Substituted quinolines and cinnolines

BACKGROUND OF THE INVENTION
Field of the Invention
This invention provides new compounds that have excellent plant fungicide activity. Some of the compounds have also demonstrated insecticidal and miticidal activity. The invention also provides compositions and combination products that contain a compound of the invention as active ingredient. The invention also provides fungicidal, miticidal, and insecticidal methods.
There is an acute need for new fungicides, insecticides, and miticides, because target pathogens are rapidly developing resistance to currently used pesticides. Widespread failure of N-substituted azole fungicides to control barley mildew was observed in 1983, and has been attributed to the development of resistance. At least 50 species of fungi have developed resistance to the benzimidazole fungicides. The field performance of DMI (demethylation inhibitor) fungicides, which are now widely relied on to protect cereal crops from powdery mildew, has declined since they were introduced in the 1970's. Even recent fungicides, like the acylalanines, which initially exhibited excellent control of potato late blight and grape downy mildew in the field, have become less effective because of widespread resistance. Similarly, mites and insects are developing resistance to the miticides and insecticides in current use. Resistance to insecticides in arthropods is widespread, with at least 400 species resistant to one or more insecticides. The development of resistance to some of the older insecticides, such as DDT, the carbamates, and the organophosphates, is well known. But resistance has even developed to some of the newer pyrethroid insecticides and miticides. Therefore a need exists for new fungicides, insecticides, and miticides.
SUMMARY OF THE INVENTION
This invention provides compounds of the formula (1) ##STR2## wherein:
R.sup.1 to R.sup.4 are independently
H, halo, (C.sub.1 -C.sub.4) alkyl, branched (C.sub.3 -C.sub.4) alkyl, halo (C.sub.1 -C.sub.4) alkyl, (C.sub.1 -C.sub.4) alkoxy, NO.sub.2, or NH.sub.2, at least two of R.sup.1 to R.sup.4 being H,
or one of R.sup.2 to R.sup.4 is --NR.sup.7 --Y--Ar or O--Y--Ar and the rest of R.sup.1 to R.sup.4 are H;
W is N, or CR.sup.5 ;
R.sup.5 is H, CH.sub.3, Cl, O--Y--Ar, or --NR.sup.7 --Y--Ar;
R.sup.6 is H, CH.sub.3, Cl or Br;
A is --O--Alk or --X--Y--Ar;
Alk is a C.sub.2 -C.sub.18 saturated or unsaturated hydrocarbon chain, straight chain or branched, optionally substituted with halo, halo (C.sub.1 -C.sub.4) alkoxy, (C.sub.3 -C.sub.8) cycloalkyl, hydroxy, or acetyl;
X is O, NR.sup.7, or CR.sup.8 R.sup.9, provided that if one of R.sup.2 to R.sup.5 is NR.sup.7 --Y--Ar or O--Y--Ar, then X--Y--Ar is an identical group;
R.sup.7 is H, (C.sub.1 -C.sub.4) alkyl, or acetyl;
R.sup.8 and R.sup.9 are independently H, (C.sub.1 -C.sub.4) alkyl, (C.sub.1 -C.sub.4) acyl, halo, or OH, or R.sup.8 and R.sup.9 combine to form a saturated or unsaturated carbocyclic ring comprising three to seven carbon atoms;
Y is an alkylene chain 2 to 8 carbon atoms long, that optionally includes an O, S, SO, SO.sub.2, or NR.sup.7 group, and optionally includes a saturated or unsaturated carbocyclic ring comprising three to seven carbon atoms, and optionally is substituted with (C.sub.1 -C.sub.3) alkyl, (C.sub.2 -C.sub.4) alkenyl, phenyl, (C.sub.3 -C.sub.8) cycloalkyl, hydroxy, halo, or (C.sub.1 -C.sub.4) acyl; and
Ar is
1,3-benzodioxolyl
fluorenyl,
pyridyl
substituted pyridyl,
indolyl,
furanyl,
substituted furanyl,
thienyl, optionally substituted with CH.sub.3 or Cl,
thiazolyl,
cyclopentyl,
1-methylcyclopentyl,
cyclohexenyl (tetrahydrophenyl),
cyclohexyl (hexahydrophenyl),
naphthyl,
substituted naphthyl,
dihydronaphthyl,
tetrahydronaphthyl,
decahydronaphthyl, or
a group of the formula (2): ##STR3## where
R.sup.10 to R.sup.14 are independently H, halo, I, (C.sub.1 -C.sub.10) alkyl, branched (C.sub.3 -C.sub.6) alkyl, halo (C.sub.1 -C.sub.7) alkyl, (C.sub.1 -C.sub.7) alkoxy, halo (C.sub.1 -C.sub.7) alkoxy, phenoxy, substituted phenoxy, phenylthio, substituted phenylthio, phenyl, substituted phenyl, NO.sub.2 NH.sub.2, acetoxy, OH, CN, SiR.sup.15 R.sup.16 R.sup.17, or OSiR.sup.15 R.sup.16 R.sup.17, where R.sup.15, R.sup.16, and R.sup.17 are independently (C.sub.1 -C.sub.4) alkyl or (C.sub.3 -C.sub.4) branched alkyl, phenyl, or substituted phenyl, provided that unless each of R.sup.10 to R.sup.14 is F, CH.sub.3, or H, then at least two of R.sup.10 to R.sup.14 are H;
or an acid addition salt of a compound of formula (1) or an N-oxide of a compound of formula (1) when W is CR.sup.5
provided that the following compounds are excluded:
1) N-[4-(4-chlorophenyl)butyl]-7-chloro-4-quinolinamine;
2) N-(2-phenylethyl)-4-quinolinamine.
The final proviso excludes compounds that are known per se or that could be considered similar to known compounds.
The fungicidal combinations of the invention comprise at least 1% by weight of a compound of formula (1), or N- [4-(4-chlorophenyl)butyl]-7-chloro-4-quinolineamine or N-(2-phenylethyl)-4-quinolinamine, in combination with a second fungicidal compound.
The fungicidal compositions of the invention comprise a disease inhibiting and phytologically acceptable amount of a compound of formula (1), or N-[4-(4-chlorophenyl)butyl]-7-chloro-4-quinolinamine, or N-(2-phenylethyl)-4-quinolinamine, in combination with a phytologically-acceptable carrier.
The fungicidal method of the invention comprises applying to the locus of a plant pathogen a disease inhibiting and phytologically acceptable amount of a compound of the formula (1), or N-[4-(4-chlorophenyl)butyl]-7-chloro-4-quinolinamine, or N-(2-phenylethyl)-4-quinolinamine.
The insecticidal or miticidal combinations of the invention comprise at least 1% by weight of a compound of formula (1) in combination with a second insecticide or miticide.
The insecticide or miticide compositions of the invention comprise an insect or mite inactivating amount of a compound of formula (1) in combination with a phytologically-acceptable carrier.
The insecticide and miticide methods of the invention comprise applying to a locus of an insect or mite an insect or mite inactivating amount of a compound of formula (1), or of a combination described above.

DETAILED DESCRIPTION OF THE INVENTION
Throughout this document, all temperatures are given in degrees Celsius, and all percentages are weight percentages unless otherwise stated.
The terms "(C.sub.1 -C.sub.3) alkyl", "(C.sub.1 -C.sub.4) alkyl", and "(C.sub.1 -C.sub.10) alkyl", when used alone, refer to straight chain alkyl radicals.
The terms "branched (C.sub.3 -C.sub.4) alkyl", and "branched (C.sub.3 -C.sub.6) alkyl" refer to all alkyl isomers containing the designated number of carbon atoms, excluding the straight chain isomers.
The terms "(C.sub.1 -C.sub.4) alkoxy" and "(C.sub.1 -C.sub.7) alkoxy" refer to straight or branched chain alkoxy groups.
The term "halo" used alone or in combination with other terms refers to F, Cl, or Br;
The term "halo (C.sub.1 -C.sub.7) alkyl" refers to a (C.sub.1 -C.sub.7) alkyl group, straight chain or branched, substituted with one or more halo groups.
The term "substituted phenyl" used alone or in combination with other terms, as in "substituted phenylthio" or "substituted phenylsulfonyl", refers to phenyl substituted with up to three groups selected from halo, I, (C.sub.1 -C.sub.10) alkyl, branched (C.sub.3 -C.sub.6) alkyl, halo (C.sub.1 -C.sub.7) alkyl, hydroxy (C.sub.1 -C.sub.7) alkyl, (C.sub.1 -C.sub.4) alkoxy, halo (C.sub.1 -C.sub.7) alkoxy, phenoxy, phenyl, NO.sub.2, OH, CN, (C.sub.1 -C.sub.4) alkanoyloxy, or benzyloxy.
The term "substituted phenoxy" refers to phenoxy substituted with up to three groups selected from halo, I, (C.sub.1 -C.sub.10) alkyl, branched (C.sub.3 -C.sub.6) alkyl, halo (C.sub.1 -C.sub.7) alkyl, hydroxy (C.sub.1 -C.sub.7) alkyl, (C.sub.1 -C.sub.7) alkoxy, halo (C.sub.1 -C.sub.7) alkoxy, phenoxy, phenyl, NO.sub.2, OH, CN, (C.sub.1 -C.sub.4) alkanoyloxy, or benzyloxy.
The terms "substituted naphthyl", "substituted pyridyl" and "substituted furanyl" refer to these ring systems substituted with halo, halo (C.sub.1 -C.sub.4) alkyl, CN, NO.sub.2, (C.sub.1 -C.sub.4) alkyl, (C.sub.3 -C.sub.4) branched alkyl, phenyl, (C.sub.1 -C.sub.4) alkoxy, or halo (C.sub.1 -C.sub.4) alkoxy.
The term "unsaturated hydrocarbon chain" refers to a hydrocarbon chain containing one or two sites of unsaturation.
The term "HPLC" refers to high-performance liquid chromatography.
Compounds
While all of the compounds of the invention are useful fungicides, certain classes are preferred for reasons of greater efficacy or ease of synthesis, viz:
1. compounds of formula (1) where W is CR.sup.5 (i.e., substituted quinolines);
2. compounds of preferred class (1) where R.sup.5 is H;
3. compounds of formula (1) where R.sup.5 is H;
4. compounds of formula (1) where at least three of R.sup.1 to R.sup.4 are H;
5. compounds of preferred class (4) where R.sup.4 is F (i.e., 8-fluoroquinolines);
6. compounds of preferred class (4) where R.sup.3 is F (i.e., 7-fluoroquinolines):
7. compounds of preferred class (4) where R.sup.3 is Cl (i.e., 7-chloroquinolines);
8. compounds of preferred class (4) where R.sup.2 is F (i.e., 6-fluoroquinolines);
9. compounds of formula (1) where Y is an alkylene chain 2 to 4 carbon atoms long.
10. compounds of preferred class (9) where Y is --(CH.sub.2).sub.2 --;
11. compounds of formula (1) where Ar is naphthyl;
12. compounds of formula (1) where Ar is thienyl;
13. compounds of formula (1) where Ar is thiazolyl;
14. compounds of formula (1) where Ar is cyclohexenyl;
15. compounds of formula (1) where Ar is a substituted phenyl group of formula (2);
16. compounds of preferred class (15) where at least three of R.sup.10 to R.sup.14 are H;
17. compounds of preferred class (15) where four of R.sup.10 to R.sup.14 are H;
18. compounds of preferred class (17) wherein one of R.sup.10 to R.sup.14 is Cl;
19. compounds of preferred class (18) where R.sup.12 is Cl;
20. compounds of preferred class (17) wherein one of R.sup.10 is CF.sub.3 ;
21. compounds of preferred class (17) wherein one of R.sup.10 to R.sup.14 is (C.sub.1 -C.sub.4) alkyl;
22. compounds of preferred class (21) wherein one of R.sup.10 to R.sup.14 is methyl;
23. compounds of preferred class (22) wherein R.sup.12 is methyl;
24. compounds of preferred class (17) wherein one of R.sup.10 to R.sup.14 is branched (C.sub.3 -C.sub.6) alkyl;
25. compounds of preferred class (24) wherein R.sup.12 is t-butyl;
26. compounds of preferred class (24) wherein R.sup.12 is i-propyl;
27. compounds of preferred class (17) wherein one of R.sup.10 to R.sup.14 is phenyl or substituted phenyl;
28. compounds of preferred class (27) wherein R.sup.12 is phenyl;
29. compounds of preferred class (17) wherein one of R.sup.10 to R.sup.14 is phenoxy or substituted phenoxy;
30. compounds of preferred class (29) wherein R.sup.12 is phenoxy.
Compounds exhibiting particularly excellent activity against downy mildew include: 8-fluoro-N-(2-phenylethyl)-4-quinolinamine; 8-fluoro-N- [2-(4-phenyl-2-thiazolyl)ethyl]-4-quinolinamine; 8-fluoro-N-[2-[2-(trifluoromethyl)phenyl]ethyl]-4-quinolinamine; N-[2-(4-chlorophenyl)ethyl]-6-methyl-4-quinolinamine; 8-chloro-N-(2-phenylethyl)-4-quinolinamine; 8-fluoro-N-[2-(4-phenyl-2-thiazolyl)ethyl]-4-quinolinamine; 8-fluoro-N-[2-(2-naphthyl)ethyl-4-quinolinamine; 8-fluoro-N-[2-[3-(trifluoromethyl)phenyl]ethyl]-4-quinolinamine; 7-chloro-N-[2-(1-cyclohexenyl)ethyl]-4-quinolinamine; N-[2-[4-(1-methylethyl)phenyl]ethyl]-8-fluoro-4-quinolinamine; 8-fluoro-N-[2-(2-thienyl)ethyl]-4-quinolinamine; 4-[2-(3-chlorophenyl)ethoxy]-8-fluoroquinoline; 8-fluoro-4- [2-(3-(trifluoromethyl)phenyl)ethoxy]-quinoline; 4-[2-(4-methylphenyl)ethoxy]quinoline; 8-fluoro-4-[2-(4-methylphenyl)ethoxy]quinoline; and 4-[2-[4-(t-butyl)phenyl]ethoxy]-8-fluoroquinoline;
Compounds exhibiting particularly excellent activity against rice blast include: N-[2-(4-chlorophenyl)ethyl]-N-(8-fluoro-4-quinolinyl)acetamide; N-[2-[4-(i-propyl)-phenyl]ethyl]-8-fluoro-4-quinolinamine; 8-fluoro-N-(2-phenylethyl)-4-quinolinamine; N-[2-[4-(t-butyl)phenyl]ethyl-8-fluoro-4-quinolinamine; 8-fluoro-N-[2-(1,1'-biphenyl)-4-yl-ethoxy]quinoline; 8-fluoro-4-[2-(3-(trifluoromethyl)phenyl)ethoxy]quinoline; 8-fluoro-4- [2-(2-naphthyl)ethoxy]quinoline; 8-fluoro-4-[2-(4-methylphenyl)ethoxy]quinoline; and 8-fluoro-4-[3-(4-(t-butyl)phenyl)propyl]quinoline;
Compounds exhibiting particularly excellent activity against a broad spectrum of plant pathogens include: 8-fluoro-N-[2-(3-phenoxyphenyl)ethyl]-4-quinolinamine; N- [2-[4-(i-propyl)phenyl]ethyl]-8-fluoro-4-quinolinamine; N-[2-(1,1'-biphenyl)-3-ylethyl]-8-fluoro-4-quinolinamine; N-[2-(2,4-dichlorophenyl)ethyl]-8-fluoro-4-quinolinamine; 8-fluoro-4-[3-(4-(t-butyl)phenyl)propyl]quinoline; 8-fluoro-4-[3-(4-(i-propyl)phenyl)propyl]quinoline; 8-fluoro-4-[2-(2-(trifluoromethyl)phenyl)ethoxy ]quinoline; 4-[2-(4-chlorophenyl)ethoxy]-8-fluoroquinoline; 4-[2-(4-methylphenyl)ethoxy]quinoline; 8-fluoro-4-[2-(4-methylphenyl)ethoxy]quinoline; 8-fluoro-4-(2-phenylethoxy)quinoline; 8-fluoro-4-[2-(3-methylphenyl)ethoxy]quinoline; 8-fluoro-4-[2-(2-fluorophenyl)ethoxy]quinoline; 8-fluoro-4-[2-(2-methoxyphenyl)ethoxy]quinoline; and 8-fluoro-4-[2-(4-(i-propyl)phenyl)ethoxy]quinoline;
Compounds exhibiting particularly excellent activity as miticides include: 8-fluoro-N-[2-(4-iodophenyl)ethyl]-4-quinolinamine; N-[2-(4-bromophenyl)ethyl]-8-fluoro-4-quinolinamine; N-[2-(4-chlorophenyl)ethyl)-8-fluoro-4-quinolinamine; N-[2-(4-chlorophenyl)ethyl]-N-ethyl-8-fluoro-4-quinolinamine; N-3-(1,1'-biphenyl)-4-ylpropyl]-8-fluoro-4-quinolinamine; 8-fluoro-N-[2-(4-phenoxyphenyl)ethyl]-4-quinolinamine; N-[2-[4-(t-butyl)phenyl]ethyl]-8-fluoro-4-quinolinamine; N- [2-4-(i-propyl)phenyl]ethyl]-8-fluoro-4-quinolinamine; N-2-(4-chlorophenyl)ethyl]-6-fluoro-4-quinolinamine; 8-fluoro-N-[2-(1,1'-biphenyl)-4-yl-ethoxy]quinoline; 4-[2-(3-chlorophenyl)ethoxy]-8-fluoroquinoline; 4-[2-[4-(t-butyl)phenyl]ethoxy]-8-fluoroquinoline; 8-fluoro-4-[2-(4-(i-propyl)phenyl)ethoxy]quinoline; 8-fluoro-4-2-(3-(trifluoromethyl)phenyl)ethoxy]-quinoline; 8-fluoro-4-2-(4-methoxyphenyl)ethoxy]quinoline; 8-fluoro-4-[2-(3-phenoxyphenyl)ethoxy]quinoline; 8-fluoro-4-[2-(2-naphthyl)ethoxy]quinoline; 8-fluoro-4-[2-(1,1'-biphenyl)-2-yl-ethoxy]quinoline; 7-chloro-4 -[2-(1,1'-biphenyl)-4-yl-ethoxy]quinoline; 7-chloro-4-[2-(4-(t-butyl)phenyl)ethoxy]quinoline; 4-[2-(4-(t-butyl)phenyl)ethoxy]-7-fluoroquinoline; 4-[2-(1,1'-biphenyl)-4-ylethoxy]-7-fluoroquinoline; 8-fluoro-4-(3-phenylpropyl)quinoline; 8-fluoro-4-[3-(4-methylphenyl)propyl]quinoline; and 8-fluoro-4-[3-[3-(trifluoromethyl)phenyl]propyl]-quinoline.
Synthesis
The compounds of this invention are made using well known chemical procedures. The required starting materials are commercially available, or they are readily synthesized using standard procedures.
Synthesis of Compounds Wherein A is O--Y--Ar or --O--Alk
The compounds of formula (1) wherein A is O--Y--Ar or O--Alk were made by condensing a compound of formula (3): ##STR4## where R.sup.1 to R.sup.4 are as previously defined, R.sup.6 ' is H or CH.sub.3, and W' is N or CR.sup.5 ', where R.sup.5 ' is H, Cl, or CH.sub.3, with an alcohol of the formula (4a or 4b):
HO--Y--Ar (4a)
HO--Alk (4b)
where
Y, Ar, and Alk are as previously defined.
The reaction is preferably carried out in the presence of a strong base, such as sodium hydride, in an inert organic solvent, such as DMF, at a temperature in the range of 0.degree. to 25.degree. C.
Synthesis of Compounds Wherein A is NR.sup.7 --Y--Ar
The compounds of formula (1) wherein A is NR.sup.7 --Y--Ar were prepared by condensing a compound of formula (3) with an amine of the formula (5) ##STR5## where
R.sup.7 is H or (C.sub.1 -C.sub.4) alkyl, and Y and
Ar are as previously defined. The chloride of formula (3) is allowed to react with an appropriate amine, preferrably at elevated temperature 100.degree.-80.degree. C.), and preferably in the presence of an acid acceptor, such as triethylamine. The reaction may be carried out neat, or in an inert organic solvent.
Compounds where R.sup.7 is acetyl were prepared by reacting amines of formula (1) where R.sup.7 is H, with an acylating agent, such as an acetyl chloride or acetic anhydride. In cases where the starting material of formula (3) is one wherein W' is CCl, a mixture of products is obtained, which are separable using HPLC.
Synthesis of Compounds Wherein A is CR.sup.8 R.sup.9 --Y--Ar
The compounds of formula (1) wherein A is CR.sup.8 R.sup.9 --Y--Ar can be made using the process described in J. Heterocyclic Chemistry, Vol. 14, p. 1081-1083 (1977) by A. Scoville and F. X. Smith. This process entails preparation of a 5-substituted-5-(4-quinolyl)barbituric acid of the formula (6) ##STR6## which is then hydrolyzed and decarboxylated by dissolving the intermediate in a solution of sodium hydroxide and water, refluxing, then making the solution slightly acidic with hydrochloric acid and again refluxing.
Derivatives
The compounds of formula (1) wherein R.sup.6 is Cl are prepared by halogenating a compound of formula (1) wherein R.sup.6 is H with POCl.sub.3 /PCl.sub.5.
The compounds of formula (1) wherein R.sup.6 is Br are prepared by reacting a compound of formula (1) wherein R.sup.6 is H with Br.sub.2 in acetic acid.
N-oxides of the compounds of formula (1) are prepared by reacting the compound of formula (1) with an oxidizing agent, such as 3-chloroperoxybenzoic acid or hydrogen peroxide, in a non-reactive organic solvent, such as methylene chloride or chloroform, at -20.degree. C. to room temperature, preferably at about 0.degree. C.
The acid addition salts of compounds of formula (1) are obtained in the usual way.
Accordingly, the invention also provides a process for preparing a compound of formula (1) which comprises:
(a) condensing a compound of formula (3): ##STR7## where R.sup.1 to R.sup.4 are as previously defined, R.sup.6 ' is H or CH.sub.3, and W' is N or CR.sup.5 ', where R.sup.5 ' is H, Cl, or CH.sub.3, with an alcohol of the formula (4a or 4b):
HO--Y--Ar (4a)
HO--Alk (4b)
where
Y, Ar, and Alk are as previously defined to provide a compound of formula (1) wherein A is O--Y--Ar or O--Alk; or
(b) condensing a compound of formula (3) with an amine of the formula (5) ##STR8## where
R.sup.7 is H or (C.sub.1 -C.sub.4) alkyl, and Y and
Ar are as previously defined to provide a compound of formula (1) wherein A is --NR.sup.7 --Y--Ar; or
(c) reacting an amine of formula (1) where R.sup.7 is H, with acetyl chloride or acetic anhydride to provide a compound of formula (1) wherein A is --NR.sup.7 --Y--Ar where R.sup.7 is acetyl; or
(d) hydrolyzing and decarboxylating a compound of the formula (6) ##STR9## to provide a compound of formula (1) wherein A is --CR.sup.8 R.sup.9 --Y--Ar; or
(e) halogenating a compound of formula (1) wherein R.sup.6 is H with POCl.sub.3 /PCl.sub.5 to provide a compound of formula (1) wherein R.sup.6 is Cl; or
(f) reacting a compound of formula (1) wherein R.sup.6 is H with Br.sub.2 in acetic acid to provide a compound of formula (1) wherein R.sup.6 is Br; or
(g) oxidizing a compound of formula (1) wherein W is CR.sup.5 to provide the corresponding N-oxide.
Preparation of Quinoline Starting Materials
Quinoline starting materials can be synthesized using a variety of known procedures.
Organic Syntheses, collective volume 3, 1955, pp. 272-75, gives a procedure for preparing 4,7-dichloroquinoline, and other polysubstituted quinolines. Another general procedure is described in Tetrahedron, vol. 41, pp. 3033-36 (1985).
Many of the quinoline starting materials used in the following examples were prepared by the protocol shown in the following reaction scheme ##STR10## In cases where mixtures of isomeric products were obtained, the mixture of substituted 4-quinolones was chlorinated under standard conditions, and the 4-chloroquinolines were separated by liquid chromatography.
Preparation of Cinnoline Starting Materials
Cinnoline analogs are prepared via published methods. (C. M. Atkinson and J. C. Simpson - J. Chem. Soc. London, 1947, 232). The substituted 2-amino-acetophenone is diazotized at 0.degree.-5.degree. C. in water using sodium nitrite and mineral acid, and the intermediate diazonium salt is trapped by the enolic component of the ketone to provide the requisite 4-hydroxycinnoline. Routine chlorination provides the desired intermediates.
EXAMPLES 1 TO 328
Tables 1-12 identify compounds actually prepared by the above described general procedures, and give each compound's melting point. Specific illustrative preparations of the compounds of Examples 4, 10, 25, 69, 97, 154, 159, 173, 181, 186, 209, 212, 221, 238, 251, and 261 follow the table.
TABLE 1______________________________________N-(2-phenylethyl)-4-quinolinaminesEXAMPLENUMBER COMPOUND M.P.______________________________________1 6-methoxy-N-(2-phenylethyl)-4- NA quinolineamine2* N-(2-phenylethyl)-4-quinolin- 159-160.degree. C. amine3 6-ethyl-N-(2-phenylethyl)-4- 119-120.degree. C. quinolinamine4 N-ethyl-N-(2-phenylethyl)-4- oil quinolinamine5 8-fluoro-N-(2-phenylethyl)- 149-150.degree. C. 4-quinolinamine6 2-methyl-N-(2-phenylethyl)- 153-154.degree. C. 4-quinolinamine7 6,8-difluoro-N-(2-phenyl- 196-197.degree. C. ethyl)-4-quinolinamine8 7-fluoro-N-(2-phenylethyl)- 160-161.degree. C. 4-quinolinamine9 6-fluoro-N-(2-phenylethyl)- 163-164.degree. C. 4-quinolinamine10 N-[2-(4-chlorophenyl)ethyl]- oil N-(8-fluoro-4-quinolinyl)- acetamide11 8-fluoro-N-[2-(4-iodo- 221-223.degree. C. phenyl)ethyl]-4-quinolin- amine12 N-2-(4-bromophenyl)ethyl]- 235-238.degree. C. 6,8-difluoro-4-quinolinamine13 N-[2-(4-bromophenyl)ethyl]- 188-190.degree. C. 8-(trifluoromethyl)-4-quinolin- amine14 N-[2-(4-chlorophenyl)ethyl]- 123-125.degree. C. 6-methyl-4-quinolinamine15 N-[2-(4-chlorophenyl)ethyl]- 113-115.degree. C. 6,8-dimethyl-4-quinolinamine16 N-[2-(4-chlorophenyl)ethyl]- 155-157.degree. C. 6-methoxy-4-quinolinamine17 N-(2-phenylethyl)-7-(tri- 138-139.degree. C. fluoromethyl)-4-quinolinamine18 N-[2-(4-bromophenyl)ethyl]- 176-177.degree. C. 4-quinolinamine19 N-[2-(4-methylphenyl)ethyl]- 159-160.degree. C. 4-quinolinamine20* N-[2-(4-chlorophenyl)ethyl]- 162-163.degree. C. 4-quinolinamine21 N-(2-phenylpropyl)-4- 126-127.degree. C. quinolinamine22 N-[2-(4-methoxyphenyl)- 127-128.degree. C. ethyl]-4-quinolinamine23 N-(2,2-diphenylethyl)-4- 154-155.degree. C. quinolinamine24 N-(1-methyl-2-phenylethyl)- 132-133.degree. C. 4-quinolinamine25 2-chloro-N-(2-phenylethyl)- 132-133.degree. C. 4-quinolinamine26 .alpha.-[(4-quinolinylamino)- 195-197.degree. C. methyl]benzenemethanol27 8-methyl-N-(2-phenylethyl)- 127-128.degree. C. 4-quinolinamine28 6,8-dimethyl-N-(2-phenyl- 114-115.degree. C. ethyl)-4-quinolinamine29 8-ethyl-N-(2-phenylethyl)- 98-99.degree. C. 4-quinolinamine30 6-methyl-N-(2-phenylethyl)- 124-125.degree. C. 4-quinolinamine31 7-chloro-N-(2-phenylethyl)- 137-138.degree. C. 4-quinolinamine32 7,8-dimethyl-N-(2-phenyl- 183-185.degree. C. ethyl)-4-quinolinamine33 8-chloro-N-(2-phenylethyl)- 156-157.degree. C. 4-quinolinamine34 N-(2,2-diphenylpropyl)-4- 110-111.degree. C. quinolinamine35 N-[2-(4-fluorophenyl)ethyl]- 121-122.degree. C. 4-quinolinamine36 8-fluoro-N-[2-(4-methoxy- 165-167.degree. C. phenyl)ethyl]-4-quinolinamine37 7-chloro-N-[2-(4-chloro- 190-192.degree. C. phenyl)ethyl]-4-quinolinamine38 N-[2-(3,4-dimethoxyphenyl)- 127-130.degree. C. ethyl]-8-fluoro-4-quinolin- amine39 8-fluoro-N-[2-(3-phenoxy- 83-85.degree. C. phenyl)ethyl]-4-quinolin- amine40 6,8-difluoro-N-(2-[1,1'- 216-218.degree. C. biphenyl]-4-ylethyl)-4- quinolinamine41 N-[2-(4-chlorophenyl)ethyl]- 218-220.degree. C. 6,8-difluoro-4-quinolinamine42 N-[2-(4-methoxyphenyl)ethyl]- 107-109.degree. C. 7-(trifluoromethyl)-4-quinolin- amine43 7-chloro-N-[2-(3-methoxy- 155-158.degree. C. phenyl)ethyl]-4-quinolinamine44 7-chloro-N-[2-(2,4-dichloro- 168-170.degree. C. phenyl)ethyl]-4-quinolinamine45 7-chloro-N-[2-(3,5-di- 117-120.degree. C. methoxyphenyl)ethyl]-4- quinolinamine46 N-[2-(4-methoxyphenyl)- 120-123.degree. C. ethyl]-6-methyl-4-quinolin- amine47 N-[2-(4-chlorophenyl)ethyl]- 153-155.degree. C. 7-(trifluoromethyl)-4-quinolin- amine48 N-[2-(3,4-dimethoxyphenyl)- oil ethyl]-7-(trifluoromethyl)-4- quinolinamine49 N-[2-(3-chlorophenoxy)ethyl]- 161-163.degree. C. 8-fluoro-4-quinolinamine50 7-chloro-N-[2-(4-methyl- 155-158.degree. C. phenyl)ethyl]-4-quinolinamine51 8-chloro-N-[2-(4-fluoro- 194-196.degree. C. phenyl)ethyl]-4-quinolinamine52 N-[2-(2,4-dichlorophenyl)- 158-160.degree. C. ethyl]-8-(trifluoromethyl)-4- quinolinamine53 N-[2-(2,4-dichlorophenyl)- 180-182.degree. C. ethyl]-6-methyl-4-quinolinamine54 7-chloro-6-methoxy-2-methyl- 180-181.degree. C. N-(2-phenylethyl)-4-quinolin- amine55 N-[2-(2-methoxyphenyl)- 127-128.degree. C. ethyl]-4-quinolinamine56 N-[2-(4-chlorophenyl)ethyl]- 134-138.degree. C. 6-fluoro-4-quinolinamine57 N-[2-(4-chlorophenyl)ethyl]- 104-106.degree. C. 2-methyl-6-fluoro-4-quinolin- amine58 6-methyl-N-[2-(4-methyl- 122-124.degree. C. phenyl)ethyl]-4-quinolinamine59 5,7-dichloro-N-[2-(4-chloro- 113-115.degree. C. phenyl)ethyl]-4-quinolinamine60 7-chloro-N-[2-(3-phenoxy- 128-130.degree. C. phenyl)ethyl]-4-quinolinamine61 8-methyl-N-[2-(4-chloro- 118-120.degree. C. phenyl)ethyl]-4-quinolinamine62 8-fluoro-N-(2-cyclohexyl-2- 74-75.degree. C. phenyl)ethyl]-4-quinolinamine63 8-fluoro-N-[2-(2-phenoxyphenyl)- 131-133.degree. C. ethyl]-4-quinolinamine64 7,8-dimethyl-N-[2-(2-phenoxyphenyl)- 124-126.degree. C. ethyl]-4-quinolinamine65 N-[2-(2,6-difluorophenyl)- 203-204.degree. C. ethyl]-8-fluoro-4-quinolin- amine66 8-fluoro-N-[2-(3-fluoro- 174-175.degree. C. phenyl)ethyl]-4-quinolinamine67 N-[2-(3,5-dimethoxyphenyl)- 122-123.degree. C. ethyl]-4-quinolinamine68 8-fluoro-N-[2-(2-methoxy- 163-164.degree. C. phenyl)ethyl]-4-quinolinamine69 3-chloro-N-(2-chloro-2- oil phenyl)ethyl]-4-quinolinamine70 N-(2-phenylethyl)-5,7-bis- oil (trifluoromethyl)-4-quinolin- amine71 8-fluoro-N-[2-(4-methyl- 176-177.degree. C. phenyl)ethyl]-4-quinolin- amine72 N-[2-(1,1'-biphenyl)-3-ylethyl]- 140-142.degree. C. 8-fluoro-4-quinolinamine73 8-fluoro-4-[(2-phenylethyl)- 107-108.degree. C. amino]-3-quinolinemethanol74 N-[2-(3-chlorophenyl)ethyl]- 191-192.degree. C. 8-fluoro-4-quinolinamine75 N-[2-(3,4-dichlorophenyl)- 204-206.degree. C. ethyl]-8-fluoro-4-quinolin- amine76 N-[2-(2,4-dichlorophenyl)- 187-189.degree. C. ethyl]-8-fluoro-4-quinolin- amine77 8-fluoro-N-(2-phenylpropyl)- 136-137.degree. C. 4-quinolinamine78 8-fluoro-N-[2-(4-fluoro- 171-173.degree. C. phenyl)ethyl]-4-quinolinamine79 N-[2-(4-chlorophenyl)- 126-127.degree. C. propyl]-8-fluoro-4-quinolin- amine80 N-(2,2-diphenylpropyl)-8- 56-58.degree. C. fluoro-4-quinolinamine81 8-fluoro-N-(2-phenylbutyl)- 114-116.degree. C. 4-quinolinamine82 N-[2-(2-chlorophenyl)ethyl] - 175-177.degree. C. 8-fluoro-4-quinolinamine83 8-fluoro-N-[2-[4-(trifluoro- 205-206.degree. C. methyl)phenyl)ethyl]-4- quinolinamine84 7-chloro-N-[2-(4-methoxy- 122-124.degree. C. phenyl)ethyl]-4-quinolinamine85 8-chloro-N-[2-(4-chloro- 185-187.degree. C. phenyl)ethyl]-4-quinolinamine86 N-[2-(4-chlorophenyl)ethyl]- 192-194.degree. C. 8-(trifluoromethyl)-4-quinolin- amine87 8-chloro-N-[2-(4-methyl- 184-186.degree. C. phenyl)ethyl]-4-quinolinamine88 N-[2-(4-chlorophenyl)ethyl]- 177-179.degree. C. 7,8-dimethyl-4-quinolinamine89 8-fluoro-N-[2-(4-methyl- 153-154.degree. C. phenyl)ethyl]-4-quinolinamine90 8-fluoro-N-[2-(4-phenoxy- 109-111.degree. C. phenyl)ethyl]-4-quinolin- amine91 3-bromo-8-fluoro-N-(2-phenyl- 95-97.degree. C. ethyl)-4-quinolinamine92 8-fluoro-N-(1-methyl-2- 166-168.degree. C. phenylethyl)-4-quinolinamine93 2,8-dichloro-N-(2-phenyl- 190-192.degree. C. ethyl)-4-quinolinamine94 N-[2-(4-bromophenyl)ethyl]- 198-199.degree. C. 8-fluoro-4-quinolinamine95 8-fluoro-N-[2-[3-(trifluoro- 161-162.degree. C. methyl)phenyl]ethyl]-4- quinolinamine96 N-[2-(4-chlorophenyl)ethyl)- 176-177.degree. C. 8-fluoro-4-quinolinamine97 8-fluoro-N-[2-[2-(trifluoro- 157-158.degree. C. methyl)phenyl]ethyl]-4- quinolinamine98 2-chloro-N-[2-(2,4-dichloro- 199-200.degree. C. phenyl)ethyl]-8-fluoro-4- quinolinamine99 N-(2-phenylethyl)-8-(tri- 151-152.degree. C. fluoromethyl)-4-quinolin- amine100 7-chloro-N-[2-(2-methoxy- 140-142.degree. phenyl)ethyl]-4-quinolinamine101 7-chloro-N-[2-(3,4-dichloro- 128- 130.degree. C. phenyl)ethyl]-4-quinolinamine102 N-[2-(4-chlorophenyl)ethyl]- 176-178.degree. C. 2-methyl-4-quinolinamine103 N-[2-(2-chloro-6-fluoro- 198-201.degree. C. phenyl)ethyl]-8-fluoro-4- quinolinamine104 N-[2-(2,4-dichlorophenyl)- 175-177.degree. C. ethyl]-7-(trifluoromethyl)- 4-quinolinamine105 N-[2-(4-chlorophenyl)ethyl]- oil N-ethyl-8-fluoro-4-quinolin- amine106 7-chloro-N-(4-fluorophenyl)- 83-85.degree. C. N-methyl-4-quinolinamine107 7-chloro-N-[2-[3-(trifluoro- 184-186.degree. C. methyl)phenyl]ethyl]-4- quinolinamine108 N-[2-(3-bromophenyl)ethyl]- 206-208.degree. C. 8-fluoro-4-quinolinamine109 N-[2-(4-chlorophenyl)ethyl]-5,8- oil dimethyl-4-quinolinamine110 N(4)-[2-(4-chlorophenyl)ethyl]- oil 4,8-quinolinediamine111 N-[2-[4-( .sub.-t-butyl)phenyl]ethyl]- 198-200.degree. C. 8-fluoro-4-quinolinamine112 N-[2-(2,3,4,5,6-tetramethyl- 204-207.degree. C. phenyl)ethyl]-8-fluoro-4- quinolinamine113 N-[2-(1,1-biphenyl)-4-yl- 178-180.degree. C. ethyl]-8-fluoro-4-quinolin- amine114 N-[2-[4-( .sub.-i-propyl)phenyl]ethyl]- 157-159.degree. C.8-fluoro-4-quinolinamine115 N-[2-(2-chlorophenyl)ethyl]- 205-207.degree. C. 8-chloro-4-quinolinamine116 2-chloro-8-fluoro-N-(2- 158-159.degree. C. phenylethyl)-4-quinolinamine117 8-fluoro-N-[2-(4-nitro- 234-236.degree. C. phenyl)ethyl]-4-quinolin- amine118 N-[2-(2,6-dichlorophenyl)- 222-224.degree. C. ethyl]-8-fluoro-4-quinolin- amine119 N-[2-(3,5-dimethoxyphenyl)- 131-132.degree. C. ethyl]-8-fluoro-4-quinolin- amine120 N-(2-phenylcyclopropyl)-4- 147-148.degree. C. quinolinamine121 N-[2-(4-chlorophenyl)ethyl]-N- 87-88.degree. C. (6-fluoro-4-quinolinyl)acetamide122 N-[2-(4-methylphenyl)ethyl]-N- 97-98.degree. C. (6-methyl-4-quinolinyl)acetamide123 8-fluoro-N-(2-phenylcyclopropyl)-4- 204-205.degree. C. quinolinamine124 N-[2-(4-chlorophenyl)ethyl]-N-(7- oil chloro-4-quinolinyl)acetamide125 N-(7-chloro-4-quinolinyl)-N-[2-(4- oil methoxyphenyl)ethyl]acetamide126 N-(7-chloro-4-quinolinyl)-N-[2-[3- oil (trifluoromethyl)phenyl]ethyl]- acetamide127 N-[2-(2,4-dichlorophenyl)ethyl]-N- oil [7-(trifluoromethyl)-4-quinolinyl]- acetamide128 N-[4-( .sub.-t-butyl)phenyl]ethyl-N-(8- 126-128.degree. C. fluoro-4-quinolinyl)acetamide129 N-[2-[4-( .sub.-i-propyl)phenyl]ethyl]- 82-84.degree. C. N-(8-fluoro-4-quinolinyl)acetamide130 N-[2-(1,1'-biphenyl)-4-ylethyl]-N- oil (8-fluoro-4-quinolinyl)acetamide131 N-[2-(pentamethylphenyl)ethyl]-N- oil (8-fluoro-4-quinolinyl)acetamide132 N-[2-(2-chlorophenyl)ethyl]-N-(8- 104-106.degree. C. chloro-4-quinolinyl)acetamide133 N-[2-(4-methoxyphenyl)ethyl]-7,8- 183-185.degree. C. dimethyl-4-quinolinamine______________________________________ *not a compound claimed per se, but one used in the claimed compositions and methods.
TABLE 2______________________________________N-(3-phenylpropyl)-4-quinolinaminesEXAMPLENUMBER COMPOUND M.P.______________________________________134 7-chloro-N-[3-(1,1'-biphenyl)-4- 122-124.degree. C. ylpropyl]-4-quinolinamine135 N-[3-(4-chlorophenyl)propyl]-8- 134-136.degree. C. fluoro-4-quinolinamine136 N-[3-(4-chlorophenyl)propyl]-7- 177-179.degree. C. chloro-4-quinolinamine137 N-[3-(1,1'-biphenyl)-4-ylpropyl]- 124-127.degree. C. 8-fluoro-4-quinolinamine138 8-fluoro-N-(1-methyl-3-phenylpropyl)- 164-166.degree. C. 4-quinolinamine139 N-(3-phenylpropyl)-4-quinolinamine 96-97.degree. C.______________________________________
TABLE 3______________________________________N-(4-phenylbutyl)-4-quinolinaminesEXAMPLENUMBER COMPOUND M.P.______________________________________140 8-fluoro-N-[4-(4-chlorophenyl)- 110-112.degree. C. butyl]-4-quinolinamine141 N-[4-(4-chlorophenyl)butyl]-N-(8- oil fluoro-4-quinolinyl)acetamide______________________________________
TABLE 4______________________________________N-Arylalkyl-4-quinolinaminesEXAMPLENUMBER COMPOUND M.P.______________________________________142 N-[2-(1-cyclohexenyl)ethyl]-5,8- 78-81.degree. C. dimethyl-4-quinolinamine143 N-[2-(1-cyclohexenyl)ethyl]-8- 153-155.degree. C. fluoro-4-quinolinamine144 N-[2-(1-cyclohexenyl)ethyl]-6,8- 114-116.degree. C. dimethyl-4-quinolinamine145 N-[2-(1-cyclohexenyl)ethyl]-6- 135-137.degree. C. ethyl-4-quinolinamine146 N-[2-(1-cyclohexenyl)ethyl]-N- 66-68.degree. C. (6-fluoro-4-quinolinyl)acetamide147 N-[2-(2-thienyl)ethyl]-4-quinolin- 153-154.degree. C. amine148 N-[2-(3-thienyl)ethyl]-4-quinolin- 156-157.degree. C. amine149 6,8-difluoro-N-[2-(2-thienyl)ethyl]- 175-176.degree. C. 4-quinolinamine150 6,8-difluoro-N-[2-(3-thienyl)ethyl]- 191-192.degree. C. 4-quinolinamine151 N-[2-(1-naphthyl)ethyl]-4- 149-150.degree. C. quinolinamine152 N-[2-(2-naphthyl)ethyl]-4- 160-161.degree. C. quinolinamine153 N-[2-(2-thienyl)ethyl]-7-(trifluoro- 131-132.degree. C. methyl)-4-quinolinamine154 8-fluoro-N-[2-(4-phenyl-2-thiazolyl)- 134-135.degree. C. ethyl]-4-quinolinamine155 8-chloro-N-[2-(1-naphthyl)ethyl]- 205-206.degree. C. 4-quinolinamine156 8-chloro-N-[2-(2-naphthyl)ethyl]- 206-208.degree. C. 4-quinolinamine157 .alpha.-[[(8-fluoro-4-quinolinyl)amino]- 182-185.degree. C. methyl]-2-naphthalenemethanol158 8-fluoro-N-[2-(1-naphthyl)ethyl]- 152-153.degree. C. 4-quinolinamine159 8-fluoro-N-[2-(2-naphthyl)ethyl]- 173-174.degree. C. 4-quinolinamine160 N-[2-(1-cyclohexenyl)ethyl]-N-(5,8- oil dimethyl-4-quinolinyl)acetamide161 N-(2-cyclohexylethyl)-N-(8-fluoro- oil 4-quinolinyl)acetamide162 8-fluoro-N-[2-(5-methyl-2-thienyl)- 161-163.degree. C. ethyl]-4-quinolinamine163 N-[2-(5-chloro-2-thienyl)ethyl]-8- 167-168.degree. C. fluoro-4-quinolinamine164 8-fluoro-N-[2-(1H-imidazol-4-yl)- 230.degree. C. ethyl]-4-quinolinamine165 7-chloro-N-[2-(1-cyclohexenyl)- 161-163.degree. C. ethyl]-4-quinolinamine166 7-chloro-N-[2-(2-naphthyl)- 156-158.degree. C. ethyl]-4-quinolinamine167 N-[2-(1-cyclohexenyl)ethyl]-7- 158-160.degree. C. (trifluoromethyl)-4-quinolinamine168 N-[2-(1-cyclohexenyl)ethyl]-6- 129-131.degree. C. fluoro-4-quinolinamine169 N-[2-(2-naphthyl)ethyl]-7-(tri- 127-130.degree. C. fluoromethyl)-4-quinolinamine170 8-fluoro-N-[1-methyl-2-(2-thienyl)- 217-219.degree. C. ethyl]-4-quinolinamine171 N-[1-methyl-2-(2-thienyl)ethyl]- 167-168.degree. C. 4-quinolinamine172 8-chloro-N-[2-(2-thienyl)ethyl]-4- 161-162.degree. C. quinolinamine173 8-fluoro-N-[2-(2-thienyl)ethyl]-4- 157-158.degree. C. quinolinamine174 N-[2-(2,3-dihydro-1,4-benzodioxin- 170-171.degree. C. 2-yl)ethyl]-8-fluoro-4-quinolinamine175 8-fluoro-N-[2-(3-thienyl)ethyl]-4- 163-164.degree. C. quinolinamine176 8-fluoro-N-[2-(H-inldol-3-yl)ethyl]- 205-206.degree. C. 4-quinolinamine177 N-(2-cyclohexylethyl)-8-fluoro-4- 145-147.degree. C. quinolinamine178 N-(2-cyclohexylethyl)-6,8-dimethyl- 155-157.degree. C. 4-quinolinamine179 N-[2-(1-cyclohexenyl)ethyl]-N-(6,8- oil dimethyl-4-quinolinyl)acetamide180 8-fluoro-N-[2-(2-pyridinyl)ethyl]- 143-144.degree. C. 4-quinolinamine______________________________________
TABLE 5______________________________________Bis[2-phenylethyl]quinolinediaminesEX-AMPLENUMBER COMPOUND M.P.______________________________________181 N,N'-bis(2-phenylethyl)-2,4- 70-71.degree. C. quinolinediamine182 N,N'-(2,4-quinolinediyl)bis[N-[2-(4- oil chlorophenyl)ethyl]acetamide]183 8-fluoro-N,N'-bis(2-phenylethyl)-2,4- oil quinolinediamine184 N,N'-bis(2-phenylpropyl)-2,4-quinoline- oil diamine185 N,N'-bis[2-(4-chlorophenyl)ethyl]- 135-137.degree. C. 4,6-quinolinediamine186 N,N'-bis[2-(4-chlorophenyl)ethyl]-4,7- 55-60.degree. C. quinolinediamine187 N,N'-bis[2-(4-methoxyphenyl)ethyl]- 140-150.degree. C. 4,7-quinolinediamine188 N,N'-bis[2-(4-chlorophenyl)ethyl]-8- oil fluoro-2,4-quinolinediamine189 N,N'-bis(2-phenylethyl)-4,8-quinoline- 83-84.degree. C. diamine190 N,N'-bis[2-(2,4-dichlorophenyl)ethyl]- 116-117.degree. C. 8-fluoro-2,4-quinolinediamine191 N,N'-(4,7-quinolinediyl)bis[N-[2-(4- oil chlorophenyl)ethyl]acetamide]______________________________________
TABLE 6______________________________________Bis[2-arylethyl]quinolinediaminesEXAMPLENUMBER COMPOUND M.P.______________________________________192 N,N'-bis[2-(1-cyclohexen-yl)ethyl]- 129-131.degree. C. 4,6-quinolinediamine______________________________________
TABLE 7______________________________________4-(2-phenylethoxy)quinolinesEXAMPLENUMBER COMPOUND M.P.______________________________________193 2-chloro-8-fluoro-4-[2-(4-methyl- 76-77.degree. C. phenyl)ethoxy]quinoline194 5,7-dichloro-4-[2-(1,1'-biphenyl)- 100-102.degree. C. 4-ylethoxy]quinoline195 4-[2-(3-methoxyphenyl)ethoxy]-8- 90-91.degree. C. fluoroquinoline196 8-fluoro-4-[2-(4-methoxyphenyl)- 70-71.degree. C. ethoxy]quinoline197 8-fluoro-4-[2-(3-phenoxyphenyl)- 73-75.degree. C. ethoxy]quinoline198 8-bromo-4-[2-(4- .sub.- t-butyl)phenyl)- 115-118.degree. C. ethoxy]quinoline199 4-[2-(3,4-dimethoxyphenyl)ethoxy]-8- 113-114.degree. C. fluoroquinoline200 8-fluoro-N-[2-(1,1'-biphenyl)-4-yl- 141-142.degree. C. ethoxy]quinoline201 4-[2-(3-chlorophenyl)ethoxy]-8-fluoro- 76-77.degree. C. quinoline202 7-chloro-4-(2-phenylethoxy)quinoline oil203 8-fluoro-4-[2-(3-(trifluoromethyl)- 98-99.degree. C. phenyl)ethoxy]quinoline204 7-chloro-4-[2-(4-methylphenyl)ethoxy]- 87-88.degree. C. quinoline205 8-fluoro-4-[2-(2-methylphenyl)ethoxy]- 72.degree. C. quinoline206 8-fluoro-4-[2-(2-(trifluoromethyl)- 60.degree. C. phenyl)ethoxy]quinoline207 8-chloro-4-(2-phenylethoxy)quinoline 73-74.degree. C.208 4-(2-phenylethoxy)quinoline oil209 4-[2-(4-chlorophenyl)ethoxy]-8-fluoro- 138-140.degree. C. quinoline210 4-[2-(4-methylphenyl)ethoxy]quinoline 59-60.degree. C.211 4-[2-(4-chlorophenyl)ethoxy]quinoline 106-107.degree. C.212 8-fluoro-4-[2-(4-methylphenyl)ethoxy]- 89-90.degree. C. quinoline213 4-(1-methyl-2-phenylethoxy)quinoline oil214 8-fluoro-4-[1-(phenylmethyl)ethoxy]- oil quinoline215 8-bromo-4-[2-(4-chlorophenyl)ethoxy]- 112-114.degree. C. quinoline216 8-chloro-4-[2-(2-chlorophenyl)ethoxy]- 90-92.degree. C. quinoline217 8-fluoro-4-[2-(2-(1-methylethyl)- oil phenyl)-ethoxy]quinoline218 8-fluoro-4-[2-(3-(phenylthio)phenyl)- oil ethoxy]quinoline219 8-fluoro-4-(2-phenylethoxy)quinoline 63-65.degree. C.220 4-(2-phenylpropoxy)-8-fluoroquinoline oil221 4-[2-[4-( .sub.- t-butyl)phenyl]ethoxy]- 81-82.degree. C. 8-fluoroquinoline222 8-fluoro-4-[2-(4-fluorophenyl)- 126-127.degree. C. ethoxy]quinoline223 4-[2-(4-bromophenyl)ethoxy]-8- 130.degree. C. fluoroquinoline224 8-fluoro-4-[2-(3-methylphenyl)ethoxy]- 92.degree. C. quinoline225 8-fluoro-4-[2-(2-fluorophenyl)ethoxy]- 75.degree. C. quinoline226 7-chloro-4-[2-(4-chlorophenyl)ethoxy]- 96-97.degree. C. quinoline227 8-fluoro-4-[2-(2,4,6-trimethylphenyl)- ethoxy]quinoline228 8-fluoro-4-[2-(2-methoxyphenyl)- 74-75.degree. C. ethoxy]quinoline229 4-[2-(2-methoxyphenyl)ethoxy]- oil quinoline230 7-chloro-4-[2-(1,1'-biphenyl)-4-yl- 95-96.degree. C. ethoxy]quinoline231 7-chloro-4-[2-(4-( .sub.- t-butyl)phenyl)- 123-124.degree. C. ethoxy]quinoline232 4-[2-(4-( .sub.- t-butyl)phenyl)ethoxy]-7- 98-99.degree. C. fluoroquinoline233 4-[2-(1,1'-biphenyl)-4-ylethoxy]-7- 73-75.degree. C. fluoroquinoline234 4-[2-(4-chlorophenyl)ethoxy]-7-fluoro- 81-82.degree. C. quinoline235 7-fluoro-4-[2-(4-methylphenyl)ethoxy]- 85-86.degree. C. quinoline236 7-chloro-4-[2-(4-fluorophenyl)ethoxy]- 80.degree. C. quinoline237 8-fluoro-4-[2-(1,1'-biphenyl)-2-yl- 55-60.degree. C. ethoxy]quinoline238 8-fluoro-4-[2-(4-( .sub.- i-propyl)phenyl)- 59-60.degree. C. ethoxy]quinoline239 4-(2-phenylethoxy)-7-(trifluoro- 55-57.degree. C. methyl)quinoline240 8-chloro-4-[2-(4-fluorophenyl)- 125-127.degree. C. ethoxy]quinoline______________________________________
TABLE 8______________________________________4-(3-phenylpropoxy)quinolinesEXAMPLENUMBER COMPOUND M.P.______________________________________241 8-fluoro-4-[3-[4-( .sub.- t-butyl)phenyl]- 103-105.degree. C. propoxy]quinoline242 8-chloro-4-[3-(4-chlorophenyl)- 117-119.degree. C. propoxy]quinoline243 8-fluoro-4-[(3-phenyl-2-propenyl)- 128-130.degree. C. oxy]quinoline______________________________________
TABLE 9______________________________________4-(2-Arylethoxy)quinolinesEXAMPLENUMBER COMPOUND M.P.______________________________________244 8-fluoro-4-[2-(1-naphthyl)- 121-122.degree. C. ethoxy]quinoline245 4-[2-(2-thienyl)ethoxy]- oil quinoline246 8-fluoro-4-[2-(2-thienyl)- 77-79.degree. C. ethoxy]quinoline247 8-fluoro-4-[2-(2-naphthyl)ethoxy]- 123-124.degree. C. quinoline248 5-chloro-4-(2-cyclohexylethoxy)-2,8- 100-102.degree. C. dimethylquinoline249 6-fluoro-4-(2-cyclohexylethoxy)-2- 113-115.degree. C. methylquinoline______________________________________
TABLE 10______________________________________Bis(2-phenylethoxy)quinolinesEXAMPLENUMBER COMPOUND M.P.______________________________________250 8-fluoro-2,4-bis[2-(4-methyl- 125-126.degree. C. phenyl)ethoxy]quinoline251 4,8-bis[2-(4-methylphenyl)ethoxy]- 142-143.degree. C. quinoline______________________________________
TABLE 11______________________________________4-(3-Arylpropyl)quinolinesEXAMPLENUMBER COMPOUND M.P.______________________________________252 4-(3-phenylpropyl)quinoline253 8-fluoro-4-(3-phenylpropyl)quinoline 43-45.degree. C.254 4-(3-phenylpropyl)-7-(trifluoro- oil methyl)quinoline255 8-chloro-4-(3-phenylpropyl)quinoline 70-71.degree. C.256 8-fluoro-4-[3-(4-( .sub.-i-propyl)phenyl)- oil propyl]quinoline257 4-[3-(1,1'-biphenyl)-4-ylpropyl]-8- oil fluoroquinoline258 8-fluoro-4-[3-(4-methylphenyl)propyl]- oil quinoline259 8-fluoro-4-[3-[3-(trifluoromethyl)- 65-66.degree. C. phenyl]propyl]quinoline260 4-[3-[4-( .sub.-t-butyl)phenyl]propyl]-8- oil fluoroquinoline261 4-[3-(4-chlorophenyl)propyl]-8-fluoro- 97.degree. C. quinoline______________________________________
TABLE 12______________________________________Additional CompoundsEXAMPLENUMBER COMPOUND M.P.______________________________________262 4-[2-[4-( .sub.- t-butyl)phenyl]ethoxy]- 67-69.degree. C. quinoline263 8-fluoro-4-[2-(1,1'-biphenyl)-4-yl- 97-99.degree. C. ethoxy]quinoline264 8-fluoro-4-[(2-phenylethyl)sulfinyl]- NA quinoline265 8-fluoro-4-[2-[4-(2-hydroxyethyl)- NA phenyl]ethoxy]quinoline266 8-fluoro-4-[3-methoxybutoxy]- oil quinoline267 8-fluoro-4-(4-pentenoxy)quinoline 75-78.degree. C.268 8-fluoro-N-(4-phenylbutyl)-4- 104-106.degree. C. quinolinamine269 4-[2-(2-chlorophenyl)ethoxy]-8- 78-80.degree. C. fluoroquinoline270 4-[2-[1,1'-biphenyl]-4-ylbutoxy]-8- oil fluoroquinoline271 N-[3-[4-( .sub.- t-butyl)phenyl]propyl]-8- oil fluoro-4-quinolinamine272 8-fluoro-4-(4-phenoxybutoxy)quinoline 87-89.degree. C.273 N-[2-(4-acetoxyphenyl)ethyl]-N-(8- oil fluoro-4-quinolinyl)acetamide274 8-fluoro-4-(3,5,5-trimethylhexyloxy)- oil quinoline275 8-fluoro-4-[2-(2,4-difluorophenyl)- 98-100.degree. C. ethoxy]quinoline276 7-chloro-4-[2-(2,4-difluorophenyl)- 103-105.degree. C. ethoxy]quinoline277 5,7-dichloro-4-[2-(4-ethoxyphenyl)- 104-105.degree. C. ethoxy]quinoline278 4-[2-(4-butoxyphenyl)ethoxy]-8- 80-82.degree. C. fluoroquinoline279 6-ethoxy-2-methyl-4-[3-(phenyl- 38-40.degree. C. methoxy)propoxy]quinoline280 8-chloro-N-[2-(3-phenoxyphenyl)- 145-147.degree. C. ethyl]-4-quinolinamine281 8-chloro-N-(4-phenylbutyl)-4-quino- 134-136.degree. C. linamine282 8-fluoro-4-[3-(4-phenoxyphenyl)pro- 94-96.degree. C. poxy]quinoline283 7-chloro-N-[2-(4-chlorophenyl)- 145-147.degree. C. propyl]-4-quinolinamine284 4-[(4,5-dibromopentyl)oxy]-8-fluoro- 70-73.degree. C. quinoline285 8-fluoro-4-[(8-phenoxyoctyl)oxy]- 80-81.degree. C. quinoline286 6-chloro-2-methyl-4-[2-[4-( .sub.- t-butyl)- 83-86.degree. C. phenyl]ethoxy]quinoline287 8-fluoro-4-[(6-phenoxyhexyl)oxy]- NA quinoline288 8-chloro-N-(2-methyl-2- 137-139.degree. C. phenylpropyl)-4-quinolinamine289 8-fluoro-N-(2-methyl-2-phenylpropyl)- 136-138.degree. C. 4-quinolinamine290 6-methoxy-2-methyl-N-[2-(3-phenoxy- NA phenyl)ethyl]-4-quinolinamine291 8-fluoro-N-[2-[4-(phenylmethoxy)- 157-159.degree. C. phenyl]ethyl]-4-quinolinamine292 7-fluoro-4-[2-(4-bromophenoxy)- 127-129.degree. C. ethoxy]quinoline293 N-[2-(4-hydroxyphenyl)ethyl]-8- 249-251.degree. C. fluoro-4-quinoline294 8-fluoro-4-[3-[3-(trifluoromethyl)- 67-69.degree. C. phenyl]propoxy]quinoline295 8-fluoro-4-(2-phenylcyclohexyloxy)- NA quinoline296 8-chloro-N-[2-(2,4-difluorophenyl)- 206-208.degree. C. ethyl]-4-quinolinamine297 8-fluoro-4-[2-[4-(1,1,2,2-tetra- 70-72.degree. C. fluoroethoxy)phenyl]ethoxy]quinoline298 N-[2-[3,4-bis(phenylmethoxy)- 137-139.degree. C. phenyl]ethyl]-8-fluoro-4-quinolinamine299 4-[2-(6-chloro-1,3-benzodioxol-5-yl)- 143-145.degree. C. ethoxy]-8-fluoroquinoline300 8-fluoro-N-[2-(4-ethoxyphenyl)ethyl]- 179-181.degree. C. 4-quinolinamine301 N-[2-(4-ethoxyphenyl)ethyl]-4- 125-126.degree. C. quinolinamine302 8-fluoro-4-[3-(4-ethoxyphenyl)propyl]- oil quinoline303 4-[3-(4-ethoxyphenyl)propyl]quinoline oil304 8-fluoro-4-[3-(4-methoxyphenyl)- oil propyl]quinoline305 8-fluoro-4-(2,2-dimethylbutoxy)- oil quinoline306 8-fluoro-N-[2-[4-(butoxy)phenyl]- 118-120.degree. C. ethyl]-4-quinolinamine307 7-[(8-fluoro-4-quinolinyl)oxy]- 94-96.degree. C. heptanenitrile308 8-fluoro-4-[2-(3,4-difluorophenyl)- 87-89.degree. C. ethoxy]quinoline309 8-fluoro-4-[2-(1,3-benzodioxol-5- 103-105.degree. C. yl)ethoxy]quinoline310 4-[2-(2,6-dichlorophenyl)ethoxy]- 128-129.degree. C. 8-fluoroquinoline311 8-chloro-4-[2-(2-chloro-4-fluoro- 104-106.degree. C. phenyl)ethoxy]quinoline312 8-fluoro-N-[2-(3-methoxyphenyl)- 153-155.degree. C. ethyl]-4-quinolinamine313 8-fluoro-N-[2-(4-ethylphenyl)- 162-164.degree. C. ethyl]-4-quinolinamine314 8-fluoro-4-[2-[4-(heptyloxy)phenyl]- 45-47.degree. C. ethoxy]quinoline315 (E)-8-fluoro-4-[(2-phenylethenyl)- 99-101.degree. C. oxy]quinoline316 (Z)-8-fluoro-4-[(2-phenylethenyl)- 95-97.degree. C. oxy]quinoline317 8-fluoro-N-[2-[4-(propoxy)phenyl]- 140-142.degree. C. ethyl]-4-quinolinamine318 8-chloro-4-[2-(3,4-difluorophenyl)- 84-86.degree. C. ethoxy]quinoline319 4-[3-[4-( .sub.- i-propyl)phenyl]propyl]- oil quinoline320 7-chloro-4-[2-(1,3-benzodioxol-5-yl)- 75-77.degree. C. ethoxy]quinoline321 8-fluoro-4-[2-(4-methoxyphenoxy)- 107-109.degree. C. ethoxy]quinoline322 8-fluoro-4-[2-[4-(3-methylphenoxy)- 98-100.degree. C. phenyl]ethoxy]quinoline323 8-chloro-4-[2-(2,4-difluorophenyl)- 118-120.degree. C. ethoxy]quinoline324 N-[2-(5-bromo-2-methoxyphenyl)- 176-178.degree. C. ethyl]-8-fluoro-4-quinolinamine325 8-fluoro-4-[2-(4-propoxyphenyl)- 108-110.degree. C. ethoxy]quinoline326 8-fluoro-4-(2-phenoxyethoxy)quinoline 118-120.degree. C.327 8-fluoro-N-[4-[4-(trifluoromethyl)- 110-112.degree. C. phenyl]butyl]-4-quinolinamine328 8-fluoro-N-[2-[4-(1,1,2,2-tetra- 168-170.degree. C. fluoroethoxy)phenyl]ethyl]-4-quinolin- amine______________________________________
The procedures described in the following detailed Examples are representative of the procedures used to prepare the compounds of the other Examples.
EXAMPLE 4N-Ethyl-N-(2-phenylethyl)-4-quinolinamine
To a suspension of 0.59 g of lithium aluminum hydride in 100 mL of dry ether was added, dropwise, a solution of 2.3 g of N-(2-phenylethyl)-N-(4-quinolinyl)acetamide dissolved in 50 mL of dry ether. The mixture was heated to reflux for seven hours. Excess lithium aluminum hydride was then destroyed by adding 100 mL of water to the mixture. The solvent was then removed, and the residue was dissolved in chloroform. After washing with water, the mixture was then dried and concentrated. Using HPLC (silica gel, CH.sub.2 Cl.sub.2 .fwdarw.EtOAc), 0.80 g of the title product was isolated. Yield 36.7%. M.P. oil.
EXAMPLE 10 N-[2-(4-Chlorophenyl)ethyl-N-[8-fluoro-4-quinolinyl]acetamide
A mixture of 2.0 g of N-[2-(4-chlorophenyl)ethyl]-8-fluoro-4-quinolinamine and 5.0 mL of acetic anhydride was refluxed overnight. The mixture was then cooled, and solvents were removed by reducing pressure. The residue was washed with water and then dried. The resulting oil was passed over a silica gel column with ethyl acetate, and the front running spot was collected, producing 0.8 g of the title product as a thick oil.
EXAMPLE 25 2-Chloro-N-(2-phenylethyl)-4-quinolinamine
To 0.6 g of 2-hydroxy-N-(2-phenylethyl)-4-quinolinamine was added 15 mL of POCl.sub.3. The mixture was heated to reflux overnight, then cooled and concentrated to dryness. A mixture of ammonium hydroxide in water was added, then the product was extracted into CH.sub.2 Cl.sub.2. This solution was concentrated to dryness, and the product was recrystallized from pentane/CH.sub.2 Cl.sub.2, giving 0.55 g of the title product. Yield 85.9%. M.P. 132.degree.-133.degree. C.
EXAMPLE 69 3-Chloro-N-(2-chloro-2-phenylethyl)-4-quinolinamine
A mixture of 4.1 g of 1-phenyl-2-(4-quinolinylamine)ethanol, 100 mL of POCl.sub.3 and 6.5 g of PCl.sub.5 was heated to reflux for 18 hours, then cooled and concentrated to dryness. An ice/water mixture was added, then the product was extracted into CH.sub.2 Cl.sub.2. This solution was concentrated to dryness, and the residue was purified by HPLC (silica gel column eluted with pentane/CH.sub.2 Cl.sub.2 (50:50)). Fractions containing the product were combined and concentrated to dryness producing 0.433 g of the title product. Yield 8.7%. M.P. oil.
EXAMPLE 97 8-Fluoro-N-[2-(2-trifluoromethyl)phenyl]-4-quinolinamine
To 2.0 g of 4-chloro-8-fluoroquinoline was added 4.1 g of 2-[2-(trifluoromethyl)phenyl]ethylamine. The mixture was stirred and heated to 160.degree.-165.degree. C. under nitrogen for two hours, then cooled, and 200 mL of a 50:50 mixture of ammonium hydroxide and water was added. The product was extracted into CH.sub.2 Cl.sub.2, which was concentrated to dryness. Recrystallization from a pentane/CH.sub.2 Cl.sub.2 mixture yielded 1.5 g of the title product. Yield 41.6%.
EXAMPLE 154 8-Fluoro-N-[2-(4-phenyl-2-thiazolyl)ethyl]-4-quinolinamine
To 1.0 g of 4-chloro-8-fluoroquinoline was added 2.6 g of 2-.beta.-aminoethyl-4-phenylthiazole monohydrochloride. The mixture was stirred under nitrogen and heated to 170.degree.-175.degree. C. for one hour. The mixture was then cooled and 250 mL of a 50:50 mixture of ammonium hydroxide and water was added. The product was extracted into CH.sub.2 Cl.sub.2, which was then concentrated to dryness. Recrystallizing from pentane/CH.sub.2 Cl.sub.2 gave 0.410 g of the title product. Yield 21.6%. M.P. 134.degree.-135.degree. C.
EXAMPLE 159 8-Fluoro-N-[2-(2-naphthyl)ethyl]-4-quinolinamine
A mixture of 2.0 g of 4-chloro-8-fluoroquinoline and 3.8 g of 2-(2-naphthyl)ethyl amine was heated under nitrogen to 160.degree.-165.degree. C. for one hour. Then 200 mL of a 50:50 mixture of ammonium hydroxide in water was added. The product was extracted from the mixture into CH.sub.2 Cl.sub.2, which was then concentrated to dryness. The residue was recrystallized from pentane/ethyl acetate to give 1.4 g of the title product. Yield 41.2%. M.P. 173.degree.-174.degree. C.
EXAMPLE 173 8-Fluoro-N- [2-(2-thienyl)ethyl]-4-quinolinamine
A mixture of 2.0 g of 4-chloro-8-fluoroquinoline and 2.8 g of 2-(2-thienyl)ethyl amine was heated under nitrogen to 160.degree.-165.degree. C. for two hours, then cooled and combined with 200 mL of a 50:50 mixture of ammonium hydroxide and water. The product was extracted into CH.sub.2 Cl.sub.2, which was then concentrated to dryness. The residue was recrystallized from pentane/CH.sub.2 Cl.sub.2 to give 1.0 g of the title product. Yield 34.5%. M.P. 157.degree.-158.degree. C.
EXAMPLE 181 Bis[2-phenylethyl ]-2,4-quinolinediamine
To 2.0 g of 2,4-dichloroquinoline was added 4.8 g of 2-phenylethylamine, and the mixture was heated to 150.degree.-160.degree. C. under nitrogen for 18 hours. The mixture was then cooled and a solution of ammonium hydroxide and water was added. The product was extracted into CH.sub.2 Cl.sub.2, which was then concentrated to dryness, giving an oil. To the oil, 100 mL of pentane and CH.sub.2 Cl.sub.2 was added and the oil went into solution. This solution was cooled, and the title product crystallized. Yield 44.4%. M.P. 70.degree.-71.degree. C.
EXAMPLE 186 N,N'-Bis[2-(4-chlorophenyl)ethyl]-2,7-quinolinediamine
A mixture of 2.0 g of 4-chloro-7-fluoroquinoline and 3.5 g of 2-(4-chlorophenyl)ethyl amine was heated neat until fuming began. The mixture was then cooled. The product was extracted into a CHCl.sub.3 /ammonium hydroxide solution, which was then washed with water. Solvent was removed by reducing pressure. The residue was placed on a silica gel column with acetone, then flushed with ethanol. Solvent was removed by reducing pressure, giving the title product as a yellow-brown foam. Yield 1.1 g. M.P. 55.degree.-60.degree. C.
EXAMPLE 209 4-[2-(4-Chlorophenyl)ethoxy]-8-fluoroquinoline
To 1.2 g of sodium hydride in 50 mL of DMF was added 3.9 g of 2-(4-chlorophenyl)ethyl alcohol. The mixture was stirred at room temperature for one hour, then 4.5 g of 4-chloro-8-fluoroquinoline in 10 mL of DMF was added, the the mixture was heated to reflux for two hours. Then the mixture was allowed to cool to room temperature while it was stirred for four hours, after which it was poured into an ice/water mixture. The mixture was filtered, and the filter cake was washed with H.sub.2 O. Recrystallization from pentane/ethyl acetate gave 0.840 g of the title product. Yield 11.2%. M.P. 139.degree.-140.degree. C.
EXAMPLE 221 4-[2- 4-(t-But yl)phenyl]ethoxy]-8-fluoroquinoline
To a mixture of 1.1 g of sodium hydride in 50 mL of DMF was added 4.0 g of 2-[4-(1,1-dimethylethyl)phenyl]ethyl alcohol, and the mixture was stirred for one hour at room temperature. Then 4.0 g of 4-chloro-8-fluoroquinoline in 20 mL of DMF were added, and the mixture was stirred at room temperature overnight. Then the mixture was poured into an ice/water mixture, and the solid was collected and recrystallized from ethyl acetate/pentane to give 2.3 g of the title product. Yield 32.4%. M.P. 81.degree.-82.degree. C.
EXAMPLE 238 8-Fluoro-4-[2-[4-(i-propyl)phenyl]ethoxy]quinoline
To a suspension of 0.96 g of sodium hydride in 10 mL of dry DMF was added 3.6 g of 4-chloro-8-fluoroquinoline. The mixture was cooled in an ice/water bath, and 3.3 g of 2-[4-(1-methylethyl)phenyl]ethyl alcohol was added. The mixture was stirred overnight, then diluted with ice and water. The pH was adjusted to 7, then the product was extracted into CH.sub.2 Cl.sub.2. The CH.sub.2 Cl.sub.2 layer was separated, filtered, and evaporated in vacuo. An azeotrope with xylene was formed to facilitate removal of residual DMF. The residue was chromatographically purified on a silica gel column, eluting with CH.sub.2 Cl.sub.2, .fwdarw.5% EtOAc/CH.sub.2 Cl.sub.2 .fwdarw.10% EtOAc/CH.sub.2 Cl.sub.2. The fractions containing product were combined and evaporated to give an oil, which crystallized on adding ether. Recrystallization yielded 2.5 g of title product. M.P. 56.degree.-60.degree. C.
EXAMPLES 212 AND 251 8-fluoro-4-[2-(4-methylphenyl)ethoxy]quinoline, 4,8-Bis[2-(4-methylphenyl)ethoxy]quinoline
To a solution of 1.2 g of sodium hydride in 50 ml of DMF was added 3.4 g of 2-(4-methylphenyl)ethanol, and the mixture was stirred for one hour at room temperature. Then 4.5 g of 4-chloro-8-fluoroquinoline were added, the mixture was heated to reflux for five hours, and then cooled to room temperature, and poured into a mixture of ice in water. The solid phase was collected and dried. TLC showed three products. These were separated by HPLC (silica gel, 70% pentane/30% EtOAc) giving
1.84 g of 8-fluoro-4-[2-(4-methylphenyl)ethoxy]quinoline (Yield: 26.3%; M.P. 89.degree.-90.degree. C.)
0.610 g of 4-chloro-8-[2-(4-methylphenyl)ethoxy]quinoline (Yield: 8.7%; M.P. 74.degree.-75.degree. C.); and 0.450 g of 4,8-bis[2-(4-methylphenyl)ethoxy]quinoline (Yield: 6.4%; M.P. 142.degree.-143.degree. C.).
EXAMPLE 261 4-[3-(4-chlorophenyl)propyl]-8-fluoroquinoline
A mixture of 3.63 g of 4-chloroquinoline and 5.3 g of 5-[2-(4-chlorophenyl)ethyl]barbituric acid was heated to 150.degree. C. for 11/4 hours, to form 5-[2-(4-chlorophenyl)ethyl]-5-(4-quinolinyl)barbituric acid. This compound was hydrolyzed, without isolation, by adding 4 g of NaOH in 40 ml of water and refluxing for four hours. The mixture was cooled, acidified with HCl and refluxed for several hours, cooled, and neutralized with dilute NaOH. The desired product was extracted into CH.sub.2 Cl.sub.2, which was then filtered through phase separating paper and evaporated to dryness. The residue was absorbed onto silica gel and chromatographed over silica gel using CH.sub.2 Cl.sub.2. Fractions containing product were combined to give 2.69 g of crystalline material. This was recrystallized from a petroleum ether/CH.sub.2 Cl.sub.2 mixture to give 2.35 g of the title product. Yield: 39%. M.P. 97.degree. C.
UTILITY Plant Pathology
The compounds of the present invention have been found to control fungi, particularly plant pathogens. When employed in the treatment of plant fungal diseases, the compounds are applied to the plants in a disease inhibiting and "phytologically acceptable amount". The term "disease inhibiting" and "phytologically acceptable amount," as used herein, refers to an amount of a compound of the invention which kills or inhibits the plant disease for which control is desired, but is not significantly toxic to the plant. This amount will generally be from about 1 to 1000 ppm, with 10 to 500 ppm being preferred. The exact concentration of compound required varies with the fungal disease to be controlled, the type formulation employed, the method of application, the particular plant species, climate conditions and the like. The compounds of the invention may also be used to protect stored grain and other non-plant loci from fungal infestation.
Greenhouse Tests
The following experiments were performed in the laboratory to determine the fungicidal efficacy of the compounds of the invention.
Test 1
This screen was used to evaluate the efficacy of the present compounds against a variety of different organisms that cause plant diseases.
The test compounds were formulated for application by dissolving 50 mg of the compound into 1.25 ml of solvent. The solvent was prepared by mixing 50 ml of "Tween 20" with 475 ml of acetone and 475 ml of ethanol. The solvent/compound solution was diluted to 125 ml with deionized water. The resulting formulation contains 400 ppm test chemical. Lower concentrations were obtained by serial dilution with the solvent-surfactant mixture.
The formulated test compounds were applied by foliar spray. The following plant pathogens and their corresponding plants were employed.
______________________________________ Designation inPathogen Following Tables Host______________________________________Erysiphe graminis tritici POWD wheat(powdery mildew) MDEWPyricularia oryzae RICE rice(rice blast) BLASPuccinia recondita tritici LEAF wheat(leaf rust) RUSTBotrytis cinerea GRAY grape berries(gray mold) MOLDPseudoperonospora cubensis DOWN squash(downy mildew) MDEWCercospora beticola LEAF sugar beet(leaf spot) SPOTVenturia inaequalis APPL apple seedling(apple scab) SCABSeptoria tritici LEAF wheat(leaf blotch) BLOT______________________________________
The formulated technical compounds were sprayed on all foliar surfaces of the host plants (or cut berry) to past run-off. Single pots of each host plant were placed on raised, revolving pedestals in a fume hood. Test solutions were sprayed on all foliar surfaces. All treatments were allowed to dry and the plants were inoculated with the appropriate pathogens within 2-4 hours.
The effectiveness of test compounds in controlling disease was rated on the following scale:
0=not tested against specific organism
-=0-19% control at 400 ppm
+=20-89% control at 400 ppm
++=90-100% control at 400 ppm
+++=90-100% control at 100 ppm.
Table 13 gives the results.
TABLE 13__________________________________________________________________________EX. POWD RICE LEAF GRAY DOWN LEAF APPL LEAFNO. MDEW BLAST RUST MOLD MDEW SPOT SCAB BLOT__________________________________________________________________________ 1 + + + + ++ 0 - - 2 - - - - +++ 0 - - 3 - ++ + - +++ 0 - - 4 + + ++ - ++ 0 - - 5 ++ ++ +++ - +++ 0 - +++ 6 ++ + + + ++ 0 - - 7 + + +++ - +++ - - +++ 8 + ++ + - +++ + ++ - + 9 + + + - +++ - - - 10 ++ +++ +++ - ++ +++ - +++ 11 - ++ +++ - ++ +++ - - 12 + ++ +++ - ++ +++ - ++ 13 - ++ ++ - ++ - - - 14 - + + - +++ +++ - - 15 - + + - +++ +++ + - 16 - + + - +++ +++ - - 17 ++ + ++ - ++ 0 - - 18 + ++ ++ + ++ 0 - - 19 + ++ ++ - +++ 0 - - 20 + + + - +++ 0 - - 21 + + + - ++ 0 - - 22 + + + - +++ 0 - - 23 + + + - +++ 0 - - 24 + + + - +++ 0 - - 25 + + ++ - +++ 0 - - 26 + + - - +++ 0 - - 27 + ++ + - +++ 0 - - 28 + ++ + - +++ 0 - - 29 - + + - - 0 0 0 30 - + + - +++ 0 - - 31 ++ + + - +++ 0 - - 32 + + - - +++ 0 - - 33 - + + - +++ 0 - - 34 + + ++ - +++ + - - 35 + + + - +++ +++ - - 36 + +++ +++ - +++ +++ - +++ 37 + - + - + 0 0 0 38 + - ++ - +++ + - - 39 +++ +++ +++ - +++ 0 0 0 40 - ++ +++ - + 0 0 0 41 + ++ +++ - ++ +++ - + 42 +++ + ++ - +++ +++ - - 43 + + - - ++ +++ - - 44 +++ + + - +++ +++ + - 45 + ++ + - ++ +++ - - 46 + ++ + - ++ +++ + + 47 + - + - + 0 0 0 48 + + + - ++ + - - 49 - + + - + 0 0 0 50 +++ - ++ - +++ - - - 51 - + + - +++ +++ - - 52 - + + - +++ + - +++ 53 +++ + + - +++ +++ - + 54 - ++ + - +++ +++ - + 55 + ++ + - ++ +++ - - 56 - ++ ++ - +++ +++ - + 57 - ++ + - ++ +++ - - 58 - - + - +++ 0 0 0 59 + + - - - 0 0 0 60 ++ +++ ++ - +++ 0 0 0 61 - ++ ++ - +++ 0 0 0 62 - ++ ++ - +++ - - + 63 - + +++ - ++ 0 0 0 64 + - + - +++ 0 0 0 65 + + ++ - +++ - - + 66 + ++ +++ - +++ +++ - + 67 - + + - ++ + - - 68 + + +++ - ++ - - +++ 69 + + + - +++ - - - 70 +++ + + - - - - - 71 + + +++ - +++ +++ - + 72 ++ +++ +++ - +++ 0 0 0 73 - + - - ++ - - - 74 + + +++ - +++ +++ - - 75 + + ++ - +++ - - + 76 ++ +++ +++ - +++ - + +++ 77 + + ++ - +++ - + - 78 + ++ +++ - +++ +++ - + 79 + ++ ++ - +++ +++ - + 80 + ++ ++ - +++ + - - 81 + ++ ++ - +++ + - - 82 + +++ +++ - +++ + - +++ 83 + ++ +++ +++ ++ + - - 84 +++ ++ ++ - ++ + - - 85 - - + - - 0 0 0 86 - - + - + 0 0 0 87 - - + - +++ - - - 88 - - ++ - ++ + - - 89 - - + - +++ 0 0 0 90 - +++ +++ - +++ 0 0 0 91 + + - - ++ - - - 92 + ++ +++ - ++ + - +++ 93 - - - - - + - + 94 + +++ +++ - ++ + +++ - + 95 + ++ +++ + +++ + + +++ 96 + +++ +++ - +++ +++ - +++ 97 + +++ +++ - +++ +++ - +++ 98 - + ++ - ++ - - - 99 - ++ +++ - +++ + - -100 + + + - + 0 0 0101 +++ - + - +++ +++ + -102 + + - - - 0 0 0103 + ++ ++ - +++ + +++ +104 - - - - ++ + + -105 +++ ++ +++ - +++ + - +106 ++ + + - + + - +107 ++ + + - +++ - - -108 + + ++ - + - - +++109 + + ++ - +++ 0 0 0110 - + ++ - ++ 0 0 0111 + ++ +++ - +++ - - +++112 - - + - +++ - - -113 + +++ +++ - +++ - - +++114 +++ +++ +++ - +++ +++ - +++115 - + - - + 0 0 0116 - + +++ - +++ + + -117 + + + - +++ + - -118 - + - - - - - -119 + + + - ++ - + +120 - + + - ++ +++ - -121 + - ++ - + 0 0 0122 - ++ + - ++ - - -123 - + + - +++ - - -124 +++ + + - - - - -125 + - - - - 0 0 0126 ++ +++ + - + - - +127 + + + - + 0 0 0128 - + + - - 0 0 0129 - + ++ - + - + -130 - - - - - 0 0 0131 - - - - + 0 0 0132 - - - - - 0 0 0133 - + + - + 0 0 0134 + ++ + - +++ 0 0 0135 - - - - +++ - - +136 + - - - +++ - - -137 + +++ + - +++ 0 0 0138 - + + - +++ 0 0 0139 + + + - ++ - - -140 + +++ +++ - +++ +++ + +++141 - ++ + - + 0 0 0142 - ++ ++ - +++ 0 0 0143 ++ ++ +++ - +++ + - +144 - + ++ - +++ + + -145 - + + - +++ + - -146 - - - - + 0 0 0147 - + + - +++ - - -148 - + + - ++ + - -149 + + ++ - ++ +++ - +150 + + ++ - ++ +++ - +++151 + + ++ - +++ + - +152 ++ +++ ++ - +++ +++ - +++153 + ++ ++ - + - - -154 ++ + +++ - +++ + + +155 - + - - +++ - - -156 - + + - +++ - - -157 - ++ ++ - +++ 0 0 0158 + +++ +++ - +++ + - +++159 ++ +++ +++ - +++ + - +++160 - + - - - 0 0 0161 + + - - + 0 0 0162 + + ++ - +++ - - -163 ++ + +++ - ++ +++ - -164 - + + + ++ + - -165 + ++ ++ - +++ +++ + -166 + + + - +++ - - +167 + - - - + 0 0 0168 + ++ ++ - +++ - - -169 + ++ + - ++ - - -170 + + ++ - + - - -171 - + + - + + - +172 + + + - + - - -173 + + ++ - +++ +++ - +174 + + ++ - +++ - - +175 + + +++ - +++ - 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+++ 0 0 0309 + +++ +++ - +++ 0 0 0310 - ++ - - - 0 0 0311 + - ++ - ++ 0 0 0312 ++ - +++ - +++ 0 0 0317 ++ +++ +++ - +++ 0 0 0318 - ++ ++ - - 0 0 0319 +++ +++ +++ - ++ 0 0 0320 + + ++ - + 0 0 0321 - + ++ - - 0 0 0322 +++ +++ +++ - + 0 0 0323 + ++ +++ - - 0 0 0324 - - + - + 0 0 0325 ++ ++ +++ - +++ 0 0 0326 - + + - - 0 0 0327 +++ - ++ - +++ 0 0 0328 + - +++ - +++ 0 0 0__________________________________________________________________________
Field Tests
Selected compounds were field tested against a variety of plant pathogens. The following table reports pathogens against which compounds of the invention showed activity in these tests.
TABLE 14______________________________________COMPOUNDEX. NO. CROP PATHOGEN______________________________________2 barley Pyrenophora teres potato Phytophthora infestans tomato Phytophthora infestans5 barley Pyrenophora teres Rhynchosporium secalis cucumber Sphaerotheca fuliginea grape Plasmopara viticola potato Phytophthora infestans rape Alternaria brassica tomato Phytophthora infestans10 barley Rhynchosporium secalis Pyrenophora teres Erysiphe graminis hordei cucumber Sphaerotheca fuliginea wheat Pseudocercosporella herpotrichoides Erysiphe graminis tritici97 grape Plasmopara viticola159 barley Rhynchosporium secalis grape Plasmopara viticola wheat Puccinia recondita173 grape Plasmopara viticola200 barley Rhynchosporium secalis Pyrenophora teres Erysiphe graminis hordei cucumber Sphaerotheca fuliginea wheat Pseudocercosporella herpotrichoides Erysiphe graminis tritici212 apple Podosphaera leucotricha barley Pyrenophora teres grape Uncinula necator Plasmopara viticola rape Alternaria brassica rice Piricularia oryzae212 barley Rhynchosporium secalis Pyrenophora teres Erysiphe graminis hordei cucumber Sphaerotheca fuliginea wheat Pseudocercosporella herpotrichoides Erysiphe graminis tritici219 barley Rhynchosporium secalis Pyrenophora teres Erysiphe graminis hordei cucumber Sphaerotheca fuliginea wheat Pseudocercosporella herpotrichoides Erysiphe graminis tritici221 sugar beet Erysiphe sp.______________________________________
Combinations
Fungal disease pathogens are known to develop resistance to fungicides. When strains resistant to a fungicide do develop, it becomes necessary to apply larger and larger amounts of the fungicide to obtain desired results. To retard the development of resistance to new fungicides, it is desirable to apply the new fungicides in combination with other fungicides. Use of a combination product also permits the product's spectrum of activity to be adjusted.
Accordingly, another aspect of the invention is a fungicidal combination comprising at least 1% by weight of a compound of formula (1) in combination with a second fungicide.
Contemplated classes of fungicides from which the second fungicide may be selected include:
1) N-substituted azoles, for example propiconazole, triademefon, flusilazol, diniconazole, ethyltrianol, myclobutanil, and prochloraz;
2) pyrimidines, such as fenarimol and nuarimol;
3) morpholines, such as fenpropimorph and tridemorph;
4) piperazines, such as triforine; and
5) pyridines, such as pyrifenox. Fungicides in these five classes all function by inhibiting sterol biosynthesis. Additional classes of contemplated fungicides, which have other mechanisms of action, include:
6) dithiocarbamates, such as maneb and mancozeb;
7) phthalimides, such as captafol;
8) isophthalonitrites, such as chlorothalonil;
9) dicarboximides, such as iprodione;
10) benzimidazoles, such as benomyl and carbendazim;
11) 2-aminopyrimidines, such as ethirimol;
12) carboxamides, such as carboxin; and
13) dinitrophenols, such as dinocap.
The fungicide combinations of the invention contain at least 1%, ordinarily 20 to 80%, and more typically 50 to 75% by weight of a compound of formula (1).
Combination Tests
Selected compounds were tested in the greenhouse in combination with other known fungicides against various plant pathogens. Results are reported in Tables 15 and 16. In the tables, the time given under "Time in hours" is the number of hours elapsing between treatment and inoculation. A negative time indicates that the pathogen was inoculated before treatment. In such cases, curative activity was being tested. A positive time indicates that the plants were treated before they were inoculated with pathogen. In such cases, residual or protectant activity was tested. The compounds were formulated and applied as foliar sprays as in Test 1. The results were evaluated on a 1-9 rating scale. These ratings represent the following percent disease control:
1=0-19%, 2=20-29%, 3=30-39%, 4=40-59%, 5=60-74%,
6=75-89%, 7=90-96%, 8=97-99%, and 9=100%.
TABLE 15______________________________________CUCURBIT DOWNY MILDEWCOMPOUND 1 RATE RATEPLUS TIME CMPD 1 CMPD 2 RE-COMPOUND 2 IN HOURS IN PPM IN PPM SULTS______________________________________Ex. 5 4 48.00 8.0 24.00 7.5 12.00 7.0 6.00 1.0nuarimol 4 2.00 1.0 1.00 1.0 0.50 1.0 0.25 1.0nuarimol + Ex. 5 4 2.00 48.00 8.5 1.00 24.00 7.5 0.50 12.00 5.0 0.25 6.00 1.0______________________________________
TABLE 16______________________________________CUCURBIT POWDERY MILDEW______________________________________Ex. 5 4 48.00 6.0 24.00 5.0 12.00 1.0 6.00 1.0nuarimol 4 2.00 9.0 1.00 8.0 0.50 7.0 0.25 6.0nuarimol + Ex. 5 4 2.00 48.00 9.0 1.00 24.00 9.0 0.50 12.00 8.0 0.25 6.00 6.0______________________________________
Insecticide and Miticide Utility
The compounds of the invention are also useful for the control of insects and mites. Therefore, the present invention also is directed to a method for inhibiting an insect or mite which comprises applying to a locus of the insect or mite an insect- or mite-inhibiting amount of a compound of formula (1).
The compounds of the invention show activity against a number of insects and mites. More specifically, the compounds show activity against melon aphid, which is a member of the insect order Homoptera. Other members of the Homoptera include leafhoppers, planthoppers, pear pyslla, apple sucker, scale insects, whiteflies, spittle bugs as well as numerous other host specific aphid species. Activity has also been observed against greenhouse thrips, which are members of the order Thysanoptera. The compounds also show activity against Southern armyworm, which is a member of the insect order Lepidoptera. Other typical members of this order are codling moth, cutworm, clothes moth, Indianmeal moth, leaf rollers, corn earworm, European corn borer, cabbage worm, cabbage looper, cotton bollworm, bagworm, eastern tent caterpillar, sod webworm, and fall armyworm.
Representative mite species with which it is contemplated that the present invention can be practiced include those listed below.
__________________________________________________________________________FAMILY SCIENTIFIC NAME COMMON NAME__________________________________________________________________________ACARIDAE Aleurobius farinae Rhizoglyphus echinopus Bulb mite Rhizoglyphus elongatus Rhizoglyphus rhizophagus Rhizoglyphus sagittatae Rhizoglyphus tarsalisERIOPHYIDAE Abacarus farinae Grain rust mite Aceria brachytarsus Acalitus essigi Redberry mite Aceria ficus Aceria fraaxinivorus Aceria granati Aceria parapopuli Eriophyes sheldoni Citrus bud mite Aceria tulipae Aculus carnutus Peach silver mite Aculus schlechtendali Apple rust mite Colomerus vitis Grape erineum mite Eriophyes convolvens Eriophyes insidiosus Eriophyes malifoliae Eriophyes padi Eriophyes pruni Epitrimerus pyri Pear leaf blister mite Eriophyes ramosus Eriophyes sheldoni Citrus bud mite Eriophyes ribis Phyllocoptes gracilis Dryberry mite Phyllocoptruta oleivora Citrus rust mite Phytoptus ribis Trisetacus pini Vasates amygdalina Vasates eurynotus Vasates quadripedes Maple bladdergall mite Vasates schlechtendaliEUPODIDAE Penthaleus major Winter grain mite Linopodes spp.NALEPELLIDAE Phylocoptella avellanae Filbert bud mitePENTHALEIDAE Halotydeus destrustorPYEMOTIDAE Pyemotes tritici Straw itch mite Siteroptes cerealiumTARSONEMIDAE Polyphagotarsonemus latus Broad mite Steneotarsonemus pallidus Cyclamen miteTENUIPALPIDAE Brevipalpus californicus Brevipalpus obovatus Privet mite Brevipalpus lewisi Citrus flat mite Dolichotetranychus floridanus Pineapple flase spider mite Tenuipalpes granati Tenuipalpes pacificusTETRANYCHIDAE Bryobia arborea Bryobia practiosa Clover mite Bryobia rubrioculus Brown mite Eotetranychus coryli Eotetranychus hicoriae Pecan deaf scorch mite Eotetranychus lewisi Eotetranychus sexmaculatus Sixspotted spider mite Eotetranychus willametti Eotetranychus banksi Texas citrus mite Oligonychus ilicis Southern red mite Oligonychus pratensis Banks grass mite Oligonychus ununguis Spruce spider mite Panonychus citri Citrus red mite Panonychus ulmi European red mite Paratetranychus modestus Paratetranychus pratensis Paratetranychus viridis Petrobia latens Brown wheat mite Schizotetranychus celarius Bamboo spider mite Schizotetranychus pratensis Tetranychus canadensis Fourspotted spider mite Tetranychus cinnabarinus Carmine spider mite Tetranychus mcdanieli McDaniel spider mite Tetranychus pacificus Pacific spider mite Tetranychus schoenei Schoene spider mite Tetranychus urticae Twospotted spider mite Tetranychus turkestani Strawberry spider mite Tetranychus desertorum Desert spider mite__________________________________________________________________________
The compounds are useful for reducing populations of insects and mites, and are used in a method of inhibiting an insect or mite population which comprises applying to a locus of the insect or arachnid an effective insect- or mite-inactivating amount of a compound of formula (1). The "locus" of insects or mites is a term used herein to refer to the environment in which the insects or mites live or where their eggs are present, including the air surrounding them, the food they eat, or objects which they contact. For example, plant-ingesting insects or mites can be controlled by applying the active compound to plant parts, which the insects or mites eat, particularly the foliage. It is contemplated that the compounds might also be useful to protect textiles, paper, stored grain, or seeds by applying an active compound to such substance. The term "inhibiting an insect or mite" refers to a decrease in the numbers of living insects or mites; or a decrease in the number of viable insect or mite eggs. The extent of reduction accomplished by a compound depends, of course, upon the application rate of the compound, the particular compound used, and the target insect or mite species. At least an insect-inactivating or mite-inactivating amount should be used. The terms "insect-inactivating amount" and "mite-inactivating amount" are used to describe the amount, which is sufficient to cause a measurable reduction in the treated insect or mite population. Generally an amount in the range from about 1 to about 1000 ppm active compound is used.
In a preferred embodiment, the present invention is directed to a method for inhibiting a mite which comprises applying to a plant an effective mite-inactivating amount of a compound of formula (1) in accordance with the present invention.
MITE/INSECT SCREEN
The compounds of Examples 1-295 were tested for miticidal and insecticidal activity in the following mite/insect screen.
Each test compound was formulated by dissolving the compound in acetone/alcohol (50:50) mixture containing 23 g of "TOXIMUL R" (sulfonate/nonionic emulsifier blend) and 13 g of "TOXIMUL S" (sulfonate/nonionic emulsifier blend) per liter. These mixtures were then diluted with water to give the indicated concentrations.
Twospotted spider mites (Tetranychus urticae Koch) and melon aphids (Aphis gossypii Glover) were introduced on squash cotyledons and allowed to establish on both leaf surfaces. Other plants in the same treatment pot were left uninfested. The leaves were then sprayed with 5 ml of test solution using a DeVilbiss atomizing sprayer at 10 psi. Both surfaces of the leaves were covered until runoff, and then allowed to dry for one hour. Two uninfested leaves were then excised and placed into a Petri dish containing southern armyworm (Spodopetra eridania Cramer).
After standard exposure periods, percent mortality was evaluated. Results are reported in Table 17, where the following abbreviations are used.
CRW refers to corn rootworm
SAW refers to Southern armyworm
SM refers to twospotted spider mites
MA refers to melon aphids.
TABLE 17__________________________________________________________________________MITE/INSECT SCREEN SAW CRW CRW SM & MA SAW SM MACOMPOUND RATE RESULTS RATE RESULTS RESULTS RESULTSEX. NO. PPM % PPM % % %__________________________________________________________________________1 12.00 0 200 0 0 02 12.00 0 200 0 0 03 12.00 0 200 0 0 04 12.00 0 200 0 0 05 12.00 0 200 0 0 06 12.00 0 200 0 0 07 12.00 0 200 0 0 08 12.00 0 200 100 0 09 12.00 0 200 0 0 010 12.00 0 200 0 0 0 24.00 0 400 0 0 011 24.00 60 400 100 0 0 12.00 0 200 80 0 012 24.00 40 400 100 0 0 12.00 0 200 0 0 013 24.00 0 400 0 0 0 12.00 0 200 0 0 014 24.00 0 400 0 0 0 12.00 0 200 0 0 015 24.00 0 400 0 0 0 12.00 0 200 0 0 016 12.00 0 200 0 0 0 24.00 0 400 0 0 017 12.00 0 200 0 0 018 12.00 0 200 0 0 019 12.00 0 200 0 0 020 12.00 0 200 0 0 021 12.00 0 200 0 0 022 12.00 0 200 0 0 023 12.00 0 200 0 0 024 12.00 0 200 0 0 025 12.00 0 200 0 0 026 12.00 0 200 0 0 027 12.00 0 200 0 0 028 12.00 0 200 0 0 029 12.00 0 200 0 0 030 12.00 0 200 0 0 031 12.00 0 200 0 0 032 12.00 0 200 0 0 033 12.00 0 200 0 0 034 12.00 0 200 0 0 035 12.00 0 200 0 0 036 12.00 0 200 0 0 0 24.00 0 400 0 0 0 24.00 0 400 0 0 037 12.00 0 200 0 0 0 24.00 0 400 0 0 038 12.00 0 200 0 0 0 24.00 0 400 0 0 039 24.00 0 400 0 0 0 12.00 0 200 0 0 040 24.00 100 400 80 0 0 12.00 0 200 0 0 041 24.00 0 400 40 0 0 12.00 0 200 80 0 042 24.00 0 400 0 0 0 12.00 0 200 0 0 043 24.00 0 400 0 0 0 12.00 0 200 0 0 044 24.00 0 400 0 0 0 12.00 0 200 0 0 045 12.00 0 200 0 0 0 24.00 0 400 0 0 046 12.00 0 200 0 0 0 24.00 0 400 0 0 047 12.00 0 200 0 0 0 24.00 0 400 0 0 048 12.00 0 200 0 0 0 24.00 0 400 0 0 049 12.00 0 200 0 0 0 24.00 0 400 0 0 050 12.00 0 200 0 0 0 24.00 0 400 0 0 051 12.00 0 200 0 0 0 24.00 0 400 20 0 052 12.00 0 200 0 0 0 24.00 0 400 0 0 053 12.00 0 200 0 0 0 24.00 0 400 0 0 054 12.00 0 200 0 0 055 12.00 0 200 0 0 056 24.00 0 400 80 0 0 12.00 0 200 100 0 057 12.00 0 200 40 0 0 24.00 0 400 50 0 058 24.00 0 400 0 0 059 24.00 0 400 0 0 0 12.00 0 200 0 0 060 24.00 0 400 0 0 0 12.00 0 200 0 0 061 24.00 0 400 0 0 0 12.00 0 200 0 0 062 24.00 0 400 0 0 063 24.00 0 400 0 0 064 24.00 0 400 0 0 0 12.00 0 200 60 0 065 12.00 0 200 0 0 066 12.00 0 200 0 0 067 12.00 0 200 0 0 068 12.00 0 200 0 0 069 12.00 0 200 0 0 070 12.00 0 200 0 0 071 12.00 0 200 0 0 0 12.00 60 200 0 0 072 24.00 0 400 0 0 073 12.00 0 200 0 0 074 12.00 0 200 20 0 0 12.00 0 200 0 0 075 12.00 0 200 0 0 076 12.00 0 200 0 0 0 12.00 0 200 90 0 077 12.00 0 200 0 0 078 12.00 0 200 20 0 0 12.00 0 200 20 0 079 12.00 0 200 10 0 0 12.00 0 200 60 0 080 12.00 0 200 0 0 081 12.00 0 200 0 0 082 12.00 0 200 0 0 083 12.00 0 200 0 0 084 12.00 0 200 10 0 0 24.00 0 400 0 0 085 12.00 0 200 0 0 0 24.00 0 400 0 0 086 12.00 0 200 0 0 0 24.00 0 400 0 0 087 12.00 0 200 0 0 0 24.00 0 400 0 0 088 24.00 0 400 0 0 0 12.00 0 200 0 0 089 24.00 0 400 0 0 0 12.00 0 200 0 0 090 24.00 0 400 0 0 0 12.00 0 200 100 80 8091 12.00 0 200 0 0 092 12.00 0 200 0 0 093 12.00 0 200 0 0 094 12.00 100 200 0 0 095 12.00 0 200 20 0 0 12.00 0 200 40 0 096 12.00 0 200 100 0 0 12.00 0 200 100 0 097 12.00 0 200 0 0 098 12.00 0 200 0 0 099 12.00 0 200 0 0 0100 12.00 0 200 0 0 0 24.00 0 400 0 0 0101 12.00 0 200 0 0 0 24.00 0 400 0 0 0102 12.00 0 200 0 0 0 24.00 0 400 50 0 0103 24.00 0 400 0 0 0 12.00 0 200 0 0 0104 12.00 0 200 0 0 0 24.00 0 400 60 0 0105 12.00 0 200 30 100 80 24.00 0 400 0 0 50106 24.00 0 400 0 0 0107 24.00 0 400 0 0 0 12.00 0 200 0 0 0108 12.00 0 200 0 0 0109 24.00 0 400 0 0 0110 24.00 0 400 0 0 0 12.00 0 200 0 0 0111 12.00 0 200 20 90 0 24.00 0 400 20 80 0112 12.00 0 200 0 0 0 24.00 0 400 0 0 0113 12.00 0 200 100 40 0 24.00 100 400 70 0 0114 24.00 0 400 70 100 30115 24.00 0 400 0 0 0 12.00 0 200 0 0 0116 12.00 0 200 0 0 0117 12.00 0 200 0 0 0 12.00 0 200 0 0 0118 12.00 0 200 0 0 0119 12.00 0 200 0 0 0120 12.00 0 200 0 0 0121 12.00 0 200 0 0 0 24.00 0 400 0 0 0122 24.00 0 400 0 0 0 12.00 0 200 0 0 0123 12.00 0 200 0 0 0124 24.00 0 400 0 0 0 12.00 0 200 0 0 0125 24.00 0 400 0 0 0 12.00 0 200 0 0 0126 12.00 0 200 0 0 0 24.00 0 400 0 0 0127 24.00 0 400 0 0 0 12.00 0 200 0 0 0128 12.00 0 200 0 0 0 24.00 0 400 0 0 0129 12.00 0 200 0 0 0 24.00 0 400 0 0 0130 12.00 0 200 0 0 0 24.00 0 400 0 0 0131 12.00 0 200 0 0 0 24.00 0 400 0 0 0132 12.00 0 200 0 0 0 24.00 0 400 0 0 0133 24.00 0 400 0 0 0 12.00 0 200 0 0 0134 24.00 0 400 0 0 0135 12.00 0 200 0 0 0 24.00 0 400 0 0 0136 12.00 0 200 0 0 0 24.00 0 400 0 0 0137 24.00 0 400 100 80 80138 24.00 0 400 0 0 0139 12.00 0 200 0 0 0140 24.00 0 400 60 0 0 12.00 0 200 0 0 0141 12.00 0 200 0 0 0 24.00 0 400 0 0 0142 12.00 0 200 0 0 0 24.00 0 400 0 0 0143 12.00 0 200 0 0 0 24.00 0 400 0 0 0144 24.00 0 400 0 0 0 12.00 0 200 0 0 0145 24.00 0 400 0 0 0 12.00 0 200 0 0 0146 12.00 0 200 0 0 0 24.00 0 400 0 0 0147 12.00 0 200 0 0 0148 12.00 0 200 0 0 0149 12.00 0 200 0 0 0150 12.00 0 200 0 0 0 12.00 0 200 0 0 0151 12.00 0 200 0 0 0152 12.00 0 200 0 0 0 12.00 0 200 0 0 0153 12.00 0 200 0 0 0154 12.00 0 200 0 0 0 12.00 0 200 0 0 0155 12.00 0 200 0 0 0156 12.00 0 200 0 0 0 12.00 0 200 0 0 0157 24.00 0 400 100 80 0158 12.00 0 200 0 0 0159 12.00 0 200 0 0 0160 24.00 0 400 0 0 0 12.00 0 200 0 0 0161 24.00 40 400 0 0 80 12.00 0 200 0 0 0162 12.00 0 200 0 0 0163 12.00 0 200 0 0 0164 12.00 0 200 0 0 0165 24.00 0 400 0 0 0 12.00 0 200 0 0 0166 12.00 0 200 0 0 0 24.00 0 400 0 0 0167 12.00 0 200 0 0 0 24.00 0 400 0 0 0168 24.00 0 400 0 0 0 12.00 0 200 0 0 0169 24.00 0 400 0 0 0 12.00 0 200 0 0 0170 12.00 0 200 0 0 0171 12.00 0 200 0 0 0172 12.00 0 200 0 0 0173 12.00 0 200 0 0 0174 12.00 0 200 0 0 0175 12.00 0 200 0 0 0176 12.00 0 200 0 0 0177 12.00 0 200 0 0 0 24.00 100 400 0 0 0178 12.00 0 200 0 0 0 24.00 0 400 0 0 0179 12.00 0 200 0 0 0 24.00 0 400 0 0 0180 12.00 0 200 0 0 0 24.00 0 400 0 0 0181 12.00 0 200 0 0 0182 12.00 0 200 0 0 0 24.00 0 400 0 0 0183 12.00 0 200 0 0 0184 12.00 0 200 0 0 0185 24.00 0 400 0 0 0 12.00 0 200 0 0 0186 24.00 0 400 0 0 0 12.00 0 200 0 0 0187 12.00 0 200 0 0 0 24.00 0 400 0 0 0188 24.00 0 400 0 0 0189 12.00 0 200 0 0 0190 12.00 0 200 0 0 0191 12.00 0 200 0 0 0 24.00 0 400 0 0 0192 24.00 0 400 0 0 0 12.00 0 200 0 0 0193 12.00 0 200 0 0 0 24.00 0 400 0 0 0194 24.00 0 400 0 0 0 12.00 0 200 0 0 0195 24.00 0 400 0 0 0196 24.00 0 400 0 100 100197 24.00 0 400 80 90 80198 24.00 0 400 0 90 80199 24.00 100 400 0 0 0200 24.00 0 400 50 100 100 12.00 0 200 0 100 100201 12.00 0 200 0 80 100 24.00 0 400 0 80 100202 12.00 0 200 0 0 0 24.00 0 400 0 0 0203 12.00 0 200 10 0 100 24.00 0 400 0 0 90204 12.00 0 200 0 0 0 24.00 0 400 100 0 50205 24.00 0 400 0 0 0206 24.00 0 400 0 0 0207 12.00 0 200 0 0 0208 12.00 0 200 0 10 10209 12.00 0 200 10 0 0 12.00 0 200 100 0 40210 12.00 0 200 0 0 0211 12.00 0 200 0 10 40212 12.00 0 200 0 0 0213 12.00 0 200 0 0 0214 24.00 0 400 0 0 02115 24.00 0 400 0 100 100216 24.00 100 400 0 0 0217 24.00 0 400 0 0 0218 24.00 0 400 100 0 0219 12.00 0 200 0 0 0220 24.00 0 400 0 0 0 12.00 0 200 0 0 0221 24.00 0 400 0 90 80 12.00 40 200 0 90 90222 24.00 0 400 0 0 40 12.00 0 200 0 0 50223 24.00 0 400 0 0 100 12.00 80 200 0 0 80224 24.00 0 400 0 0 0225 24.00 0 400 0 0 0226 24.00 0 400 0 0 0 12.00 0 200 0 0 0227 12.00 0 200 0 0 0 24.00 0 400 0 0 0228 12.00 0 200 0 0 0 24.00 0 400 0 0 80229 12.00 0 200 0 50 50 24.00 0 400 0 0 0230 12.00 0 200 0 100 90 24.00 0 400 0 80 0231 12.00 0 200 0 90 0 24.00 0 400 0 40 50232 24.00 0 400 30 80 40 12.00 0 200 0 100 70233 12.00 0 200 0 100 50 24.00 0 400 0 80 80234 12.00 0 200 60 50 50 24.00 0 400 0 30 100235 24.00 0 400 0 0 50 12.00 0 200 80 0 0236 24.00 40 400 0 0 30 12.00 0 200 0 0 0 24.00 0 400 0 0 0237 24.00 0 400 0 100 0 12.00 0 200 0 0 0238 24.00 0 400 100 0 0 12.00 0 200 0 100 100239 24.00 0 400 0 0 0 12.00 0 200 0 0 0240 24.00 0 400 0 0 0241 24.00 0 400 0 0 0242 24.00 0 400 0 0 0 12.00 0 200 0 0 0243 24.00 0 400 0 0 0244 12.00 0 200 0 0 40245 12.00 0 200 0 0 0246 12.00 0 200 0 0 0247 24.00 0 400 50 0 0 12.00 0 200 20 90 0248 24.00 0 400 0 0 0249 24.00 0 400 0 0 0250 24.00 0 400 0 0 0251 12.00 0 200 0 0 0252 24.00 0 400 0 90 100 12.00 0 200 0 90 100253 24.00 0 400 0 100 100 12.00 0 200 0 100 90254 24.00 0 400 0 0 0255 24.00 0 400 0 0 0256 24.00 100 400 100 0 0257 24.00 0 400 0 0 0258 24.00 0 400 0 90 100259 24.00 0 400 0 80 80 12.00 0 200 0 100 90260 24.00 40 400 40 0 0 12.00 0 200 100 100 100261 24.00 100 400 80 50 100 12.00 0 200 100 90 100262 12.00 0 200 0 100 100 24.00 0 400 0 100 100263 12.00 0 200 0 0 0 24.00 0 400 0 0 0264 12.00 0 200 0 0 0 24.00 0 400 0 0 0265 12.00 0 200 0 0 0 24.00 0 400 0 0 0266 12.00 0 200 0 0 0 24.00 0 400 0 0 0267 12.00 0 200 0 40 20 24.00 0 400 0 100 100268 12.00 0 200 0 0 0 24.00 0 400 0 80 0269 12.00 0 200 0 30 24.00 40 400 0 0 0270 12.00 0 200 20 0 0 24.00 0 400 0 80 0271 12.00 0 200 0 0 0 24.00 0 400 0 0 0272 12.00 0 200 0 0 0 24.00 0 400 0 20 0273 24.00 0 400 0 0 0274 12.00 0 200 0 100 100 24.00 0 400 0 0 100275 12.00 0 200 0 0 90 24.00 0 400 0 60 100276 12.00 0 200 0 0 0 24.00 0 400 0 60 80277 24.00 0 400 0 0 0278 12.00 0 200 0 60 90 24.00 0 400 100 0 0279 12.00 0 200 0 0 0 24.00 0 400 0 0 80280 12.00 0 200 60 0 0 24.00 0 400 0 0 0281 12.00 0 200 0 0 0 24.00 0 400 0 0 0282 12.00 0 200 0 0 0 24.00 0 400 0 0 0283 12.00 0 200 0 0 80 24.00 0 400 0 80 0284 12.00 0 200 0 0 0 24.00 0 400 0 0 0285 12.00 0 200 0 40 80 24.00 0 400 0 0 0286 12.00 0 200 0 0 0 24.00 0 400 0 0 0287 12.00 0 200 0 0 80 24.00 0 400 0 0 0288 12.00 0 200 0 0 0 24.00 0 400 0 0 0289 12.00 0 200 0 0 0 24.00 0 400 0 0 0290 12.00 0 200 0 80 80 24.00 0 400 0 0 0291 12.00 0 200 0 0 100 24.00 0 400 0 0 0292 12.00 0 200 0 0 30 24.00 0 400 0 0 0293 12.00 0 200 0 0 0 24.00 0 400 0 0 0294 12.00 0 200 0 0 0 24.00 0 400 0 0 0295 12.00 0 200 0 0 0 24.00 0 400 0 0 0296 12.00 0 200 0 0 0 24.00 0 400 0 0 80297 12.00 0 200 100 100 100 24.00 0 400 100 100 100298 12.00 0 200 0 0 0 24.00 0 400 0 0 0299 12.00 0 200 0 0 0 24.00 0 400 0 0 0300 12.00 0 200 20 0 0 24.00 0 400 0 0 0301 12.00 0 200 40 0 0 24.00 0 400 0 0 0302 12.00 0 200 100 100 100 24.00 0 400 0 0 100303 12.00 0 200 0 100 100 24.00 0 400 0 0 100304 12.00 0 200 0 100 100 24.00 0 400 0 100 80305 12.00 0 200 0 0 0 24.00 0 400 0 0 0306 12.00 0 200 0 100 100 24.00 100 400 100 0 0307 12.00 0 200 0 0 0 24.00 0 400 0 0 0308 12.00 0 200 0 0 80 24.00 0 400 0 0 80309 12.00 0 200 0 40 60 24.00 0 400 100 0 0310 12.00 0 200 0 0 0 24.00 0 400 0 0 90311 12.00 0 200 0 0 0 24.00 0 400 0 0 40312 12.00 0 200 0 0 0 24.00 0 400 0 0 0313 12.00 200 24.00 0 400 0 30 0314 24.00 100 400 0 100 100317 12.00 0 200 80 80 80 24.00 0 400 0 0 60318 12.00 200 24.00 0 400 0 0 0319 12.00 200 24.00 0 400 0 100 100320 12.00 0 200 0 0 0 24.00 0 400 0 0 0321 12.00 0 200 0 0 0 24.00 0 400 0 0 0322 12.00 0 200 60 100 80 24.00 0 400 60 80 100323 12.00 0 200 0 0 0 24.00 0 400 0 0 0324 12.00 0 200 0 0 0 24.00 0 400 0 0 0325 12.00 0 200 0 0 80 24.00 0 400 80 0 0326 12.00 0 200 0 0 0 24.00 0 400 0 0 0327 12.00 0 200 80 0 100 24.00 60 400 0 80 60328 12.00 100 200 100 80 80 24.00 100 400 100 0 0__________________________________________________________________________
Field Trips
4-[2-]4-(t-Butyl)phenyl]ethoxy]-8-fluoroquinoline (Example 221) was evaluated in a number of field trials. The following table reports the host plants on which it was tested and the pest species against which it showed activity.
TABLE 18______________________________________HOST PEST______________________________________alfalfa (Lucerne) pea aphid, potato leaf hopper, tarnished plant bug, green cloverwormapples mites, apple aphid, European red mite, green peach aphid, white apple leafhopper, apple rust mite, rosy apple aphidazaleas greenhouse thripbean, faba broad bean aphidbroccoli twospotted spider mitecotton cotton aphidgrape (European) grape thrip, grape leafhopperhops Dawson-hop aphidpea, garden (English) pea aphidpecan nut yellow hickory aphidprivet thripsugar beet green peach aphidwheat wheat aphid______________________________________
Compositions
The compounds of this invention are applied in the form of compositions which are important embodiments of the invention, and which comprise a compound of this invention and a phytologically-acceptable inert carrier. The compositions are either concentrated formulations which are dispersed in water for application, or are dust or granular formulations which are applied without further treatment. The compositions are prepared according to procedures and formulae which are conventional in the agricultural chemical art, but which are novel and important because of the presence therein of the compounds of this invention. Some description of the formulation of the compositions will be given, however, to assure that agricultural chemists can readily prepare any desired composition.
The dispersions in which the compounds are applied are most often aqueous suspensions or emulsions prepared from concentrated formulations of the compounds. Such water-soluble, water-suspendable or emulsifiable formulations are either solids usually known as wettable powders, or liquids usually known as emulsifiable concentrates or aqueous suspensions. Wettable powders, which may be compacted to form water dispersible granules, comprise an intimate mixture of the active compound, an inert carrier and surfactants. The concentration of the active compound is usually from about 10% to about 90% by weight. The inert carrier is usually chosen from among the attapulgite clays, the montmorillonite clays, the diatomaceous earths, or the purified silicates. Effective surfactants, comprising from about 0.5% to about 10% of the wettable powder, are found among the sulfonated lignins, the condensed naphthalenesulfonates, the naphthalenesulfonates, the alkylbenzenesulfonates, the alkyl sulfates, and nonionic surfactants such as ethylene oxide adducts of alkyl phenols.
Emulsifiable concentrates of the compounds comprise a convenient concentration of a compound, such as from about 50 to about 500 grams per liter of liquid, equivalent to about 10% to about 50%, dissolved in an inert carrier which is either a water miscible solvent or a mixture of water-immiscible organic solvent and emulsifiers. Useful organic solvents include aromatics, especially the xylenes, and the petroleum fractions, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, such as the terpenic solvents including rosin derivatives, aliphatic ketones such as cyclohexanone, and complex alcohols such as 2-ethoxyethanol. Suitable emulsifiers for emulsifiable concentrates are chosen from conventional nonionic surfactants, such as those mentioned above.
Aqueous suspensions comprise suspensions of water-insoluble compounds of this invention, dispersed in an aqueous vehicle at a concentration in the range from about 5% to about 50% by weight. Suspensions are prepared by finely grinding the compound, and vigorously mixing it into a vehicle comprised of water and surfactants chosen from the same types discussed above. Inert ingredients, such as inorganic salts and synthetic or natural gums, may also be added, to increase the density and viscosity of the aqueous vehicle. It is often most effective to grind and mix the compound at the same time by preparing the aqueous mixture, and homogenizing it in an implement such as a sand mill, ball mill, or pistontype homogenizer.
The compounds may also be applied as granular compositions, which are particularly useful for applications to the soil. Granular compositions usually contain from about 0.5% to about 10% by weight of the compound, dispersed in an inert carrier which consists entirely or in large part of clay or a similar inexpensive substance. Such compositions are usually prepared by dissolving the compound in a suitable solvent, and applying it to a granular carrier which has been pre-formed to the appropriate particle size, in the range of from about 0.5 to 3 mm. Such compositions may also be formulated by making a dough or paste of the carrier and compound, and crushing and drying to obtain the desired granular particle size.
Dusts containing the compounds are prepared simply by intimately mixing the compound in powdered form with a suitable dusty agricultural carrier, such as kaolin clay, ground volcanic rock and the like. Dusts can suitably contain from about 1% to about 10% of the compound.
It is equally practical, when desirable for any reason, to apply the compound in the form of a solution in an appropriate organic solvent, usually a bland petroleum oil, such as the spray oils, which are widely used in agricultural chemistry.
Insecticides and miticides are generally applied in the form of a dispersion of the active ingredient in a liquid carrier. It is conventional to refer to application rates in terms of the concentration of active ingredient in the carrier. The most widely used carrier is water.
The compounds of the invention can also be applied in the form of an aerosol composition. In such compositions the active compound is dissolved or dispersed in an inert carrier, which is a pressure-generating propellant mixture. The aerosol composition is packaged in a container from which the mixture is dispensed through an atomizing valve. Propellant mixtures comprise either low-boiling halocarbons, which may be mixed with organic solvents, or aqueous suspensions pressurized with inert gases or gaseous hydrocarbons.
The actual amount of compound to be applied to loci of insects and mites is not critical and can readily be determined by those skilled in the art in view of the examples above. In general, concentrations of from 10 ppm to 5000 ppm of compound are expected to provide good control. With many of the compounds, concentrations of from 100 to 1500 ppm will suffice. For field crops, such as soybeans and cotton, a suitable application rate for the compounds is about 0.5 to 1.5 lb/A, typically applied in 50 gal/A of spray formulation containing 1200 to 3600 ppm of compound. For citrus crops, a suitable application rate is from about 100 to 1500 gal/A spray formulation, which is a rate of 100 to 1000 ppm.
The locus to which a compound is applied can be any locus inhabited by an insect or arachnid, for example, vegetable crops, fruit and nut trees, grape vines, and ornamental plants. Inasmuch as many mite species are specific to a particular host, the foregoing list of mite species provides exemplification of the wide range of settings in which the present compounds can be used.
Because of the unique ability of mite eggs to resist toxicant action, repeated applications may be desirable to control newly emerged larvae, as is true of other known acaricides.
The following formulations of compounds of the invention have been prepared, and are typical of compositions useful in the practice of the present invention.
______________________________________A. Aqueous Suspension8-Fluoro-N-[2-(2-naphthyl)ethyl]-4-quinolinamine 12.5%"TERGITOL TMN-6" (nonionic surfactant) 1.0%"ZEOSYL 200" (silica) 1.0%"AF-100" (silicon based antifoam agent) 0.2%2% xanthan solution 10.0%"MAKON 10" (10 moles ethyleneoxide 9.0%nonylphenol surfactant)tap water 66.3%B. Emulsifiable Concentrate4-[2-[4-( .sub.-t-Butyl)phenyl]ethoxy]-8-fluoroquinoline 12.4%"EXXON 200" (naphthalene solvent) 83.6%"TOXIMUL H" (nonionic/anionic surfactant blend) 2.0%"TOXIMUL D" (nonionic/anionic surfactant blend) 2.0%______________________________________

Number	Name	Date
2838514	Surrey et al.	Jun 1958
3936461	Schwender et al.	Feb 1976
4167638	Chen et al.	Sep 1979
4743601	Schonafinger et al.	May 1988
5102892	Geiss et al.	Apr 1992

Number	Date	Country
29319	May 1981	EPX
326330	Aug 1989	EPX
2052481	May 1979	GBX

Substituted quinolines and cinnolines

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US Referenced Citations (5)

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Non-Patent Literature Citations (8)

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Entry
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Russell et al., Chemical Abstracts, vol. 74, 1970, Abstract 64187b.
Renault et al., Chimie Therapeutique, 66, (5-6), 1977, pp. 339-346.
Mal-Kovskaya et al., Chemical Abstracts, vol. 84, 1976, Abstract 150039t.
Berlot et al., Bull. Soc. Chim., France, 1973(11), 3175-3178.
Singh et al., J. Med. Chem., 1971, 14(4), pp. 283-286.
Renault et al., Bull. Soc. Chim., France, 1975(1), 211-214.