-atherosclerotic agents
US4065584A (en) Sulphur containing arylamine derivatives
JP2637737B2 (en) New drugs
US4348399A (en) Antiatherosclerotic and hypolipidemic 4-(monoalkylamino)phenyl alkane, alkene and alkyne carbinols, aldehydes, carboxylic acids and derivatives
KR870001916B1 (en) Process for preparation of pyridyl compound
GB2043632A (en) Phenoxyphenylpiperidines
US4205085A (en) Hypolipidemic and antiatherosclerotic 4-(polyfluoroalkylamino)phenyl compounds
EP0106565A1 (en) Leukotriene antagonists, their production, and compositions containing them
GB2062622A (en) Aniline Derivatives
US4230878A (en) Hypolipidemic and antiatherosclerotic 4-[(cyclopropyl alkyl)amino]benzoic acids and derivatives
US4310545A (en) Hypolipidemic and antiatherosclerotic 4-(polyfluoroalkylamino) phenyl compounds
BG100070A (en) 5-LIPOXYGENASE INHIBITORS
US4388459A (en) Certain cinnamic acid or propiolic acid derivatives
US4318914A (en) Hypolipidemic and antiatherosclerotic 4-(polyfluoro-alkylamino)phenyl compounds
JPH05320103A (en) Propaneamine and its medicine composition for medical treatment, especially stegnotic treatment
BE1004530A3 (en) Aminopropanol NOVEL METHOD FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SUCH DERIVATIVES.
US4227014A (en) 4-[(Cycloalkyl or cycloalkenyl substituted)amino, alkylamino or alkenylamino]benzoic acids and salts thereof
US4305959A (en) Hypolipidemic and antiatherosclerotic 4-(polyfluoro-alkylamino)phenyl compounds
US4339576A (en) Anti-asthmatic, anti-allergic, anti-cholinergic, bronchodilator and anti-inflammatory 1-[(benzoylphenyl)-lower-alkyl]piperidines and analogs thereof
US4281019A (en) 4-[(Unsaturated or cyclopropylated alkyl)amino]phenyl compounds useful as hypolipidemic and antiatherosclerotic agents
EP0003663A2 (en) Amino-substituted phenyl and heteroaryl compounds, process for their preparation and pharmaceutical compositions containing them
US3997608A (en) N-substituted-dihydroxyphenethylamines
US3228984A (en) 1, 4-bis-cyclic and aryl-amino-[2.2.2] bicyclooctane derivatives
GB2061913A (en) Novel 2-or 3-[(cycloalkyl- or cycloalkenyl- substituted)-amino, alkylamino or alkanylamino] phenyl compounds and derivatives
US4499303A (en) Antihyperlipidemic N-benzoylsulfamates, N-benzylsulfamates and benzylsulfonamides

Legal Events

Date Code Title Description
WAP Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1)