A heterocyclic derivative of the formula (I)
##STR00001##
wherein each symbol is as defined in the specification, and pharmaceutically acceptable salts thereof. The compound (I) of the present invention and pharmaceutically acceptable salts thereof exhibit superior ACAT inhibitory activity and lipoperoxidation inhibitory activity in mammals, and are useful as ACAT inhibitors and lipoperoxidation inhibitors. Specifically, they are useful for the prophylaxis and treatment of arteriosclerosis, hyperlipemia, arteriosclerosis in diabetes, and cerebrovascular and cardiovascular ischemic diseases.
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0. 1. A heterocyclic compound of the formula (I)
##STR00041##
wherein
one of R1, R2 and R3 is hydroxy, carboxy, alkoxycarbonyl, a group of the formula —NR9R10 wherein R9 and R10 are each independently hydrogen atom or lower alkyl, or alkyl or alkenyl substituted by hydroxy, carboxy, sulfonic add group or phosphoric acid group, alkoxy-carbonyl or a group of the formula —NR9R10 wherein R9 and R10 are each independently hydrogen atom or lower alkyl, and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy;
either R3 or R4 is a group of the formula —NHCOR7 wherein R7 is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula —NHR8 wherein R8 is alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy;
R6 is alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl or arylalkyl; and Z is
##STR00042##
or a pharmaceutically acceptable salt thereof, provided that when one of R1, R2 and R3 its carboxy or alkoxycarbonyl, Z should be a group of the formula
##STR00043##
0. 2. The heterocyclic compound of
0. 3. The heterocyclic compound of
or a pharmaceutically acceptable salt thereof.
0. 4. The heterocyclic compound of
0. 5. The heterocyclic compound of
0. 6. The heterocyclic compound of
0. 7. The heterocyclic compound of
0. 8. The heterocyclic compound of
0. 9. The heterocyclic compound of
wherein R1a is hydrogen atom or lower alkyl, R3a is lower alkyl, R2a is alkyl substituted by hydroxy or carboxy, R4a is a group of the formula —NHCOR7a wherein R7a is alkyl, cycloalkyl or cycloalkylalkyl, and R6a is alkyl, cycloalkyl or cycloalkylalkyl, or a pharmaceutically acceptable salt thereof.
0. 10. The heterocyclic compound of
11. The A heterocyclic compound of
(1) N-(1-hexyl-5-carboxythyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
(1) N-(1-hexyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
(2) N-(1-heptyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
(3) N-(1-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
(4) N-(1-nonyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
(5) N-(1-decyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
(6) N-(1-undecyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, and
(7) N-(1-dodecyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
(8) N-(1-hexyl-5-hydroxymethyl-6-methylindolin-7-yl)-2,2-dimethylpropanamide,
(9) N-(1-hexyl-5-hydroxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
(10) N-(1-heptyl-5-hydroxymethyl-6-methylindolin-7-yl)-2,2-dimethylpropanamide,
(11) N-(1-heptyl-5-hydroxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
(12) N-(1-octyl-5-hydroxymethyl-6-methylindolin-7-yl)-2,2-dimethylpropanamide, and
(13) N-(1-octyl-5-hydroxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
or a pharmaceutically acceptable salt thereof.
0. 12. The heterocyclic compound of
0. 13. The heterocyclic compound of
wherein one of R1c, R2c and R3c is hydroxy, carboxy, alkoxycarbonyl or a group of the formula —NR9cR10c wherein R9c and R10c are each independently hydrogen atom or lower alkyl and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy, either R3c or R4c is a group of the formula —NHCOR7c, wherein R7c is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula —NHR8c wherein R8c is alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl and the other is hydrogen atom, lower alkyl or lower alkoxy, and R6c is alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl or arylalkyl, or a pharmaceutically acceptable salt thereof.
0. 14. The heterocyclic compound of
0. 15. The heterocyclic compound of
0. 16. The heterocyclic compound of
(1) N-(1-hexyl-5-carboxy-6-methylindolin-7-yl)-2,2-dimethylpropanamide,
(2) N-(1-octyl-5-carboxy-6-methylindolin-7-yl)-2,2-dimethylpropanamide,
(3) N-(1-decyl-5-carboxy-6-methylindolin-7-yl)-2,2-dimethylpropanamide,
(4) N-(1-hexyl-5-carboxy-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
(5) N-(1-octyl-5-carboxy-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, and
(6) N-(1-decyl-5-carboxy-4,6dimethylindolin-7-yl)-2,2-dimethylpropanamide,
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising an effective amount of a heterocyclic compound of claim 1 11 or a pharmaceutically acceptable salt thereof.
18. A method of inhibiting acyl-CoA:cholesterol acyl-transferase in a patient in need of same which comprises administering to such patient the composition of
19. A method of inhibiting lipoperoxidation in a patient in need of same which comprises administering to such patient the composition of
0. 20. The heterocyclic compound of
0. 21. The heterocyclic compound of
0. 22. The heterocyclic compound of
0. 23. The heterocyclic compound of
0. 24. The heterocyclic compound of
0. 25. The heterocyclic compound of
0. 26. The heterocyclic compound of
0. 27. The heterocyclic compound of
0. 28. The heterocyclic compound of
0. 29. The heterocyclic compound of
0. 30. The heterocyclic compound of
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This is a national stage of international application no. PCT/JP96/02852 filed Sep. 30, 1996.
The present invention relaters to novel heterocyclic derivatives and pharmaceutical use thereof. More particularly, the present invention relates to novel heterocyclic derivatives having an indoline ring, indole ring or tetrahydroquinoline ring, which derivatives having an inhibitory activity on aryl CoA: cholesterol acyltransferase (hereinafter ACAT) and lipoperoxidation inhibitory activity, and to pharmaceutical use thereof.
It is a well-known fact that arteriosclerosis is an extremely important factor causing various circulatory diseases, and active studies have been undertaken in an attempt to achieve suppression of the evolution of arterial sclerosis or regression thereof. In particular, although the usefulness of a pharmaceutical agent which reduces cholesterol in blood or arterial walls has been acknowledged, an ideal pharmaceutical agent exhibiting positive clinical effects while causing less side-effects has not been realized. A pharmaceutical agent which directly inhibits deposition of cholesterol in arterial walls has been desired as a pharmaceutical agent which effectively prevents or treats arterial sclerosis, and studies in this field are thriving. Yet, an ideal pharmaceutical agent has not been developed.
In recent years, it has been clarified that cholesterol in blood is accumulated in arterial walls in the ester form thereof, and that it significantly evolves arteriosclerosis. A decrease in cholesterol level in blood leads to the reduction of accumulation of cholesterol ester in arterial walls, and is effective for the suppression of evolution of arteriosclerosis and regression thereof.
Cholesterol in food is esterified in mucous membrane of small intestine, and taken into blood as chylomicron. ACAT is known to play an important role in the generation of cholesterol ester in mucous membrane of small intestine. Thus, if esterification of cholesterol can be suppressed by inhibiting ACAT in mucous membrane of small intestine, absorption of cholesterol by mucous membrane and into blood can be presumably prevented to ultimately result in lower cholesterol level in blood.
In arterial walls, ACAT esterifies cholesterol and causes accumulation of cholesterol ester. Inhibition of ACAT in arterial walls is expected to effectively suppress accumulation of cholesterol ester.
From the foregoing, it is concluded that an ACAT inhibitor will make an effective pharmaceutical agent for hyperlipemia and arteriosclerosis, as a result of suppression of absorption of cholesterol in small intestine and accumulation of cholesterol in arterial walls.
Conventionally, there have been reported, for example, as such ACAT inhibitors, amide and urea derivatives [J. Med. Chem., 29: 1131 (1986), Japanese Patent Unexamined Publication Nos. 117651/1990, 7259/1990, 234839/1992, 327564/1992 and 32666/1993]. However, creation and pharmacological studies of these compounds have been far from sufficient.
Meanwhile, hyperoxidation of low density lipoprotein (LDL) is also highly responsible for intracellular incorporation of cholesterol accumulated as cholesterol ester in arterial walls. In addition, it is known that hyperoxidation of lipids in a living body is deeply concerned with the onset of arteriosclerosis and cerebrovascular and cardiovascular ischemic diseases.
Accordingly, a compound having both an ACAT inhibitory activity and lipoperoxidation inhibitory activity is highly useful as a pharmaceutical product, since it effectively reduces accumulation of cholesterol ester in arterial walls and inhibits lipoperoxidation in living organisms, thereby preventing and treating various vascular diseases caused thereby.
It is therefore an object of the present invention to provide a compound having ACAT inhibitory activity and lipoperoxidation inhibitory activity, as well as pharmaceutical use thereof, particularly ACAT inhibitor and lipoperoxidation inhibitor.
The present inventors have conducted intensive studies to achieve the above-mentioned objects and found that a certain heterocyclic derivative having an indoline ring, indole ring or tetrahydroquinoline ring is superior in water solubility as compared to conventional ACAT inhibitors, and has lipoperoxidation inhibitory activity in addition to strong ACAT inhibitory activity, and that said compound permits superior oral absorption, strong anti-hyperlipemia effect and anti-arteriosclerosis effect, which resulted in the completion of the present invention.
Thus, the present invention relates to heterocyclic derivatives of the formula (I)
##STR00002##
wherein
The present invention also relates to pharmaceutical compositions. ACAT inhibitors and lipoperoxidation inhibitors containing the above-mentioned heterocyclic derivative or a pharmaceutically acceptable salt thereof.
In the present specification, each symbol denotes the following.
Lower alkyl at R1, R1a, R1b, R1c, R2, R2c, R3, R3a, R3b, R3c, R4, R4c, R5, R5c, R9, R9c, R10 and R10c may be linear or branched and has 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tent-butyl, pentyl, isopentyl, neopentylhexyl an the like.
Lower alkoxy at R1, R1b, R1c, R2, R2a, R3, R3b, R3c, R4, R4c, R5 and R5c may be linear or branched and has 1 to 6 carbon atoms. Examples thereof include methoxy, ethoxy propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
Alkyl at R6, R6a, R6b, R6c, R7, R7a, R7b, R7c, R8, R8b and R8c may be linear or branched and preferably has 1 to 20 carbon atoms. Examples thereof include methyl, ethyl propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, nonadecyl, icosyl, 1,1-dimethylpropyl, 1,1-dimethylbutyl, 1,1-dimethylhexyl, 1,1-dimethylheptyl, 3,3-dimethylbutyl, 4,4-dimethylbutyl and the like.
In alkoxyalkyl at R6, R6b, R6c, R7, R7b and R7c, the alkoxy moiety thereof preferably has 1 to 6 carbon atoms and alky moiety thereof preferably has 1 to 6 carbon atoms. Examples of alkoxyalkyl include ethoxybutyl, ethoxyhexyl, butoxybutyl, butoxyhexyl, hexyloxybutyl, hexyloxyhexyl and the like.
In alkylthioalkyl at R6, R6b, R6c, R7, R7b and R7c, both alkyl moieties preferably have 1 to 6 carbon atoms Examples of alkylthioalkyl include ethylthioethyl ethylthiohexyl, butylthiobutyl, butylthiohexyl, hexylthiobutyl, hexylthiohexyl and the like.
Cycloalkyl at R6, R6a, R6b, R6c, R7, R7a, R7b, R7c, R8, R8b and R8c preferably has 3 to 8 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
In cycloalkylalkyl at Rd, Rda, Rdb, Rdc, R7, R7a, R7b, R7c, R8, R8b, and R8c its cycloalkyl moiety preferably has 3 to 6 carbon atoms and alkyl moiety preferably has 1 to 3 carbon atoms. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopropylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylmethyl, cyclooctlmethyl and the like.
Examples of aryl at R7, R7b, R7c, R8, R8b, and R8c include phenyl, naphthyl and the like.
Arylalkyl at R6, R6b, R6c, R7, R7b, R7c, R8, R8b and R8c has the aforementioned aryl moiety and its alkyl moiety preferably has 1 to 4 carbon atoms. Examples of arylalkyl include benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl and the like.
Alkenyl at R6, R6b and R6c may be linear or branched and preferably has 3 to 12 carbon atoms. Examples thereof include propenyl, isopropenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, 3,3-dimethyl-2-propenyl and the like.
Acidic group at R1, R2 and R3 is exemplified by carboxy, sulfonic acid group, phosphoric acid group and the like. Examples of alkoxycarbonyl at R1, R1c, R2, R2b, R2c, R5 and R5c include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like.
Alkyl to be substituted at R1, R2, R2a, R2b and R3 may be linear or branched and preferably has 1 to 8 carbon atoms. Examples thereof include methyl, ethyl, propyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, 2,2-dimethylpropyl and the like. Examples of substituted alkyl include hydroxymethyl, hydroxyethyl, carboxymethyl, carboxyethyl, carboxypropyl, ethoxycarbonylmethyl, dimethylaminomethyl, dimethylaminoethyl, sulfomethyl, phosphonomethyl and the like.
Alkenyl to be substituted at R1, R2 and R3 may be linear or branched and preferably has 2 to 8 carbon atoms. Examples thereof include vinyl, propenyl, isopropenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, 3,3-dimethyl-2-propenyl and the lace. Examples of substituted alkenyl include carboxyvinyl, carboxypropenyl, hydroxypropenyl and the like.
Z is preferably ##STR00003##
In the compounds of the present invention, {circle around (1)} when one of R1, R2 and R5 is alkyl or alkenyl substituted by hydroxy, acidic group, alkoxycarbonyl or a group of the formula —NR9R10 wherein R9 and R10 are each independently hydrogen atom or lower alkyl, and the other two are independently hydrogen atom, lower alkyl or lower alkoxy, the compound may be (a) indoline or indole derivative, or (b) tetrahydroquinoline derivative.
A more preferable compound is that of the above-mentioned formula (I) wherein R2 and R3 are each independently hydrogen atom, lower alkyl or lower alkoxy; either R2 or R3 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula —NR9R10 wherein R9 and R10 are each independently lower alkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy; R4 is a group of the formula —NHCOR7 wherein R7 is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula —NHR8 wherein R8 is alkyl; and R6 is as defined above.
A still more preferable compound is that of the above-mentioned formula (I) wherein R1 and R3 are each independently hydrogen atom, lower alkyl or lower alkoxy; either R2 or R3 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula —NR9R10 wherein R9 and R10 are each independently lower alkyl, and the other is hydrogen atom; R4 is a group of the formula —NHCOR7 wherein R7 is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula —NHR8 wherein R8 is alkyl; and R6 is as defined above.
A still more preferable compound is that of the above-mentioned formula (I) wherein R1 and R3 am each independently hydrogen atom or lower alkyl; either R2 or R5 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula —NR9R10 wherein R9 and R10 are each independently lower alkyl, and the other is hydrogen atom R4 is a group of the formula —NHCOR7 wherein R7 is alkyl cycloalkyl or cycloalkylalkyl; and R6 is alkyl, cycloalkyl or cycloalkylalkyl.
A still more preferable compound is that of the above mentioned formula (I) wherein R1 and R3 are each independently hydrogen atom or lower alkyl; R2 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula —NR9R10 wherein R9 and R10 are each independently lower alkyl, and R5 is hydrogen atom; R4 is a group of the formula —NHCOR7 wherein R7 is alkyl, cycloalkyl or cycloalkylalkyl; and R6 is alkyl, cycloalkyl or cycloalkylalkyl.
A still more preferable compound is that of the following formula (IIa):
##STR00004##
wherein R3a is hydrogen atom or lower alkyl; R3a is lower alkyl; R2a is alkyl substituted by hydroxy or carboxy R4a is a group of the formula —NHCOR7a wherein R7a is alkyl, cycloalkyl or cycloalkylalkyl:: and R6a is alkyl, cycloalkyl or cycloalkylalkyl.
A still more preferable compound is that of the above formula (IIa) wherein R3a is hydrogen atom or lower alkyl; R3a is lower alkyl; R2a is alkyl substituted by hydroxy or carboxy; R4a is a group of the formula —NHCORla wherein R7a is alkyl; and R6a is alkyl.
Examples of the most preferable compound include N-(1-hexyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-heptyl-5-carboxymethyl -4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-octyl-5-carboxymethyl-4,5-dimethylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-nonyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-decyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-undecyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-dodecyl-5-carboxymethyl-4,6-dimethylinodolin-7-yl)-2,2-dimethylpropanamide, N-(1-hexyl-5-hydroxymethyl-6-methylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-hexyl-5-hydroxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-heptyl-5-hydroxymethyl-6-methylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-heptyl-5-hydroxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-octyl-5-hydroxymethyl-6-methylindolin-7-yl)-2,2-dimethylpropanamide, N-(1 -octyl-5-hydroxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide and the like, and pharmaceutically acceptable salts thereof.
A still more preferable compound is that of the formula (IIb) wherein R1b and R3b are each independently lower alkyl or lower alkoxy; R2b is alkyl substituted by hydroxy, carboxy or alkoxycarbonyl; R4b is a group of the formula —NHCOR7b wherein R7b is alkyl, cycloalkylalkyl, arylalkyl or a group of the formula —NHR8b wherein R8b is alkyl; and Rdb is alkyl, alkoxyalkyl, alkylthioalkyl or cycloalkylalkyl.
A still more preferable compound is that of the formula (IIb) wherein R1b and R3b are each independently lower alkyl; R2b is alkyl substituted by hydroxy or carboxy; R4b is a group of the formula —NHCOR7b herein R4b is alkyl; and R6b is alkyl.
Examples of the most preferable compound include N-(1-hexyl-6-carboxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-heptyl-6-carboxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-octyl-6-carboxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-nonyl-6-carboxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-decyl-6-carboxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-hexyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-heptyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl-2,2-dimethylpropanamide, N-(1-octyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-nonyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-decyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide and the like, and pharmaceutically acceptable salts thereof.
{circle around (2)} When the compound of the present invention is that wherein one of R1, R2 and R4 is hydroxy, carboxy, alkoxycarbonyl or a group of the formula —NR9R10 wherein R9 and R10 are each independently hydrogen atom or lower alkyl, and the other two are independently hydrogen atom, lower alkyl or lower alkoxy, the compound of the following formula (IIc) is preferable.
##STR00006##
wherein one of R1c, R2c and R5c is hydroxy, carboxy alkoxycarbonyl or a group of the formula —NR9CR10C wherein R9c and R10c are each independently hydrogen atom or lower alkyl, and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy; either R3c or R4c is a group of the formula —NHCOR7C wherein R7c is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl cycloalkylalkyl, aryl, arylalkyl or a group of the formula —NHR8c wherein R8c is alkyl, cycloalkyl, cycloalkylalkyl aryl or arylalkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy; and Rc is alkyl, alkenyl, alkoxyalkyl alkylthioalkyl, cycloalkyl, cycloalkylalkyl or arylalkyl.
More preferable compound is a compound of the above formula (IIc) wherein R1c and R3c are each independently hydrogen atom, lower alkyl or lower alkoxy; R2c is carboxy R4c is a group of the formula —NHCOR wherein R7c is alkyl, cycloalkyl or cycloalkylalkyl; R5c is hydrogen atom and R6c is alkyl, cycloalkyl or cycloalkylalkyl.
A still more preferable compound is a compound of the above formula (IIc) wherein R1c is hydrogen atom or lower alkyl; R3c is lower alkyl; R2c is carboxy; R4c is a group of the formula —NHCOR7c wherein R7c is alkyl; R5c is hydrogen atom; and R6c is alkyl.
Examples of the mast preferable compound include N-(1-hexyl-5-carboxy-6-methylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-octyl-5-carboxy-6-methylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-decyl-5-carboxy-6-methylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-hexyl-5-carboxy-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-octyl-5-carboxy-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-decyl-5-carboxy-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide and the like, and pharmaceutically acceptable salt thereof.
The compound (I) may form pharmaceutically acceptable salts. When compound (I) has a basic group, it an form acid addition salts. The acid to germ such acid addition salts is subject to no particular limitation as long as it can form a salt with a basic moiety and is a pharmaceutically acceptable acid. Examples of such acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric add and the like, and organic scuds such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulphonic acid, toluenesulphonic acid and the like.
When compound (I) has an acidic group such as carboxy, it can form, for example, alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt and the hate; and organic base salts such as triethylamine salt, dicyclohexylamine salt, pyridine salt and the like.
The compound (I) of the present invention and pharmaceutically acceptable salts thereof can be produced by any one of the following methods 1 to 7. ##STR00007## ##STR00008## ##STR00009## ##STR00010## ##STR00011## ##STR00012## ##STR00013##
In each of the above formulas, R6, R7, R8, R9 and R10 are each as defined above; R11 and R12 are each independently hydrogen atom, lower alkyl or lower alkoxy; R13 is amino protecting group; R14 is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; R15 is alkyl or alkenyl substituted by halogen atom; R16 is alkyl or alkenyl substituted by hydroxy, protected hydroxy, acidic group, protected acidic group, alkoxycarbonyl or —NR18R19 wherein R18 and R19 are each independently hydrogen atom, lower alkyl or amino protecting group; R17 is alkyl or alkenyl substituted by hydroxy, acidic group, alkoxycarbonyl or —NR9R10; R20 is protected carboxy; R21 is protected hydroxy; and R22 is —NR18R19 wherein R18 and R19 are as defined above.
Amino protecting group at R13, R18 and R19 is, for example, formyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trimethylsilyl, 2-methylsulfonylethyloxycarbonyl, tert-butoxycarbonyl or trityl.
Hydroxy protecting group at R16 and R21 is, for example, formyl, acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzoyl, trityl, tetrahydropyranyl, trimethylsilyl or the like.
Acidic group protecting group at R16 and R20 is, when carboxy protecting group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, tert-amyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, methylthiomethyl, trityl, 2,2,2-trichloroethyl, trimethylsilyl, diphenylmethoxybenzene-sulfonylmethyl, dimethylaminoethyl and the like.
The above-mentioned protecting groups can be removed by a method known per se, and the method for removing them may be determined according to the kind of the protecting group. Exemplified am a decomposition by an acid (e.g., that by an acid such as hydrochloric acid, trifluoroacetic acid and the like for formyl, tert-butoxycarbonyl, trityl, tetrahydropyranyl and the like); a decomposition by a base (e.g., that by a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and the like for acetyl, dichloroacetyl, trifluoroacetyl and the like); and catalytic reduction (e.g., decomposition by palladium-carbon and the like for benzyl, benzyloxycarbonyl and the like). The production methods of the objective compounds of the present invention and starting material compound are described in detail in the following.
Production Method 1
The compound (IV) can be produced by reducing compound (III) [J. Eric Nordlander, et al., J. Org. Chem., 46, 778-782 (1981), Robin D. Clark, et al., Heterocycle, 22, 195-221 (1994), Vernon H. Brown, et al., J. Heterocycle. Chem., 6(4), 539-543 (1969)]to introduce an indoline skeleton, protecting amino, introducing nitro on benzene ring by a method known per se, and reducing nitro using a catalyst such as palladium-carbon.
The compound (VII) can be produced by reacting compound (IV) with compound (V) or reactive derivative thereof at carboxy group, or compound (VI).
Said reaction is generally carried out in an inert solvent. Examples of the inert solvent include acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, water and mixed solvents thereof.
In addition, a base such as triethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate and the like can be used.
The reaction temperature: is generally −10-160° C., preferably 0-60° C., and reaction time is generally from 30 min to 10 hr.
The compound (V) can be subjected to the instant reaction as a free carboxylic acid or a reactive derivative thereof, and the both modes are encompassed in the present invention. That is, it is used in this reaction as a free acid or a salt such as sodium, potassium, calcium, triethylamine, pyridine and the like, or as a reactive derivative such as its acid halide (e.g., acid chloride, acid bromide and the like), acid anhydride, mixed acid anhydride [e.g., substituted phosphoric acid (dialkyl phosphate and the like), alkyl carbonate (monoethylcarbonate and the like) and the like], active amide (amide with imidazole and the like), ester (cyanomethyl ester, 4-nitrophenyl ester etc.), and the like.
When compound (V) is used as a free acid or a salt in this reaction, a condensing agent is preferably used. Examples of the condensing agent include dehydrating agents such as N,N′-disubstituted carbodiimides (e.g., N,N′-dicyclohexylcarbodiimide); carbodiimide compounds (e.g., 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide, N-cyclohexyl-N′-morpholinoethyl carbodiimide and N-cyclohexyl-N′-(4-diethylaminocyclohexyl) carbodiimide); azolide compounds (e.g., N,N′-carbonyldiimidazole and N,N′-thionyldiimidazole); and the like. When these condensing; agents are used, the reaction is considered to proceed via a reactive derivative of carboxylic acid. The compound (VIII) an be produced by halo-genoalkylation of compound (VII) [R. C. Fuson et al., Org. React., 1, 63 (1969), G. A. Olah et al., “Fricdel Crafts and Related Reactions” Vol. 2. 659 (1964)].
The compound (IX) can be produced by converting halogenoalkyl of compound (VIII) to hydroxy, an acidic group such as carboxy or a group of the formula —NR9R10 by a substituent conversion reaction known per se, and if necessary, introducing a corresponding protecting group.
The compound (XII) can lie produced by eliminating the amino protecting group at R13 of compound (IX) by a method known per se to give compound (X) and by N-alkylation using compound (XI).
Said N-alkylation can be generally carried out in an inert solvent. Examples of the inert solvent include acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, water and mixed solvents thereof.
In addition, a base such as triethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate and the like can be used.
The reaction temperature is generally −10-100° C., preferably 0-60° C., and reaction time is generally from 30 min to 10 hr.
The compound (Ia) can be produced by eliminating the protecting group at R16 of compound (XII) by a method known per se.
Production Method 2
The compound (XIII) can be produced by hydroxyalkylation of compound (III) [Adof H. Phlipp., et al., J. Med. Chem., 19(3), 391-395 (1976)], reducing, introducing an indoline skeleton, protecting amino, and halogenating hydroxy.
The compound (XIV) can be produced from compound (XIII) according to the method for obtaining compound (IX) from compound (VIII) as described in Production Method 1.
The compound (XV) can be produced from compound (XIV) by introducing nitro and reducing nitro by a method known per se.
The compound (XVI) can be produced from compound (XV) according to the method for obtaining compound (VII) from compound (IV) as described in Production Method 1.
The compound (Ib) can be produced from compound (XVI) via compound (XVII) and compound (XIII) according to the method for obtaining compound (Ia) from compound (IX) as described in Production Method 1.
Production Method 3
The compound (XIX) can be produced by oxidation of compound (X) by a method known per se (e.g., oxidation using chloranil, palladium-carbon and the like).
The compound (Ic) an be produced from compound (XIX) via compound (XX) according to the method for obtaining compound (Ia) from compound (X) as described in Production Method 1.
Production Method 4
The compound (XXI) can be produced by reducing 2,3-dihydroquinolin-4-One derivative [J. R Merchant, et al., J. Chem. Soc. Perkin I, 932-935 (1972)]using a reducing agent such as lithium aluminum hydride-aluminum chloride and the like.
The compound (XXIII) can be produced from compound (XXII) by protecting amino of compound (XXI) by a method known per se to give compound (XXII) and according to the method for obtaining compound (VIII) from compound (VII) as described in Production Method 1.
The compound (XXV) can be produced from compound (XXIII) via compound (XXIV) according to the method for obtaining compound (XII) from compound (VIII) via compound compound(IX) and compound (X) as described in Production Method 1.
The compound (XXVI) an be produced from compound (XXV) by introducing nitro and reducing nitro by a method known per se.
The compound (XXVII) an be produced from compound (XXVI) according to The method for obtaining compound (VII) from compound (IV) as described in Production Method 1.
The compound (Id) an be produced from compound (XXVII) according to the method for obtaining compound (Ice) from compound (XII) as described in Production Method 1.
Production Method 5
The compound (XXIX) an be produced from compound (XXVIII) (W. G. Gall, et al., J. Org. Chem., 20,1538 (1955)] according to the method for obtaining compound (XII) from compound (X) as described in Production Method 1.
The compound (XXX) an be produced by converting halogen of compound (XXIX) to cyano by a method known per se, hydrolysis of cyano, and introducing a protecting group into the obtained carboxy.
The compound (XXXI) can be produced from compound (XXX) by reducing nitro of compound (XXX) by a method known per se, and according to the method for obtaining compound (VII) from compound (IV) as described in Production Method 1.
The compound (Ie) can be produced by eliminating the protecting group al R20 of compound (XXXI) by a method known per se.
Production Method 6
The compound (XXXII) cm be produced by converting amino of compound (IV) to hydroxy by a method known per se and introducing a protecting group into hydroxy.
The compound (XXXIII) can be produced from compound (XXXII) by introducing nitro and reducing nitro by a method known per se.
The compound (XXXIV) can be produced from compound (XXXIII) according to the method for obtaining compound (VII) from compound (IV) as described in Production Method 1.
The compound (XXXV) can be produced from compound (XXXIV) according to the method for obtaining compound (XII) from compound (IX) via compound (X) as describe in Production Method 1.
The compound (If) can be produced by eliminating the protecting group at R21 of compound (XXXV) by a method known per se.
Production Method 7
The compound (XXXVI) can be produced by alkylation of amino or by introducing a protecting group of amino of compound (IV) by a method :known per se.
The compound (XXXVII) can be produced from compound (XXXVI) by introducing nitro and reducing nitro by a method known per se.
The compound (XXXVII) can be produced from compound (XXXVII) according, to the method for obtaining compound (VII) from compound (IV) as described in Production Method 1.
The compound (XXXIX) can be produced from compound (XXXVIII) according to the method for obtaining compound (XII) from compound (IX) via compound (X) as described in Production Method 1.
The compound (Ig) can be produced by eliminating the protecting group at R22 of compound (XXXIX) by a method known per se.
The compound (I) of the present invention obtained by the above methods can be purified by a method conventionally known such as chromatography and recrystallization.
Said compound (I) can be converted to pharmaceutically acceptable salts by a method known per se.
A pharmaceutical composition containing the compound (I) of the present invention or a pharmaceutically acceptable salt thereof can further contain additives. Examples of the additive include excipients (e.g., starch, lactose, sugar calcium carbonate and calcium phosphate), binders (e.g., starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose and crystalline cellulose), lubricants (e.g., magnesium stearate and talc:), and disintegrators (e.g., carboxymethyl-cellulose calcium and talc), and the like.
The above-mentioned ingredients am minced and the mixture is prepared into oral preparations such as capsules, tablets, fine granules, granules; and dry syrups, or parenteral preparations such as injections and suppositories by a method known per se.
While the dose of the compound (I) of the present invention and pharmaceutically acceptable salts thereof varies depending on administration targets, symptoms and others, when, for example, orally administered to adult patients of hypercholesterolemia, it is generally 0.1 mg-50 mg/kg body weight per dose which is administered about 1 to 3 time(s) a day.
The compound (I) of the present invention and pharmaceutically acceptable salts thereof exhibit superior ACAT inhibitory activity and lipoperoxidation inhibitory activity in mammals (e.g., human, cow, horse, dog, cat, rabbit, rat, mouse, hamster etc.) and are useful as ACAT inhibitors and lipoperoxidation inhibitors. In other words, they are useful for the prophylaxis and treatment of arteriosclerosis, hyperlipemia, arteriosclerosis in diabetes, cerebrovascular and cardiovascular ischemic diseases, and the like.
The present invention is described in more detail by way of Examples, to which the present invention is not limited.
N-(1-octyl-5-ethoxycarboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (3.5 g) was dissolved in EtOH (50 ml) and a solution of NaOH (1.6 g) in water (20 ml) was added, which was followed by stirring at 60° C. for 1 hr. EtOH was evaporated under reduced pressure. The residue was dissolved in water (20 ml) and the mixture was washed with AcOEt (20 ml). The aqueous layer was neutralized with 2N-hydrochloric acid and extracted with AcOEt (50 ml). The AcOEt layer was washed with saturated brine and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure to give 2.4 g of the title compound.
IR (Nujol)cm−1: 1732, 1651, 1,600.
1H-NMR (CDCl3) δ:
0.70-1.10 (3H, br, —(CH2)7CH3), 1.10-1.70 (12H, m, —CH2(CH2)6CH3), 1.33 (9H, s, —C(CH3), 2.01, 2.15 (6H, s×2, —CH3×2), 2.70-3.20 (4H, m, Indoline C3—H, >NCH2—), 3.41 (2H, t, J=8.5 Hz, Indoline C2—H), 3.56 (2H, s, —CH2CO2H), 7.60 (hH, br, >NH), 7.90 (1H, br, —CO2H).
N-(1-octyl-5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (3.5 g) was dissolved in EtOH (50 ml) and a solution of NaOH (1.6 g) in water (20 ml) was added, which was followed by stirring at 60° C. for 1 hr. EtOH was evaporated under reduced pressure. The residue was dissolved in water (20 ml) and the mixture was washed with AcOEt (20 ml). The aqueous layer was adjusted to pH 1-2 with hydrochloric acid and extracted with AcOEt (50 ml). The AcOEt layer was washed with saturated brine and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure to give 2.0 g of the title compound.
IR (Nujol)cm−1: 1722, 1654.
3H-NMR (CDCl3) δ:
0.70-1.10 (3H, br, —(CH2)7CH3), 1.10-1.70 (12H, m, —CH2(CH2)6CH3), 1.39 (9H, s, —C(CH3)3, 2.06, 2.26 (6H, s×2, —CH3×2), 2.90-3.30 (4H, m, Indoline C3—H, >NCH2—), 3.50-3.90 (2H, br-t, Indoline C3—H), 3.72 (2H, s, —CH2CO2H), 6.00-7.00 (1H, br, HCl), 9.05 (2H, br, >NH, —CO2H).
N-(1-octyl-5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (4.0 g) was dissolved in EtOH (57 ml) and a solution of NaOH (1.8 g) in water (23 ml) was added, which was followed by stirring at 60° C. for 1 hr. EtOH was evaporated under reduced pressure. The residue was dissolved in water (30 ml) and the mixture was washed with AcOEt (30 ml). The aqueous layer was adjusted to pH 1-2 with sulfuric acid and extracted with AcOEt (50 ml). The AcOEt layer was washed with saturated brine and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure to give 2.5 g of the title compound.
IR (Nujol)cm−1: 1718, 1654, 1637.
3H-NMR (CDCl3) δ:
0.70-1.10 (3H, br, —(CH2)7CH3), 1.10-1.70 (12H, m, —CH2(CH2)6CH3), 1.33 (9H, s, —C(CH3)3), 2.02, 2.16 (6H, s×2, —CH3×2), 2.80-3.30 (4H, m, Indoline C3—H, >NCH2—), 3.30-3.70 (2H, br-t, Indoline C2—H), 3.59 (2H, s, CH2CO2H), 6.00-7.00 (2H, br, H2SO4), 7.20 (1H, br, —CO2H), 8.30 (1H, br, >NH.
N-(1-octyl-5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (3.0 g) was dissolved in EtOH (42 ml) and a solution of NaOH (1.4 g) in water (17 ml) was added, which was followed by stirring at 60° C. for 1 hr. EtOH was evaporated under reduced pressure. The residue was dissolved in water (20 ml) and the mixture was washed with AcOEt (20 ml). The aqueous layer was adjusted to pH 1-2 with nitric acid and extracted with AcOEt (50 ml). The AcOEt layer was washed with saturated brine and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure to give 2.0 g of the title compound.
IR (Nujol)cm−1: 1724, 1654
3H-NMR (CDCl3) δ:
0.70-1.10 (3H, br, —(CH2),CH3), 1.10-1.70 (12H, m, —CH2(CH2)6CH3), 1.33 (9H, s, —(CH3)3). 2.02, 2.21 (6H, s×2, CH3×2), 2.80-3.30 (4H, m, Indoline C3—H, >NCH2—), 3.50-3.80 (2H, br-t, Indoline C2—H), 3.64 (2H, s, CH2CO2H), 6.00-7.00 (1H, br, HNO3), 9.03 (2H, br, >NH, —CO2H).
N-(1-Octyl-5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (3.5 g) was dissolved in EtOH (50 ml) and a solution of NaOH (1.6 g) in water (20 ml) was added, which was followed by stirring at 60° C. for 1 hr. EtOH was evaporated under reduced pressure. The residue was dissolved in water (20 ml) and the mixture was adsorbed onto DIAION® HP-21 (70 ml). After washing with water, the mixture was elided with 50% aqueous methanol. The objective fraction was concentrated under reduced pressure. The residue was freeze-dried to give 1.0 g of the title-compound.
IR (Nujol)cm−1: 1630, 1605.
1H-NMR (CDCl3) δ:
0.70-1.10 (3H, br, —(CH2)7(CH3), 1.10-1.70 (12H, m, —CH2(CH2)6CH3), 1.38 (9H, s, —C(CH3)3), 1.93, 2.08 (6H, s×2, —CH3×2), 2.70-3.20 (4H, m, Indoline C3—H, >NCH2 ), 3.30-3.40 (2H, br-t, Indoline C2-H), 3.15 (2H, s, —CH2CO2Na), 8.54 (1H, br, >NH).
N-[(1-octyl-3-(2-methoxycarbonylethyl)-4,6-dimethylindolin-7-yl)]-2,2-dimethylpropanamide (1.1 g) was dissolved in EtOH (10 ml) and a solution of NaOH (494 mg) in water (3 ml) was added, which was followed by stirring at roam temperature for 30 min. EtOH was evaporated under reduced pressure and CHCl3 (50 ml) was added. After washing successively with 5% aqueous citric acid and saturated brine, the mixture was dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=50/1-10/1) to give 800 mg of the title compound.
IR (Nujol) cm−1: 1700, 1680.
1H-NMR (CDCl3) δ:
0.70-1.00 (3H, br-t, —(CH2)7CH4), 1.38 (9H, s, —C(CH3)3), 1.00-1.60 (12H, m, —(CH2)6CH3), 1.60-2.20 (2H, m, —CH2CH2CO2H), 2.07, 2.16 (6H, s×2, —CH3×2), 2.20-2.40 (2H, m, CH2CH2CO2H), 3.10-3.80 (3H, m, Indoline C2—H, C3—H), 3.27 (2H, br-t, >NCH2—), 6.45 (1H, s, Indoline C3—H), 7.20 (1H, br, —CONH—), 7.60 (1H, br, —CO2H).
According to the method as described in any of the above-mentioned Examples 1-12, the compounds of Tables 1-9 were obtained.
TABLE 1
##STR00014##
Example
R1
R2
R3
R7
R6
13
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)4CH3
14
—CH3
—CH2CO2H
—CH3
—C(CH3)3
##STR00015##
15
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)2CH(CH3)2
16
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—CH2CH—C(CH3)2
17
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)2OCH2CH3
18
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)5CH3
19
—CH3
—CH2CO2H
—CH3
—C(CH3)3
##STR00016##
20
—CH3
—CH2CO2H
—CH3
—C(CH3)3
##STR00017##
21
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)3CH(CH3)2
22
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—CH2CH(CH2CH3)2
23
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)2O(CH2)7CH3
24
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)6CH3
25
—CH3
—CH2CO2H
—CH3
—C(CH3)3
##STR00018##
26
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)4CH(CH3)2
TABLE 2
##STR00019##
Example
R1
R2
R3
R7
R6
27
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)2CH(CH2CH3)2
28
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)2O(CH2)3CH3
29
—CH3
—CH2CO2H
—CH3
—C(CH3)3
##STR00020##
30
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)5CH(CH3)2
31
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)5CH(CH2CH3)2
32
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)2O(CH2)4CH3
33
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)8CH3
34
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)6CH(CH3)2
35
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)4CH(CH2CH3)2
36
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)8CH2
37
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)7CH(CH3)2
38
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)20CH3
39
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)8CH(CH3)2
40
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)11CH3
41
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)9CH(CH3)2
TABLE 3
##STR00021##
Example
R1
R2
R3
R7
R6
42
—CH3
—CH2CO2H
—CH3
—C(CH3)2C4H9
—(CH2)5CH3
43
—CH3
—CH2CO2H
—CH3
—C(CH3)2C4H9
—(CH2)6CH3
44
—CH3
—CH2CO2H
—CH3
—C(CH3)2C4H9
—(CH2)7CH3
45
—CH3
—CH2CO2H
—CH3
—C(CH3)2C6H13
—(CH2)5CH3
46
—CH3
—CH2CO2H
—CH3
—C(CH3)2C6H13
—(CH2)6CH3
47
—CH3
—CH2CO2H
—CH3
—C(CH3)2C6H13
—(CH2)7CH3
48
—CH3
—CH2CO2H
—CH3
—C(CH3)2C8H17
—(CH2)5CH3
49
—CH3
—CH2CO2H
—CH3
—C(CH3)2C8H17
—(CH2)6CH3
50
—CH3
—CH2CO2H
—CH3
—C(CH3)2C8H17
—(CH2)7CH3
51
—CH2CH3
—CH2CO2H
—CH2CH3
—C(CH3)3
—(CH2)5CH3
52
—CH2CH3
—CH2CO2H
—CH2CH3
—C(CH3)3
—(CH2)6CH3
53
—CH2CH3
—CH2CO2H
—CH2CH3
—C(CH3)3
—(CH2)7CH3
54
—CH2CH3
—CH2CO2H
—CH2CH3
—C(CH3)3
—(CH2)8CH3
55
—CH2CH3
—CH2CO2H
—CH2CH3
—C(CH3)3
—(CH2)9CH3
56
—OCH3
—CH2CO2H
—OCH3
—C(CH3)3
—(CH2)5CH3
57
—OCH3
—CH2CO2H
—OCH3
—C(CH3)3
—(CH2)6CH3
58
—OCH3
—CH2CO2H
—OCH3
—C(CH3)3
—(CH2)7CH3
59
—OCH3
—CH2CO2H
—OCH3
—C(CH3)3
—(CH2)8CH3
60
—OCH3
—CH2CO2H
—OCH3
—C(CH3)3
—(CH2)9CH3
61
—CH3
—CH2OH
—CH3
—C(CH3)3
—(CH2)5CH3
62
—CH3
—CH2OH
—CH3
—C(CH3)3
—(CH2)6CH3
TABLE 4
##STR00022##
Ex-
am-
ple
R1
R2
R3
R7
R6
63
—CH3
—CH2OH
—CH3
—C(CH3)3
—(CH2)8CH3
64
— CH3
—CH2OH
—CH3
—C(CH3)3
—(CH2)9CH3
65
—CH3
—CH2N(CH3)2
—CH3
—C(CH3)3
—(CH2)5CH3
66
—CH3
—CH2N(CH3)2
—CH3
—C(CH3)3
—(CH2)6CH3
67
—CH3
—CH2N(CH3)2
—CH3
—C(CH3)3
—(CH2)8CH3
68
—CH3
—CH2N(CH3)2
—CH3
—C(CH3)3
—(CH2)9CH3
69
—H
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)5CH3
70
—H
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)6CH3
71
—H
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)7CH3
72
—H
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)8CH3
73
—H
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)9CH3
74
—H
—CH2OH
—CH3
—C(CH3)3
—(CH2)5CH3
75
—H
—CH2OH
—CH3
—C(CH3)3
—(CH2)6CH3
76
—H
—CH2OH
—CH3
—C(CH3)3
—(CH2)7CH3
77
—H
—CH2OH
—CH3
—C(CH3)3
—(CH2)8CH3
78
—H
—CH2OH
—CH3
—C(CH3)3
—(CH2)9CH3
79
—H
—CH2N(CH3)2
—CH3
—C(CH3)3
—(CH2)5CH3
80
—H
—CH2N(CH3)2
—CH3
—C(CH3)3
—(CH2)6CH3
81
—H
—CH2N(CH3)2
—CH3
—C(CH3)3
—(CH2)7CH3
82
—H
—CH2N(CH3)2
—CH3
—C(CH3)3
—(CH2)8CH3
83
—H
—CH2N(CH3)2
—CH3
—C(CH3)3
—(CH2)9CH3
TABLE 5
##STR00023##
Example
R1
R2
R3
R7
R5
R6
84
—CH3
—H
—CH3
—C(CH3)3
—(CH2)2CO2H
—(CH2)5CH3
85
—CH3
—H
—CH3
—C(CH3)3
—(CH2)2CO2H
—(CH2)6CH3
86
—CH3
—H
—CH3
—C(CH3)3
—(CH2)2OH
—(CH2)5CH3
87
—CH3
—H
—CH3
—C(CH3)3
—(CH2)2OH
—(CH2)6CH3
88
—CH3
—H
—CH3
—C(CH3)3
—(CH2)2N(CH3)2
—(CH2)5CH3
89
—CH3
—H
—CH3
—C(CH3)3
—(CH2)2N(CH3)2
—(CH2)6CH3
90
—CH3
—H
—CH3
—C(CH3)3
—(CH2)2N(CH3)2
—(CH2)7CH3
TABLE 6
##STR00024##
Example
R1
R2
R3
R7
R6
91
—CH3
—CH2CO2H
—CH3
—(CH2)3CH3
—(CH2)7CH3
92
—CH3
—CH2CO2H
—CH3
—(CH2)3CH3
—(CH2)8CH3
93
—CH3
—CH2CO2H
—CH3
—(CH2)3CH3
—(CH2)9CH3
94
—CH2CH3
—CH2CO2H
—CH2CH3
—(CH2)3CH3
—(CH2)7CH3
95
—CH2CH3
—CH2CO2H
—CH2CH3
—(CH2)3CH3
—(CH2)8CH3
96
—CH2CH3
—CH2CO2H
—CH2CH3
—(CH2)3CH3
—(CH2)9CH3
97
—OCH3
—CH2CO2H
—OCH3
—(CH2)3CH3
—(CH2)7CH3
98
—OCH3
—CH2CO2H
—OCH3
—(CH2)3CH3
—(CH2)8CH3
99
—OCH3
—CH2CO2H
—OCH3
—(CH2)3CH3
—(CH2)9CH3
TABLE 7
##STR00025##
Example
R1
R2
R3
R7
R6
100
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)8CH3
101
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)9CH3
102
—CH2CH3
—CH2CO2H
—CH2CH3
—C(CH3)3
—(CH2)7CH3
103
—CH2CH3
—CH2CO2H
—CH2CH3
—C(CH3)3
—(CH2)8CH3
104
—CH2CH3
—CH2CO2H
—CH2CH3
—C(CH3)3
—(CH2)9CH3
105
—OCH3
—CH2CO2H
—OCH3
—C(CH3)3
—(CH2)7CH3
106
—OCH3
—CH2CO2H
—OCH3
—C(CH3)3
—(CH2)8CH3
107
—OCH3
—CH2CO2H
—OCH3
—C(CH3)3
—(CH2)9CH3
TABLE 8
##STR00026##
Example
R1
R2
R3
R7
R6
108
—CH3
—CH2CO2H
—CH3
—(CH2)9CH3
—(CH2)7CH3
109
—CH3
—CH2CO2H
—CH3
—(CH2)9CH3
—(CH2)7CH3
110
—CH3
—CH2CO2H
—CH3
##STR00027##
—(CH2)7CH3
111
—CH3
—CH2CO2H
—CH3
##STR00028##
—(CH2)7CH3
112
—CH3
—CH2CO2H
—CH3
##STR00029##
—(CH2)7CH3
113
—CH3
—CH2CO2H
—CH3
##STR00030##
—(CH2)7CH3
114
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)2S(CH2)3CH3
115
—CH3
—CH2CO2H
—CH3
—C(CH3)3
##STR00031##
116
—H
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)7CH3
TABLE 9
##STR00032##
Exam-
ple
R1
R2
R4
R7
R6
117
—CH2CO2H
—CH3
—CH3
—C(CH3)3
—(CH2)5CH3
118
—CH2CO2H
—CH3
—CH3
—C(CH3)3
—(CH2)8CH3
119
—CH2CO2H
—CH3
—CH3
—C(CH3)3
—(CH2)20CH3
The 1H-NMR values old the compound of the above Examples 13-119 are shown in the following.
Example 13: 0.7-1.1 (3H, br-t), 1.1-1.7 (6H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1. (2H, br).
Example 14: 0.70-1.70 (8H, m), 1.1-1.7 (6H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (3H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 15: 0.87 (6H, d), 1.1-1.8 (3H, m), 133 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3: 41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 16: 1.65 (6H, s), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (41, m) 3.41 (2H, t), 3.56 (2H, s), 5.20 (1H, br-t), 7.6-8.1 (2H, br).
Example 17: 1.59 (3H, t), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.3-3.6 (6H, m), 3.56 (2H, s), 3.56 (2H, s), 7.6-5.1 (2H, br).
Example 18: 0.7-1.1 (3H, br-t), 1.1-1.7 (8H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 19: 0.7-1.70 (10H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (3H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 20: 0.7-1.70 (9H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 21: 0.87 (6H, d), 1.1-1.8 (5H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 22: 0.7-1.0 (6H, br-t), 1.0-1.7 (5H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 23: 1.59 (3H, br-t), 1.0-1.7 (2H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.3-3.6 (6H, m), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 24: 0.7-1-10 (3H, br-t), 1.1-1.7 (10H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, ml 3.41 (2H, t), 3.56 (2H, s), 7.6-73.1 (2H, br).
Example 25: 0.7-1.70 (11H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 26: 0.87 (6H, d), 1.1-1.8 (7H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 3.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 27: 1.59 (6H, br-t), 1.1-1.7 (7H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 28: 1.59 (3H, hr-t), 1.0-1.7 (4H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.3-3.6 (6H, m), 3.56 (2H, s), 7.63.1 (2H, br).
Example 29: 0.7-1.70 (13H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 30: 0.87 (6H, d), 1.1-1.8 (9H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 31: 1.59 (6H, br-t), 1.0-1.7 (9H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 32: 1.59 (3H, br-t ), 1.0-1.7 (6H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.3-3.6 (6H, m), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 33: 0.7-1.10 (3H, br-t), 1.1-1.7 (14H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 34: 0.87 (6H, d), 1.1-1.8 (11H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-5.1 (2H, br).
Example 35: 1.59 (6H, br-t), 1.0-1.7 (11H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 36: 0.7-1.10 (3H, br-t), 1.1-1.7 (16H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 37: 0.87 (6H, d), 1.1-1.8 (13H, m), 1.33 (9H, s), 2.01 (3H, s), 215 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 38: 0.7-1.10 (3H, br-t), 1.1-1.7 (18H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-51.1 (2H, br).
Example 39: 0.87 (6H, d), 1.1-1.8 (15H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 40: 0.7-1.10 (3H, br-t), 1.1-1.7 (20H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 41: 0.87 (6H, d), 1.1-1.8 (17H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.10-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s) 7.6-8.1 (2H, br).
Example 42: 0.7-1.10 (6H, br-t), 1.1-2.0 (20H, m), 201 (3H, s), 2.15 (3H, s), 2.70-3,10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 43: 0.7-1.10 (6H, br-t), 1.0-2.0 (21H, m), 201 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 44: 0.7-1.10 (6H, br-t), 1.0-2.0 (24H, m), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 45: 0.7-1.10 (6H, br-t), 1.0-2.0 (24H, m), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 46: 0.7-1.10 (6H, br-t), 1.0-2.0 (26H, m), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 47: 0.7-1.10 (6H, br-t), 1.0-2.0 (28H, m), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 48: 0.7-1.10 (6H, br-t), 1.0-2.0 (28H, m), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 49: 0.7-1.10 (6H, br-t), 1.0-2.0 (30H, m), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-5.1 (2H, br).
Example 50: 0.7-1.10 (6H, br-t), 1.0-2.0 (32H, m), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6-8.1 (2H, br).
Example 51: 0.7-1.1 (3H, br-t), 1.1-1.7 (14H, m), 1.33 (9H, s), 2.42 (2H, q), 2.46 (2H, q), 2.7-3.1 (4H, m), 3.41 (2H, t), 3.56 (2H, t), 7.6-8.1 (2H, br).
Example 52: 0.7-1.1 (3H, br-t), 1.0-1.7 (16H, m), 1.33 (9H, s), 2.42 (2H, q), 2.46 (2H, q), 2.7-3.1 (4H, m), 3.41 (2H, t), 3.56 (2H, t). 7.6-8.1 (2H, br).
Example 53: 0.7-1.1 (3H, br-t), 1.0-1.7 (18H, m), 1.33 (9H, s), 2.42 (2H, q), 2.46 (2H, q), 2.7-3.1 (4H, m), 3.41 (2H, t), 3.56 (2H, t), 7.6-8.1 (2H, br).
Example 54: 0.7-1.1 (3H, br-t), 1.0-1.7 (20H, m), 1.33 (9H, s), 2.42 (2H, q), 2.46 (2H, q), 2.7-3.1 (4H, m), 3.41 (2H, t), 3.56 (2H, 1), 7.6-8.1 (2H, br).
Example 55: 0.7-1.1 (3H, br-t), 1.0-1.7 (22H, m), 1.33 (9H, s), 2.42 (2H, q), 2.46 (2H, q), 2.7-3.1 (4H, m), 3.41 (2H, t), 3.56 (2H, t), 7.6-8.1 (2H, br).
Example 56: 0.7-1.1 (3H, br-t), 1.1-1.7 (8H, m), 1.33 (9H, s), 2.50-3.10 (4H, m), 3.32 (2H, t), 3.45 (2H, s), 3.73 (3H, s), 3.77 (3H, s), 7.6-8.1 (2H, br).
Example 57: 0.7-1.1 (3H, br-t), 1.0-1.7 (10H, m), 1.33 (9H, s), 2.50-3.10 (4H, m), 3.32 (2H, t), 3.45 (2H, s), 3.73 (3H, s), 3.77 (3H, s), 7-6,8.1 (2H, br).
Example 58: 0.7-1.1 (3H, br-t), 1.0-1.7 (12H, m), 1.33 (9H, s), 2.50-3.10 (4H, m), 3.32 (2H, t), 3.45 (2H, s), 3.73 (3H, s), 3.77 (3H, s), 7.6-8.1 (2H, br).
Example 59: 0.7-1.1 (3H, br-t), 1.11-1.7 (14H, m), 1.33 (9H, s), 2.50-3.10 (4H, m), 3.32 (2H, t), 3.45 (2H, s), 3.73 (3H, s), 3.77 (3H, s), 7.6-5.1 (2H, br).
Example 60: 0.7-1.1 (3H, br-t), 1.0-1.7 (16H, m), 1.33 (9H, s), 2.50-3.10 (4H, m), 3.32 (2H, t), 3.45 (2H, s), 3.73 (3H, s), 3.77 (3H, s), 7.6-8.1 (2H, br).
Example 61: 0.7-1.1 (3H, br-t), 1.1-1.7 (8H, m), 1.33 (9H, s), 2.14 (3H, s), 2.22 (3H, s), 2.70-3.10 (4H, s), 3.41 (2H, t), 4.62 (2H, s), 6.86 (2H, br).
Example 62: 0.7-1.1 (3H, br-t), 1.1-1.7 (10H, m), 1.33 (9H, s), 2.14 (3H, s), 2.22 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 4.62 (2H, s), 6.86 (2H, br).
Example 63: 0.7-1.1 (3H, br-t), 1.1-1.7 (14H, m), 1.33 (9H, s), 2.14 (3H, s), 2.22 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 4.62 (2H, s), 6.86 (2H, br).
Example 64: 0.7-1.1 (3H, br-t), 1.1-1.7 (16H, m), 1.33 (9H, s), 2.14 (3H, s), 2.22 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 4.62 (2H, s), 6.86 (2H, br).
Example 65: 0.7-1.1 (3H, br-t), 1.1-1.7 (8H, m), 1.33 (9H, s), 2.00 (6H, s), 2.09 (3H, s), 2.23 (3H, s), 2.70-3.20 (4H, m), 3.31 (2H, s), 3.38 (2H, t), 6.84 (1H, br).
Example 66: 0.7-1.1 (3H, br-t), 1.1-1.7 (10H, m), 1.33 (9H, s), 2.00 (6H, s), 2.09 (3H, s), 2.23 (3H, s), 2.70-3.20 (4H, m), 3.31 (2H, s), 3.38 (2H, t), 6.84 (1H, br).
Example 67: 0.7-1.1 (3H, br-t), 1.1-1.7 (14H, m), 1.33 (9H, s), 2.00 (6H, s), 2.09 (3H, s), 2.23 (3H, s), 2.70-3.20 (4H, m), 3.31 (2H, s), 3.38 (2H, t), 6.84 (1H, br).
Example 68: 0.7-1.1 (3H, br-t), 1.1-1.7 (16H, m), 1.33 (9H, s), 2.00 (6H, s), 2.09 (3H, s), 2.23 (3H, s), 2.70-3.20 (4H, m), 3.31 (2H, s), 3.38 (2H, t), 6.84 (1H, br).
Example 69: 0.7-1.0 (3H, br), 1.0-1.7 (8H, m), 1.33 (9H, s), 1.97 (3H, s), 2.7-3.1 (4H, m), 3.35 (2H, t), 3.47 (2H, s), 6.90 (1H, s), 7.6-8.1 (2H, br).
Example 70: 0.7-1.0 (3H, br), 1.0-1.7 (10H, m), 1.33 (9H, s), 1.97 (3H, s), 2.7-3.1 (4H, m), 3.35 (2H, t), 3.47 (2H, s), 6.90 (1H, s), 7.6-8.1 (2H, br).
Example 71: 0.7-1.0 (3H, br), 1.0-1.7 (12H, m), 1.33 (9H, s), 1.97 (3H, s), 2.7-3.1 (4H, m), 3.35 (2H, t), 3.47 (2H, s), 6.90 (1H, s), 7.6-8.1 (2H, br).
Example 72: 0.7-1.0 (3H, br), 1.0-1.7 (4H, m), 1.33 (9H, s), 1.97 (3H, s), 2.7-3.1 (4H, m), 3.35 (2H, t), 3.47 (2H, s), 6.90 (1H, s), 7.6-8.1 (2H, br).
Example 73: 0.7-1.0 (3H, br), 1.0-1.7 (16H, m), 1.33 (9H, s), 1.97 (3H, s), 2.7-3.1 (4H, m), 3.35 (2H, t), 3.47 (2H, s), 6.90 (1H, s), 7.6-8.1 (2H, br).
Example 74: 0.7-1.0 (3H, br), 1.0-1.7 (8H, m), 1.33 (9H, s), 2.07 (3H, s), 2.89 (2H, t), 3.09 (2H, t), 3.40 (2H, t), 4.51 (2H, s), 6.90 (1H, s), 7.0-7.4 (2H, br).
Example 75: 0.7-1.0 (3H, br), 1.0-1.7 (10H, m), 1.33 (9H, s), 2.07 (3H, s), 2.89 (2H, t), 3.09 (2H, t), 3.40 (2H, t), 4.51 (2H, s), 6.90 (1H, s), 7.0-7.4 (1H, br).
Example 76: 0.7-1.0 (3H, br), 1.0-1.7 (12H, m), 1.33 (9H, s), 2.07 (3H, s), 2.89 (2H, t), 3.09 (2H, t), 3.40 (2H, t), 4.51 (2H, s), 6.90 (1H, s), 7.0-7.4 (2H, br).
Example 77: 0.7-1.0 (3H, br), 1.0-1.7 (14H, m), 1.33 (9H, s), 2.07 (3H, s), 2.89 (2H, t), 3.09 (2H, t), 3.40 (2H, t), 4.51 (2H, s), 6.90 (1H, s), (1H, s), 7.0-7.4 (2H, br).
Example 78: 0.7-1.0 (3H, br), 1.0-1.7 (16H, m), 1.33 (9H, s), 2.07 (3H, s), 2.89 (2H, t), 3.09 (2H, t), 3.40 (2H, t), 4.51 (2H, s), 6.90 (1H, s), 7.0-7.4 (2H, br).
Example 79: 0.7-1.0 (3H, br), 1.0-1.7 (8H, m), 1.33 (9H, s), 2.08 (3H, s), 2.23 (6H, s), 2.89 (2H, t), 3.14 (2H, t), 3.30 (2H, s), 3.38 (2H, t), 6.84 (1H, s), 6.90 (1H, br).
Example 80: 0.7-1.0 (3H, br), 1.0-1.7 (10H, m), 1.33 (9H, s), 2.08 (3H, s), 2.23 (5H, s), 2.89 (2H, t), 3.14 (2H, t), 3.30 (2H, s), 3.38 (2H, t), 6.84 (1H, s), 6.90 (1H, br).
Example 81: 0.7-1.0 (3H, br), 1.0-1.7 (12H, m), 1.33 (9H, s), 2.08 (3H, s), 2.23 (6H, s), 2.89 (2H, t), 3.14 (2H, t), 3.30 (2H, s), 3.38 (2H, t), 6.84 (1H, s), 6.90 (1H, br).
Example 82: 0.7-1.0 (3H, br), 1.0-1.7 (14H, m), 1.33 (9H, s), 2.08 (3H, s), 2.23 (6H, s), 2.89 (2H, t), 3.14 (2H, t), 3.30 (2H, s), 3.38 (2H, t), 6,84 (1H, s), 6.90 (1H, br).
Example 83: 0.7-1.0 (3H, br), 1.0-1.7 (16H, m), 1.33 (9H, s), 2.08 (3H, s), 2.23 (6H, s), 2.89 (2H, t), 3.14 (2H, t), 3.30 (2H, s), 3.38 (2H, t), 6.84 (1H, s), 6.90 (1H, br).
Example 84: 0.7-1.0 (3H, br-t), 1.00-1.60 (8H, m), 1.38 (9H, s), 1.60-2.20 (2H, m), 2.07 (3H, s), 2.16 (3H, s), 2.20-2.40 (2H, m), 3.10-3.80 (3H, m), 3.27 (2H, br-t), 6.45 (1H, s), 7.20-7.60 (2H, br).
Example 85: 0.7-1.0 (3H, br-t), 1.00-1.60 (10H, m), 1.38 (9H, s), 1.60-2.20 (2H, m), 2.07 (3H, s), 2.16 (3H, s), 2.20-2.40 (2H, m), 3.10-3.80 (3H, m), 3.27 (2H, br-t), 6.45 (1H, s), 7.20-7.60 (2H, br).
Example 86: 0.7-1.0 (3H, br-t), 1.0-2.0 (10H, m), 1.33 (9H, s), 2.07 (3H, s), 2.16 (3H, s), 2.60-3.60 (7H, m), 6.44 (1H, s), 6.78 (2H, br).
Example 87: 0.7-1.0 (3H, br-t), 1.0-2.0 (12H, m), 1.33 (9H, s), 2.07 (3H, s), 2.16 (3H, s), 2.60-3.60 (7H, m), 6.44 (1H, s), 6.78 (2H, br).
Example 88: 0.7-1.0 (3H, br-t), 1.0-2.0 (10H, m), 1.35 (9H, s), 2.07 (3H, s), 1.16 (3H, s), 2.19 (6H, s), 2.21 (2H, t), 2.6-3.6 (5H, m), 6.45 (1H, s), 7.2 (1H, br).
Example 89: 0.7-1.0 (3H, br-t), 1.0-2.0 (12H, m), 1.35 (9H, s), 2.07 (3H, s), 2.16 (3H, s), 2.19 (6H, s), 2.21 (2H, t), 2.6-3.6 (8H, m), 6.45 (1H, s), 7.2 (1H, br).
Example 90: 0.7-1.0 (3H, br-t), 1.0-2.0 (14H, m), 1.35 (9H, s), 2.07 (3H, s), 2.16 (3H, s), 2.19 (6H, s), 2.21 (2H, t), 2.6-3.6 (5H, m), 6.45 (1H, s), 7.2 (1H, br).
Example 91: 0.70-1.10 (6H, m), 1.10-1.90 (16H, m), 2.10 (6H, s), 1.80-2.00 (2H, br-t), 2.00-4.00 (6H, m), 3.55 (2H, s), 4.80 (1H, br), 5.50 (1H, br), 6.40 (1H, br).
Example 92: 0.70-1.10 (6H, m), 1.10-1.90 (18H, m), 2.10 (6H, s), 1.80-2.00 (2H, br-t), 2.00-4.00 (6H, m), 3.55 (2H, s), 4.80 (1H, br), 5.50 (1H, br), 6.40 (1H, br).
Example 93: 0.70-1.10 (6H, m), 1.10-1.90 (20H, m), 2.10 (6H, s), 1.80-2.00 (2H, br-t), 2.00-4.00 (6H, m), 3.55 (2H, s), 4.80 (1H, br), 5.50 (1H, br), 6.40 (1H, br).
Example 94: 0.70-1.10 (6H, m), 1.10-1.90 (22H, m), 2.09 (4H, br-t), 1.80-2.00 (2H, br-t), 2.00-4.00 (6H, m), 3.55 (2H, s), 4.80 (1H, br), 5.50 (1H, br), 6.40 (1H, br).
Example 95: 0.70-1.10 (6H, m), 1.1.0-1.90 (24H, m), 2.09 (4H, br-t), 1.80-2.00 (2H, br), 2.00-4.00 (6H, m), 3.55 (2H, s), 4.80 (1H, br), 5.50 (1H, br), 6.40 (1H, br).
Example 96: 0.70-1.10 (6H, m), 1.10-1.90 (26H, m), 2.09 (4H, br-t), 1.80-2.00 (2H, br-5), 2.00-4.00 (6H, m), 3.55 (2H, s), 4.80 (1H, br), 5.50 (1H, br), 6.40 (1H, br).
Example 97: 0.70-1.10 (6H, m), 1.10-1.90 (16H, m), 1.80-2.00 (2H, br-t), 2.00-4.00 (6H, m), 3.35 (2H, s), 3.74 (3H, s), 3.78 (3H, s), 4.80 (1H, br), 5.50 (1H, br), 6.40 (1H, br).
Example 98: 0.70-1.10 (6H, m), 1.10-1.90 (18H, m), 1.80-2.00 (2H, br-t), 2.00-4.00 (6H, m), 3.35 (2H, s), 3.74 (3H, s), 3.78 (3H, s), 4,80 (1H, br), 5.50 (1H, br), 6.40 (1H, br).
Example 99: 0.70-1.10 (6H, m), 1.10-1.90 (20H, m), 1.84-2.00 (2H, br-t), 2.00-4.00 (6H, m), 3.35 (2H, s), 3.74 (3H, s), 3.78 (3H, s), 4.80 (1H, br), 5.50 (1H, br), 6.40 (1H, br).
Example 100: 0.70-1.10 (3H, br-t), 1.10-1.70 (14H, m), 1.33 (9H, s), 2.10 (3H, s), 2.39 (3H, s), 3.71 (2H, br), 3.99 (2H, br-t), 4.15 (2H, s), 6.38 (1H, d), 6.89 (1H, d).
Example 101: 0.70-1.10 (3H, br-t), 1.10-1.70 (10H, m), 1.33 (9H, s), 2.10 (3H, s), 2.39 (3H, s), 3.71 (2H, br), 3.99 (2H, br-t), 4.15 (2H, s), 638 (1H, d), 6.89 (1H, d).
Example 102: 0.70-1.10 (3H, br-t), 1.10-1.70 (18H, m), 1.33 (9H, s), 2.08 (2H, q), 2.46 (2H, q), 3.71 (2H, br), 3.99 (2H, br-t), 4.15 (2H, s), 6.38 (1H, d), 6.89 (1H, d).
Example 103: 0.70-1.10 (3H, br-t), 1.10-1.70 (20H, m), 1.33 (9H, s), 2.08 (2H, q), 2.46 (2H, q), 3.71 (2H, br), 3.99 (2H, br-t), 4.15 (2H, s), 6.38 (1H, d), 6.89 (1H, d).
Example 104: 0.70-1.10 (3H, br-t), 1.10-1.70 (22H, m), 1.33 (9H, s), 2.42 (2H, q), 2.46 (2H, q), 3.71 (2H, br), 3.99 (2H, br-t), 4.15 (2H, s), 6.38 (1H, d), 6.89 (1H, d).
Example 105: 0.70-1.10 (3H, br-t), 1.10-1.70 (12H, m), 1.33 (9H, s), 3.60 (3H, s), 3.65 (3H, s), 3.71 (2H, br), 3.99 (2H, br-t), 4.15 (2H, s), 6.15 (1H, d), 6.70 (1H, d).
Example 106: 0.70-1.10 (3H, br-t), 1.10-1.70 (14H, m), 1.33 (9H, s), 3.60 (3H, s), 3.65 (3H, s), 3.71 (2H, br), 3.99 (2H, br-t), 4.15 (2H, s), 6.15 (1H, d), 6.70 (1H, d).
Example 107: 0.70-1.110 (3H, br-t), 1.10-1.70 (16H, m), 1.33 (9H, s), 3.60 (3H, s), 3.65 (3H, s), 3.71 (2H, br), 3.99 (2H, br-t), 4.15 (2H, s), 6.15 (1H, d), 6.70 (1H, d).
Example 108: 0.70-1.10 (3H, br-t), 1.10-2.00 (15H, m), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.37 (3H, s), 3.40 (2H, t), 3.41 (2H, t), 3.56 (2H, s), 7.60-8.10 (2H, br).
Example 109: 0.70-1.10 (3H, br-t), 1.10-2.00 (15H, m), 2.01 (3H, s), 2.15 (3s), 2.17 (3H, s), 2.45 (2H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.60-8.10 (2H, br).
Example 110: 0.70-1.10 (3H, br-t), 1.10-2.00 (23H, m), 2.01 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.60-8.10 (2H, br).
Example 111: 0.70-1.10 (3H, br-t), 1.10-2.00 (25H, m), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 336 (2H, s), 7.60-9.10 (2H, br).
Example 112: 0.70-1.10 (3H, br-t), 1.10-1.70 (12H, m), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.30-7.80 (3H, m), 7.60-8.10 (2H, br), 8.12 (2H, d).
Example 113: 0.70-1.10 (3H, br-t), 1.10-1.70 (12H, m), 2.01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.53 (2H, s), 3.56 (2H, s), 7.30 (5H, s), 7.60-8.10 (2H, br).
Example 114: 1.59 (3H, br-t), 1.10-1.70 (4H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.10-2.50 (4H, m), 2.70-3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.60-8.10 (2H, br).
Example 115: 1.33 (9H, s) 2.01 (3H, s), 2.15 (3H, s), 3.02 (2H, t), 3.41 (2H, t), 3.56 (2H, s), 4.30 (2H, s), 7.30 (5H, s) 7.60-8.10 (2H, br).
Example 116: 0.70-1.10 (3H, br-t), 1.10-1.60 (15H, m), 134 (9H, s), 2.02 (3H, s), 2.90 (2H, t), 3.13 (2H, t), 3.38 (2H, t), 3.50 (2H, s), 4.12 (2H, q), 6.80 (1H, br), 6.85 (1H, s).
Example 117: 0.70-1.10 (3H, br-t), 1.10-2.00 (5H, m), 1.23 (9H, s), 2.07 (3H, s), 2.24 (3H, s), 2.70-3.10 (4H, m), 3.39 (2H, t), 3.35 (2H, s), 6.60-7.50 (2H, br).
Example 118: 0.70-1.10 (3H, br-t), 1.10-2.00 (12H, m), 1.23 (9H, s), 2.07 (3H, s), 2.24 (3H, s), 2.70-3.10 (4H, m), 3.39 (2H, t), 3.35 (2H, s), 6.60-7.50 (2H, br).
Example 119: 0.70-1.10 (3H, br-t), 1.10-2.00 (16H, m), 1.23 (9H, s), 2.07 (3H, s), 2.24 (3H, s), 2.70-3.10 (4H, m), 3.39 (2H, t), 3.35 (2H, s), 6.60-7.50 (2H, br).
The compounds of Table 10 were obtained according to the method of the above Example 120.
TABLE 10
##STR00033##
Example
R1
R2
R3
R7
R6
121
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)6S(CH2)3CH3
122
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)3S(CH2)3CH3
123
—CH3
—(CH2)3CO2H
—CH3
—C(CH3)3
—(CH2)7CH3
The 1H-NMR values of the compounds of the above Examples 121-123 are shown in the following.
Example 121: 0.91 (3H, br-t), 1.00-1.80 (12H, m), 1.37 (9H, s), 1.93 (3H, s), 2.06 (3H, s), 2.47 (4H, br-t), 3.00 (4H, br), 3.30-3.90 (4H, m), 8.60-9.90 (2H, br).
Example 122: 0.90 (3H, br-t), 1.00-1.80 (6H, m), 2.08 (3H, s), 2.21 (3H, s), 2.48 (4H, br-t), 2.90-3.40 (4H, m), 3.40-3.80 (2H, m), 3.61 (2H, s), 7.34 (1H, br), 8.48 (1H, br).
Example 123: 0.86 (3H, br-t), 1.00-150 (12H, m), 1.42 (9H, s), 2.00-2.90 (6H, m), 2.11 (3H, s), 2.23 (3H, s) 2.90-330 (4H, m), 3.70 (2H, br), 6.10 (1H, br), 9.21 (1H, br).
N-(1-octyl-6-ethoxycarbonylmethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide (230 mg) was dissolved in ethanol (5 ml), and a solution of NaOH (100 mg) in water (2 ml) was added, which was followed by stirring at 50° C. for 1 hr. The solvent of the reaction mixture was evaporated under reduced pressure. The residue was dissolved in water (50 ml) and washed with ethyl acetate (20 ml). The aqueous layer was adjusted to pH 1-2 with 2N sulfuric acid and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 130 mg of powdery title compound.
TLC; Silica gel 60F254 Art. 5714 (Merck), CHCl3-MeOH (10:1), Rf value 0.5.
IR (Nujol) cm−1; 1732, 1722.
1H-NMR (CDCl3) δ;
0.70-1.00 (3H, br-t, —(CH2)7CH3), 1.10-1.70 (12H, m, —(CH2)6CH3), 1.35 (9H, s, —C(CH3), 1.80-2.10 (2H, M, C3—H2), 2.10 (6H, s, C5.7—CH3), 2.40-2.70 (4H, m, C4—H2, >NCH2—), 2.80-2.90 (2H, m, C2—H2), 3.68 (2H, s, —CH2CO—), 7.35 (1H, br, —CONH—), 9.50 (2H, br, ½H2SO4, —CO2H).
The compounds of Tables 11 and 12 were obtained according to the method of the above Example 124.
TABLE 11
##STR00034##
Example
R1
R2
R3
R7
R6
126
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)5CH3
127
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—CH2CH(CH2CH3)2
128
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)6CH3
129
—CH3
—CH2CO2H
—CH3
—C(CH3)3
##STR00035##
130
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)2CH(CH2CH3)2
131
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)2O(CH2)3CH3
132
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)7S(CH2)3CH3
133
—CH3
—CH2CO2H
—CH3
—C(CH3)3
##STR00036##
134
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)3CH(CH2CH3)2
135
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)3O(CH2)3CH3
136
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)3S(CH2)3CH3
137
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)8CH3
138
—CH3
—CH2CO2H
—CH3
—C(CH3)3
—(CH2)9CH3
139
—CH2CH3
—CH2CO2H
—CH2CH3
—C(CH3)3
—(CH2)5CH3
140
—CH2CH3
—CH2CO2H
—CH2CH3
—C(CH3)3
—(CH2)7CH3
141
—CH2CH3
—CH2CO2H
—CH2CH3
—C(CH3)3
—(CH2)9CH3
TABLE 12
##STR00037##
Example
R1
R2
R3
R7
R6
142
—OCH3
—CH2CO2H
—OCH3
—C(CH3)3
—(CH2)5CH3
143
—OCH3
—CH2CO2H
—OCH3
—C(CH3)3
—(CH2)7CH3
144
—OCH3
—CH2CO2H
—OCH3
—C(CH3)3
—(CH2)9CH3
145
—CH3
—CH2OH
—CH3
—C(CH3)3
—(CH2)5CH3
146
—CH3
—CH2OH
—CH3
—C(CH3)3
—(CH2)7CH3
147
—CH3
—CH2OH
—CH3
—C(CH3)3
—(CH2)9CH3
148
—CH3
—CH2CO2H
—CH3
—C(CH3)2(CH2)3CH3
—(CH2)7CH3
149
—CH3
—CH2CO2H
—CH3
—C(CH3)2(CH2)5CH3
—(CH2)7CH3
150
—CH3
—CH2CO2H
—CH3
##STR00038##
—(CH2)7CH3
151
—CH3
—CH2CO2H
—CH3
##STR00039##
—(CH2)7CH3
152
—CH3
—CH2CO2H
—CH3
—NH(CH2)3CH3
—(CH2)5CH3
153
—CH3
—CH2CO2H
—CH3
—NH(CH2)3CH3
—(CH2)7CH3
154
—CH3
—CH2CO2H
—CH3
—NH(CH2)3CH3
—(CH2)9CH3
The 1H-NMR values of the compounds of the above Examples 126-154 are shown in the following.
Example 126: 0.70-1.00 (3H, br-t), 1.10-1.70 (8H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 127: 0.70-1.00 (6H, br-t), 1.10-1.70 (5H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 128: 0.70-1.00 (3H, br-t), 1.10-1.70 (10H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 129: 0.80-1.70 (11H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 130: 0.70-1.00 (6H, br-t), 1.10-1.70 (7H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (21H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 131: 0.70-1.10 (3H, br-t), 1.10-1.70 (4H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.30-3.60 (4H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 132: 0.70-1.10,(3H, br-t), 1.10-1.70 (4H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.20-3.50 (4H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 133: 0.80-1.70 (13H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 134: 0.70-1.00 (6H, br-t), 1.10-1.70 (9H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 135: 0.70-1.10 (3H, br-t), 1.10-1.70 (6H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.30-3.60 (4m, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 136: 0.70-1.10 (3H, br-t), 1.10-1.70 (6H, m), 1.35 (9H, s), 1.80-2.l0 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.20-3.50 (4H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 137: 0.70-1.10 (1H, br-t), 1.10-1.70 (14H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 138: 0.70-1.10 (3H, br-t), 1.10-1.70 (16H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 139: 0.70-1.10 (3H, br-t), 1.10-1.70 (14H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.40 (2H, q), 2.43 (2H, q), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 140: 0.70-1.10 (3H, br-t), 1.10-1.70 (18H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.40 (2H, q), 2.43 (2H, q), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 141: 0.70-1.10 (3H, br-t), 1.10-1.70 (22H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.40 (2H, q), 2.43 (2H, q), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 142: 0.70-1.10 (3H, br-t), 1.10-1.70 (8H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.52 (2H, s), 3.73 (3H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 143: 0.70-1.10 (3H, br-t), 1.10-1.70 (12H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.52 (2H, s), 3.73 (3H, s), 3.77 (3H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 144: 0.70-1.10 (3H, br-t), 1.10-1.70 (16H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.52 (2H, s), 3.73 (3H, s), 3.77 (3H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 145: 0.70-1.10 (3H, br-t), 1.10-1.70 (8H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.17 (3H, s), 2.23 (3H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 4.65 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 146: 0.70-1.10 (3H, br-t), 1.10-1.70 (12H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.17 (3H, s), 2.23 (3H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 4.65 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 147: 0.70-1.10 (3H, br-t), 1.10-1.70 (16H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.17 (3H, s), 2.23 (3H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 4.65 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 148: 0.70-1.10 (6H, br-t), 1.10-1.70 (18H, m), 1.35 (6H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 149: 0.70-1.10 (6H, br-t), 1.10-1.70 (22H, m), 1.35 (6H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 150: 0.70-1.10 (3H, br-t), 1.10-2.00 (27H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 151: 0.70-1.10 (3H, br-t), 1.10-1.70 (12H, m), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, m), 3.53 (2H, s), 3.68 (2H, s), 7.30 (5H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 152: 0.70-1.10 (6H, br-t), 1.10-1.70 (12H, m), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.90 (8H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 153: 0.70-1.10 (6H, br-t), 1.10-1.70 (16H, m), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.90 (8H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 154: 0.70-1.10 (6H, br-t), 1.10-1.70 (20H, m), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.90 (8H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
The compounds of Table 13 were obtained according to the method of the above Example 155.
TABLE 13
##STR00040##
Example
R1
R2
R3
R7
R6
156
—H
—CO2H
—CH3
—C(CH3)3
—(CH2)5CH3
157
—H
—CO2H
—CH3
—C(CH3)3
—(CH2)9CH3
158
—CH3
—CO2H
—CH3
—C(CH3)3
—(CH2)5CH3
159
—CH3
—CO2H
—CH3
—C(CH3)3
—(CH2)7CH3
160
—CH3
—CO2H
—CH3
—C(CH3)3
—(CH2)9CH3
The 1H-NMR values of the compounds of the above Examples 156-160 are shown in the following.
Example 156: 0.79 (3H, br-t), 0.80-1.80 (8H, m), 1.34 (9H, s), 2.38 (3H, s), 2.94 (2H, t), 3.27 (2H, t), 3.54 (2H, t), 6.80 (2H, br), 7.67 (1H, s).
Example 157: 0.79 (3H, br-t), 0.80-1.80 (16H, m), 1.34 (9H, s), 2.38 (3H, s), 2.94 (2H, t), 3.27 (2H, t), 3.54 (2H, t), 6.80 (2H, br), 7.67 (1H, s).
Example 158: 0.79 (3H, br-t), 0.80-1.80 (8H, m), 1.33 (9H, s), 2.40 (3H, s), 2.45 (3H, s), 2.95 (2H, t), 3.26 (2H, t), 3.54 (2H, t), 6.80 (2H, br).
Example 159: 0.79 (3H, br-t), 0.80-1.80 (12H, m), 1.33 (9H, s), 2.40 (3H, s), 2.45 (3H, s), 2.95 (2H, t), 3.26 (2H, t), 3.54 (2H, t), 6.80 (2H, br).
Example 160: 0.79 (3H, br-t), 0.80-1.80 (16H, m), 1.33 (9H, s), 2.40 (3H, s), 2.45 (3H, s), 2.95 (2H, t), 3.26 (2H, t), 3.54 (2H, t), 6.80 (2H, br).
With the aim of demonstrating the superior properties of the compound of the present invention, ACAT inhibitory activity, serum total cholesterol reducing effect, in vitro plasma lipoperoxidation inhibitory activity, ex vivo plasma lipoperoxidation inhibitory, activity, solubility in water at pH 6.8 and plasma concentration on oral administration were determined
A high cholesterol feed [a feed added with cholesterol (1%), Clea Japan, Inc.] was fed to male Japanese white rabbits weighing 2-2.5 kg at 100 g per day and the rabbits were bred for 4 weeks. The rabbits were killed by bleeding under anesthesia and small intestine was removed. The mucosal membrane of small intestine was peeled, collected and homogenated. The homogenate was centrifuged at 4° C. and 10,000 rpm for 15 min. The obtained supernatant was further centrifuged at 4° C. and 41,000 rpm for 30 minutes to give microsomal fractions. The microsomal suspension as an enzyme sample, dimethyl sulfoxide (DMSO, 5μl) or a test compound dissolved in DMSO (test compound solution 5μl), and reaction substrate [1-14C] oleoyl CoA were added to 0.15M phosphate buffer to the total amount of 500 μl. After incubation at 37° C. for 7 minutes, a chloroform-methanol mixture was added to slop the reaction. Water was added thereto and mixed, and chloroform layer was separated. The solvent was evaporated to dryness, and the residue was it-dissolved in a-hexane. The mixture was subjected to thin layer chromatography using a silica gel plate. The spots of cholesteryl oleate on the silica gel plate were scraped, and quantitatively assayed on a liquid scintillation counter. The ACAT inhibitory activity of the test compound was expressed as a proportion (%) of inhibition of cholesterol oleate, namely, the proportion of inhibition of cholesteryl oleate production as compared to control, the results of which are shown in Table 14.
TABLE 14
Test compound
ACAT inhibition (%)
Example 1
99.2
Example 3
92.5
Example 4
93.6
Example 36
94.0
Example 40
92.7
Example 76
94.7
Example 116
92.0
Example 120
92.3
Example 121
92.5
Example 122
92.0
Example 125
93.0
YM-750
92.0
YM-750: 1-cycloheptyl-1-[(2-fluorenyl)methyl]-3-(2,4,6-trimethyl-phenyl) urea
Mile Wister rats weighing 180-200 g were bred under free access to a high cholesterol feed [added with cholesterol (1%), cholic acid (0.5%) and coconut oil (10%), Clea Japan, Inc.] for 3 days, during which period a test compound (3 mg/kg and 10 mg/kg) suspended in 5% gum arabic solution was forcibly administered once a day orally for 3 days. Only 5% gum arabic solution was administered to control animals. After final administration, the test animals were fasted and blood was taken 5 hours later. The serum total cholesterol level was determined using a commercially available assay lit (cholesterol-CII-Test Wako, Wako Pure Chemical Industries, Ltd.). The activity of the test compound was expressed as a proportion (%) of reduction of serum total cholesterol level, namely, the proportion of reduction of serum total cholesterol as compared to control, the results of which are shown in Table 15.
TABLE 15
Reduction (%) of serum total cholesterol
Test compound
3 mg/kg/day
10 mg/kg/day
Example 1
52.8
57.1
Example 3
54.2
61.2
Example 4
58.8
57.5
Example 18
45.1
56.6
Example 25
45.0
52.3
Example 36
60.0
58.9
Example 40
51.3
56.2
Example 71
26.5
52.3
Example 81
31.7
53.8
Example 116
26.5
50.9
Example 120
45.8
44.6
Example 121
87.8
48.1
Example 122
88.2
50.0
Example 125
30.2
47.9
Example 155
55.2
58.5
Example 159
53.8
57.5
YM-750
37.7
46.4
YM-750: 1-cycloheptyl-1-[(2-fluorenyl)methyl]-3-(2,4,6-trimethyl-phenyl) urea
Under ether anesthesia, blood was taken from male Wister rats weighing 160-190 g that had been fasted for 16 hours, and heparinized plasma was separated by conventional method. DMSO (10 μl) or a test compound (final concentration 10−5M) dissolved in DMSO (test compound solution 10 μl) was added to plasma (1.0 ml), and the mixture was incubated at 37° C. for 5 minutes. Distilled water (10 μl) or aqueous solution (10 μl) of (copper sulfate (final concentration 1M) was added, followed by incubation at 37° C. for 4 minutes. After incubation, the concentration of lipid peroxide in the sample was determined using a commercially available assay kit (Lipoperoxide Test Wako, Wako Pure Chemical industries, Ltd.). Specifically, lipid peroxide in the sample was allowed to develop color by thiobarbiturate method and assayed as malondialdehyde. The activity of the test compound was expressed as a proportion (%) of inhibition of malondialdehyde production, namely, the proportion of inhibition of malondialdehyde production as compared to control, the results of which are shown in Table 16.
TABLE 16
Test compound
Inhibition (%) of plasma lipoperoxidation
Example 1
51.7
Example 3
49.2
Example 4
51.2
Example 11
44.5
Example 18
44.0
Example 25
63.5
Example 36
41.5
Example 71
48.1
Example 76
51.7
Example 81
47.1
Example 116
45.5
Example 121
41.6
Example 125
48.0
Example 155
47.7
Example 159
48.3
A test compound suspended in 5% gum arabic solution was forcibly administered orally to male Wister rats weighing 160-190 g that had been fasted for 16 hr. Only 5% gum arabic solution was administered to control animals. At 1 hour after administration, blood was taken under ether anesthesia and heparinized plasma was separated by conventional method. The plasma (1.0 ml) was processed in the same manner as in Experimental Example 3 and the amount of produced malondialdehyde was determined. The activity of the test compound was expressed as a proportion (%) of inhibition of malondialdehyde production, namely, the proportion of inhibition of malondialdehyde production as compared to control, the results of which are shown in Table 17.
TABLE 17
Inhibition (%) of plasma lipoperoxidation
Dose
Example 4
Example 18
Example 36
Probucol
10 mg/kg
39.0
27.1
41.6
—
100 mg/kg
—
—
—
15.4
Probucol: 4,4-isopropylidenedithiobis(2,6-di-t-butylphenol)
A pulverized test compound (10 mg) was added to buffer (1 ml, pH 6.8), and the mixture was shaken for 1 br at 25° C. The mixture was passed through a membrane filter and the concentration of the test compound in the filtrate was determined by high performance liquid chromatography, the results of which are shown in Table 18.
TABLE 18
Test compound
Solubility (mg/ml)
Example 4
6.9
Example 18
7.3
Example 25
0.8
Example 36
4.2
Example 71
0.1
YM-750
<0.01
YM-750: 1-cycloheptyl-1-[(2-fluorenyl)methyl]-3-(2,4,6-trimethyl-phenyl) urea
A test compound (30 mg)kg) suspended in 5% gum arabic solution was forcibly administered orally to male Wister rats weighing 200-250 g that had been fasted for 16 hr. At 0.5, 1, 2, 4 and 6 hours after administration, blood was taken and heparinized plasma was separated by conventional method. The concentration of the test compound in the plasma was determined by high performance liquid chromatography, the results of which are shown in Table 19.
TABLE 19
Test compound
Highest concentration in plasma (μg/ml)
Example 4
1.4
Example 36
2.2
A test compound (30 mg/kg) suspended in 5% gum arabic solution was forcibly administered orally to male SD rats weighing 200-250 g that had been fasted for 16 hr. At 0.5, 1, 2, 4 and 6 hours after administration, blood was taken and heparinized plasma was separated by conventional method. The concentration of the test compound in the plasma was determined by high performance liquid chromatography, the results of which are shown in Table 20.
TABLE 20
Test compound
Highest concentration in plasma (μg/ml)
Example 4
13.6
Example 36
12.2
Matsui, Hiroshi, Nakamura, Shohei, Kamiya, Shoji, Shirahase, Hiroaki, Wada, Katsuo
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