CA2233842C - Novel heterocyclic derivatives having indoline, indole or tetrahydroquinoline ring and pharmaceutical use thereof - Google Patents
Novel heterocyclic derivatives having indoline, indole or tetrahydroquinoline ring and pharmaceutical use thereof Download PDFInfo
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- CA2233842C CA2233842C CA002233842A CA2233842A CA2233842C CA 2233842 C CA2233842 C CA 2233842C CA 002233842 A CA002233842 A CA 002233842A CA 2233842 A CA2233842 A CA 2233842A CA 2233842 C CA2233842 C CA 2233842C
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Abstract
A heterocyclic derivative of the formula (I) (see formula I) 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.
Description
SPECIFICATION
NOVEL HETEROCYCLIC DERIVATIVES HAVING INDOLINE, INDOLB OR
TETRAHYDROQUINOLINE RING AND PHARMACEUTICAL USE THEREOF
Technical Field The present invention relates 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 acyl-CoA : cholesterol acyltransferase (hereinafter ACAT) and lipoperoxidation inhibitory activity, and to pharmaceutical use thereof.
. Background Art 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 Z
can be suppre;ssed 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 accumu-lation 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 arterio-sclerosis, 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, 23839/1992, 32756/1992 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 lipoperoxidat,ion inhibitory activity is highly useful as a pharmaceutical product, since it effectively reduces accumulation of cholesterol eater 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.
NOVEL HETEROCYCLIC DERIVATIVES HAVING INDOLINE, INDOLB OR
TETRAHYDROQUINOLINE RING AND PHARMACEUTICAL USE THEREOF
Technical Field The present invention relates 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 acyl-CoA : cholesterol acyltransferase (hereinafter ACAT) and lipoperoxidation inhibitory activity, and to pharmaceutical use thereof.
. Background Art 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 Z
can be suppre;ssed 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 accumu-lation 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 arterio-sclerosis, 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, 23839/1992, 32756/1992 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 lipoperoxidat,ion inhibitory activity is highly useful as a pharmaceutical product, since it effectively reduces accumulation of cholesterol eater 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.
Disclosure of the Invention 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-arteriosclero:>is effect, which resulted in the completion of the present invention.
Thus, thE: present invention relates to heterocyclic derivatives of the formula (J=) R' RS
RZ w / Z
R3 . \ ~ N ~ (I) a wherein one of R', R2 and R5 is hydroxy, carboxy, alkoxycarbonyl, a group of the formula -NR9R'° wherein R9 and R'° are each independently hydrogen atom or lower alkyl, or alkyl or alkenyl substituted by hydroxy, acidic group, alkoxycarbonyl or a group of the formula -NR9R'° wherein R9 and R'° 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 R'~ is a group of the formula -NHCOR' wherein R' is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cyclo-alkylalkyl, aryl, arylalkyl or a group of the , formula -NHR$ wherein R$ is alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy;
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-arteriosclero:>is effect, which resulted in the completion of the present invention.
Thus, thE: present invention relates to heterocyclic derivatives of the formula (J=) R' RS
RZ w / Z
R3 . \ ~ N ~ (I) a wherein one of R', R2 and R5 is hydroxy, carboxy, alkoxycarbonyl, a group of the formula -NR9R'° wherein R9 and R'° are each independently hydrogen atom or lower alkyl, or alkyl or alkenyl substituted by hydroxy, acidic group, alkoxycarbonyl or a group of the formula -NR9R'° wherein R9 and R'° 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 R'~ is a group of the formula -NHCOR' wherein R' is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cyclo-alkylalkyl, aryl, arylalkyl or a group of the , formula -NHR$ wherein R$ 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 a binding group forming a 5- or 6-membered ring together with the nitrogen atom substituted by R6, the carbon atom of benzene ring to which the nitrogen atom binds and the carbon atom adjacent to the carbon atom, and pharmaceutically acceptable salts thereof, provided that when one of R1, Rz and Rs is carboxyl or alkoxylcarbonyl, then Z is other than a group of the formula:
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, Rla, Rlb, R1°, Rz, Rz°, Ra~ R3a~ R3b R3°, R4, R4°, Rs, Rs°, R9, R9°, Rl~ and Rl°° may be linear or branched and has 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentylhexyl and the like.
Lower alkoxy at R1, Rlb, R1°, Rz, Rz°, R3, R3b~ R3c~ R4~
R''°, Rs, and Rs° 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.
3 0 Alkyl at R6 , R6a, Rsb, Rsc ~ R~ ~ Rya ~ Rib ~ R~° , Ra , R8b and RB° 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, R6°, R', R'b, and R'°, the alkoxy moiety thereof perferably has 1 to 6 carbon atoms and alkyl 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, R6°, R', R'b, and R'°, 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~ Rsc~ R~~ R~a~ Rib, R'~, R8, Rab and R8° preferably has 3 to 8 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
In cycloalkylalkyl at R6, R6a, Rsb, R6~, R', R'a, R'b, R'°, Ra, Rab, and Rg°, its cycloalkyl moiety preferably has 3 to 8 carbon atoms and alkyl moiety preferably has 1 to 3 carbon atoms. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopropylpropyl, cycloheptylmethyl, cyclooctylmethyl and the like.
Examples of aryl at R', R'b, R'°, R8, RBb, and R8°
include phenyl, naphthyl and the like.
Arylalkyl at R6, R6b, Rs°, R', R'b, R'°, Re, Rab and Ra°
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.
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, Rla, Rlb, R1°, Rz, Rz°, Ra~ R3a~ R3b R3°, R4, R4°, Rs, Rs°, R9, R9°, Rl~ and Rl°° may be linear or branched and has 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentylhexyl and the like.
Lower alkoxy at R1, Rlb, R1°, Rz, Rz°, R3, R3b~ R3c~ R4~
R''°, Rs, and Rs° 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.
3 0 Alkyl at R6 , R6a, Rsb, Rsc ~ R~ ~ Rya ~ Rib ~ R~° , Ra , R8b and RB° 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, R6°, R', R'b, and R'°, the alkoxy moiety thereof perferably has 1 to 6 carbon atoms and alkyl 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, R6°, R', R'b, and R'°, 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~ Rsc~ R~~ R~a~ Rib, R'~, R8, Rab and R8° preferably has 3 to 8 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
In cycloalkylalkyl at R6, R6a, Rsb, R6~, R', R'a, R'b, R'°, Ra, Rab, and Rg°, its cycloalkyl moiety preferably has 3 to 8 carbon atoms and alkyl moiety preferably has 1 to 3 carbon atoms. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopropylpropyl, cycloheptylmethyl, cyclooctylmethyl and the like.
Examples of aryl at R', R'b, R'°, R8, RBb, and R8°
include phenyl, naphthyl and the like.
Arylalkyl at R6, R6b, Rs°, R', R'b, R'°, Re, Rab and Ra°
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 R6° 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, Rz and R5 is exemplified by carboxyl, sulfonic acid group, phosphoric acid group and the like.
Examples of alkoxycarbonyl at R1, R1°, Rz, Rzb, Rz°~ Rs and Rs° include those having 1 to 4 carbon atoms in the alkoxy moiety, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-5a butoxycarbony7l and the like.
Alkyl to be substituted at R', Rz, Rza, Rzb and RS 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 iro be substituted at R', Rz and RS may be linear or branched and ~~referably has 2 to 8 carbon atoms. Examples thereof include vinyl, propenyl, isopropenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, 3,3-dimethyl-2-propenyl and the like. Examples of substituted a:Lkenyl include carboxyvinyl, carboxypropenyl, hydroxypropen;yl and the like.
Z is pre:f'erably In the compounds of the present invention, 1Q when one of R', Rz and R5 is alkyl or alkenyl substituted by hydroxy, acidic group, alkoxycarbonyl or a group of the formula -NR9R'° wherein R9 and R'° 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) When the compound of the present invention is indoline or indole derivative, preferable compound is that of the above-mentioned formula (I) wherein one of R', Rz and RS is alkyl substituted by hydroxy, carb~oxy, alkoxycarbonyl or a group of the formula -NR9R'° wherein R9 and R'° are each independently lower alkyl, and the other two are: independently hydrogen atom, lower alkyl or lower alkoxy;
either R3 or R4 is a group of the formula -NHCOR' wherein R~ is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula -NHR8 wherein R8 is alkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy; and R6 is as defined above,.
A more preferable compound is that of the above-mentioned formula (I) wherein R' and R3 are each independently hydrogen atom, lower alkyl or lower alko~~y; either R2 or R5 is alkyl substituted by hydroxy, carboxy, alko3~ycarbonyl or a group of the formula -NR9R'° wherein R9 and R'° are each :independently lower alkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy; R° is a group of the formula -NHCOR' wherein R' is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalk;,rl, aryl, arylalkyl or a group of the formula -NHR8 wherein R$ is alkyl; and R6 is as defined above.
A still snore preferable compound is that of the above-mentioned formula (I) wherein R' and R3 are each independently hydrogen atom, lower alkyl oar lower alkoxy; either R2 or R5 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9R'°
wherein R9 and R'° are each independently lower alkyl, and the other is hydrogen atom; Ra is a group of the formula -NHCOR' wherein R' is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or .a group of the formula -NHR8 wherein R$ is alkyl; and R6 is as defined above.
A still more preferable compound is that of the above-mentioned formula (I) wherein R' and R3 are each independently hydrogen atom or lower alkyl; either R2 or R5 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9R'° wherein R9 and R'° are each independently lower alkyl, and the other is hydrogen atom; R4 is a group of the formula -NHCOR' wherein R' is alkyl, cycloalkyl or cyclo-alkylalkyl; and R6 is alkyl, cycloalkyl or cycloalkylalkyl.
A still more preferable compound is that of the above-mentioned formula (I) wherein R' and R3 are each independently hydrogen atom or lower alkyl; R2 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9R'° wherein R9 and R'° are each independently lower alkyl, and RS is hydrogen atom; R° is a group of the formula -NHCOR' wherein R' is alkyl, cycloalkyl or cycloalkylalkyl; and R6 is alkyl, cycloalkyl or cycloalkylalkyl.
A still nnore preferable compound is that of the following formula (IIa) R' R2a w/
(IIa) R3°' ~ ~N
a.
Rs a wherein R'a i:~ hydrogen atom or lower alkyl; R3a is lower alkyl; R2a is alkyl substituted by hydroxy or carboxy; R4° is a group of the formula -NHCOR'g wherein R'a is alkyl, cycloalkyl or cycloalkylalkyl; and R6a is alkyl, cycloa:Lky1 or cycloalkylalkyl.
A still more preferable compound is that of the above formula (IIa) wherein R'° is hydrogen atom or lower alkyl; R3a is lower alkyl; R2a is alkyl substituted by hydroxy or carboxy; Rya is a group of the formula -NHCOR'a wherein R'~ is alkyl; and R6° 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-~4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide, 1V-(1-nonyl-5-carboxymethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylpropa~namide, N-(1-decyl-5-carboxymethyl-~+,6-dimethylindolin-~-yl)-2,2-dimetlhylpropanamide, N-(1-undecyl-5-carboxymethyl-4,6-dimethyl-indolin-'l-yl)-2,2-dimethylpropanamide, N-(1-dodecyl-5-carboxymethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-hexyl-5-hydroxy-methyl-6-methylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-hexyl-5-hydroxymethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-heptyl-5-hydroxymethyl-6-methylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-heptyl-5-hydroxymethyl-~,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide, 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 a acceptable sa:Lts thereof.
(b) When the compound of the present invention is a tetrahydro-quinoline derivative, a compound of the following (IIb) is preferable.
R'b Rz» .
3 b ~ ~ ~ ~ (IIb) R ~N
4b Rsb wherein R'b and R3b are each independently hydrogen atom, lower alkyl or lower alkoxy; R2b is alkyl substituted by hydroxy, carboxy or alkoxycarbonyl; R4b is a group of the formula -NHCOR''b wherein R'b is alkyl, alkoxy,alkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula -NHR$b wherein Rsb is alkyl, cycloalkyl, c;ycloalkylalkyl, aryl or arylalkyl; and R6b is alkyl, alkenyl, alko:xyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl or arylalkyl.
A still more preferable compound is that of the formula (IIb) wherein R'b and R3b are each independently lower alkyl or lower alkoxy;
R2b is alkyl ;substituted by hydroxy, carboxy or alkoxycarbonyl; Rib is a group of the formula-NHCOR''b wherein R'b is alkyl, cycloalkylalkyl, arylalkyl or a group of the formula -NHRsb wherein R$b is alkyl; and R6b is alkyl, alkoxyalkyl, alkylthioalkyl or cycloalkylalkyl.
A still more preferable compound is that of the formula (IIb) wherein R'b and R3b are each independently lower alkyl; R2b is alkyl substituted by hydroxy or carboxy; R4b is a group of the formula -NHCOR'b wherein R'b is alkyl; and R6b is alkyl.
Examples of the most preferable compound include N-(1-hexyl-6-carboxymethyl-5,'7-dimethyl-1,2,3,~-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-heptyl-5-carboxymethyl-5,'7-dimethyl-1,2,3,~-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-octyl-6-carboxymethyl.-5,'7-dimethyl-1,2,3,~-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-nonyl-6-carboxymethyl-5,7-dimethyl-1,2,3,~-tetrahydroqui.nolin-8-yl)-2,2-dimethylpropanamide, N-(1-decyl-6-carboxy-methyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethyl-propanamide, Nf-(1-hexyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,x-tetra-hydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-heptyl-6-hydroxy-methyl-5,7-dimethyl-1,2,3,~-tetrahydroquinolin-8-yl)-2,2-dimethyl-propanamide, Df-(1-octyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,x-tetra-hydroquinolin--8-yl)-2,2-dimethylpropanamide, N-(1-nonyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,~-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-decyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,~t-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide and the like, and pharmaceutically acceptable salts thereof.
~ When t;he compound of the present invention is that wherein one of R', R2 and R5 is hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9R'° wherein R9 and R'° 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,.
R'°
R2~\ R5~
(IIc) R3 ° ~ wN
R6~
wherein one ojf R'°, R2~ and R5° is hydroxy, carboxy, alkoxycarbonyl or a group of thE~ formula -NR9~R'°° wherein R9° and R'°~ 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 -NHCOR'° wherein R'~~ is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula -NHR8~ wherein R8° is alkyl, cycloalkyl, c;ycloalkylalkyl, aryl or arylalkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy; and R6~ is alkyl, alkenyl, alkoxyalkyl, .alkylthioalkyl, cycloalkyl, cycloalkylalkyl or arylalkyl.
More preferable compound is a compound of the above formula (IIc) wherein R'° and R3° are each independently hydrogen atom, lower alkyl or lower alko:~y; RZ~ is carboxy; R''~ is a group of the formula -NHCOR~~ wherein R~° is alkyl, cycloalkyl or cycloalkylalkyl; R5~ is hydrogen atom; and R6~ is alkyl, cycloalkyl or cycloalkylalkyl.
A still more preferable compound is a compound of the above formula (IIc) wherein R'° is hydrogen atom or lower alkyl; R3~ is lower alkyl;
R2~ is carboxy; Ra° is a group of the formula -NHCOR'°
wherein R°'~ is alkyl; R5° is hydrogen atom; and R6~ is alkyl.
Examples of the most preferable compound include N-(1-hexyl-5-carboxy-6-met~hylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-octyl-5-carboxy-6-met:hylindolin-~-yl)-2,2-dimethylpropanamide, N-(1-decyl-5-carboxy-6-methylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-hexyl-5-carboxy-~t,6-dimethylindolin-~-yl)-2,2-dimethylpropanamide, N-{1-octyl-5-carboxy-~,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 salts thereof.
The compound (I) may form pharmaceutically acceptable salts. When compound (I) has a basic group, it~can form acid addition salts. The acid to form 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 acid and the like, and organic acids such as oxalic acid, fumaric acid, malefic acid, citric acid, tartaric acid, methanesulfonic acid, tolueneaulfonic 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; all~;aline earth metal salts such as calcium salt, magnesium salt and the like; and organic base salts such as triethylamine salt, dicyclohexylaunine 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 ~.
uct1.017. MetnOd R~1 1) reduction R12~_ ~ ~ ~ 2) protection of amino R.12 N' 3) introduction of vitro N
( I. T I ) H ~) reduction of vitro H2N Rls (I V) R~~~C 02H (V) or its RII
reactive derivative / ~lo~~~tion at, carboxyl Ri2 or' R$NCO (VI) HN .Rls COR7 (V I i') RII Rii F31 1) introduction of hydroxyl, Rls acidic group or NR'R'°
R12 _ , R~12 N 2) protection of hydroxyl, ~N
HN ~~3 acidic group or amino HN~ f Is l R
CORD ~R7 (Y I I I_) ( I X) Rls RI'1 Rls Rm elimination of Ft' s RI~ ' ~ ~ . R 6-X ( X I' ) R12 . -~t- HN ~' ~ HN ~ s R
COR (x) COR (X I I ) R1i Rlt elimination of protecting pup ~ R~ 6 ~ RI~ , , N
HN Rs CORD ( I a ) Production Method 2 tt R R
R 1) hydroxyalkylation 12 W ~. ~ 2) reduction R ~- Rt2 N 3) protection of amino H ~.) halogenation ( I I I ) (X I I I.) Rt3 1) introduction of hydroxyl, 1) introductian of nitro acidic group or -NR9R'° R12 2) reduction of nitro -it 2) protecltion of hydroxyl, acidic group or amino (X I V.) gt3 Rtt R1s R14002H~ (V) or its R11 Rts reactive derivative Rt,2 (- i ~ ~ at carboxyl R12 or R$NCO (VI) H2~1 Rt3 H~ R13 (xw) coR~ (x:~r I ) Rrt Rts Rt1 Rts elimination of R' 3 - Rt2 / ~ _ R~X (X hRt2 I J
N N
HN H HN. Rs COR7 ( X Q I I ) COR7 (..X ~ T I ~ I ) eli.minat:ion of protecting group ire R' 6 n ~. Rs .
COR7 ( I h ) .
Production Met;nod 3 Ri6 Rji . R.~g Rit oxidation R ~-X ( X I ) R12 ~ -----i~ i2 ~ /
~, ~ R ~ ~ --~-N
H~N, (-lN . H
~~R7 (g) CORD
(X T X}
R16 R elimination of protecting R1~ Rj~
Rj2 , ~ group in R's Nv Riz N
HN R8 HN Rs C013~ CpR~
(x,x>
( I .c m Production Method ~4 ,~ 1 "
protection of amino R~ R~
IV
H
(X~:X I ) (XX. I I ) R'3 1) introduction of rox~l, halogenoalkylation carboxyl or N1~9R' 2) protection of Y~ydroxyl, carboxyl or amino '(X X I L..I.). . Ras ,~,~ ., ..,,~ ...
elimination 1 ) of R' ' Rj 2 ) :'R s-X ( X I ) (XXV) c.x x t v: ~ ~g R11 Ri~C02;H~ (Vr. or its 1) introduction of nitro reactive derivative 2 reduction of nitro at carboxyl R1, ~ I ~
or R$NCO (VI) H.2N F3j3.
(XXV I?
R,_~~ __ . _ _.
elimination of protecting group in R's i~z . - R~
N
,~
HCOR~ qis CORD R
(X:KV~:T~I) (I: d.) Prjoduction Method 5 Ri1 X R1~
1 introduction of cyano R s-X ( X I ) 2~ hydrolysis of cyano R w ~ _ R~ v ' ~ --i~
~ N H 3) protection of carboxyl N02 H NOz ~ Rs (XXV I l: I ) (XX I X) R2o ~j R2o Ro 1) reduction of nitro _ R~z ~N 2 ) R14C 02H (V) or its N
NO ~s reactive derivative HN Is R at carboxyl ( R
(XXX) or R$NCO (VI) COR' (XXXI) elimination of protecting ~ R
pup ~ RZo 'N
HN Rs COR' (I e) Production Method 6 H2 R11 R~ R11 R1 ~ I) hydroxylation \ ~ N 2 ) protection of \ N
x'Yl Ris (I V) (XXX I I) R21 11 Ri4C O2H (V) or its 1) introduction reactive derivative of~nitro ~ at carboxyl 2) reduction R1 ~ ~ or R$NCO (VI) of vitro N
R
(XXX I I I ) 1) elimination of R' ' R1 ~ ~ ( ~ -~ R12 N 2 ) R6-X EX I ) N
HN R1s H
CORD COR
(X:KX I V) (XXXV) elimination of protecting group in Rz' ._ R12 N
H ~ . Rs CORD .
_ (I f) a Production Method 7 H 11, R~ Ri1 R1 ~ alkylation or R1 protection of amino . \
N
(I Vy (XXXV I) R~4C O2~i (V) or its 1) introduction R~ ~ R11 reactive derivative of vitro at carboxyl 2) reduction R ~ _ ~ or R$NCO (VI) of vitro N
(XXXV I I) .
R~ R11 1 ) elimination R~ R
of R' ' R1 ~ -~ R1.
2 ) R6-X (X I ) N N
H1 R13 Hi Rs CCiR7 COR
(XXXV I I I) (XXXI X) R10- ~ 11 elimination of protecting pup ~ Ra2 R1 ~, N
HN E s R
( I 8) In each of the above formulas, R6, R'', R8, R9 and R'° are each as defined above; R" and R'2 are each independently hydrogen atom, lower alkyl or lower alkoxy; R'3 is amino protecting group; R'" is alkyl, alkoxyalkyl, a.lkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; R'S is alkyl or alkenyl substituted by halogen atom; R'6 is alkyl or alkenyl substituted by hydroxy, protected hydroxy, acidic group, protected acidic group, alkoxycarbonyl or -NR'8R'9 wherein R'$
and R'9 are each independently hydrogen atom, lower alkyl or amino protecting group; R" is alkyl or alkenyl substituted by hydroxy, acidic group, alkoxycarbonyl or -NR9R'°; RZ° is protected carboxy; R2' is protected tiydroxy; and Ra2 is -NR'$R'9 wherein R'$ and R'9 are as defined above.
Amino protecting group at R'3, R'$ and R'9 is, for example, formyl, acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl, methoxy-carbonyl, ethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, diphenylmethy:Loxycarbonyl, methoxymethyloxycarbonyl, 2,2,2-trichloro-ethoxycarbony:L, trimethylsilyl, 2-methylsulfonylethyloxycarbonyl, tert-butoxycarbony:L or trityl.
Hydroxy protecting group at R'6 and R2' is, for example, formyl, acetyl, monoclhloroacetyl, dichloroacetyl, trifluoroacetyl, methoxycarbon;yl, ethoxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloroetho;xycarbonyl, benzoyl, trityl, tetrahydropyranyl, trimethylsilyl or the like.
Acidic group protecting group at R'6 and R2° is, when carboxy protecting group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, tent-amyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, methylthiomethyl, trityl, 2,2,2-trichloroethyl, trimethylsilyl, diphenylmethoxybenzenesulfonylmethyl, dimethylamino-ethyl and the: like.
The above-mentioned protecting groups can be removed by a method known her se, and the method for removing them may be determined according to the kind of the protecting group. Exemplified are a decomposition by an acid (e. g., that by an acid such as hydrochloric acid, trifluor~oacetic 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, benzyloxycarbcrnyl and the like). The production methods of the objective compounds of the present invention and starting material compound are ctescribed in detail in the following.
Production Method 1 The compound (IV) can be produced by reducing compound (III) [J.
Eric Nordlande~r, et al., J. Org. Chem., X46, '7~8-782 (1981), Robin D.
Clark, et al." Heterocycle, 22, 195-221 (1980 , Vernon H. Brown, et al., J. Heterocycle. Chem., 6(~4), 539-5~3 (1969)] to introduce an indoline skelE~ton, protecting amino, introducing nitro on benzene ring by a method known her 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 tlhe inert solvent include acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofur.an, 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 encompas~;ed 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'-morpholinoeahyl 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 a.s considered to proceed via a reactive derivative of carboxylic acid. The compound (VIII) can be produced by halogenoalH;.ylation of compound (VII) [R. C. Fuson et al., Org.
React., 1, 63 (1969), G.A. Olah et al., "Friedel Crafts and Related Reactions" Vol. 2. 659 (1964)].
~'he compound (IX) can be produced by converting halogenoall~:yl of compound (VIII) to hydroxy, an acidic group such as carboxy or a group of the formula -NR9R10 by a substitueni: conversion reaction known per se, and if necessary, introducing a corresponding protecting group.
The compound (XII) can be 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.
21a In addition, a base such as triethylamine, pyridine, ~-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 R'6 of compound (XII) by a method known her 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)], reduc:ing, 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 vitro and reducing vitro 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 her se (e. g., oxidation using chloranil, palladium-carbon and the like).
The compound (Ic) can be produced from compound (XIX) via compound (XX) accordin;g to the method for obtaining compound (Ia) from compound (X) as descrilbed in Production Method 1.
Production Method ~
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 (XXI7=) 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) can be produced from compound (XXV) by introducing nitre and reducing nitre by a method known her se.
The compound (XXVII) can be produced from compound (XXVI) according to the method for obtaining compound (VII) from compound (IV) as described in 1?reduction Method 1.
The compound (Id) can be produced from compound (XXVII) according to the method for obtaining compound (Ia) from compound (XII) as described in l?reduction Method 1.
Production Method 5 The compound (XXIX) can 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) can be produced by converting halogen of compound (XXIX) to cyano by a method known her se, hydrolysis of cyano, and introducing a protecting group into the obtained carboxy.
The compound (XXXI) can be produced from compound (XXX) by reducing nitre 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 at R2° of compound (XXXI) by a method known her se.
Production Method 6 The compound (XXXII) can be produced by converting amino of compound (IV) to hydroxy by a method known per se and introducing a protecting gra~up into hydroxy.
The compound (XXXIII) can be produced from compound (XXXII) by introducing ni.tro and reducing nitro by a method known per se.
The compound (XXXIV) can be produced from compound (XXXIII) according to t:he method for obtaining compound (VII) from compound (IV) as described i.n 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 described in Production Method 1.
The compound (If) can be produced by eliminating the protecting group at R2~ of compound (XXXV) by a method known per se.
Production Method 7 The compound (~~CXVI) can be produced by alkylation of amino or by introducing a protecting group of amino of compound (IV) by a method known her se.
The compound (X)QCVII) can be produced from compound (X)CXVI) by introducing nitro and reducing nitro by a method known per se.
The compound (3~CXVIII) can be produced from compound (XXXVII) according to ithe method for obtaining compound (VII) from compound (IV) as described :in Production Method 1.
The compound (XXXIX) can be produced from compound (XXXVTII) 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 Ra2 of compound (XXXIX) by a method known per se.
The compound (I) of the present invention obtained by the above methods can b~e 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 her 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, hydroxypropylc;ellulose and crystalline cellulose), lubricants (e. g., magnesium stearate and talc), and disintegrators (e. g., carboxymethyl-cellulose talc;ium and talc), and the like.
The above:-mentioned ingredients are mixed 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 her se.
GJhile 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 i~o adult patients of hypercholesterolemia, it is generally 0.1 mg - 50 mg/kg body weight per dose which is administered about 1 to 3 times) a day.
The compound (I) of the present invention and pharmaceutically acceptable salts thereof exhibit superior ACAT inhibitory activity and lipoperoxidat.ion 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.
Example 1 N-(1-Octyl-5-hydroxymethyl-~,6-dimethylindolin-'7-yl)-2,2-dimethylpropanamide (1) N-(1-Acetyl-5-chloromethyl-4,6-dimethylindolin-~-yl)-2,2-dimethylpropanamide ('l.0 g) was dissolved in a mixed solvent (50 ml) of CHsCN/DMF=1/1. Potassium acetate (12.0 g) was added and the mixture was stirred a.t 60°C for 1 hr. CHsCN was evaporated under reduced pressure and AcOEt (200 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate, and AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHC1,/MeOH=1/0 - 10/1) to give ?.5 g of N-(1-acetyl-5-acetoxymethyl-4,6-dimethylihdolin-?-yl)-2,2-dimethylpropanamide.
'H-NMR (CDC1~) 1.2? (9H, s, --C(CH3),), 2.Ob (3H, s, OCOCH,), 2.23, 2.26, 2.30 (9H, s x 3, -CH, x 2, >NCOCH~), 3.00 (2H, br, Indoline C3-H), 4.05 (2H, br, Indoline Ci-E1), 5.20 (2H, s, -CHiO-), 9.10 (1H, br, >NH).
(2) N-(1-Acetyl-5-acetoxymethyl-4,6-dimethylindolin-?-yl)-2,2-dimethyl-propanamide (?.5 g) was dissolved in EtOH (?0 ml) and a solution of NaOH
' (8.3 g) in water (20 ml) was added, which was followed by refluxing for 10 hr. EtOH was evaporated under reduced pressure and CHC13 (200 ml) .
was added. After washing with water, the mixture was dried over anhydrous sodium sulfate and CHC1, was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHC1~/MeOH=1/0 - 10/1) to give 3.0 g of N-(5-hydroxymethyl-4,6-dimethylindolin-?-yl)-2,2-dimethylpropanamide.
'H-NMR (CDC1,) ~
1.35 (9H, s, -C(CH~),), 2.23, 2.26 (6H, s x 2, -CH, x 2), 2.99 (2H, t, J=8.5Hz, Indoline C~-H), 3.58 (2H, t, J=8.5Hz, Indoline C~-H), 4.65 (2H, s, -CH_xOH), ?.10 (2H, br, ON,~>NH).
(3) N-(5-Hydroxymethyl-4,6-dimethylindolin-?-yl)-2,2-dimethylpropanamide (1.5 g) was dissolved in DMF (15 ml) and 1-iodooctane (2.6 g) and KzCO~
(1.5 g) were added, which was followed by stirring under a nitrogen atmosphere at 50°C for 2 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by 3o silica gel column chromatography (eluent: CHC13/MeOH=1/0 - 10/1) to give 1.0 g of the title compound.
IR (Nujol) cm'': 1652, 1600, 1508.
'H-NMR (CDC13) *Trade-mark 0.70---1.10 (3H, br, -(CHZ ) TCHs ) , 1.10---1.70 (12H, m, -CHZ (CHZ ) sCHs ) , 1.37 (9H, s, -C(CHs)s), 2.1~, 2.22 (6H, s x 2, -CHs x 2), 2.87 (2H, t, J=8.5Hz, Indoline C3-H), 3.14 (2H, t, J=7.5Hz, >NCHZ-), 3.~2 (2H, t, J=8.5Hz, Indoline CZ-H), x.62 (2H, s, -CHZOH), 6.86 (2H, br, OH, >NH).
FxamnlP 2 N-(1-Octyl-F.-dimethylaminomethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (1) N-(1-Acetyl-5-chloromethyl-~,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (~'_.0 g) was dissolved in CHCls (~0 ml) and (CHs)zNH~ HC1 (3.5 g) and K;:COs (11.8 g) were added, which was followed by stir.~ring at room temperature for ~ hr. CHCls (300 ml) was added, and the mixture was washed successively with 2N-hydrochloric acid, 2N aqueous NaOH and saturated brine, and dried over anhydrous sodium sulfate. CHCls was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHC13/MeOH=10/1 - 1/1) to give 700 mg of N-(1-acety:L-5-dimethylaminomethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylpropa~aamide.
'H-NMR (CDCls) 1.26 (9H, s, -C(CHs)s), 2.12, 2.15 (6H, s x 2, -CHs x 2), 2.2~. (6H, s, -N(CHs)2), 2.31 (3H, s, >NCOCHs), 3.00 (2H, br, Indoline Cs-H), 3.35 (2H, s, >NCHZ-), x.15 (2H, br, Indoline Cz-H), 9.23 (1H, br, >NH).
(2) N-(1-Acetyl-5-dimethylaminomethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (1.0 g) was dissolved in MeOH (10 ml) and a solution of NaOH (580 mg) in water (3 ml) was added, which was followed by stirring at 60°C for 2 hr. MeOH was evaporated under reduced pressure and CHCls (100 ml) was added. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. CHCls was evaporated under reducedl pressure to give 700 mg of N-(5-dimethylaminomethyl-~,6-dimethylindo7.in-7-yl)-2,2-dimethylpropanamide.
' H-NMR (CDCI.s ) 8 1.30 (9H, s, -C(CHs)s), 2.19 (12H, s, -CHs x 2, -N(CHs)z), 3.00 (2H, t, J=8.5Hz, Indoline C3-H), 3.28 (2H, s, >NCH2-), 3.55 (2H, t, J=8.5Hz, Indoline C2-H), 4.40 (1H, br, >NH), 7.20 (1H, b;r, >NH) .
(3) N-(5-Di~methylaminomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (700 mg) was dissolved in DMF (7 ml) and NaH (P=60~. 160 mg) was added under a nitrogen atmosphere at 5°C. After stirring at the same temperature for 30 min, 1-iodooctane (240 mg) was added, which was followed by stirring at 30°C for 3 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate.
AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:
CHC13/MeOH=10/1 - 3/1) to give 500 mg of the title compound.
IR (Nujol) cm-1: 1654, 1600.
1H-NMR (CDC13) b .
0.701.10 (3H, br, - (CH2) 7CH3) , 1.101.70 (12H, m, -CH2(CH2)6C'H3), 1.33 (9H, s, -C(CH3)3), 2.00, 2.09 (6H, sx2, -CH3x2), 2.23 (6H, s, -N(CH3)2), 2.85 (2H, t, J=8.5Hz, Indoline C3-H), 3.18 (2H, br-t, >NCH2-), 3.31 (2H, s, -CIi2N<), 3.38 (2H, t., J=8.5Hz, Indoline C2-H), 6.84 (1H, br, >NH).
Example 3 r(-(1-Octyl-5-ethoxycarbonylmethyl-4,6-dimethylindLolin-7-yl)-2,2-dimethylpropanamide (1) 1-Acety~1-5-bromo-4,6-dimethyl-7-nitroindoline (30 g) was dissolved in a mixture (600 ml) of CHC13/MeOH=1/1 and 5~ Pd-C
(5.0 g) was added, which was followed by catalytic hydrogenation at 35°C, The precipitate was collected by filtration together with Pd-C, and dissolved in CHC13 (300 27:L03-179 ml). The mixture was washed with saturated aqueous solution of sodium h;ydrogencarbonate. The solvent was evaporated under reduced pressure from the filtrate and CHC13 (300 ml) was added. The mixture was washed with saturated aqueous solution of sodium h,ydrogencarbonate and combined with the layer of above-mentioned CHC13. The combined CHC13 layer was washed with saturated brine and dried over anhydrous sodium sulfate.
CHC13 was evaporated under reduced pressure and the 28a 271.03-179 residue was dissolved in CHC13 (150 ml). Thereto were successively added at 10°C,pivaloyl chloride (11.7 g) and EtsN (10.8 g). The mixture was stirred at room temperature for 1 hr and CHC13 (200 ml) was added. The mixture was washed successively with 5~ aqueous citric acid and water, and dried over anhydrous sodium sulfate. CHCls was evaporated under reduced pressure and the obtained crude residue was washed with cool Et20 (100 ml) to give 21 g of N-(1-acetyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
IR (Nujol)cm -' : 1676, 1639, 1581.
' H-NMR (CDCls ) cS
1.2~+ (9H, s, -C(CH3)s), 2.17 (6H, s, -CHs x 2), 2.30 (3H, s, >NCOCH3), 2.99 (2H, t, J=8.5Hz, Indoline Cs-H), 4.10 (2H, t, J=8.5Hz, Indoline CZ-H), 6.87 (1H, s, Indoline Cs-H), 9.10 (1H, br, >NH).
(2) N-(1-Acetyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (20.0 g) was dissolved in conc. hydrochloric acid (100 ml), and 35~ formalin (8.5 g) and zinc chloride (1.8 g) were added. The mixture was stirred at 40-50°C for 2 hr while blowing hydrogen chloride therein. The reaction mixture was poured into ice water and extracted with CHC13 (400 ml). The CHCls layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. CHC13 was evaporated under reduced pressure to give 21 g of N-(1-acetyl-5-chloromethyl-4,6-dimethylindolin-7-yl)-2,2-dia~ethylpropanamide.
IR (Nujol)cm '' : 1679, 1645, 1587.
' H-NMR (CDCl.s ) 1.27 (9H, s, -C(CHs)s), 2.25 (3H, s, -CHs), 2.30 (6H, s, -CH3, >NCOCHs), 3.00 (2H, br~, Indoline C3-H), 4.05 (2H, br, Indoline Cz-H), x.68 (2H, s, -CH2C1), 9.16 (1H, br, >NH).
(3) N-(1-Acet:yl-5-chlor~omethyl-~+,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (21 g) was suspended in CH3CN (150 ml), and NaCN (8.1 g) and 18-crown-6 (870 mg) were added, which was followed by refluxing for 15 hr. CH3CN waus evaporated under reduced pressure and CHCls (300 ml) was added. The mixture was washed with water and dried over anhydrous sodium sulfate. CHCls was evaporated under reduced pressure. The obtained residue was washed with boiling MeOH to give 15.5 g of N-(1-acetyl-5-cyanomethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
IR (Nujol)cm '-' : 2232, 1678, 1639.
' H-NMR (CDC1~3 ) 1.27 (9H, s, -C(CHs)s), 2.26, 2.30, 2.~0 (9H, s x 3, -CHs x 2, >NCOCH3), 3.00 (2H, br, Indoline Cs-H), 3.66 (2H, s, -CHZCN), x.05 (2H, br, Indoline Cz-H), 9.21 (1H, br, >NH).
.) N-(1-Acet;yl-5-cyanomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (5.0 g) was suspended in n-PrOH (25 ml) and a solution of NaOH (9.6 g) in water (10 ml) was added, which was followed by stirring at 90°C for 8 hr in an autoclave under a nitrogen atmosphere. 'The aqueous layer was separated, and the organic layer wa.s neutralized with 2N-hydrochloric acid. The solvent was evaporated under reduced pressure. The residue was suspended in EtOH
(200 ml), and 10N HC1-EtOH (7.2 ml) was added, which was followed by refluxing for 1 hr. EtOH was evaporated under reduced pressure, and the mixture was neutralized with saturated aqueous solution of sodium hydrogencarbonate and extracted with AcOEt (200 ml). The AcOEt layer was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: CHCls/MeOH=1/0 - 20/1) to give 3.0 g of N-(5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
IR (Nujol)cm~ -' : 1732, 165.
' H-NMR (CDC1.3 ) 8 1.3~ (9H, s, -C(CHs)s), 2.14, 2.18 (6H, s x 2, -CHs x 2), 2.99 (2H, t, J=8.5Hz, Indoline C3-H), 3.56 (2H, t, J=8.5Hz, Indoline C2-H), 3.60 (2H, s, -CHzC02-), 4.11 (2H, q, J=7.8Hz, -CHZCHs), x.20 (1H, br~, >NH), 7.00 (1H, br, >NH).
(5) N-(5-Ethoxycarbonylmethyl-~4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (3.5 g) was dissolved in DMF' (15 ml), and 1-iodooctane (5.0 g) and KZCOs (2.9 g) were added, which was followed by stirring under a nitrogen atmosphere at 50°C for 2 hr. AcOEt (200 ml) was added, and the mixture wa.s washed with water and dried over anhydrous sodium sulfate. AcOE;t was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCls/MeOH=1/0 -50/1) to give 3.5 g of the title compound.
IR (Neat) cm -' : 1732, 1654, 1600.
' H-NMR (CDCl3; ) 8 0.70~1.10 (~iH, br, -(CHz)7CHs), 1.10 ~1.70 (15H, m, -CH2CH3, -CH2(CHz)sCH~), 1.33 (9H, s, -C(CHs)s), 2.0~., 2.13 (6H, s x 2, -CHs x~'_), 2.87 (2H, t, J=8.5Hz, Indoline C3-H), 3.12 (2H, t, J=7.5Hz, >NCHz-), 3.39 (2H, t, J=8.5Hz, Indoline Cz-H), 3.58 (2H, s, -CHzCOz-), x.12 (2H, q, J=7.5Hz, -CHzCHs), 6.79 (1H, br, >NH).
Example ~
N-(1-Octyl-5-carboxymethyl-~+,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide N-(1-Oct;,rl-5-ethoxycarbonylmethyl-~+,6-dirnethylindolin-7-yl)-2,2-dimethylpropaulamide (3.5 g) was dissolved in EtOH (50 ml) and a solution of NaOH (1.6 ») 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 -' :1732, 1651, 1600.
'H-NMR (CDCls) 0.70~1.10 (3H, br, -(CH2)~CH3), 1.10~1.70 (12H, m, -CHz(CHz)6CH.3), 1.33 (9H, s, -C(CHs)s), 2.01, 2.15 (6H, s x 2, -CHs x 2), 2.703.20 (~H, m, Indoline Cs-H, >NCHz-), 3.~1~1 (2H, t, J=8.5Hz, Indoline Cz-H), 3.56 (2H, s, -CH2COzH), 7.60 (1H, br, >NH), 7.90 (1H, br, -COzH).
Example 5 N-(1-Octyl-~i-carboxymethyl-~.,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide ~hydrochloride N-(1-Oct3i1-5-ethoxycarbonylmethyl-~,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 wii~h 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. Ac01?t was evaporated under reduced pressure to give 2.0 g of the title compound.
IR (Nujol)cm -' : 1722, 1654.
'H-NMR (CDCls) 0.70~-1.10 (3H, br, -(CH2)7CH3), 1.10~-1.70 (12H, m, -CHz(CHz)sCH3), 1. 39 (9H, s, -C (CHs ) s ) , 2. 06, 2. 26 (6H, s x 2, -CH3 x 2) , 2. 90---3.
(~H, m, Indoline C3-H, >NCH2-), 3.50---3.90 (2H, br-t, Indoline CZ-H), 3.72 (2H, s, -CHzCO2H), 6.00-~-7.00 (1H, br, HC1), 9.05 (2H, br, >NH, -C02H).
FxamnlP 6 N-(1-Octyl-5-carboxymethyl-~t,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide~ sulfate N-(1-Octyl-5-ethoxycarbonylmethyl-~,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 -' : 1718, 165, 1637.
' H-NMR (CDCl:~ ) c~
0.70~1.10 (3H, br, -(CHZ)~CHs), 1.10~1.70 (12H, m, -CHz(CHZ)sCHs), i.33 (9H, s, -C(CHs)s), 2.02, 2.16 (6H, s x 2, -CHs x 2), 2.80~3.30 (~H, m, Indo=Line C3-H, >NCHz-), 3.30-~-3.70 (2H, br-t, Indoline Cz-H), 3.59 (2H, s, -CHzCOzH), 6.00~7.00 (2H, br, HzSOa), x.20 (1H, br, -COzH), 8.30 (1H, br, >NH).
Example 7 N-(1-Octyl-!~-carboxymethyl-~,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide ~ nitrate N-(1-Oct;,rl-5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (3.0 g) was dissolved in EtOH (~2 ml) and a solution of NaOH (1.~4~~) 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 (Nu jol) cm -' : 172~t, 165 'H-NMR (CDC13) 8 0.70-~-1.10 (3H, br, -(CHz)~CH3), 1.10-~-1.70 (12H, m, -CHz(CHz)sCH3), 1.33 (9H, s, -C(CHs)s), 2.02, 2.21 (6H, s x 2, -CH3 x 2), 2.80~3.30 (~H, m, Indoline Cs-H, >NCHz-), 3.50-~-3.80 (2H, br-t, Indoline Cz-H), 3.6~t (2H, s, -CHZCOzH), 6.00---7.00 (1H, br, HNOs), 9.03 (2H, br, >NH, -COzH).
Fzramnl P 8 N-(1-Octyl-~5-carboxymethyl-~,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide~ sodium salt N-(1-Octyl-5-ethoxycarbonylmethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylprop2mamide (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 Ei0°C for 1 hr. EtOH was evaporated under reduced pressure. The: residue was dissolved in water (20 ml) and the mixture was adsorbed cmto DIA IONS HP-21 (70 ml). After washing with water, the mixture was eluted with 50~ aqueous methanol. The objective fraction was concentrated under reduced pressure. The residue was freeze-dried t:o give 1.0 g of the title compound.
IR (Nujol)cm -' : 1630, 1605.
' H-NMR (CDCl:~ ) 0.70---1 .10 (;3H, br, -(CHZ ) NCH, ) , 1 .10-~-1 .70 ( 12H, m, -CHZ (CHz ) 6CH3 ) , 1.38 (9H, s, -C(CH3)3), 1.93, 2.08 (6H, s x 2, -CH3 x 2), 2.70-~-3.20 to (~H~ m, Indoline C3-H, >NCHZ-), 3.30-~-3.40 (2H, br-t, Indoline C2-H), 3.15 (2H, s, -CHZCOzNa), 8.51 (1H, br, >NH).
Example 9 N-[(1-Octyl-3-(2-hydroxyethyl)-~t,6-dimethylindolin-7-yl)]-2,2-dimethylpropa~lamide (1) 4,6-Dimetlhylindole (130 g) was dissolved in Et20 (130 ml), and oxalyl chloride (23.0 g) was dropwise added at 0°C. The mixture was stirred at room temperature for 5 hr, and EtzO was evaporated under reduced pressure. EtOH (200 ml) was added to the residue and the mixture was stirred at room temperature for 15 hr. EtOH was evaporated 2 o under reduced pressure. The residue was dissolved in CHC13 (200 ml).
After washing' with water, the mixture was dried over anhydrous sodium sulfate. CHC13 was evaporated under reduced pressure. The obtained residue was added to a suspension of LiAlHn (17.0 g) in Et20 (200 ml), which was followed by refluxing for 2 hr. The reaction mixture was poured into i.ce water and extracted with AcOEt (200 ml). The AcOEt layer was wa~~hed with water and dried over anhydrous sodium sulfate.
AcOEt was evaporated under reduced pressure. The residue was purified by silica ge7L column chromatography (eluent: CHCls/MeOH=50/1 - 10/1) to give 13.0 g of 3-(2-hydroxyethyl)-4,6-dimethylindole.
3o IR (Nujol)crn -' : 1456, 1377.
' H-NMR (CDC:L3 ) 2.39, 2.63 (6H, s x 2, -CH3 x 2), 3.13 (2H, t, J=7.OHz, -CHZCHZOH), 3.86 (2H, t, J=7.OHz, -CHZCHZOH), 6.69 (1H, s, Indole Cs-H), 6.91 (2H, m, 7Cndole Cz-H, C7-H), 6.92 (1H, br, -OH), 7.90 (1H, br, >NFi).
(2) 3-(2-Hydro~ryethyl)-4,6-dimethylindole (13.0 g) was dissolved in AcOH (100 ml) rind NaBHaCN (8.7 g) was added by portions under ice-cooling.
After stirring at the same temperature for 1 hr, the reaction mixture was poured into ice water and neutralized with aqueous NaOH. The mixture was extracted with CHC13 (200 ml). The CHCls layer was washed with water and dried over anhydrous sodium sulfate. CHC13 was evaporated under reduced pressure. The residue was dissolved in benzene (100 ml), and AczO (15 g) and Et,N (8.3 g) were added, which was 1o followed by stirring at room temperature for 1 hr. AcOEt (200 ml) was added and the mixture was washed successively with saturated aqueous solution of sodium hydrogencarbonate, 5~ aqueous citric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCla/MeOH=50/1 - 10/1) to give 13.0 g of 1-acetyl-3-(2-acetoxyethyl)-~,6-dimethylindoline.
IR (Nujol)cm -' : 1652, 160.
' H-NMR (CDC13~ ) 8 1.60-~-2.20 (~'_H, m, -CH_ZCHzO-), 2.04 (3H, s, -OCOCH3), 2.24 (3H, s, 2 0 >NCOCH, ) , 2. a'_~I, 2. 30 (6H, s x 2, -CH3 x 2) , 3. 3~I ( 1 H, m, Indoline C3-H) , 3.9~ (2H, m, Indoline Cz-H), 4.12 (2H, t, J=7.lHz, -CHZCHzO-), 6.67 (1H, s, Indoline Cs-H), 7.90 (1H, s, Indoline C~-H).
(3) 1-Acetyl ;3-(2-acetoxyethyl)-X4,6-dimethylindoline (2.0 g) was dissolved in AcOH (40 ml) and Brz (1.9 g) was added, which was followed by stirring a't room temperature for 30 min. The reaction mixture was poured into ice water and precipitate was collected by filtration. The precipitate w,as dissolved in CHC13, and the mixture was washed with water and dried over anhydrous sodium sulfate. CHC13 was evaporated under reduced pressure. The residue was purified by silica gel column 3o chromatography (eluent: CHCla/MeOH=50/1 - 10/1) to give 2.7 g of crude crystals of 1-acetyl-3-(2-acetoxyethyl)-5-bromo-~,6-dimethylindoline.
The crude crystals were added by portions to a mixture of nitric acid (0.47 ml), AcOH (10 ml) and conc. hydrochloric acid (10 ml) under ice-cooling, and the mixture was stirred at the same temperature for ~ hr.
The reaction mixture was poured into ice water and precipitate was collected by filtration. The precipitate was dissolved in CHCls.
After washing with water, the mixture was dried over anhydrous sodium sulfate and CHC13 was evaporated under xeduced pressure. The residue was purified by silica gel column chromatography (eluent:
CHCls/MeOH=50,11 - 10/1) to give 1.~ g of 1-acetyl-3-(2-acetoxyethyl)-5-bromo-4,6-dimethyl-7-nitroindoline.
'H-NMR (DMSO-d6) 8 1.60~2.20 (2H, m, -CH_2CH20-), 1.99 (3H, s, -OCOCHs), 2.21 (3H, s, >NCOCH3), 2.38 (6H, s, -CHs x 2), 3.40 (1H, m, Indoline Cs-H), x.11 (2H, t, J=7.OHz, -CHZCH20-), ~.1~ (2H, d, J=8.5Hz, Indoline CZ-H).
1-Acetyl-3-(2-acetoxyethyl)-5-bromo-~,6-dimethyl-7-nitroindoline (1.~+ g) was dissolved in benzene (20 ml) and 5~ Pd-C (500 mg) was added, which was followed by catalytic hydrogenation at room temperature under atmospheric pressure. Pd-C was filtered off and benzene was evaporated under reduced pressure. The residue was dissolved in CHC13 (50 ml) and the mixture was washed successively with saturated aqueous solution of sodium hydro~;encarbonate and saturated brine, and dried over anhydrous sodium sulfate. Pivaloyl chloride (~+~40 mg) and EtsN (~~8 mg) were added to the obtained solution and the mixture was stirred at room temperature for 30 min. The mixture was washed successively with 5~
aqueous citr~:c acid and saturated brine, and dried over anhydrous sodium sulfate. CHC13 was evaporated under reduced pressure. The residue was purified by :silica gel column chromatography (eluent: CHC13/MeOH=50/1 -10/1) to givE~ 1.0 g of N-[1-acetyl-3-(2-acetoxyethyl)-~,6-dimethylindo:Lin-7-yl]-2,2-dimethylpropanamide.
IR (Nujol)cm -' : 1730, 169.
' H-NMR ( CDC.1 s ) 8 1.27 (9H, s, -C(CHs)s), 1.60~ 2.20 (2H, m, -CHzCH20-), 2.06 (3H, s, -OCOCH3), 2.17, 2.22 (6H, s, -CHs x 2), 2.30 (3H, s, >NCOCH3), 3.10 (1H, m, Indoline Cs-H), 4.03 (2H, d, J=8.5Hz, Indoline CZ-H), x.14 (1H, t, J=7.OHz, -CHzCH20-), 6.88 (1H, s, Indoline Cs-H), 9.00 (1H, br, >NH) (5) N-[1-Acetyl-3-(2-acetoxyethyl)-~,6-dimethylindolin-7-yl]-2,2-dimethylpropan.amide (~.0 g) was dissolved in EtOH (~t0 ml) and a solution ~of NaOH (2.2 g;) in water (10 ml) was added, which was followed by stirring at 6C1°C for 10 hr. EtOH was evaporated under reduced pressure, and CHCIs (100 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate, and CHCls was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCls/MeOH=50/1 - 10/1) to give 1.6 g of N-[3-(2-hydroxyethyl)-~,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide.
' H-NMR (CDC1;3 ) 8 1.3~ (9H, s, -C(CHs)s), 1.60-~-2.20 (2H, m, -CHzCHzOH), 2.17, 2.19 (6H, s x 2, -I~H3 x 2) , 3. 20~3. 80 (7H, m, Indoline CZ-H, C3-H, >NH, -CHzCH20H), X6.45 (1H, s, Indoline Cs-H), 7.20 (1H, br, --CONH-).
(6) N-[3-(2-HYd~xyethyl)-~,6-dimethylindolin-7-yl]-2,2-dimethyl-propanamide (1.6 g) was dissolved in DMF (15 ml) and 1-iodooctane (3.9 g) and KZCOs (2.3 g) were added, which was followed by stirring at 70°C
for 10 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt=5/1 - 1/2) to give 300 mg of the title compound.
IR (Nujol)cm -' : 165, 1600.
' H-NMR ( CDC7. s ) 0.70~1.00 1;3H, brt, -(CHZ)sCHs), 1.33 (9H, s, -C(CHs)s), 1.00~ 2.00 (14H, m, -(CHZ)sCHs, -CHZCHZOH), 2.07, 2.16 (6H, s x 2, -CH3 x 2), 2.60-~-3.60 (8H, m, Indoline C2-H, Cs-H, >NCHZ-, -CHZOH), 6.4~ (1H, s, Indoline Cs-H), 6.78 (1H, br, -CONH-).
Example 10 N-[(1-Octy.l-3-(2-methoxycarbonylethyl)-~,6-dimethylindolin-7-yl)]-2,2-dimethylpropatiamide (1) 1-Acetyl-3-(2-acetoxyethyl)-~,6-dimethylindoline (2.0 g) was dissolved in a. mixture of CHCls/MeOH=1/1 (25 ml), and a solution of NaOH (1.5 g) i,n water (5 ml) was added, which was followed by stirring at room temperature for 1 hr. The solvent was evaporated under reduced pressure. CHCls (100 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. CHC13 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHC13/MeOH=50/1 - 10/1) to give 1.2 g of 1-acetyl-3-(2-h3rdroxyethyl)-~,6-dimethylindoline.
' H-NMR (CDC1:, ) 1.60~-2.00 (3H, m, -CH_zCHzO_H) , 2.26, 2.30, 2.39 (9H, s x 3, -CHs x 2, >NCOCHs), 3.50 (1H, m, Indoline Cs-H), 3.77 (2H, t, J=7.OHz, -CH2CHZOH), 3.97 (2H, m, Indoline C2-H), 6.67 (1H, s, Indoline Cs-H), 7.89 (1H, s, Indoline C7-H).
(2) 1-Acetyl-:3-(2-hydroxyethyl)-~,6-dimethylindoline (7.0 g) and CBrn (g.g g) were dissolved in CHsCN (70 ml), and PhsP (9.~ g) was added, which was followed by stirring at room temperature for 30 min. CHsCN
was evaporated under reduced pressure. AcOEt (100 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. Ac0'Et was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt=
50/1 - 10/1) to give 5.~ g of 1-acetyl-3-(2-bromoethyl)-~,6-dimethyl-indoline.
IR (Nujol)cm -' : 1650, 160.
'H-NMR (CDCls) 8 1.80~2. 20 (2H, m, -CH_aCH2Br) , 2. 23, 2. 26, 2.30 (9H, s x 3, -CHs x 2, >NCOCHs), 3.42 (2H, t, J=7.OHz, -CHZCH2Br), 3.20~3.60 (1H, m, Indoline Cs-H), x.00 (2H, m, Indoline Cz-H), 6.68 (1H, s, Indoline Cs-H), 7.89 (1H, s, Indoline C7-H).
(3) 1-Acetyl--3-(2-bromoethyl)-~,6-dimethylindoline (5.4 g), NaCN (3.7 g) and 18-crown--6 (480 mg) were suspended in CHsCN (50 ml), and the suspension was refluxed for 15 hr. CH3CN was evaporated under reduced pressure. CHCls (100 ml) was added, and the mixture was washed with water and dr_'i.ed over anhydrous sodium sulfate. CHCls was evaporated under reduced pressure. The residue was purified by silica gel column chromatography' (eluent: CHCls/MeOH=50/1 - 10/1) to give 4.5 g of 1-acetyl-3-(2-cy'~oethyl)-4,6-dimethylindoline.
IR (Nujol)cm -' : 2364, 16.7.
'H-NMR (CDC13) ~ : .
1 .'l0~--2. 20 (2H, m, -CH_2CHzCN) , 2. 26, 2. 31 (9H, s x 3, -CH3 x 2, >NCOCHs), 2.x'.0-~-2.40 (2H, m, -CHzCH2CN), 3.~~+ (1H, m, Indoline C3-H), 3.70-~-x.20 (2H, m, Indoline CZ-H), 6.69 (1H, s, Indoline Cs-H), 7.90 (1H, s, Indoline Cz-H).
1-Acetyl-:;-(2-cyanoethyl)-~+,6-dimethylindoline (4.5 g) was dissolved in EtOH (150 cnl), and a solution of KOH (10.~ g) in water (50 ml) was added, which was followed by refluxing for 15 hr. EtOH was evaporated under reduced pressure, and the aqueous layer was adjusted to weak acidic with 61~t hydrochloric acid and extracted with CHCls (100 ml).
The CHCls layer was washed with water and dried over anhydrous sodium sulfate. CHC:ls was evaporated under reduced pressure. The residue was dissolved in CHC13 (20 ml) and Ac20 (1.9 g) was added, which was followed by stirring at room temperature for 1 hr. CHC13 (100 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. CHCls was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:
CHC13/MeOH=50/1 - 10/1) to give 3.~ g of 1-acetyl-3-(2-carboxyethyl)-~,6-dimethylindoline.
'H-NMR (CDCls) 1 . 60-~-2. 20 (2H, m, -CH_ZCHZCOzH) , 2. 26, 2. 29 (9H, s x 3, -CH3 x 2, >NCOCHs), 2.20-~-2.40 (2H, m, -CHzCH2CO2H), 3.37 (1H, m, Indoline Cs-H), 3.80~~-x.10 (2H, m, Indoline Cz-H), 6.68 (1H, s, Indoline Cs-H), 7.50 (1H, br~, -COZH), 7.88 (1H, s, Indoline C7-H).
(5) 1-Acetyl--3-(2-carboxyethyl)-4,6-dimethylindoline (3.~ g) was dissolved in EtOH (50 ml) and lON HC1-EtOH (3.9 ml) was added, which was followed by refluxing for 30 min. EtOH was evaporated under reduced pressure and AcOEt (100 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatograph3r (eluent: CHCls/MeOH=50/1 - 10/1) to give 3.3 g of 1-acetyl-3-(2-el;hoxycarbonylethyl)-~,6-dimethylindoline.
' H-NMR (CDCl:~ ) 8 1.2~ (3H, t, J= 7.lHz, -CH2CHs), 1.60~ 2.20 (2H, m, -CHzCH2C02-), 2.22, 2.27, 2.30 (9H, s x 3, -CH3 x 2, >NCOCH3), 2.00-~-2.20 (2H, m, -CH2C_Fi2CO2-), 3.10~-3.30 (1H, m, Indoline Cs-H), 3.90 (2H, m, Indoline CZ-H), x.10 (2H, q, J= 7.lHz, -CHZCH3), 6.76 (1H, s, Indoline Cs-H), 7.90 (1H, s, Indoline C7-H).
(6) 1-Acetyl ;3-(2-ethoxyca.rbonylethyl)-~,6-dimethylindoline (3.3 g) was dissolved in ~4cOH (30 ml) and Br2 (0.93 ml) was added, which was followed by stirring for 30 min. The reaction mixture was poured into ice water and precipitated crude crystals were collected by filtration.
The obtained crystals were dissolved in CHCls (100 ml). After washing with water, the mixture was dried over anhydrous sodium sulfate. CHC13 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHC13/MeOH=50/1 - 10/1) to give 3.0 g of 1-acetyl-5-bromo-3-(2-ethoxycarbonylethyl)-~,6-dimethylindoline.
IR (Nujol)cm -' : 1729, 1641.
'H-NMR (CDCls) 1.24 (3H, t, J= 7.lHz, -CH2CH3), 1.60~2.20 (2H, m, -CHZCH2COz-), 2.00-~-2.20 (2H, m, -CHxCHzC02-), 2.21 (3H, s, >NCOCHs), 2.36, 2.39 (6H, s x 2, -CHs x 2), 3.10~3.60 (1H, m, Indoline Cs-H), 3.90 (2H, m, Indoline C2-~H), x.10 (2H, q, J= 7.lHz, -CHZCHs), 8.08 (1H, s, Indoline C7-H).
(7) To a mixture of AcOH (10 ml), conc, sulfuric acid (10 ml) and nitric acid (0.55 ml.) was added by portions 1-acetyl-5-bromo-3-(2-ethoxy-carbonylethy7_)-~,6-dimethylindoline (3.0 g) at 0°C, and the mixture was stirred at tree same temperature for 5 hr. The reaction mixture was poured into ice water and extracted with CHC13 (100 ml). After washing with water, t;he mixture was dried over anhydrous sodium sulfate. CHCls was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCls/MeOH=50/1 - 10/1) to give 2.7 g of 1-acetyl-5-bromo-3-(2-ethoxycarbonylethyl)-X4,6-dimethyl-7-nitroindoline.
'H-NMR (CDCls) 8 1.26 (3H, t, J= 7.lHz, -CHZCHs), 1.60-~<2.20 (2H, m, -CHzCH2C02-), 2. 00-~-2. 20 (2'.H, m, -CHZCH_ZCOz-) , 2. 23 (3H, s, >NCOCHs ) , 2. ~~4, 2.
(6H, s x 2, -CHa x 2), 3.10-y3.60 (1H, m, Indoline C3-H), x.00 (2H, m, Indoline CZ-H), x+.10 (2H, q, J= 7.lHz, -CHZCHs).
Acidic group at R1, Rz and R5 is exemplified by carboxyl, sulfonic acid group, phosphoric acid group and the like.
Examples of alkoxycarbonyl at R1, R1°, Rz, Rzb, Rz°~ Rs and Rs° include those having 1 to 4 carbon atoms in the alkoxy moiety, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-5a butoxycarbony7l and the like.
Alkyl to be substituted at R', Rz, Rza, Rzb and RS 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 iro be substituted at R', Rz and RS may be linear or branched and ~~referably has 2 to 8 carbon atoms. Examples thereof include vinyl, propenyl, isopropenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, 3,3-dimethyl-2-propenyl and the like. Examples of substituted a:Lkenyl include carboxyvinyl, carboxypropenyl, hydroxypropen;yl and the like.
Z is pre:f'erably In the compounds of the present invention, 1Q when one of R', Rz and R5 is alkyl or alkenyl substituted by hydroxy, acidic group, alkoxycarbonyl or a group of the formula -NR9R'° wherein R9 and R'° 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) When the compound of the present invention is indoline or indole derivative, preferable compound is that of the above-mentioned formula (I) wherein one of R', Rz and RS is alkyl substituted by hydroxy, carb~oxy, alkoxycarbonyl or a group of the formula -NR9R'° wherein R9 and R'° are each independently lower alkyl, and the other two are: independently hydrogen atom, lower alkyl or lower alkoxy;
either R3 or R4 is a group of the formula -NHCOR' wherein R~ is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula -NHR8 wherein R8 is alkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy; and R6 is as defined above,.
A more preferable compound is that of the above-mentioned formula (I) wherein R' and R3 are each independently hydrogen atom, lower alkyl or lower alko~~y; either R2 or R5 is alkyl substituted by hydroxy, carboxy, alko3~ycarbonyl or a group of the formula -NR9R'° wherein R9 and R'° are each :independently lower alkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy; R° is a group of the formula -NHCOR' wherein R' is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalk;,rl, aryl, arylalkyl or a group of the formula -NHR8 wherein R$ is alkyl; and R6 is as defined above.
A still snore preferable compound is that of the above-mentioned formula (I) wherein R' and R3 are each independently hydrogen atom, lower alkyl oar lower alkoxy; either R2 or R5 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9R'°
wherein R9 and R'° are each independently lower alkyl, and the other is hydrogen atom; Ra is a group of the formula -NHCOR' wherein R' is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or .a group of the formula -NHR8 wherein R$ is alkyl; and R6 is as defined above.
A still more preferable compound is that of the above-mentioned formula (I) wherein R' and R3 are each independently hydrogen atom or lower alkyl; either R2 or R5 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9R'° wherein R9 and R'° are each independently lower alkyl, and the other is hydrogen atom; R4 is a group of the formula -NHCOR' wherein R' is alkyl, cycloalkyl or cyclo-alkylalkyl; and R6 is alkyl, cycloalkyl or cycloalkylalkyl.
A still more preferable compound is that of the above-mentioned formula (I) wherein R' and R3 are each independently hydrogen atom or lower alkyl; R2 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9R'° wherein R9 and R'° are each independently lower alkyl, and RS is hydrogen atom; R° is a group of the formula -NHCOR' wherein R' is alkyl, cycloalkyl or cycloalkylalkyl; and R6 is alkyl, cycloalkyl or cycloalkylalkyl.
A still nnore preferable compound is that of the following formula (IIa) R' R2a w/
(IIa) R3°' ~ ~N
a.
Rs a wherein R'a i:~ hydrogen atom or lower alkyl; R3a is lower alkyl; R2a is alkyl substituted by hydroxy or carboxy; R4° is a group of the formula -NHCOR'g wherein R'a is alkyl, cycloalkyl or cycloalkylalkyl; and R6a is alkyl, cycloa:Lky1 or cycloalkylalkyl.
A still more preferable compound is that of the above formula (IIa) wherein R'° is hydrogen atom or lower alkyl; R3a is lower alkyl; R2a is alkyl substituted by hydroxy or carboxy; Rya is a group of the formula -NHCOR'a wherein R'~ is alkyl; and R6° 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-~4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide, 1V-(1-nonyl-5-carboxymethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylpropa~namide, N-(1-decyl-5-carboxymethyl-~+,6-dimethylindolin-~-yl)-2,2-dimetlhylpropanamide, N-(1-undecyl-5-carboxymethyl-4,6-dimethyl-indolin-'l-yl)-2,2-dimethylpropanamide, N-(1-dodecyl-5-carboxymethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-hexyl-5-hydroxy-methyl-6-methylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-hexyl-5-hydroxymethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-heptyl-5-hydroxymethyl-6-methylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-heptyl-5-hydroxymethyl-~,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide, 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 a acceptable sa:Lts thereof.
(b) When the compound of the present invention is a tetrahydro-quinoline derivative, a compound of the following (IIb) is preferable.
R'b Rz» .
3 b ~ ~ ~ ~ (IIb) R ~N
4b Rsb wherein R'b and R3b are each independently hydrogen atom, lower alkyl or lower alkoxy; R2b is alkyl substituted by hydroxy, carboxy or alkoxycarbonyl; R4b is a group of the formula -NHCOR''b wherein R'b is alkyl, alkoxy,alkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula -NHR$b wherein Rsb is alkyl, cycloalkyl, c;ycloalkylalkyl, aryl or arylalkyl; and R6b is alkyl, alkenyl, alko:xyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl or arylalkyl.
A still more preferable compound is that of the formula (IIb) wherein R'b and R3b are each independently lower alkyl or lower alkoxy;
R2b is alkyl ;substituted by hydroxy, carboxy or alkoxycarbonyl; Rib is a group of the formula-NHCOR''b wherein R'b is alkyl, cycloalkylalkyl, arylalkyl or a group of the formula -NHRsb wherein R$b is alkyl; and R6b is alkyl, alkoxyalkyl, alkylthioalkyl or cycloalkylalkyl.
A still more preferable compound is that of the formula (IIb) wherein R'b and R3b are each independently lower alkyl; R2b is alkyl substituted by hydroxy or carboxy; R4b is a group of the formula -NHCOR'b wherein R'b is alkyl; and R6b is alkyl.
Examples of the most preferable compound include N-(1-hexyl-6-carboxymethyl-5,'7-dimethyl-1,2,3,~-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-heptyl-5-carboxymethyl-5,'7-dimethyl-1,2,3,~-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-octyl-6-carboxymethyl.-5,'7-dimethyl-1,2,3,~-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-nonyl-6-carboxymethyl-5,7-dimethyl-1,2,3,~-tetrahydroqui.nolin-8-yl)-2,2-dimethylpropanamide, N-(1-decyl-6-carboxy-methyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethyl-propanamide, Nf-(1-hexyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,x-tetra-hydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-heptyl-6-hydroxy-methyl-5,7-dimethyl-1,2,3,~-tetrahydroquinolin-8-yl)-2,2-dimethyl-propanamide, Df-(1-octyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,x-tetra-hydroquinolin--8-yl)-2,2-dimethylpropanamide, N-(1-nonyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,~-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide, N-(1-decyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,~t-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide and the like, and pharmaceutically acceptable salts thereof.
~ When t;he compound of the present invention is that wherein one of R', R2 and R5 is hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9R'° wherein R9 and R'° 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,.
R'°
R2~\ R5~
(IIc) R3 ° ~ wN
R6~
wherein one ojf R'°, R2~ and R5° is hydroxy, carboxy, alkoxycarbonyl or a group of thE~ formula -NR9~R'°° wherein R9° and R'°~ 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 -NHCOR'° wherein R'~~ is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula -NHR8~ wherein R8° is alkyl, cycloalkyl, c;ycloalkylalkyl, aryl or arylalkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy; and R6~ is alkyl, alkenyl, alkoxyalkyl, .alkylthioalkyl, cycloalkyl, cycloalkylalkyl or arylalkyl.
More preferable compound is a compound of the above formula (IIc) wherein R'° and R3° are each independently hydrogen atom, lower alkyl or lower alko:~y; RZ~ is carboxy; R''~ is a group of the formula -NHCOR~~ wherein R~° is alkyl, cycloalkyl or cycloalkylalkyl; R5~ is hydrogen atom; and R6~ is alkyl, cycloalkyl or cycloalkylalkyl.
A still more preferable compound is a compound of the above formula (IIc) wherein R'° is hydrogen atom or lower alkyl; R3~ is lower alkyl;
R2~ is carboxy; Ra° is a group of the formula -NHCOR'°
wherein R°'~ is alkyl; R5° is hydrogen atom; and R6~ is alkyl.
Examples of the most preferable compound include N-(1-hexyl-5-carboxy-6-met~hylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-octyl-5-carboxy-6-met:hylindolin-~-yl)-2,2-dimethylpropanamide, N-(1-decyl-5-carboxy-6-methylindolin-7-yl)-2,2-dimethylpropanamide, N-(1-hexyl-5-carboxy-~t,6-dimethylindolin-~-yl)-2,2-dimethylpropanamide, N-{1-octyl-5-carboxy-~,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 salts thereof.
The compound (I) may form pharmaceutically acceptable salts. When compound (I) has a basic group, it~can form acid addition salts. The acid to form 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 acid and the like, and organic acids such as oxalic acid, fumaric acid, malefic acid, citric acid, tartaric acid, methanesulfonic acid, tolueneaulfonic 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; all~;aline earth metal salts such as calcium salt, magnesium salt and the like; and organic base salts such as triethylamine salt, dicyclohexylaunine 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 ~.
uct1.017. MetnOd R~1 1) reduction R12~_ ~ ~ ~ 2) protection of amino R.12 N' 3) introduction of vitro N
( I. T I ) H ~) reduction of vitro H2N Rls (I V) R~~~C 02H (V) or its RII
reactive derivative / ~lo~~~tion at, carboxyl Ri2 or' R$NCO (VI) HN .Rls COR7 (V I i') RII Rii F31 1) introduction of hydroxyl, Rls acidic group or NR'R'°
R12 _ , R~12 N 2) protection of hydroxyl, ~N
HN ~~3 acidic group or amino HN~ f Is l R
CORD ~R7 (Y I I I_) ( I X) Rls RI'1 Rls Rm elimination of Ft' s RI~ ' ~ ~ . R 6-X ( X I' ) R12 . -~t- HN ~' ~ HN ~ s R
COR (x) COR (X I I ) R1i Rlt elimination of protecting pup ~ R~ 6 ~ RI~ , , N
HN Rs CORD ( I a ) Production Method 2 tt R R
R 1) hydroxyalkylation 12 W ~. ~ 2) reduction R ~- Rt2 N 3) protection of amino H ~.) halogenation ( I I I ) (X I I I.) Rt3 1) introduction of hydroxyl, 1) introductian of nitro acidic group or -NR9R'° R12 2) reduction of nitro -it 2) protecltion of hydroxyl, acidic group or amino (X I V.) gt3 Rtt R1s R14002H~ (V) or its R11 Rts reactive derivative Rt,2 (- i ~ ~ at carboxyl R12 or R$NCO (VI) H2~1 Rt3 H~ R13 (xw) coR~ (x:~r I ) Rrt Rts Rt1 Rts elimination of R' 3 - Rt2 / ~ _ R~X (X hRt2 I J
N N
HN H HN. Rs COR7 ( X Q I I ) COR7 (..X ~ T I ~ I ) eli.minat:ion of protecting group ire R' 6 n ~. Rs .
COR7 ( I h ) .
Production Met;nod 3 Ri6 Rji . R.~g Rit oxidation R ~-X ( X I ) R12 ~ -----i~ i2 ~ /
~, ~ R ~ ~ --~-N
H~N, (-lN . H
~~R7 (g) CORD
(X T X}
R16 R elimination of protecting R1~ Rj~
Rj2 , ~ group in R's Nv Riz N
HN R8 HN Rs C013~ CpR~
(x,x>
( I .c m Production Method ~4 ,~ 1 "
protection of amino R~ R~
IV
H
(X~:X I ) (XX. I I ) R'3 1) introduction of rox~l, halogenoalkylation carboxyl or N1~9R' 2) protection of Y~ydroxyl, carboxyl or amino '(X X I L..I.). . Ras ,~,~ ., ..,,~ ...
elimination 1 ) of R' ' Rj 2 ) :'R s-X ( X I ) (XXV) c.x x t v: ~ ~g R11 Ri~C02;H~ (Vr. or its 1) introduction of nitro reactive derivative 2 reduction of nitro at carboxyl R1, ~ I ~
or R$NCO (VI) H.2N F3j3.
(XXV I?
R,_~~ __ . _ _.
elimination of protecting group in R's i~z . - R~
N
,~
HCOR~ qis CORD R
(X:KV~:T~I) (I: d.) Prjoduction Method 5 Ri1 X R1~
1 introduction of cyano R s-X ( X I ) 2~ hydrolysis of cyano R w ~ _ R~ v ' ~ --i~
~ N H 3) protection of carboxyl N02 H NOz ~ Rs (XXV I l: I ) (XX I X) R2o ~j R2o Ro 1) reduction of nitro _ R~z ~N 2 ) R14C 02H (V) or its N
NO ~s reactive derivative HN Is R at carboxyl ( R
(XXX) or R$NCO (VI) COR' (XXXI) elimination of protecting ~ R
pup ~ RZo 'N
HN Rs COR' (I e) Production Method 6 H2 R11 R~ R11 R1 ~ I) hydroxylation \ ~ N 2 ) protection of \ N
x'Yl Ris (I V) (XXX I I) R21 11 Ri4C O2H (V) or its 1) introduction reactive derivative of~nitro ~ at carboxyl 2) reduction R1 ~ ~ or R$NCO (VI) of vitro N
R
(XXX I I I ) 1) elimination of R' ' R1 ~ ~ ( ~ -~ R12 N 2 ) R6-X EX I ) N
HN R1s H
CORD COR
(X:KX I V) (XXXV) elimination of protecting group in Rz' ._ R12 N
H ~ . Rs CORD .
_ (I f) a Production Method 7 H 11, R~ Ri1 R1 ~ alkylation or R1 protection of amino . \
N
(I Vy (XXXV I) R~4C O2~i (V) or its 1) introduction R~ ~ R11 reactive derivative of vitro at carboxyl 2) reduction R ~ _ ~ or R$NCO (VI) of vitro N
(XXXV I I) .
R~ R11 1 ) elimination R~ R
of R' ' R1 ~ -~ R1.
2 ) R6-X (X I ) N N
H1 R13 Hi Rs CCiR7 COR
(XXXV I I I) (XXXI X) R10- ~ 11 elimination of protecting pup ~ Ra2 R1 ~, N
HN E s R
( I 8) In each of the above formulas, R6, R'', R8, R9 and R'° are each as defined above; R" and R'2 are each independently hydrogen atom, lower alkyl or lower alkoxy; R'3 is amino protecting group; R'" is alkyl, alkoxyalkyl, a.lkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; R'S is alkyl or alkenyl substituted by halogen atom; R'6 is alkyl or alkenyl substituted by hydroxy, protected hydroxy, acidic group, protected acidic group, alkoxycarbonyl or -NR'8R'9 wherein R'$
and R'9 are each independently hydrogen atom, lower alkyl or amino protecting group; R" is alkyl or alkenyl substituted by hydroxy, acidic group, alkoxycarbonyl or -NR9R'°; RZ° is protected carboxy; R2' is protected tiydroxy; and Ra2 is -NR'$R'9 wherein R'$ and R'9 are as defined above.
Amino protecting group at R'3, R'$ and R'9 is, for example, formyl, acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl, methoxy-carbonyl, ethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, diphenylmethy:Loxycarbonyl, methoxymethyloxycarbonyl, 2,2,2-trichloro-ethoxycarbony:L, trimethylsilyl, 2-methylsulfonylethyloxycarbonyl, tert-butoxycarbony:L or trityl.
Hydroxy protecting group at R'6 and R2' is, for example, formyl, acetyl, monoclhloroacetyl, dichloroacetyl, trifluoroacetyl, methoxycarbon;yl, ethoxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloroetho;xycarbonyl, benzoyl, trityl, tetrahydropyranyl, trimethylsilyl or the like.
Acidic group protecting group at R'6 and R2° is, when carboxy protecting group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, tent-amyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, methylthiomethyl, trityl, 2,2,2-trichloroethyl, trimethylsilyl, diphenylmethoxybenzenesulfonylmethyl, dimethylamino-ethyl and the: like.
The above-mentioned protecting groups can be removed by a method known her se, and the method for removing them may be determined according to the kind of the protecting group. Exemplified are a decomposition by an acid (e. g., that by an acid such as hydrochloric acid, trifluor~oacetic 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, benzyloxycarbcrnyl and the like). The production methods of the objective compounds of the present invention and starting material compound are ctescribed in detail in the following.
Production Method 1 The compound (IV) can be produced by reducing compound (III) [J.
Eric Nordlande~r, et al., J. Org. Chem., X46, '7~8-782 (1981), Robin D.
Clark, et al." Heterocycle, 22, 195-221 (1980 , Vernon H. Brown, et al., J. Heterocycle. Chem., 6(~4), 539-5~3 (1969)] to introduce an indoline skelE~ton, protecting amino, introducing nitro on benzene ring by a method known her 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 tlhe inert solvent include acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofur.an, 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 encompas~;ed 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'-morpholinoeahyl 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 a.s considered to proceed via a reactive derivative of carboxylic acid. The compound (VIII) can be produced by halogenoalH;.ylation of compound (VII) [R. C. Fuson et al., Org.
React., 1, 63 (1969), G.A. Olah et al., "Friedel Crafts and Related Reactions" Vol. 2. 659 (1964)].
~'he compound (IX) can be produced by converting halogenoall~:yl of compound (VIII) to hydroxy, an acidic group such as carboxy or a group of the formula -NR9R10 by a substitueni: conversion reaction known per se, and if necessary, introducing a corresponding protecting group.
The compound (XII) can be 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.
21a In addition, a base such as triethylamine, pyridine, ~-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 R'6 of compound (XII) by a method known her 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)], reduc:ing, 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 vitro and reducing vitro 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 her se (e. g., oxidation using chloranil, palladium-carbon and the like).
The compound (Ic) can be produced from compound (XIX) via compound (XX) accordin;g to the method for obtaining compound (Ia) from compound (X) as descrilbed in Production Method 1.
Production Method ~
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 (XXI7=) 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) can be produced from compound (XXV) by introducing nitre and reducing nitre by a method known her se.
The compound (XXVII) can be produced from compound (XXVI) according to the method for obtaining compound (VII) from compound (IV) as described in 1?reduction Method 1.
The compound (Id) can be produced from compound (XXVII) according to the method for obtaining compound (Ia) from compound (XII) as described in l?reduction Method 1.
Production Method 5 The compound (XXIX) can 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) can be produced by converting halogen of compound (XXIX) to cyano by a method known her se, hydrolysis of cyano, and introducing a protecting group into the obtained carboxy.
The compound (XXXI) can be produced from compound (XXX) by reducing nitre 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 at R2° of compound (XXXI) by a method known her se.
Production Method 6 The compound (XXXII) can be produced by converting amino of compound (IV) to hydroxy by a method known per se and introducing a protecting gra~up into hydroxy.
The compound (XXXIII) can be produced from compound (XXXII) by introducing ni.tro and reducing nitro by a method known per se.
The compound (XXXIV) can be produced from compound (XXXIII) according to t:he method for obtaining compound (VII) from compound (IV) as described i.n 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 described in Production Method 1.
The compound (If) can be produced by eliminating the protecting group at R2~ of compound (XXXV) by a method known per se.
Production Method 7 The compound (~~CXVI) can be produced by alkylation of amino or by introducing a protecting group of amino of compound (IV) by a method known her se.
The compound (X)QCVII) can be produced from compound (X)CXVI) by introducing nitro and reducing nitro by a method known per se.
The compound (3~CXVIII) can be produced from compound (XXXVII) according to ithe method for obtaining compound (VII) from compound (IV) as described :in Production Method 1.
The compound (XXXIX) can be produced from compound (XXXVTII) 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 Ra2 of compound (XXXIX) by a method known per se.
The compound (I) of the present invention obtained by the above methods can b~e 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 her 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, hydroxypropylc;ellulose and crystalline cellulose), lubricants (e. g., magnesium stearate and talc), and disintegrators (e. g., carboxymethyl-cellulose talc;ium and talc), and the like.
The above:-mentioned ingredients are mixed 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 her se.
GJhile 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 i~o adult patients of hypercholesterolemia, it is generally 0.1 mg - 50 mg/kg body weight per dose which is administered about 1 to 3 times) a day.
The compound (I) of the present invention and pharmaceutically acceptable salts thereof exhibit superior ACAT inhibitory activity and lipoperoxidat.ion 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.
Example 1 N-(1-Octyl-5-hydroxymethyl-~,6-dimethylindolin-'7-yl)-2,2-dimethylpropanamide (1) N-(1-Acetyl-5-chloromethyl-4,6-dimethylindolin-~-yl)-2,2-dimethylpropanamide ('l.0 g) was dissolved in a mixed solvent (50 ml) of CHsCN/DMF=1/1. Potassium acetate (12.0 g) was added and the mixture was stirred a.t 60°C for 1 hr. CHsCN was evaporated under reduced pressure and AcOEt (200 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate, and AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHC1,/MeOH=1/0 - 10/1) to give ?.5 g of N-(1-acetyl-5-acetoxymethyl-4,6-dimethylihdolin-?-yl)-2,2-dimethylpropanamide.
'H-NMR (CDC1~) 1.2? (9H, s, --C(CH3),), 2.Ob (3H, s, OCOCH,), 2.23, 2.26, 2.30 (9H, s x 3, -CH, x 2, >NCOCH~), 3.00 (2H, br, Indoline C3-H), 4.05 (2H, br, Indoline Ci-E1), 5.20 (2H, s, -CHiO-), 9.10 (1H, br, >NH).
(2) N-(1-Acetyl-5-acetoxymethyl-4,6-dimethylindolin-?-yl)-2,2-dimethyl-propanamide (?.5 g) was dissolved in EtOH (?0 ml) and a solution of NaOH
' (8.3 g) in water (20 ml) was added, which was followed by refluxing for 10 hr. EtOH was evaporated under reduced pressure and CHC13 (200 ml) .
was added. After washing with water, the mixture was dried over anhydrous sodium sulfate and CHC1, was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHC1~/MeOH=1/0 - 10/1) to give 3.0 g of N-(5-hydroxymethyl-4,6-dimethylindolin-?-yl)-2,2-dimethylpropanamide.
'H-NMR (CDC1,) ~
1.35 (9H, s, -C(CH~),), 2.23, 2.26 (6H, s x 2, -CH, x 2), 2.99 (2H, t, J=8.5Hz, Indoline C~-H), 3.58 (2H, t, J=8.5Hz, Indoline C~-H), 4.65 (2H, s, -CH_xOH), ?.10 (2H, br, ON,~>NH).
(3) N-(5-Hydroxymethyl-4,6-dimethylindolin-?-yl)-2,2-dimethylpropanamide (1.5 g) was dissolved in DMF (15 ml) and 1-iodooctane (2.6 g) and KzCO~
(1.5 g) were added, which was followed by stirring under a nitrogen atmosphere at 50°C for 2 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by 3o silica gel column chromatography (eluent: CHC13/MeOH=1/0 - 10/1) to give 1.0 g of the title compound.
IR (Nujol) cm'': 1652, 1600, 1508.
'H-NMR (CDC13) *Trade-mark 0.70---1.10 (3H, br, -(CHZ ) TCHs ) , 1.10---1.70 (12H, m, -CHZ (CHZ ) sCHs ) , 1.37 (9H, s, -C(CHs)s), 2.1~, 2.22 (6H, s x 2, -CHs x 2), 2.87 (2H, t, J=8.5Hz, Indoline C3-H), 3.14 (2H, t, J=7.5Hz, >NCHZ-), 3.~2 (2H, t, J=8.5Hz, Indoline CZ-H), x.62 (2H, s, -CHZOH), 6.86 (2H, br, OH, >NH).
FxamnlP 2 N-(1-Octyl-F.-dimethylaminomethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (1) N-(1-Acetyl-5-chloromethyl-~,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (~'_.0 g) was dissolved in CHCls (~0 ml) and (CHs)zNH~ HC1 (3.5 g) and K;:COs (11.8 g) were added, which was followed by stir.~ring at room temperature for ~ hr. CHCls (300 ml) was added, and the mixture was washed successively with 2N-hydrochloric acid, 2N aqueous NaOH and saturated brine, and dried over anhydrous sodium sulfate. CHCls was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHC13/MeOH=10/1 - 1/1) to give 700 mg of N-(1-acety:L-5-dimethylaminomethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylpropa~aamide.
'H-NMR (CDCls) 1.26 (9H, s, -C(CHs)s), 2.12, 2.15 (6H, s x 2, -CHs x 2), 2.2~. (6H, s, -N(CHs)2), 2.31 (3H, s, >NCOCHs), 3.00 (2H, br, Indoline Cs-H), 3.35 (2H, s, >NCHZ-), x.15 (2H, br, Indoline Cz-H), 9.23 (1H, br, >NH).
(2) N-(1-Acetyl-5-dimethylaminomethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (1.0 g) was dissolved in MeOH (10 ml) and a solution of NaOH (580 mg) in water (3 ml) was added, which was followed by stirring at 60°C for 2 hr. MeOH was evaporated under reduced pressure and CHCls (100 ml) was added. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. CHCls was evaporated under reducedl pressure to give 700 mg of N-(5-dimethylaminomethyl-~,6-dimethylindo7.in-7-yl)-2,2-dimethylpropanamide.
' H-NMR (CDCI.s ) 8 1.30 (9H, s, -C(CHs)s), 2.19 (12H, s, -CHs x 2, -N(CHs)z), 3.00 (2H, t, J=8.5Hz, Indoline C3-H), 3.28 (2H, s, >NCH2-), 3.55 (2H, t, J=8.5Hz, Indoline C2-H), 4.40 (1H, br, >NH), 7.20 (1H, b;r, >NH) .
(3) N-(5-Di~methylaminomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (700 mg) was dissolved in DMF (7 ml) and NaH (P=60~. 160 mg) was added under a nitrogen atmosphere at 5°C. After stirring at the same temperature for 30 min, 1-iodooctane (240 mg) was added, which was followed by stirring at 30°C for 3 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate.
AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:
CHC13/MeOH=10/1 - 3/1) to give 500 mg of the title compound.
IR (Nujol) cm-1: 1654, 1600.
1H-NMR (CDC13) b .
0.701.10 (3H, br, - (CH2) 7CH3) , 1.101.70 (12H, m, -CH2(CH2)6C'H3), 1.33 (9H, s, -C(CH3)3), 2.00, 2.09 (6H, sx2, -CH3x2), 2.23 (6H, s, -N(CH3)2), 2.85 (2H, t, J=8.5Hz, Indoline C3-H), 3.18 (2H, br-t, >NCH2-), 3.31 (2H, s, -CIi2N<), 3.38 (2H, t., J=8.5Hz, Indoline C2-H), 6.84 (1H, br, >NH).
Example 3 r(-(1-Octyl-5-ethoxycarbonylmethyl-4,6-dimethylindLolin-7-yl)-2,2-dimethylpropanamide (1) 1-Acety~1-5-bromo-4,6-dimethyl-7-nitroindoline (30 g) was dissolved in a mixture (600 ml) of CHC13/MeOH=1/1 and 5~ Pd-C
(5.0 g) was added, which was followed by catalytic hydrogenation at 35°C, The precipitate was collected by filtration together with Pd-C, and dissolved in CHC13 (300 27:L03-179 ml). The mixture was washed with saturated aqueous solution of sodium h;ydrogencarbonate. The solvent was evaporated under reduced pressure from the filtrate and CHC13 (300 ml) was added. The mixture was washed with saturated aqueous solution of sodium h,ydrogencarbonate and combined with the layer of above-mentioned CHC13. The combined CHC13 layer was washed with saturated brine and dried over anhydrous sodium sulfate.
CHC13 was evaporated under reduced pressure and the 28a 271.03-179 residue was dissolved in CHC13 (150 ml). Thereto were successively added at 10°C,pivaloyl chloride (11.7 g) and EtsN (10.8 g). The mixture was stirred at room temperature for 1 hr and CHC13 (200 ml) was added. The mixture was washed successively with 5~ aqueous citric acid and water, and dried over anhydrous sodium sulfate. CHCls was evaporated under reduced pressure and the obtained crude residue was washed with cool Et20 (100 ml) to give 21 g of N-(1-acetyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
IR (Nujol)cm -' : 1676, 1639, 1581.
' H-NMR (CDCls ) cS
1.2~+ (9H, s, -C(CH3)s), 2.17 (6H, s, -CHs x 2), 2.30 (3H, s, >NCOCH3), 2.99 (2H, t, J=8.5Hz, Indoline Cs-H), 4.10 (2H, t, J=8.5Hz, Indoline CZ-H), 6.87 (1H, s, Indoline Cs-H), 9.10 (1H, br, >NH).
(2) N-(1-Acetyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (20.0 g) was dissolved in conc. hydrochloric acid (100 ml), and 35~ formalin (8.5 g) and zinc chloride (1.8 g) were added. The mixture was stirred at 40-50°C for 2 hr while blowing hydrogen chloride therein. The reaction mixture was poured into ice water and extracted with CHC13 (400 ml). The CHCls layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. CHC13 was evaporated under reduced pressure to give 21 g of N-(1-acetyl-5-chloromethyl-4,6-dimethylindolin-7-yl)-2,2-dia~ethylpropanamide.
IR (Nujol)cm '' : 1679, 1645, 1587.
' H-NMR (CDCl.s ) 1.27 (9H, s, -C(CHs)s), 2.25 (3H, s, -CHs), 2.30 (6H, s, -CH3, >NCOCHs), 3.00 (2H, br~, Indoline C3-H), 4.05 (2H, br, Indoline Cz-H), x.68 (2H, s, -CH2C1), 9.16 (1H, br, >NH).
(3) N-(1-Acet:yl-5-chlor~omethyl-~+,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (21 g) was suspended in CH3CN (150 ml), and NaCN (8.1 g) and 18-crown-6 (870 mg) were added, which was followed by refluxing for 15 hr. CH3CN waus evaporated under reduced pressure and CHCls (300 ml) was added. The mixture was washed with water and dried over anhydrous sodium sulfate. CHCls was evaporated under reduced pressure. The obtained residue was washed with boiling MeOH to give 15.5 g of N-(1-acetyl-5-cyanomethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
IR (Nujol)cm '-' : 2232, 1678, 1639.
' H-NMR (CDC1~3 ) 1.27 (9H, s, -C(CHs)s), 2.26, 2.30, 2.~0 (9H, s x 3, -CHs x 2, >NCOCH3), 3.00 (2H, br, Indoline Cs-H), 3.66 (2H, s, -CHZCN), x.05 (2H, br, Indoline Cz-H), 9.21 (1H, br, >NH).
.) N-(1-Acet;yl-5-cyanomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (5.0 g) was suspended in n-PrOH (25 ml) and a solution of NaOH (9.6 g) in water (10 ml) was added, which was followed by stirring at 90°C for 8 hr in an autoclave under a nitrogen atmosphere. 'The aqueous layer was separated, and the organic layer wa.s neutralized with 2N-hydrochloric acid. The solvent was evaporated under reduced pressure. The residue was suspended in EtOH
(200 ml), and 10N HC1-EtOH (7.2 ml) was added, which was followed by refluxing for 1 hr. EtOH was evaporated under reduced pressure, and the mixture was neutralized with saturated aqueous solution of sodium hydrogencarbonate and extracted with AcOEt (200 ml). The AcOEt layer was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: CHCls/MeOH=1/0 - 20/1) to give 3.0 g of N-(5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
IR (Nujol)cm~ -' : 1732, 165.
' H-NMR (CDC1.3 ) 8 1.3~ (9H, s, -C(CHs)s), 2.14, 2.18 (6H, s x 2, -CHs x 2), 2.99 (2H, t, J=8.5Hz, Indoline C3-H), 3.56 (2H, t, J=8.5Hz, Indoline C2-H), 3.60 (2H, s, -CHzC02-), 4.11 (2H, q, J=7.8Hz, -CHZCHs), x.20 (1H, br~, >NH), 7.00 (1H, br, >NH).
(5) N-(5-Ethoxycarbonylmethyl-~4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (3.5 g) was dissolved in DMF' (15 ml), and 1-iodooctane (5.0 g) and KZCOs (2.9 g) were added, which was followed by stirring under a nitrogen atmosphere at 50°C for 2 hr. AcOEt (200 ml) was added, and the mixture wa.s washed with water and dried over anhydrous sodium sulfate. AcOE;t was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCls/MeOH=1/0 -50/1) to give 3.5 g of the title compound.
IR (Neat) cm -' : 1732, 1654, 1600.
' H-NMR (CDCl3; ) 8 0.70~1.10 (~iH, br, -(CHz)7CHs), 1.10 ~1.70 (15H, m, -CH2CH3, -CH2(CHz)sCH~), 1.33 (9H, s, -C(CHs)s), 2.0~., 2.13 (6H, s x 2, -CHs x~'_), 2.87 (2H, t, J=8.5Hz, Indoline C3-H), 3.12 (2H, t, J=7.5Hz, >NCHz-), 3.39 (2H, t, J=8.5Hz, Indoline Cz-H), 3.58 (2H, s, -CHzCOz-), x.12 (2H, q, J=7.5Hz, -CHzCHs), 6.79 (1H, br, >NH).
Example ~
N-(1-Octyl-5-carboxymethyl-~+,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide N-(1-Oct;,rl-5-ethoxycarbonylmethyl-~+,6-dirnethylindolin-7-yl)-2,2-dimethylpropaulamide (3.5 g) was dissolved in EtOH (50 ml) and a solution of NaOH (1.6 ») 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 -' :1732, 1651, 1600.
'H-NMR (CDCls) 0.70~1.10 (3H, br, -(CH2)~CH3), 1.10~1.70 (12H, m, -CHz(CHz)6CH.3), 1.33 (9H, s, -C(CHs)s), 2.01, 2.15 (6H, s x 2, -CHs x 2), 2.703.20 (~H, m, Indoline Cs-H, >NCHz-), 3.~1~1 (2H, t, J=8.5Hz, Indoline Cz-H), 3.56 (2H, s, -CH2COzH), 7.60 (1H, br, >NH), 7.90 (1H, br, -COzH).
Example 5 N-(1-Octyl-~i-carboxymethyl-~.,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide ~hydrochloride N-(1-Oct3i1-5-ethoxycarbonylmethyl-~,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 wii~h 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. Ac01?t was evaporated under reduced pressure to give 2.0 g of the title compound.
IR (Nujol)cm -' : 1722, 1654.
'H-NMR (CDCls) 0.70~-1.10 (3H, br, -(CH2)7CH3), 1.10~-1.70 (12H, m, -CHz(CHz)sCH3), 1. 39 (9H, s, -C (CHs ) s ) , 2. 06, 2. 26 (6H, s x 2, -CH3 x 2) , 2. 90---3.
(~H, m, Indoline C3-H, >NCH2-), 3.50---3.90 (2H, br-t, Indoline CZ-H), 3.72 (2H, s, -CHzCO2H), 6.00-~-7.00 (1H, br, HC1), 9.05 (2H, br, >NH, -C02H).
FxamnlP 6 N-(1-Octyl-5-carboxymethyl-~t,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide~ sulfate N-(1-Octyl-5-ethoxycarbonylmethyl-~,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 -' : 1718, 165, 1637.
' H-NMR (CDCl:~ ) c~
0.70~1.10 (3H, br, -(CHZ)~CHs), 1.10~1.70 (12H, m, -CHz(CHZ)sCHs), i.33 (9H, s, -C(CHs)s), 2.02, 2.16 (6H, s x 2, -CHs x 2), 2.80~3.30 (~H, m, Indo=Line C3-H, >NCHz-), 3.30-~-3.70 (2H, br-t, Indoline Cz-H), 3.59 (2H, s, -CHzCOzH), 6.00~7.00 (2H, br, HzSOa), x.20 (1H, br, -COzH), 8.30 (1H, br, >NH).
Example 7 N-(1-Octyl-!~-carboxymethyl-~,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide ~ nitrate N-(1-Oct;,rl-5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (3.0 g) was dissolved in EtOH (~2 ml) and a solution of NaOH (1.~4~~) 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 (Nu jol) cm -' : 172~t, 165 'H-NMR (CDC13) 8 0.70-~-1.10 (3H, br, -(CHz)~CH3), 1.10-~-1.70 (12H, m, -CHz(CHz)sCH3), 1.33 (9H, s, -C(CHs)s), 2.02, 2.21 (6H, s x 2, -CH3 x 2), 2.80~3.30 (~H, m, Indoline Cs-H, >NCHz-), 3.50-~-3.80 (2H, br-t, Indoline Cz-H), 3.6~t (2H, s, -CHZCOzH), 6.00---7.00 (1H, br, HNOs), 9.03 (2H, br, >NH, -COzH).
Fzramnl P 8 N-(1-Octyl-~5-carboxymethyl-~,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide~ sodium salt N-(1-Octyl-5-ethoxycarbonylmethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylprop2mamide (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 Ei0°C for 1 hr. EtOH was evaporated under reduced pressure. The: residue was dissolved in water (20 ml) and the mixture was adsorbed cmto DIA IONS HP-21 (70 ml). After washing with water, the mixture was eluted with 50~ aqueous methanol. The objective fraction was concentrated under reduced pressure. The residue was freeze-dried t:o give 1.0 g of the title compound.
IR (Nujol)cm -' : 1630, 1605.
' H-NMR (CDCl:~ ) 0.70---1 .10 (;3H, br, -(CHZ ) NCH, ) , 1 .10-~-1 .70 ( 12H, m, -CHZ (CHz ) 6CH3 ) , 1.38 (9H, s, -C(CH3)3), 1.93, 2.08 (6H, s x 2, -CH3 x 2), 2.70-~-3.20 to (~H~ m, Indoline C3-H, >NCHZ-), 3.30-~-3.40 (2H, br-t, Indoline C2-H), 3.15 (2H, s, -CHZCOzNa), 8.51 (1H, br, >NH).
Example 9 N-[(1-Octyl-3-(2-hydroxyethyl)-~t,6-dimethylindolin-7-yl)]-2,2-dimethylpropa~lamide (1) 4,6-Dimetlhylindole (130 g) was dissolved in Et20 (130 ml), and oxalyl chloride (23.0 g) was dropwise added at 0°C. The mixture was stirred at room temperature for 5 hr, and EtzO was evaporated under reduced pressure. EtOH (200 ml) was added to the residue and the mixture was stirred at room temperature for 15 hr. EtOH was evaporated 2 o under reduced pressure. The residue was dissolved in CHC13 (200 ml).
After washing' with water, the mixture was dried over anhydrous sodium sulfate. CHC13 was evaporated under reduced pressure. The obtained residue was added to a suspension of LiAlHn (17.0 g) in Et20 (200 ml), which was followed by refluxing for 2 hr. The reaction mixture was poured into i.ce water and extracted with AcOEt (200 ml). The AcOEt layer was wa~~hed with water and dried over anhydrous sodium sulfate.
AcOEt was evaporated under reduced pressure. The residue was purified by silica ge7L column chromatography (eluent: CHCls/MeOH=50/1 - 10/1) to give 13.0 g of 3-(2-hydroxyethyl)-4,6-dimethylindole.
3o IR (Nujol)crn -' : 1456, 1377.
' H-NMR (CDC:L3 ) 2.39, 2.63 (6H, s x 2, -CH3 x 2), 3.13 (2H, t, J=7.OHz, -CHZCHZOH), 3.86 (2H, t, J=7.OHz, -CHZCHZOH), 6.69 (1H, s, Indole Cs-H), 6.91 (2H, m, 7Cndole Cz-H, C7-H), 6.92 (1H, br, -OH), 7.90 (1H, br, >NFi).
(2) 3-(2-Hydro~ryethyl)-4,6-dimethylindole (13.0 g) was dissolved in AcOH (100 ml) rind NaBHaCN (8.7 g) was added by portions under ice-cooling.
After stirring at the same temperature for 1 hr, the reaction mixture was poured into ice water and neutralized with aqueous NaOH. The mixture was extracted with CHC13 (200 ml). The CHCls layer was washed with water and dried over anhydrous sodium sulfate. CHC13 was evaporated under reduced pressure. The residue was dissolved in benzene (100 ml), and AczO (15 g) and Et,N (8.3 g) were added, which was 1o followed by stirring at room temperature for 1 hr. AcOEt (200 ml) was added and the mixture was washed successively with saturated aqueous solution of sodium hydrogencarbonate, 5~ aqueous citric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCla/MeOH=50/1 - 10/1) to give 13.0 g of 1-acetyl-3-(2-acetoxyethyl)-~,6-dimethylindoline.
IR (Nujol)cm -' : 1652, 160.
' H-NMR (CDC13~ ) 8 1.60-~-2.20 (~'_H, m, -CH_ZCHzO-), 2.04 (3H, s, -OCOCH3), 2.24 (3H, s, 2 0 >NCOCH, ) , 2. a'_~I, 2. 30 (6H, s x 2, -CH3 x 2) , 3. 3~I ( 1 H, m, Indoline C3-H) , 3.9~ (2H, m, Indoline Cz-H), 4.12 (2H, t, J=7.lHz, -CHZCHzO-), 6.67 (1H, s, Indoline Cs-H), 7.90 (1H, s, Indoline C~-H).
(3) 1-Acetyl ;3-(2-acetoxyethyl)-X4,6-dimethylindoline (2.0 g) was dissolved in AcOH (40 ml) and Brz (1.9 g) was added, which was followed by stirring a't room temperature for 30 min. The reaction mixture was poured into ice water and precipitate was collected by filtration. The precipitate w,as dissolved in CHC13, and the mixture was washed with water and dried over anhydrous sodium sulfate. CHC13 was evaporated under reduced pressure. The residue was purified by silica gel column 3o chromatography (eluent: CHCla/MeOH=50/1 - 10/1) to give 2.7 g of crude crystals of 1-acetyl-3-(2-acetoxyethyl)-5-bromo-~,6-dimethylindoline.
The crude crystals were added by portions to a mixture of nitric acid (0.47 ml), AcOH (10 ml) and conc. hydrochloric acid (10 ml) under ice-cooling, and the mixture was stirred at the same temperature for ~ hr.
The reaction mixture was poured into ice water and precipitate was collected by filtration. The precipitate was dissolved in CHCls.
After washing with water, the mixture was dried over anhydrous sodium sulfate and CHC13 was evaporated under xeduced pressure. The residue was purified by silica gel column chromatography (eluent:
CHCls/MeOH=50,11 - 10/1) to give 1.~ g of 1-acetyl-3-(2-acetoxyethyl)-5-bromo-4,6-dimethyl-7-nitroindoline.
'H-NMR (DMSO-d6) 8 1.60~2.20 (2H, m, -CH_2CH20-), 1.99 (3H, s, -OCOCHs), 2.21 (3H, s, >NCOCH3), 2.38 (6H, s, -CHs x 2), 3.40 (1H, m, Indoline Cs-H), x.11 (2H, t, J=7.OHz, -CHZCH20-), ~.1~ (2H, d, J=8.5Hz, Indoline CZ-H).
1-Acetyl-3-(2-acetoxyethyl)-5-bromo-~,6-dimethyl-7-nitroindoline (1.~+ g) was dissolved in benzene (20 ml) and 5~ Pd-C (500 mg) was added, which was followed by catalytic hydrogenation at room temperature under atmospheric pressure. Pd-C was filtered off and benzene was evaporated under reduced pressure. The residue was dissolved in CHC13 (50 ml) and the mixture was washed successively with saturated aqueous solution of sodium hydro~;encarbonate and saturated brine, and dried over anhydrous sodium sulfate. Pivaloyl chloride (~+~40 mg) and EtsN (~~8 mg) were added to the obtained solution and the mixture was stirred at room temperature for 30 min. The mixture was washed successively with 5~
aqueous citr~:c acid and saturated brine, and dried over anhydrous sodium sulfate. CHC13 was evaporated under reduced pressure. The residue was purified by :silica gel column chromatography (eluent: CHC13/MeOH=50/1 -10/1) to givE~ 1.0 g of N-[1-acetyl-3-(2-acetoxyethyl)-~,6-dimethylindo:Lin-7-yl]-2,2-dimethylpropanamide.
IR (Nujol)cm -' : 1730, 169.
' H-NMR ( CDC.1 s ) 8 1.27 (9H, s, -C(CHs)s), 1.60~ 2.20 (2H, m, -CHzCH20-), 2.06 (3H, s, -OCOCH3), 2.17, 2.22 (6H, s, -CHs x 2), 2.30 (3H, s, >NCOCH3), 3.10 (1H, m, Indoline Cs-H), 4.03 (2H, d, J=8.5Hz, Indoline CZ-H), x.14 (1H, t, J=7.OHz, -CHzCH20-), 6.88 (1H, s, Indoline Cs-H), 9.00 (1H, br, >NH) (5) N-[1-Acetyl-3-(2-acetoxyethyl)-~,6-dimethylindolin-7-yl]-2,2-dimethylpropan.amide (~.0 g) was dissolved in EtOH (~t0 ml) and a solution ~of NaOH (2.2 g;) in water (10 ml) was added, which was followed by stirring at 6C1°C for 10 hr. EtOH was evaporated under reduced pressure, and CHCIs (100 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate, and CHCls was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCls/MeOH=50/1 - 10/1) to give 1.6 g of N-[3-(2-hydroxyethyl)-~,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide.
' H-NMR (CDC1;3 ) 8 1.3~ (9H, s, -C(CHs)s), 1.60-~-2.20 (2H, m, -CHzCHzOH), 2.17, 2.19 (6H, s x 2, -I~H3 x 2) , 3. 20~3. 80 (7H, m, Indoline CZ-H, C3-H, >NH, -CHzCH20H), X6.45 (1H, s, Indoline Cs-H), 7.20 (1H, br, --CONH-).
(6) N-[3-(2-HYd~xyethyl)-~,6-dimethylindolin-7-yl]-2,2-dimethyl-propanamide (1.6 g) was dissolved in DMF (15 ml) and 1-iodooctane (3.9 g) and KZCOs (2.3 g) were added, which was followed by stirring at 70°C
for 10 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt=5/1 - 1/2) to give 300 mg of the title compound.
IR (Nujol)cm -' : 165, 1600.
' H-NMR ( CDC7. s ) 0.70~1.00 1;3H, brt, -(CHZ)sCHs), 1.33 (9H, s, -C(CHs)s), 1.00~ 2.00 (14H, m, -(CHZ)sCHs, -CHZCHZOH), 2.07, 2.16 (6H, s x 2, -CH3 x 2), 2.60-~-3.60 (8H, m, Indoline C2-H, Cs-H, >NCHZ-, -CHZOH), 6.4~ (1H, s, Indoline Cs-H), 6.78 (1H, br, -CONH-).
Example 10 N-[(1-Octy.l-3-(2-methoxycarbonylethyl)-~,6-dimethylindolin-7-yl)]-2,2-dimethylpropatiamide (1) 1-Acetyl-3-(2-acetoxyethyl)-~,6-dimethylindoline (2.0 g) was dissolved in a. mixture of CHCls/MeOH=1/1 (25 ml), and a solution of NaOH (1.5 g) i,n water (5 ml) was added, which was followed by stirring at room temperature for 1 hr. The solvent was evaporated under reduced pressure. CHCls (100 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. CHC13 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHC13/MeOH=50/1 - 10/1) to give 1.2 g of 1-acetyl-3-(2-h3rdroxyethyl)-~,6-dimethylindoline.
' H-NMR (CDC1:, ) 1.60~-2.00 (3H, m, -CH_zCHzO_H) , 2.26, 2.30, 2.39 (9H, s x 3, -CHs x 2, >NCOCHs), 3.50 (1H, m, Indoline Cs-H), 3.77 (2H, t, J=7.OHz, -CH2CHZOH), 3.97 (2H, m, Indoline C2-H), 6.67 (1H, s, Indoline Cs-H), 7.89 (1H, s, Indoline C7-H).
(2) 1-Acetyl-:3-(2-hydroxyethyl)-~,6-dimethylindoline (7.0 g) and CBrn (g.g g) were dissolved in CHsCN (70 ml), and PhsP (9.~ g) was added, which was followed by stirring at room temperature for 30 min. CHsCN
was evaporated under reduced pressure. AcOEt (100 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. Ac0'Et was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt=
50/1 - 10/1) to give 5.~ g of 1-acetyl-3-(2-bromoethyl)-~,6-dimethyl-indoline.
IR (Nujol)cm -' : 1650, 160.
'H-NMR (CDCls) 8 1.80~2. 20 (2H, m, -CH_aCH2Br) , 2. 23, 2. 26, 2.30 (9H, s x 3, -CHs x 2, >NCOCHs), 3.42 (2H, t, J=7.OHz, -CHZCH2Br), 3.20~3.60 (1H, m, Indoline Cs-H), x.00 (2H, m, Indoline Cz-H), 6.68 (1H, s, Indoline Cs-H), 7.89 (1H, s, Indoline C7-H).
(3) 1-Acetyl--3-(2-bromoethyl)-~,6-dimethylindoline (5.4 g), NaCN (3.7 g) and 18-crown--6 (480 mg) were suspended in CHsCN (50 ml), and the suspension was refluxed for 15 hr. CH3CN was evaporated under reduced pressure. CHCls (100 ml) was added, and the mixture was washed with water and dr_'i.ed over anhydrous sodium sulfate. CHCls was evaporated under reduced pressure. The residue was purified by silica gel column chromatography' (eluent: CHCls/MeOH=50/1 - 10/1) to give 4.5 g of 1-acetyl-3-(2-cy'~oethyl)-4,6-dimethylindoline.
IR (Nujol)cm -' : 2364, 16.7.
'H-NMR (CDC13) ~ : .
1 .'l0~--2. 20 (2H, m, -CH_2CHzCN) , 2. 26, 2. 31 (9H, s x 3, -CH3 x 2, >NCOCHs), 2.x'.0-~-2.40 (2H, m, -CHzCH2CN), 3.~~+ (1H, m, Indoline C3-H), 3.70-~-x.20 (2H, m, Indoline CZ-H), 6.69 (1H, s, Indoline Cs-H), 7.90 (1H, s, Indoline Cz-H).
1-Acetyl-:;-(2-cyanoethyl)-~+,6-dimethylindoline (4.5 g) was dissolved in EtOH (150 cnl), and a solution of KOH (10.~ g) in water (50 ml) was added, which was followed by refluxing for 15 hr. EtOH was evaporated under reduced pressure, and the aqueous layer was adjusted to weak acidic with 61~t hydrochloric acid and extracted with CHCls (100 ml).
The CHCls layer was washed with water and dried over anhydrous sodium sulfate. CHC:ls was evaporated under reduced pressure. The residue was dissolved in CHC13 (20 ml) and Ac20 (1.9 g) was added, which was followed by stirring at room temperature for 1 hr. CHC13 (100 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. CHCls was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:
CHC13/MeOH=50/1 - 10/1) to give 3.~ g of 1-acetyl-3-(2-carboxyethyl)-~,6-dimethylindoline.
'H-NMR (CDCls) 1 . 60-~-2. 20 (2H, m, -CH_ZCHZCOzH) , 2. 26, 2. 29 (9H, s x 3, -CH3 x 2, >NCOCHs), 2.20-~-2.40 (2H, m, -CHzCH2CO2H), 3.37 (1H, m, Indoline Cs-H), 3.80~~-x.10 (2H, m, Indoline Cz-H), 6.68 (1H, s, Indoline Cs-H), 7.50 (1H, br~, -COZH), 7.88 (1H, s, Indoline C7-H).
(5) 1-Acetyl--3-(2-carboxyethyl)-4,6-dimethylindoline (3.~ g) was dissolved in EtOH (50 ml) and lON HC1-EtOH (3.9 ml) was added, which was followed by refluxing for 30 min. EtOH was evaporated under reduced pressure and AcOEt (100 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatograph3r (eluent: CHCls/MeOH=50/1 - 10/1) to give 3.3 g of 1-acetyl-3-(2-el;hoxycarbonylethyl)-~,6-dimethylindoline.
' H-NMR (CDCl:~ ) 8 1.2~ (3H, t, J= 7.lHz, -CH2CHs), 1.60~ 2.20 (2H, m, -CHzCH2C02-), 2.22, 2.27, 2.30 (9H, s x 3, -CH3 x 2, >NCOCH3), 2.00-~-2.20 (2H, m, -CH2C_Fi2CO2-), 3.10~-3.30 (1H, m, Indoline Cs-H), 3.90 (2H, m, Indoline CZ-H), x.10 (2H, q, J= 7.lHz, -CHZCH3), 6.76 (1H, s, Indoline Cs-H), 7.90 (1H, s, Indoline C7-H).
(6) 1-Acetyl ;3-(2-ethoxyca.rbonylethyl)-~,6-dimethylindoline (3.3 g) was dissolved in ~4cOH (30 ml) and Br2 (0.93 ml) was added, which was followed by stirring for 30 min. The reaction mixture was poured into ice water and precipitated crude crystals were collected by filtration.
The obtained crystals were dissolved in CHCls (100 ml). After washing with water, the mixture was dried over anhydrous sodium sulfate. CHC13 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHC13/MeOH=50/1 - 10/1) to give 3.0 g of 1-acetyl-5-bromo-3-(2-ethoxycarbonylethyl)-~,6-dimethylindoline.
IR (Nujol)cm -' : 1729, 1641.
'H-NMR (CDCls) 1.24 (3H, t, J= 7.lHz, -CH2CH3), 1.60~2.20 (2H, m, -CHZCH2COz-), 2.00-~-2.20 (2H, m, -CHxCHzC02-), 2.21 (3H, s, >NCOCHs), 2.36, 2.39 (6H, s x 2, -CHs x 2), 3.10~3.60 (1H, m, Indoline Cs-H), 3.90 (2H, m, Indoline C2-~H), x.10 (2H, q, J= 7.lHz, -CHZCHs), 8.08 (1H, s, Indoline C7-H).
(7) To a mixture of AcOH (10 ml), conc, sulfuric acid (10 ml) and nitric acid (0.55 ml.) was added by portions 1-acetyl-5-bromo-3-(2-ethoxy-carbonylethy7_)-~,6-dimethylindoline (3.0 g) at 0°C, and the mixture was stirred at tree same temperature for 5 hr. The reaction mixture was poured into ice water and extracted with CHC13 (100 ml). After washing with water, t;he mixture was dried over anhydrous sodium sulfate. CHCls was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCls/MeOH=50/1 - 10/1) to give 2.7 g of 1-acetyl-5-bromo-3-(2-ethoxycarbonylethyl)-X4,6-dimethyl-7-nitroindoline.
'H-NMR (CDCls) 8 1.26 (3H, t, J= 7.lHz, -CHZCHs), 1.60-~<2.20 (2H, m, -CHzCH2C02-), 2. 00-~-2. 20 (2'.H, m, -CHZCH_ZCOz-) , 2. 23 (3H, s, >NCOCHs ) , 2. ~~4, 2.
(6H, s x 2, -CHa x 2), 3.10-y3.60 (1H, m, Indoline C3-H), x.00 (2H, m, Indoline CZ-H), x+.10 (2H, q, J= 7.lHz, -CHZCHs).
(8) 1-Acetyl-5-bromo-3-(2-ethoxycarbonylethyl)-4,6-dimethyl-7-nitro-indoline (2.7 g) was dissolved in benzene (100 ml), and 596 Pd-C (500 mg) was added, which was followed by catalytic hydrogenation at room temperature under atmospheric pressure. Pd-C was filtered off and benzene was evaporated under reduced pressure. CHC13 (100 ml) was added to the residue, and the mixture was washed successively with saturated aqufsous solution of sodium hydrogencarbonate and saturated brine and dried over anhydrous sodium sulfate. CHCls was evaporated under reduced pressure. The residue was dissolved in CHCls (20 ml) and pivaloyl chloride (790 mg) and EtsN (80 mg) were added, which was followed by stirring at room temperature for 30 min. CHCls (100 ml) was added, and the mixture was washed successively with 5~ aqueous citric acid and saturated brine and dried over anhydrous sodium sulfate. CHCls was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCls/MeOH=50/1 -10/1) to give 2.6 g of N-[1-acetyl-3-(2-ethoxycarbonylethyl)-~,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide.
' H-NMR (CDCl.s ) 1.25 (9H, s, -C(CHs)s), 1.26 (3H, t, J= 7.lHz, -CHZCHs), 1.60-~-2.20 (2H,~m, -CH_zCH2C02-), 2.00-2.20 (2H, m, -CHzCHzC02-), 2.17, 2.20, 2.27 (9H, s x 3, -CH3 x 2, >NCOCHs), 3.00-~-3.20 (1H, m, Indoline C3--H), 3.90 (2H, m, Indoline Cz-H), x.10 (2H, q, J= 7.lHz, -CH_ZCH3), 6.88 (1H, s,. Indoline Cs-H), 9.00 (1H, br, -CONH-).
' H-NMR (CDCl.s ) 1.25 (9H, s, -C(CHs)s), 1.26 (3H, t, J= 7.lHz, -CHZCHs), 1.60-~-2.20 (2H,~m, -CH_zCH2C02-), 2.00-2.20 (2H, m, -CHzCHzC02-), 2.17, 2.20, 2.27 (9H, s x 3, -CH3 x 2, >NCOCHs), 3.00-~-3.20 (1H, m, Indoline C3--H), 3.90 (2H, m, Indoline Cz-H), x.10 (2H, q, J= 7.lHz, -CH_ZCH3), 6.88 (1H, s,. Indoline Cs-H), 9.00 (1H, br, -CONH-).
(9) N-[1-Acet:yl-3-(2-ethoxycarbonylethyl)-~,6-dimethylindolin-7-yl]-2,2-dimethylprop~inamide (2.6 g) was dissolved in EtOH (~0 ml), and a solution of KCIH (1.3 g) in water (10 ml) was added, which was followed by refluxing for 20 hr. EtOH was evaporated under reduced pressure, and the mixture ways adjusted to pH 5 with 2N hydrochloric acid and extracted with CHCla (100 ml). The CHC13 layer was washed with water and dried over' anhydrous sodium sulfate.. CHCls was evaporated under reduced pressure to give 1.5 g of N-[3-(2-carboxyethyl)-~1,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide.
' H-NMR ( CDC 1 a~ ) 1.33 (9H, s, -C(CH3)s), 1.60~2.20 (2H, m, -CHZCHzCOzH), 2.11, 2.26 (6H, s x 3, -(=H, x 2) , 2. 20~2. ~t0 (2H, m, -CHZCHzCOzH) , 3.10-~-3. 80 (3H, m, Indo7Line Cz-H, C3-H), 6.~t~4 (1H, s, Indoline C5-H), 6.74 (2H, br;, -COZH, >NH).
' H-NMR ( CDC 1 a~ ) 1.33 (9H, s, -C(CH3)s), 1.60~2.20 (2H, m, -CHZCHzCOzH), 2.11, 2.26 (6H, s x 3, -(=H, x 2) , 2. 20~2. ~t0 (2H, m, -CHZCHzCOzH) , 3.10-~-3. 80 (3H, m, Indo7Line Cz-H, C3-H), 6.~t~4 (1H, s, Indoline C5-H), 6.74 (2H, br;, -COZH, >NH).
(10) N-[3-(2-Carboxyethyl)-~,6-dimethylindolin-~-yl]-2,2-dimethyl-propanamide ('1.5 g) was dissolved in AcOEt (10 ml) and a solution of CHzNz in ether was added. AcOEt (100 ml) was added, and after washing with water, the mixture was dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHC13/MeOH=50/1 - 10/1) to give 1.0 g of N-[3-(2-methoxycarbonylethyl)-X1,6-dimethylindolin-7-yl]-2 0 2,2-dimethylpropanamide.
'H-NMR (CDCls) 8 1.3~ (9H, s, -C(CHs)s), 1.60---2.20 (2H, m, -CHzCHzCOz-), 2.15, 2.23 (6H, s x 2, -CH3 x 2) , 2. 20-~-2. X10 (2H, m, -CHZCHZCOzCH3 ) , 3.10~3.80 (3H, m, Indoline Cz-H, C3-H), 3.64 (2H, s, -COzCH3), 6.~0 (1H, s, Indoline Cs-H), 7.05 (1H, br, >NH).
'H-NMR (CDCls) 8 1.3~ (9H, s, -C(CHs)s), 1.60---2.20 (2H, m, -CHzCHzCOz-), 2.15, 2.23 (6H, s x 2, -CH3 x 2) , 2. 20-~-2. X10 (2H, m, -CHZCHZCOzCH3 ) , 3.10~3.80 (3H, m, Indoline Cz-H, C3-H), 3.64 (2H, s, -COzCH3), 6.~0 (1H, s, Indoline Cs-H), 7.05 (1H, br, >NH).
(11) N-[3-(2-Methoxycarbonylethyl)-~,6-dimethylindolin-7-yl]-2,2-dimethylpropa.namide (1.0 g) was dissolved in DMF (10 ml) and 1-iodooctane (1.14 g) and KzCOs (830 mg)were added, which was followed by stirring at ~I~O°C for 10 hr. AcOEt (100 ml) was added, and after washing 3o with water, t:he mixture was dried over anhydrous sodium sulfate. AcOEt was evaporatE;d under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt=
20/1 - 5/1) t:o give 1.1. g of the title compound.
a IR (Nujol) cm-': 1730, 1620.
' H-NMR (CDCl;~ ) 0.70~1.00 (:;H, br-t, -(CHz)6CHs), 1.32 (9H, s, -C(CHs)3), 1.00-~-1.60 (12H, m, -(CHz)6CHs), 1.60~2.20 (2H, m, -CHzCH2COz-), 2.05, 2.18 (fiH, s x 2, -CHs x 2) , 2. 20-~-2. ~0 (2H, m, -CHZCHZCOzCH~ ) , 3.10-~-3.80 (5H, m, Indoline Cz-H, Cs-H, >NCHz-) , 3.6~+ (3H, s, -COzCH3), 6.~;8 (1H, s, Indoline Cs-H), 6.70 (1H, br, -CONH-).
Fv~mr, l 0 1 1 N-[(1-Octyl--3-(2-carboxyethyl)-~,6-dimethylindolin-7-yl)]-2,2-dimethyl-propanamide N-((1-tJci;yl-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 (49~ mg) in water (3 ml) was added, which was followed by stirring ai: room temperature for 30 min. EtOH was evaporated under reduced pressure and CHC13 (50 ml) was added. After washing successively caith 59~ aqueous citric acid and saturated brine, the mixture was dried over anhydrous sodium sulfate. CHCls was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHC13/MeOH=50/1 - 10/1) to give 800 mg of the title compound.
I R (Nujol) crn-' : 1700, 1680.
' H-NMR (CDCl :3 ) 0.70~1.00 (3H, br-t, -(CHz)7CHs), 1.38 (9H, s, -C(CHs)s), 1.00~1.60 (12H, m, -(Cl3z)sCHs), 1.60~2.20 (2H, m, -CHZCHZCOzH), 2.07, 2.16 (6H, s x 2, -t;Hs x 2) , 2. 20~2. X40 (2H, m, -CH2CHzCOzH) , 3.10-~-3. 80 (3H, m, Indo:line Cz-H, C3-H), 3.27 (2H, br-t, >NCHz-), 6.45 (1H, s, Indoline Cs-l~), 7.20 (1H, br, -CONH-), 7.60 (iH, br, -COzH).
Fxamnla 1~
N-(1-Octyl-!~-carboxymethyl-~,6-dimethylindol-7-yl)-2,2-dimethyl-propanamide (1) N-(5-ethosxycarbonylmethyl-~,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (1.0 g) was dissolved in xylene (75 ml), and 10~ Pd-C (250 mg) was added, which was followed by refluxing for 1 hr. Pd-C was filtered off and xylene was evaporated under,reduced pressure. The residue was purified by silica gel column chromatography (eluent:
benzene-CHCls) to give 0.9 g of N-(5-ethoxycarbonylmethyl-~,6-dimethylindol--7-yl)-2,2-dimethylpropanamide.
IR (Nujol) cnn-': 1732, 1629.
' H-NMR (CDCl:, ) 8 1.23 (3H, t, J=7.OHz, -CHZCH3), 1.~0 (9H, s, -C(CH3)s), 2.32 (3H, s, -CH3), 2.52 (3H, s, -CHs), 3.80 (2H, m, -CHZCOz-), X4.13 (2H, q, J=7.OHz, -CH_rCH3), 6.50 (1H, t, J=2.OHz, Indole Cs-H), 7.11 (lIi, t, J=2.OHz, Indole Cz-H), 7.35 (1H, br, -CONH-), 8.88 (1H, br, >NH ).
(2) N-(5-Ethos;ycarbonylmethyl-X4,6-dimethylindol-7-yl)-2,2-dimethylpropaulamide (1.~5 g) was dissolved in DMF (10 ml) and NaI~
(P=60%, 132 mg) was added under a nitrogen atanosphere, which was followed by shirring at room temperature for 1 hr. Then, 1-iodooctane (1.06 g) was added and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was poured into ice water. The mixture was extracted with AcOEt (100 ml), washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent:
benzene/AcOEt=1/0 - 1/1) to give 1.02 g of N-(1-octyl-5-ethoxycarbonylmethyl-~,6-dimethylindol-7-yl)-2,2-dimethylpropanamide.
IR (Nujol) cm-': 1735, 1651.
'H-NMR (CDCls) 0.70~1.10 (3H, br-t, -(CHz)TCHs), 1.10~1.70 (15H, m, -CHaCHs, -(CHz)sCHs), 1.38 (9H, s, -C(CHs)s), 2.21 (3H, s, -CHs), 2.47 (3H, s, -CHs), 3.79 (2H, m, -CHZCOz-), 3.90~ x.30 (4H, m, -CH_zCHs, >NCHz-), 6.42 (1H, t, J=3.5Hz, Indole Cs-H), 6.91 (1H, t, J=3.5Hz, Indole Cz-H), 7.12 (1H, br, -CONH-).
(3) N-(1-Octyl-5-ethoxycarbonylmethyl-X4,6-dimethylindol-7-yl)-2,2-dimethylpropanamide (3.5 g) was dissolved in EtOH (50 ml), and a solution of TfaOH (1.6 g) in water (20 ml) was added, which was followed by stirring apt 60°C for 1 hr. EtOH was evaporated under reduced pressure, and the residue was dissolved in water (20 ml), and washed with AcOEt (l0i ml). The aqueous layer was neutralized with 2N HCl and extracted with. AcOEt (50 ml). The AcOEt layer was washed successively with saturated. brine and dried over anhydrous sodium sulfate. AcOEt was evaporatedi under reduced pressure to give 2.0 g of the title compound.
IR (Nujol) cm-': 1705, 167.
' H-NMR (CDC13 ) ~S
0. 70-~-1 .10 (~iH, br, -(CHz ) 7CHs ) , 1.10-1 . 70 ( 12H, m, -CHz (CHz ) sCHs ) , 1.33 (9H, s, -C(CHs)s), 2.10 (3H, s, -CH3), 2.39 (3H, s, -CHs), 3.65 (1H, br, -COZH), x.07 (2H, br-t, >NCHz-), 4.15 (2H, s, -CHjCOz-), 6.38 (1H, t, J=3.5Hz, Indole C3-H), 6.89 (1H, t, J=3.5Hz, Indole Cz-H), 7.25 (1H, br,. -CONH-).
Examples 13-119 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 R4=-NHCOR' Ra. R°
sample R 1 R 2 R 3 R T R 6 -13 -CHs -CHaCOzH -CHs -C(C~I3}s-(CHz)4CHs 14 -CHs -CH2C02H -CHs -C(CHs)s I ~ -CHs -CHzCOzH -CHs -C(CHs}s-(CHz)zCH(CHs}a 16 -CHs 'CH2CO2II -CHs -C(CHs}s-CH2CH=C(CHs}2 t 7 -CHs -CH2C02H wCH3 -C(CHs)s-(CH2}20CH2CHs I8 -CHs -CH2C02H -CH3 -C(CHs)3-(CH2}SCHs I ~ -CHs -CH2C02H -CHs '-C(CH3)3--2 0 -CHs -CHzC02H -CHs -C(CHs)s-CH2-~H
2I -CHs -CH2COzH -CHs -C(CHs}s-(CHz)sCH(CHs)z 2 2 -CHa -CH2CO2H -CHs -C(CHs)s-CHzCH(CH2CHs}z 2 3 -CHs -CHzC02H -CHs -C(CHs)3-(CH2)2O(CH2}2CFis 2 4 -CH3 -CH2COzH -CHs -C(CHs)s-(CH2)sCHs 2 5 -CHs -CH2COzH -CH3 -C(CHs)s-CH2 2 6 -CHs -CH2COzH -CHs -C(CHs)s-(CHz)~CH(CH3)z Table 2 R~
R.2 /
;s ~ ~ ~ R4=-NHCORT
R ~ R
a R.2 R3 R7 Rs 2 7 -CHs -CH2CO2H -CH3 -C(CH3)~ -(CH2)2CH(CH2CHs)2 ~ 8 -CHa -CH2C02H -GH3 -C(CH3)s -(CH2)20(CH2)aCHa 2 9 -CHs -CH2CO2H -~H3 -C(CHs)s -(CH2)z-( g -CHs -CH2C0~2H -CHs -C(CHs)s -(CH2)sCH(CHs)2 31 -CHs -CHaCOaH -CH3 -C(CHs)s -tCH2)sCH(CHaCHs)2 3 2 -CHa -CH2C02H -CHa -C(CHs)s -(CHa)zO(CHZ)4CHs 3 3 -CHs -CHaCOzH -CHs -C(CH3)3~-(GHz)sC,Hs 3 4 -CH3 -CH2C02H -CHs -C~CH3~3~-(CH2)sCH(CHs)2 .
3 5 -CHs -CH2CO2H~ -CH3 -C(CHs)s -(CHa)4CH(CHaCHs)a 3 6 -CHs -CH2COZH -CHs -C(CHs)s -(CH2)~CH3 3 7 -CH3 -CH2CO2H -CHs -C(CHs)s -(CH2)~CH(CH3)2 3 8 -CHs -CH2CO2H -CHs -C(CHs)s -(CH2)loCHs 3 9~ -CHs -CH2CO2H =CH3 -C(CHs)s -(CH2)sCH(CHs)2 -CHs -CH2COZH -CHs -C(CHa)3 -(CHz)lCHs 4 1 -CHs -CH2C02H -CHs -C(CHs)s -(CH2)9CH(CH3)2~
~
Table 3 Rs \ ~~ R4=-NHCOR' R4 Rs ~p~ R1 R2 R3 R7 R6 4 2 -CH3 -CHzCO2H -CH3 -C(CHs)aC4H9-(CHz)SCHs 4 3 -CH3 -CH2CO2~T -CH3 -C(CH3)2C:~Hs-(CHz)sCHs -CHs rC.H2CO2H .-CHa. -CfCH3~C~Hs-(CHa)7CHs , 4 5 -CHs -CH2C.O2H -CH3 -C(CHs)2CsHn-(CH2)SCHs 4 6 -CHs -CH2C02H -CH3 -C(CHs)2CsH13-(CH2)sCHs 4 7 -CHs -CHzCOaH -CH3 -C(CH~)zCsHi3-(CH2)?CH3 4 $ -CH3 -CHaCOaH -CH3 -C(CH3~C8H1?-(CHa)sCHa -CHs -GHaC02H -CHs -C(CHs)aCBHm. -(CHz)sCHs -CH3 -CH2CO2H -CHs -C(CHa)2CsIii7-(CH2)7CH3 1 -CHzCHs -CHaCOzH -CHzCHs -C(CHs)s . -(CHa)sCHs .
5 2 "~~~H3 -CHaCOzH -CHzCHa -C(CHs)s -(CHz)sCHs 5 3 -CH2CHs -CH2C02H -CH2CHs -C(CHs)s -(CH2)7CH3 5 4 -CHzCHs -CH2CO2H -CHaCHs -C(CHa)s -(CH2)aCH3 ~ ~
5 5 -CHaCHs -CHzCO2H -CH2CHa -C(CHs)s -(CH2)sCHs 5 6 -OCHs -CHzC02H -OCHa -C(CHa)s -(CHZ)sCHs 5 7 -OCHs -CH2C02H -OCHs -C(CHa)s -(CH2)sCHa .
5 $ -OCHs -CH2C02H -OCHs -C(CHs)s -(CH2~rCH3 5 9 -OCHs -GH2C02H -OCHs -C(CHs)3 =(CH2)BCHs 6 0 -OCHs -CH2CO2H -OCH3 -G(CHs)a -(CH2)sCH3 6 1 -GHQ -GHZOH . -CHs -C(CHs)s -(CH2)SCHs 6 2 ' -CHs -CH~OH -CHs -C(CHs)s -(CH2)sCHs Table ~
R~=-,~1~HC0R' RZ. R3. R7. Rs 6 3 -CHs -CH2~H -CH3 -C(CHs)s -(CHa)sCHa 6 4 -CHa -CHzOH -CH3 -C(CHs)s -(CHZ)sCHa 6 5 .-CHs -CHaN(CHs)z-CHs -C(CH8)s -(CHz)sCHa 6 6 ~-CH3 -CH2N(CHs)2-CHs -C(CHs)3 -(CH2)sCHs ~
~ 7 -CH3 -CH2N(CHs)2-CHa ~C(CH3)3 -(CHz)sCH3 g $ -CHs ~ -CH2N(CH3~ ~ =GHs ~: C(CHa)s -(CHa)sCHs .
6 9 -Hv vCIi.~CC2H -CHs' -C(CHs)s -(CH2)sCH3 7 0 .-H -CH2CO2H -CHs -C(CHs)s -(CH2)sCHs 7 1 ' -H -CH2C~2H -CHs -C(CHs)s -(CH2)~CH3.
7 2 -H -CH2C02H -CH3 -C(CHa)s -(CH2)BCHa -H =CHaC02H -CHs -C(CHs)s -(CH2~CHs.
~
7 4 -H -CH2~H ' -CHa -C(CH3)s -(CH2)sCH3 7 ~- -H' ' -CH2CH =CH3 -C(CHs)a -(CHz)sCHs .
7 6~ -H -CH2~H -CHs -C(CH3)s -(CH2)7CH3 -H .-CH2~H -CHs -C(CHs)s -(CH2)aCHs , 7 8 ~ ' -H -CH2CH -CHs -C(CHs)s -(CH2)sCHs . 7 -H -CH2N(CH3)2-CHs -C(CHs)s -(CH2)5CH3~
g , $ ~ -H -CH2N(CHa)2-CHs -C(CHs)s -(CH2)sCHs $ 1 , -H . -CHZN(CHs)2-CHs -C(CHs)s -(CHz)7CHs $ 2 -H -CHaN(CHs)z-GHs -C(CH3)s -(CHz)sCHs $ 3 . -H -CH2N(CHs)z-CHs -C(CH3)s -(CHz)sCHs Table 5 R1 R$
~2 R4=-NHCOR' Rs ExampleR I R 2 ' R 3 R.7 ~ R~ R s $ 4 -C:EIs -H -CH3 -C(CH3)s-(CH2)2CO2H -(CH2)SCHs $ 5 -CFi3 -H -CHs -C(CHs)3-(CH2)2C02H -(CH2)sGH3 $ 6 -CHa -H -CHa -C(CHs)s(CH2)zOH -(CH2)sCHs -$ 7 -CFi3 -H, -CHs -C(CH3)3-(CH2)20H -(CH2)sCH3 $ $ -C.Fi3 -H -CHs -C(CHs)s-(CHa)aN(CHs)a-(CH2)sCHa .
$ 9 -CHs -H. -CH$ -C(CH3)~-(CH2)21V(CH3)2-(CH2)6CH3 9 0 -CHs -H -CH3 -C(CH3)s-(CH2)2N(CHs)2-(CH2)7CHs y Table 6 R4=-NHCONHR'~
R4 R°
Example R 1 R 2 R 3 R 7~ R s -CH3 -CH2CO2H -CHs -(CHz)sCHa -(CH2)~CH3 g 2 -CFi3 -CHaCOaH -CHa -(CH2)sCH.~ -(CH2)sGH~~
9 3 -CHs -CH2C02H -CH3 -(CH2)3CH3 -(CH2)sCHs g 4 -CHzCHs -CH2C02H -CH2CHa -(CHz)aCH3 =(CH2)~CH3 .
9 5 -CH2CH3 -CH2CO2H -CH2CHs -(CHa)sCHs -(CHz)sCHs ~
9 6 -CHaCH3 -CH2COaH -CH2CHs -(CH2)sCHa -(CH~)sCHs ~ 7 -OCH3 -CH2C02H -OCH3 -(CHa)sCHs -(CH2)~CH3 g $ -OnHs ~ -CH2C02H -OCHs -(CH2)3CH3 -(CH2)BCHs g g -O'CH3 -CH2C02H -OCH3 -(CHz)aCH3 -(CHz)9CHs Table 7 R~
R3 \ N~ R~=-NHCOR' R4 Rs Ri R2 R3 R7 R6 1 0 0 -C;Hs -CH2CO2H -CHs -C(CHs)a -(CH2)$CHs 1 ~ 1 -C:Hs -CH2C02H, -CHa -C(CH3)3 -(CH2)sCHs 1 ~ 2 -CH2CHs -CH2C02H -CH2CHs -C(CHs)s -(CH2)~CHa I 0 3 -GH2CHs -CH2C02H -CH2CHs -G(CHs)s -(CH2)aCHs 1 ~ 4 -CH:2CHs -CH2C.02H -CHaCHs -C(CHa)s -(CH2)sCH3 1 0 5 -~CH3 -CH2C02H -~CH3 -C(CHa)s -(CH2)7CH3 1 d 6 -OCHs -CH2C02H -OCH3 -C(CH3)3 -(CH2)sCHs 1 0 7 -OCH3 -CH2CO2H -OCH3 -C(CHa)s -(CH2)sCHa _ CA 02233842 1998-04-02 Table $
R4 Rb R~=-NHCOR' R1 Rz Rs Rr Rs 1 ~ -CHs =CIi2CO2H-CH3 -(CH2)2OCH3=(CH2~tCH3 8 ~
1 0 -CHs -CH2CO2H~ -CHs-(CH2)2$CH~-(GH2nCH3 1 1.0 -CHa -CH2C02H. -CHs~ -(CH2ytCHa.
1 1 -CHs -CH2CO2H-CH3 _~2~ -{CH2yrCHa 1 .
1 ~ -CH3 -CH2C02H-CHs -~ ~-(CH2nCH3 1 '2 1 1 -CHs -CH2CO2H-CHs -~2 ~ -(CH2nCHa:
~3 .
I i -CHs -CH2CO2H-CHa -C(CH3)s "-(CH2~2S(CH2)3CH3 1 I -CHa -CH2C02H' -CH3-C{CHs)a I 1 =H ~-G~C02Ft-CHs -C(CHs)3 -(CH2y~CH~:
Table 9 R 3=-N. H C 0 R' 'N
.R4 Rs Examp R i . R z. RQ-. . R z R s 1 7 -CH2C02H -CH3 -CHs -C(CH~3)3 -(CH2)SCHs-1 1 $ -CH2CO2H -CHs -CHs -C(CI-i3)& -(CH2)aCHa 1 1 9 'CH2!CO2H -CHs -CHa -C(CHs)s -(CH2)~.OCH3 The 'H-NMR values of the compound of the above Examples 13-119 are shown in the following.
Examp le 13 : 0 . 7 -~-1.1 ( 3H, br-t ) , 1 .1 -~-1. 7 ( 6H, m ) , 1. 33 ( 9H, s ) , 2. O1 (3H, s) , 2.15 (3H, s) , 2.70---3.10 (~4H, m) , 3. ~+1 (2H, t) , 3. 56 (2H, s) , 7. 6 -~-8.1 (2H, br) .
Example 1~ : 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), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (~4H, m), 3.~1 (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 (~H, m), 3.~1 (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 (~H, m), 3.3 - 3.6 (6H, m), 3.56 (2H, s), 7.6 - 8.1 (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 (~tH, m), 3.~1 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br).
Example 19 : 0.7 - 1.70 (IOH, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.'70 - 3.10 (3H, m), 3.~t1 (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.~1 (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 (~H, 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.~1 (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 (uH, m), 3.3 - 3.6 (6H, m), 3.56 (2H, s), 7.6 - 8.1 (2H, br).
Example 2~ : 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 (~H, m), 3..41 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (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), 2.70 - 3.10 (4H, m), 3.~1 (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 (~H, m), 3.~1 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br).
Example 28 : 1.59 (3H, br-t), 1.0 - 1.7 (~tH, 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 29 : 0.7 - 1.70 (13H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (~H, m), 3.~1 (2H, t), 3.56 (2H,s), 7.6 8.1 (2H,br).
-Example30 : (6H,d), 1.1 1.8 (9H,m), 3H, s), 0.87 - 1.33 (9H, s), 2.01 ( 2.15 (3H,s), 2.70 - 0 , 3.~1 (2H, t), 3.1 (4H, m) 3.56 (2H,s), 7.6 8.1 (2H,br).
-Example31 : (6H,br-t), 0 .Z 9H, ), 1.33 (9H, s), 1.59 1. - ( m 2.01 (3H,s), 2.15 (3H,s), 2.703.10 (4H, m), 3.~1 (2H,t), 3.56 (2H,s), 7.6 8.1 (2H, br).
-Example32 : (3H,br-t), 0 .7 6H, ), 1.33 (9H, s), 1.59 1. - ( m 2.01 (3H,s), 2.15 (3H,s), 2.70- 3.10 (~H, m), 3.3 - 3.6 (6H,m), 3.56(2H,s), 7.6 - 8.1 (2H, br).
Example33 : 1.10 .1 1.7 (1~H, m), 1.33 s), 0.7 (3H, - (9H, - br-t), 2.01 (3H,s), 2.15 (3H,s), 2.70- 3.10 (4H, m), 3.~1 (2H,t), 3.56 (2H,s), 7.6 8.1 (2H, br).
-Example3~ : (6H,d), 1.1 1.8 (11H, 1.33 (9H, s), 0.87 - 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).
-Example35 : (6H,br-t), 0 m), 1.33 (9H, s), i"59 1. -1.7 (11H, 2,.01 (3H,s), 2.15 (3H,s), 2.70- 3.10 (~H, m), 3"~1 (2H,t), 3.56 (2H,s), 7.6 8.i (2H, br).
-Example36 : 1.10 1.7 (16H, m), 1.33 s), 0"~ (3H, (9H, - br-t), 1.1 -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).
-Example37 : (6H,d), 1.1 - (13H, 1.33 (9H, s), 0.87 1.8 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).
-Example38 : - 0 1.1 - (18H, m), 1.33 s), 0.7 1.1 (3H, 1.7 (9H, br-t), 2.01 (3H,s), 2.15 (3H,s), 2.70- 3.10 (~H, m), 3.~1 (2H,t), 3.56 (2H,s), 7.6 - 8.1 (2H, br).
Example39 : (6H,d), 1.1 - (15H, 0.87 1.8 m), 1.33 (9H, s), 2.01 (3H,s), 2.i5 (3H,s), 2.70- 3.10 (4H, m), 3.41 (2H,t), 3.56 (2H,s), 7.6 - 8.1 (2H, br).
Example~0 : - 0 -t),1.1 - (20H, m), 1.33 s), 0.7 1.1 (3H, 1.7 (9H, br 2.01 (3H,s), 2.15 (3H,s), 2.70- 3.10 (~H, m), 3.~1 (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), 2.70 - 3.10 (~H, m), 3.u1 (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), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (~H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br).
Example ~3 : 0.7 - 1.10 (6H, br-t), 1.0 - 2.0 (22H, m), 2.01 (3H, s), 2..15 (3H, s), 2.70 - 3.10 (~H, m), 3.~1 (2H, t), 3..56 (2H, s), 7.6 - 8.1 (2H, br).
Example ~4~.: 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 (~H, m), 3.~1 (2H, t), 3..56 (2H, s), 7.6 - 8.1 (2H, br).
Example ~5 : 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 (~H, m), 3.41 (2H, t), 3..56 (2H, s), 7.6 - 8.1 (2H, br).
Example ~6 : 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 (~H, m), 3.41 (2H, t), 3..56 (2H, s), 7.6 - 8.1 (2H, br).
Example ~7 : 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.~1 (2H, t), v 3.56 (2H, s), 7.6 - 8.1 (2H, br).
Example ~8 : 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 (~H, m), 3.~t1 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br).
Example ~9 : 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.~1 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (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 (~tH, 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 (1~H, m), 1.33 (9H, s), 2.~2 (2H, q), 2.46 (2H, q), 2.7 - 3.1 (~H, 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.~2 (2H, q), 2.46 (2H, q), 2.7 - 3.1 (~H, m), 3.~1 (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.~2 (2H, q), 2.~6 (2H, q), 2.7 - 3.1 (~4H, m), 3.~1 (2H, t), 3.56 (2H, t), 7.6 - 8.1 (2H, br).
Example 5~ : 0.7 - i.1 (3H, br-t), 1.0 - 1.7 (20H, m), 1.33 (9H, s), 2.~2 (2H, q), 2.46 (2H, q), 2.7 - 3.1 (~H, m), 3.~1 (2H, t), 3.56 (2H, t), 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.~2 (2H, q), 2.46 (2H, q), 2.7 - 3.1 (~H, m), 3.~t1 (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 (~+H, m), 3.32 (2H, t), 3.~5 (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 (IOH, m), 1.33 (9H, s), 2..50 - 3.10 (~H,im), 3.32 (2H, t), 3.~5 (2H, s),T
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 - i.7 (12H, m), 1.33 (9H, s), .2.50 - 3.10 (4H, m), 3.32 (2H, t), 3.~5 (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), 1.0 - 1.7 (1~4H, m), 1.33 (9H, s), 2..50 - 3.10 (~tH, m), 3.32 (2H, t), 3.45 (2H, s), 3.73 (3H, s), 3.77 (3H, s), 7.6 - 8.1 (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.~5 (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), l.i - 1.7 (8H, m), 1.33 (9H, s), 2.1~t (3H, s), 2.22 (3H, s), 2.70 - 3.10 (~H, m), 3.~1 (2H, t), x.62 (2H, s), 6.86 (2H, br).
Example 62 : 0.7 - 1.1 (3H, br-t), 1.1 - 1.7 (IOH, m), 1.33 (9H, s), 2.14 (3H, s), 2.22 (3H, s), 2.70 - 3.10 (4H, m), ~
3.~1 (2H, t), x.62 (2H, s), 6.86 (2H, br).
Example63 : 1.1 (3H, br-t), 1.1 - 1.7 (1~.H, m), 1.33 (9H, s), 0.7 -2.14 (3H, s), 2.22 (3H, s), 2.70 - 3.10 (~H, m), 3.41 (2H, t), 4.62 (2H, s), 6.86 (2H, br).
Example64 : 1.1 (3H, br-t), 1.1 -.1.7 (16H, m), 1.33 (9H, s), 0.7 -2.1~ (3H, s), 2.22 (3H, s), 2.70 - 3.10 (4H, m), 3.~1 (2H, t), x.62 (2H, s), 6.86 (2H, br).
Example65 : 1.1 (3H, br-t), 1.1 - 1.7 (8H, m), 1.33 (9H, s), 0.7 -2.00 (6H, s), 2.09 (3H, s), 2.23 (3H, s), 2.70 -3.20 (~H, m), 3.31 (2H, s), 3.38 (2H, t), 6. 8~4 ( br) .
H, Example66 : 1.1 (3H, br-t), 1.1 - 1.7 (10H, m), 1.33 (9H, s), 0.7 ~
-2.00 (6H, s), 2.23 (3H, s), s), 2.09 (3H, 2.70 -3.20 (~H, m), 3.31 (2H, s), 3.38 (2H, t), 6.84 (1H, br).
Example67 : 1.1 (3H, br-t), i.1 - 1.7 (1~4H, m), 1.33 (9H, s), 0.7 -2,.00 (6H, s), 2.09 (3H, s), 2.23 (3H, s), 2"70 -3.20 (~tH, m), 3.31 (2H, s), 3.38 (2H, t), 6"8~ (1H, br).
Example68 : 1.1 (3H, br-t), 1.1 - 1.7 (16H, m), 1.33 (9H, s), 0"7 -2"00 (6H, s), 2.09 (3H, s), 2.23 (3H, s), 2..70 -3.20~(~H, m), 3.31 (2H, s), 3.38 (2H, t), 6.. 84 ( br) .
H, Example69 : - (3H, br), 1.0 - 1.7 (8H, m), 1.33 (9H, s), 0..7 1.0 ~
1.97 (3H, , 2.7 - 3.1 (~H, m), 3.35 (2H, t), s) 3.~7 (2H, s), 6.90 (1H, s), 7.6 - 8.1 (2H, br).
Example70 : - (3H, br), 1.0 - 1.7 (10H, m), 1.33 (9H, s), 0.7 1.0 1.97 (3H, s), 2.7 - 3.i (~H, m), 3.35 (2H, t), 3.~7 (2H, s), 6.90 (1H, s), 7.6 - 8.1 (2H, br).
Example71 : - (3H, br), 1.0 - 1.7 (12H, m), 1.33 (9H, s), 0.7 1.0 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).
Example72 : - (3H, br), 1.0 - 1.7 (14H, m), 1.33 (9H, s), 0.7 1.0 1.97 (3H, s),2.7 3.1 (~H, m), 3.35 (2H, t), -3.~7 (2H, s),6.90 (1H,s), 7.6 - 8.1 (2H, br).
Example73 : 1.0 (3H,br), 1.0 1.7 (16H, m), 1.33 (9H, s), 0.7 -1.97 (3H, s),2.7 3.1 (~H, m), 3.35 (2H, t), -3.~7 (2H, s),6.90 (1H,s), 7.6 - 8.1 (2H, br).
Example7~ : 1.0 (3H,br), 1.0 - 1.7 (8H, m), 1.33 (9H, s), 0.7 -2.07 (3H, s),2.89 (2H,t), 3.09 (2H, t), 3.~0 (2H, t), x.51 (2H, s),6.90 (1H,s), 7.0 - 7.~ (2H, br).
Example75 : 1.0 (3H,br), 1.0 - 1.7 (10H, m), 1.33 (9H, s), 0.7 -2.07 (3H, s),2.89 (2H,t), 3.09 (2H, t), 3.~0 (2H, t), x.51 (2H, s),6.90 (1H,s), 7.0 - 7.~ (2H, br).
Example76 : 1.0 (3H,br), 1.0 - 1.7 (12H, m), 1.33 (9H, s), 0.7 -2.07 (3H, s),2.89 (2H,t), 3.09 (2H, t), 3.40 (2H, t), x.51 (2H, s),6.90 (1H,s), 7.0 - 7.4 (2H, br).
Example77 : 1.0 (3H, 1.0 - 1.7 (1~H, m), 1.33 (9H, s), 0.7 br), -2.07 (3H, s),2.89 (2H,t), 3.09 (2H, t), 3.~0 (2H, t), 4.51 (2H, s),6.90 (1H,s), 7.0 - 7.~ (2H, br).
Example78 : 1.0 (3H, 1.0 - 1.7 (16H, m), 1.33 (9H, s), 0.7 br), -2.07 (3H, s),2.89 (2H,t), 3.09 (2H, t), 3.~0 (2H, t), x..51 (2H, s),6.90 (1H,s), 7.0 - 7.~ (2H, br).
Example79 : 1.0 (3H, 1.0 - 1.7 (8H, m), 1.33 (9H, s), 0.7 br), -2.,08 (3H, s),2.23 (6H,s), 2.89 (2H, t), 3.1~ (2H, t), 3..30 (2H, s),3.38 (2H,t), 6.84 (1H, s), 6.90 (1H, br).
Example80 : 1.0 (3H, 1.0 - 1.7 (10H, m), 1.33 (9H, s), 0,.7 br), -2,.08 (3H, s),2.23 (6H,s), 2.89 (2H, t), 3.1~ (2H, t), 3.30 (2H, s),3.38 (2H,t), 6.8~ (1H, s), 6.90 (1H, br).
Example81 : - (3H, - 1.7 (12H, m), 1.33 (9H, s), 0.7 1.0 br), 1.0 2.08 (3H, s),2.23 (6H,s), 2.89 (2H, t), 3.1~ (2H, t), 3.30 (2H, s),3.38 (2H,t), 6.8~ (1H, s), 6.90 (1H, br).
Example82 : - (3H, - 1.7 (1~H, m), 1.33 (9H, s), 0.7 1.0 br), 1.0 2.08 (3H, s),2.23 (6H,s), 2.89 (2H, t), 3.1~ (2H, t), 3.30 (2H, s),3.38 (2H,t), 6.8~ (1H, s), 6.90 (1H, br).
Example83 : - , - 1.7 (16H, m), 1.33 (9H, s), 0.7 1.0 1.0 (3H, br) 2.08 (3H, s), 2.23 (6H, s), 2.89 (2H, t), 3.1.4 (2H, t), 3.30 (2H, s), 3.38 (2H, t), 6.8~ (iH, s), 6.90 (1H, br).
Example 8~t: 0.7 - i.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.i6 (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 (IOH, m), 1.38 (9H, s), 1.60 - 2.20 (2H, m), 2.07 (3H, s), 2.16 (3H, s), 2.20 - 2.~0 (2H, m), 3.10 - 3.80 (3H, m), 3.27 (2H, br-t), 6.~5 (1H, s), 7.20 - 7.60 (2H, br).
Example 86 : 0.7 - 1.0 (3H, br-t), 1.0 - 2.0 (iOH, m), 1.33 (9H, s), 2.07 (3H, s), 2.16 (3H, s), 2.60 - 3.60 (7H, m), 6.~~ (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.~~ (1H, s), 6.78 (2H, br).
Example 88 : 0.7 - 1.0 (3H, br-t), 1.0 - 2.0 (IOH, 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.~5 (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 (5H, m), 6.~5 (1H, s), 7.2 (1H, br).
Example 90 : 0,.7 - 1.0 (3H, br-t), 1.0 - 2.0 (1~H, 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 -~~..00 (6H, m), 3.55 (2H, s), ~+. 80 ( 1 H, br) , 5. 50 ( 1 H, br) , 6. X40 ( 1 H, br) .
Example 92 : 0.70 - 1.10 (6H, m), 1.10 - 1.90 (18H, m), 2.10 (6H, s), i.80 - 2.00 (2H, br-t), 2.00 - x..00 (6H, m), 3.55 (2H, s), 4.80 (1H, br), 5.50 (1H, br), 6.~0 (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 - x.00 (6H, m), 3.55 (2H, s), ~. ( 1 H, br) , 5. 50 ( 1 H, br) , 6. ~0 ( 1 H, br) 80 .
Example 0.70- 1.10 (6H, m), 1.10 - 1.90 (22H, m), 2.09 (4H, 9~ : br-t), 1.80- 2.00 (2H, br-t), 2.00 - x.00 (6H, m), 3.55 (2H, s), ~. ( 1 H, br) , 5. 50 ( 1 H, br) , 6. ~+0 ( 1 H, br) 80 .
Example 0.70- 1.10 (6H, m), 1.10 - 1.90 (2~H, m), 95 :
2.09(~H, br-t), 1.80 - 2.00 (2H, br-t), 2.00- 4.00 (6H, m), 3.55 (2H, s), X4.80 (1H, br), 5.50(1H, br), 6.40 (1H, br).
Example 0.70- 1.10 (6H, m), 1.10 - 1.90 {26H, m), 96 :
2.09(~H, br-t), 1.80 - 2.00 (2H, br-t), 2.00- 4.00 (6H, m), 3.55 (2H, s), x+.80 (1H, br), 5..50(1H, br), 6.~0 (1H, br).
Example 0..70- 1.10 (6H, m), 1.10 - 1.90 (16H, m), 97 :
1"80- 2.00 (2H, br-t), 2.00 - x.00 (6H, m), 3..35(2H, s), 3.7~ (3H, s), 3.78 (3H, s), X4.80 (1H, br), 5.50(1H, br), 6.40 (1H, br).
Example 0.70- 1.10 (6H, m), 1.10 - 1.90 (18H, m), 98 :
1.80- 2.00 (2H, br-t), 2.00 - 4.00 (6H, m), 3.35(2H, s), 3.7~ (3H, s), 3.78 (3H, s), 4.80 (1H, br), 5.50(1H, br), 6.~0 (1H, br).
Example 0.70- 1.10 (6H, m), 1.10 - 1.90 (20H, m), 99 :
1.80- 2.00 (2H, br-t), 2.00 - 4.00 (6H, m), 3.35(2H, s), 3.7~t (3H, s), 3.78 (3H, s), x.80 (1H, br), 5.50(1H, br), 6.~0 (1H, br).
Example 70 - 1.10 (3H, br-t), 1.10 - 1.70 (1~H, m), 100 : 0.
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 : 70 - 1.10 (3H, br-t), 1.10 - 1.70 (IOH, m), 101 0.
1. 33 (9H, s), 2.10 (3H, s), 2.39 (3H, s), 3.71 (2H, br), 3. 99 (2H, br-t), x.15 (2H, s), 6.38 (1H, d), 6.89 (1H, d).
Example 70 - 1.10 (3H, br-t), 1.10 - 1.70 (18H, m), 102 : 0.
1.33 (gH, s), 2.08 (2H, q), 2.~6 (2H, q), 3.71 (2H, br), 3.99 (2H, br-t), x.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.~6 (2H, q), 3.71 (2H, br), 3.99 (2H, br-t), 4.15 (2H, s), 6.38 (1H, d), 6.89 (1H, d).
Example 10~.; - 1.10 (3H, br-t), 1.10 - 1.70 (22H, m), 0.70 1.33 (9H, s), 2.~2 (2H, q)., 2.~6 (2H, q), 3.71 (2H, br), 3.99 (2H, br-t), x.15 (2H, s), 6.38 (1H, d), 6.89 (1H, d).
Example 105 : - 1.10 (3H, br-t), 1.10 - 1.'70 (12H, m), 0.70 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 : - 1.10 (3H, br-t), 1.10 - 1.70 (1~4H, m), 0.70 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 : - 1.10 (3H, br-t), 1.10 - 1.70 (16H, m), 0.70 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 : - 1.10 (3H, br-t), 1.10 - 2.00 (15H, m), 0.70 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (~tH, m), 3.37 (3H, s), 3.~0 (2H, t), 3.41 (2H, t), 3.56 (2H, s), 7.60 - 8.10 (2H, br).
Example 109 : - 1.10 (3H, br-t), 1.10 - 2.00 (15H, m), 0.70 2.01 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.~5 (2H, s), 2.70 - 3.10 (~H, m), 3.~1 (2H, t), 3.56 (2H, s), 7.60 - 8.10 (2H, br).
Example li0 ; - 1.10 (3H, br-t), 1.10 - 2.00 (23H, m), 0.70 T
=
2.01 (2H, t), 3.10 (~H, m), 3.~1 (3H, s), 2.70 -3.56 (2H, s), 7.60 - 8.10 (2H, br).
Example 111 : - 1.10 (3H, br-t), 1.10 - 2.00 (25H, m), 0.70 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.60 - 8.10 (2H, br).
Example 112 ;; - 1.10 (3H, br-t), 1.10 - 1.70 (12H, m), 0.70 2.Oi (3H, s), 2.15 (3H, s), 2.70 - 3.10 (~H, m), 3.~1 (2H, t), 3.56 (2H, s), 7.30 - 7.80 (3H, m), 7.60 - 8.10 (2H, br), 8.12 (2H, d).
Example 113 :~~.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.~1 (2H, t), 3.53 (2H, s), 3.56 (2H, s), '7.30 (5H, s), 7.60 - 8.10 (2H, br).
Example 11~ :_1.59 (3H, br-t), 1.10 - 1..70 (~H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.10 - 2.50 (~H, m), 2.70 - 3.10 (~H, m) , 3. ~1 (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), x.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), 1.3~ (9H, s), 2.02 (3H, s), 2.90 (2H, t), 3.13 (2H, t), 3.38 (2H, t), 3.50 (2H, s), ~t.12 (2H, q), 6.80 (1H, br), 6.85 (1H, s).
Example 117 : 0.70 - 1.10 (3H, br-t), 1.10 - 2.00 (8H, m), 1.23 (9H, s), 2.07 (3H, s), 2.24 (3H, s), 2.70- 3.10 (~+H, 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 (~H, 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 (~tH, m), 3.39 (2H, t), 3.35 (2H, s), 6.60 - 7.50 (2H, br).
Example 120 N-(1-Octyl-5. carboxyethyl-~,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (1) N-(1-Octyl-5-chloroethyl-~,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (3.0 g) was dissolved in CH3CN (30 ml), and NaCH (3.7 g) and 18-crown-6 (0.1 g) were added, which was followed by refluxing for 17 hr under a nitrogen atmosphere. CHsCN was evaporated under reduced pressure, and water (100 ml) was added to the obtained residue. The mixture was extracted twice with AcOEt (100 ml). The AcOEt layer was washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate, and AcOEt was evaporated under reduced pressure. The obtained residue was purified by silica geI column chromatography (eluent: AcOEt/benzene=1/i0 - 1/5) to give l.i~ g of N-(1-octyl-5-cyanoethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
IR (Nujol)cm -' : 2243, 1647, 1601.
'H-NMR (CDCls) Q
0.88 (3H, br-t, J=6.OHz, -(CHz)~CHs), 1.10-.-1.90 (12H, m, -CHz(CHz)sCHs), 1.33 (9H, s, -C(CHs)3), 2.05, 2.15 (3H x 2, s x 2, indoline C4,6 -CH3), 2.38 (2H, t, J=7Hz, -CHZCN), 2.70-3.30 (6Ei, m, indoline C3-Hz, >NCHz-, -CHZCHaCN), 3.~1 (2H, t, .J=9Hz, indoline Cz-Hz), 6.81 (1H, br, -CONH-).
(2) N-(1-Octyl-5-cyanoethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (1.1~ g) was dissolved in EtOH (26 ml), and a solution of NaOH (1.1 g) i:n water (7.5 ml) was added, which was followed by refluxing for 1~ hr under a nitrogen atmosphere. EtOH was evaporated under reduced ;pressure. The obtained residue was dissolved in warm water (30 ml) .and washed with AcOEt (30 ml). The aqueous layer was neutralized with 2N HC1 and extracted with CHC13 (50 ml). CHC13 layer was evaporated under reduced pressure to give 830 mg of the title compound.
IR (Nujol)cm -': 172, 1655, 1618.
'H-NMR (CDCls) Q
0.86 (3H, br-t, J=5.OHz, -(CHz)~CH3 ), 1.10~ 2.10 (12H, m, ' CA 02233842 1998-04-02 -CHz(CHz)sCH3), 1.42 (9H, s, -C(CHs)3), 2.12, 2.26 {3Hx 2, s x 2, indoline Ca , s -CH3 ) , 2. 30-~-r2.60 (2H, m, -CHZCOz-) , 2. 90-~-3. ~t0 (E~H, m, indoline C3-H2, >NCHz-, -CH2CHzCOz-) , 3.78 (1H, br, indoline Cz-Hz), 7.70 (1H, br -COzH), 9.91 (1H, br, -CONH-).
Examples 121-123 The compounds of Table 10 were obtained according to the method of the above Exacruple 120.
Table 10 R~
/w R4 = -Nt-(COR7 ~R R
. ExampleE2' R 2 R 3 R 7 ft s 1 2 1 -CHa -CH2C02H -CHs -C{CHs}~ -(Cti2)sS(CHZ)3C(-I~
1 2 2 -GH3 -CHzG02H -GHQ -C(GHs}s -tEH2}3S(CH2)3G.H3 ~ .
1 2 3 -CH3 -{CH2}3C02H -CH3 -C(CH3)3 -{Ct-f2}7CH3 The 'H-NI~iR values of the compounds of the above Examples 121-123 are shown in t;he following.
Example 121 : 0. 91 (3H, br-t) , 1. 00 -~-1.80 ( 12H, m) , 1.3'7 (9H, s) , 1.93 (3H, s), 2.06 (3H, s), 2.~7 (~H, 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.~8 (4H, br-t), 2.90 ~-3.~0 (4H, m), 3.~0---3.80 (2H, m), 3.61 (2H, s), 7.34 (1H, br), 8.~8 (1H, br).
Example 123 : 0.86 (3H, br-t), 1.00 -~-1.50 (12H, m), 1.42 (9H, s), 2.00-~-2.90 (6H, m), 2.11 (3H, s), 2.23 (3H, s), 2.90-3.30 (4H, m), 3.~0 (2H, br), 6.10 (1H, br), 9. 21 ( 1 H, br) .
Example 12~+
N-(1-Octyl-Ei-ethoxycarbonylmethyl-5,'7-dimethyl-1,2,3,x-tetrahydro-quinolin-8-yl~i-2,2-dimethylpropanamide (1) 3,5-Xylidine (5.0 g) and acrylonitrile (2.3 g) were dissolved in acetic acid (~'_ ml) , and the mixture was stirred at 60°C for 20 lv~.
Ethyl acetate (200 ml) was added to the reaction mixture and neutralized with saturated aqueous solution of sodium hydrogencarbonate.
The mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/benzene=1/10 - 1/3) to give 4.5 g of oily j3-(3,5-dimethyl-anilino)propionitrile.
IR (Nujol) cm-' ; 2248, 1602.
' H-NMR (CDC1:; ) 8 ;
2.2~ (6H, s, Cs.S-CH3), 2.60 (2H, t, J=7.5Hz, -CHzCHzCN), 3.48 (2H, t, J=7.5Hz, -CHZCH2CN), 3.90 (1H, br, >NH), 6.2~ (2H, s, C2,s-H), 6.~3 (1H, s, Co-H).
(2) ~3-(3,5-Dicnethylanilino)propionitrile (~..5 g) was dissolved in ethanol (50 m:1), and a solution of NaOH (5.1 g) in water (25 ml) was added, which was followed by refluxing for ~ hr. The solvent was evaporated under reduced pressure. 2N Hydrochloric acid was added to adjust the residue acidic, and the mixture was washed with chloroform (100 ml). The aqueous layer was concentrated to about 20 ml and allowed to stand. The precipitated crystals were collected by filtration and dried to give ~.0 g of j3-(3,5-dimethylanilino)propionic acid.
IR (Nujol) cm-' ; 1560.
'H-NMR (DMSO-ds) 2.29 (6H, s, Cs.s-CHs), 2.73 (2H, t, J=7.5Hz, -CHZCHZCO-), 3.~~ (2H, t, J=7.5Hz, -CHzCH2C0-), 7.0 (3H, s, C2.a.s-H), 9.80 (2H, br, -COZH, >NH).
(3) j3-(3,5-Dimethylanilino)propionic acid (1.2 g) was added by portions to sulfuric acid (60°C, 12 ml), and the mixture was stirred at the same temperature for 0.5 hr. The reaction mixture was poured ini:o ice water (100 ml) and extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/benzene=1/5 - 1/1) to give 750 mg of 5,7-dimethylquinolone as crystals.
IR (Nujol) cm-' ; 165, 1614.
' H-NMR (CDC1:, ) 8 ;
2.19 (3H, s, C5-CH3), 2.57 (3H, s, C~-CHs), 2.63 (2H, t, J=7.5Hz, C3-Hi), 3.~9 (2H, t, J=7.5Hz, C2-Hz), x.39 (1H, br, >NH), 6.32 (2H, s, C6.a-H).
Lithium a7Luminum hydride (687 mg) was suspended in ether (16 ml), and aluminum chloride (~+.2 g) was added. A solution of 5,7-dimethylquinolone (1.6 g) in ether (16 ml) was dropwise added and the mixture was refluxed for 0.5 hr. The reaction mixture was poured into ice water (100 ml) and extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfates. The solvent was evaporated under reduced pressure.
The obtained 5,7-dimethyl-1,2,3,4-tetrahydroquinoline was dissolved in chloroform (30 ml), and acetic anhydride (929 mg) was added, which was followed by stirring at room temperature for 1 hr. Chloroform (100 ml) was added to the reaction mixture, and the mixture was washed successively caith saturated aqueous solution of sodium hydrogencarbonate and water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/benzene=1/5 - 1/1) to give 1.5 g of oily 1-acetyl°5,7-dimethyl-1,2,3,x-tetrahydroquino7.ine.
IR (Nujol) cm-' ; 1625, 1614.
'H-NMR (CDC13) ~ ;
1.70-2.10 (2H, m, Cs-Hi), 2.21 (6H, s x 2, -COCHs, Ar-CHs), 2.29 (3H, s, Ar-CH3), 2.5~t (2H, t, J=7.lHz, C4-HZ), 3.77 (2H, t, J=7.lHz, C2-H2), 6.83 (2H, s, CG,8-H).
(5) 1-Acetyl-5,7-dimethyl-1,2,3,x-tetrahydroquinoline (3.0 g) was dissolved in c;onc. hydrochloric acid (6 ml), and 35~ formaldehyde solution (2.5 g) and zinc chloride 0400 mg) were added. The mixture was stirred at 40--50°C for 2 hr while blowing hydrogen chloride. The reaction mixture was poured into ice water (100 ml) and extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over° anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained 1-acetyl-6-chloromethyl-5,7-dimethyl-1,2,;3,x-tetrahydroquinoline was dissolved in acetonitrile (30 ml), and sodiiun cyanide (3.6 g) and 18-crown-6 (780 mg) were added, which was fol:Lowed by refluxing for 5 hr. The solvent was evaporated under reduced pressure, and the residue was extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform - chloroform/methanol=10/1) to give~2.~ g of oily 1-acetyl-6-cyanomethyl-5,7-dimethyl-1,2,3,x-tetrahydroquinoline.
IR (Nujol) cm-' ; 228, 1650.
'H-NMR (CDCls) cs ;
1. 80-2. 20 (2:H, m, C3-H2 ) , 2. 21 , 2. 29 (3H x 2, s x 2, Cs. T-CH3 ) , 2.37 (3H, s, -COCHs), 2.68 (2H, t, J=7.5Hz, C4-HZ), 3.66 (2H, s, -CH2CN), 3.'76 (2H, t, J=7.5Hz, C2-Hi), 7.00 (1H, s, Ca-H).
. ' CA 02233842 1998-04-02 (6) 1-Acetyl-6-cyanomethyl-5,7-dimethyl-1,2,3,~+-tetrahydroquinoline (2.7 g) was dissolved in ethanol (30 ml), and a solution of NaOH (~.~4 g) in water (10 ml) was added, which was followed by refluxing for 10 hr under nitrogen. The. solvent was evaporated under reduced pressure, and the residue was extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate.
The solvent wa.s evaporated under reduced pressure. The obtained 6-carbamoylmethyl-5,7-dimethyl-1,2,3,x-tetrahydroquinoline was dissolved in N,N-dimethylformamide (10 ml), and octyl bromide (1.6 g), potassium carbonate (1.c'. g) and potassium iodide (166 mg) were added, which was followed by stirring at ~0°C far 10 hr in nitrogen. The reaction mixture was extracted with ethyl acetate (100 ml). After washing with water, the ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/
methanol=50/1 - 10/1) to give 600 mg of 1-octyl-6-carbamoylmethyl-5,7-dimethyl-1,2,5,4-tetrahydroquinoline as crystals.
IR (Nujol) cm-' ; 165, 162.
' H-NMR (CDC13~ ) 0.60-1.10 (3Ft, br-t, -(CH2)7CHs), 1.10-1.80 (12H, m, -(CHZ)eCHs), 1. 80-2.10 (2Fi, m, Cs-H2 ) , 2.16, 2. 2~ (3H x 2, s x 2, Cs, 7-CH3 ) , 2.63 (2H, t, J=7.5Hz, C4-Hi), 3.00-3.50 (~H, m, C2-Hi, >NCH2-), 3.57 (2H, s, -CH2C0-), 3.~~ (2H, br, -CONH2), 6.35 (1H, s, Ca-H).
(7) 1-Octyl-6--carbamoylmethyl-5,7-dimethyl-1,2,3,x-tetrahydroquinoline (2.5 g) was dLssolved in n-propanol (50 ml) and a solution of NaOH (3.0 g) in water (30 ml) was added, which was followed by stirring at 130°C
for 20 hr under nitrogen. The organic layer of the reaction mixture was separated and the solvent was evaporated under reduced pressure. The residue was dissolved in water (300 ml) and washed with ethyl acetate (100 ml). The aqueous layer was adjusted to pH 1-2 with 6N hydrochloric acid and extr<3cted with chloroform (200 ml). The chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained 1-octyl-6-carboxymethyl-5,7-dimethyl-1,2,3,4-tetrah.ydroquinoline was dissolved in ethanol (50 ml), and conc.
hydrochloric acid (4 ml) was added, which was followed by stirring at 70°C for 1 hr. The solvent was evaporated under reduced pressure.
The residue was neutralized with saturated aqueous solution of sodium hydrogencarbon.ate and extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography {eluent:
benzene) to give 1.0 g of oily 1-octyl-b-ethoxycarbonylmethyl-5,7-dimethyl-1,2,3.,4-tetrahydroquinoline.
IR (Nujol) cm-' ; i732, 1599.
'H-NMR (CDCIs) 8 ;
0.70-1.00 {3Hf, br-t, -(CHZ)~CHs), 1.10-1.80 (15H, m, -(CHa)sCHs, -COCH2CHs), 1.80-2.10 (2H, m, Cs-Hz), 2.12, 2.26 (3H x 2, s x 2, C5,7-CH3), 2.62 (2H, t, J=7.5Hz, C4-Hi), 3.00-3.30 (4H, m, C2-Hi, >NCHz-), 3.59 (2H, s, -CH2C0-), 4.13 (2H, q, J=7.OHz, -COCHZ-), 6.33 (1H, s, Cs-H).
(8) 1-Octyl-6-ethoxyca.rbonylmethyl-5,7-dimethyl-1,2,3,x-tetrahydro-quinoline (1.0 g) was dissolved in acetic anhydride (5 ml), and a solution of 7C)% nitric acid (517 mg) in acetic anhydride {3 ml) was dropwise added, which was followed by stirring at the same temperature for 0.5 hr. The reaction mixture was poured into ice water (50 ml), neutralized w9_th saturated aqueous solution of sodium hydrogencarbonate, and extracted with chloroform (50 ml). After washing with water, the chloroform la5rer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate/n-hexane=1/5) to give 700 mg of oily 1-octyl-6-ethoxycarbonylmethyl-5,7-dimethyl-8-nii:ro-1,2,3,4-tetrahydroquinoline.
IR (Nujol) cm-' ; 1732, 1527.
'H-NMR (CDCls) 8 0.70-1.00 (3H, br-t, -(CHZ)7CHs), 1.10-1.70 (15H, m, -(CHZ)sCHs, -COCH2CHs), 'i1.80-2.10 (2H, m, Cs-Hz), 2.16 (6H, s, Cs,~-CH3), > CA 02233842 1998-04-02 2.6~ (2H, t, J=7.5Hz, C4-H2), 2.70-3.20 (~H, m, C2-Hi, >NCHz-), 3.65 (2H, s, -CH2C0-), x.13 (2H, q, J=7.OHz, -COCH2-).
(9) 1-Octyl-6--ethoxycarbonylmethyl-5,7-dimethyl-8-nitro-1,2,3,4-tetra-hydroquinoline: (700 mg) was dissolved in ethanol (500 ml), and 10~
palladium-carton (200 mg) was added. The mixture was subjected to hydrogenation at room temperature under atmospheric pressure. 10~
Palladium-carbon was filtered off and the solvent was evaporated under reduced pressure. The obtained 1-octyl-6-ethoxycarbonylmethyl-5,7-dimethyl-8-ampno-1,2,3,4-tetrahydroquinoline was dissolved in chloroform {50 ml). Pivaloyl chloride (207 mg) and triethylamine (192 mg) were added under ice-cooling, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was washed successively with 596 aqueous citric acid and water, and dried over anhydrous sod:~Lum sulfate. The solvent was evaporated under reduced pressure. The: residue was purified by silica gel column chromatography (eluent: chlo»form - chloroform/methanol=10/1) to give 230 mg of oily title compound.
IR (Nujol) cm-' ; 1732, 1483.
' H-NMR (CDCl:a ) S ;
0.70-1.00 (3H, br-t, -(CH2)~CHs), 1.10-1.70 (15H, m, -(CHz)6CHs, -COCHZCHs), '1.35 (9H, s, -C(CH3)s), 1.80-2.10 (2H, m, Cs-Hi), 2.05, 2.11 {;3Hx 2, s x 2, Cs, z-CHs ) , 2. ~0-2.70 (~4H, m, C4-Hi, >NCH2-) , 2.80-2.90 (2H, m, C2-H2), 3.68 (2H, s, -CH2C0-), ~.1~. (2H, q, J=7.OHz, -COCH2-), 7.35 (1H, br, -CONH-).
Example 125 N-(1-Octyl-i5-carboxymethyl-5,7-dimethyl-1,2,3,x-tetrahydroquinolin-8-yl)-2,2-dimetllylpropanamide N-{1-Oct;yl-6-ethoxycarbonylmethyl-5,7-dimethyl-1,2,3,x-tetrahydro-quinolin-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 arid 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 60F25~ Art. 5714 (Merck), CHC13-MeOH (10:1), Rf value 0.5.
IR (Nujol) cm-' ; 1732, 1722.
' H-NMR (CDCls ) cs ;
0.70-1.00 (3H, br-t, -(CHa)~CH3), 1.10-1.70 (12H, m, -(CHz)sCHs), 1.35 (9H, s, -C(CHs)3), 1.80-2.10 (2H, m, Cs-Hz), 2.10 (6H, s, Cs,7-CHs), 2.~0-2.70 (~tH, m, C~-Hz, >NCHz-), 2.80-2.90 (2H, m, Cx-Hx), 3.68 (2H, s, -CH2C0-), 7.35 (1H, br, -CONH-), 9.50 (2H, br, 1/2H2S04, -COzH).
Examples 126-154 The compounds of Tables 11 and 12 were obtained according to the method of the above Example 12~..
Table 11 . Rj R2.
/.
R$ ~ ~N
R4 R6 R4 = -NHCOR~.
E~amPleR ~ R 2 R 3 R 7 . R -1 2 -GH3 -CH2CO2H -CH3 -C(CH3)3-(CH2)5CH3 1 2 -CH3 -CH2C0.2H -CH3 -C(CH3)3-CH2CH(CH2CH3)2 1 2 -CH.3 -CH2C02H -CH3 -C(CH3)3-(CH2)sCH3 1 2 -CHs -CH2G02H -CH3 -C(CHs)s-CH2 9 .
1. 3 -CH3 -CH2C02H -CH3w C(CH3)3 -(GH2)2CH(CH2CH3)2 7 ' -CH3 -CH2C02H -.GH3 -G(GH3)s'-(GH2)20(GH2~sGH3 3 ~
1 3 -CH3 -CH2C02H -CH3 -C(CH3)s-(CH2)2S(CH2)3CH3 -cHs -cr~co2H -cHs -c(GHs?s -CH2C:H 2-~~
1 S -GH3 -GH2G02H -CH3 -G(GH~)3-(~H2~3GH(GH2GH3)2 1 3 -CH3 -GH2CO2N -GH3 -C(CH3)3-(CH2)30(GH2)3CH3 1 3 -CHs -CH2C02H -CHs -C(CHs)s-(CH2)3S(CH2)3CH3 '~ 3 -GH3 -H2fl2H -y-f3 -(~GH3)3-(GH23sH3 1 3 -CH3 -CH2C02H -GH3 -C(CH3)3-{CH2)9CH3 1 3 -CH2C:H3 -CH2CO2H -CH2CH3 -C(CH3)3.- -(CH2)5GH3 i 4 -CH2~:1-is-GH2CO2H -CH2GH3 -C(CH3)3-(Gf-i2)7GH3 1 4 -CH2C;H3 wGH2C02H -CH2cH3 -C(CH3~3.-(GH2)sCHs Table 12 R3 w R4 _ -NHCOR~
R2 Rs R7 Rs i 4 -OCH3 -CH2C02H -OCH3 -CtCH3)3 =(CH2)5CH3 7 4 -OCH3 -GH2G02H -OCH3 -G(GH3)3 -(CH2)7GH3 1 4 -OCH3 -CH2C02H -OCH3 -C(CH3)3 -(CH2)9CH3 7 4 -CH3 -GH2OH -CH3 -C(CH3)3 -(CH2)5CH3 .
1 4 -CH3 -CH20H -CH3 -C(,GH3)3' -(CH2)7CH3 6 ~
i 4 -CH3 -GHZOH -CH3 -C(GH3)3 -(GH2)gCH3 7 4.8 -CH3 -CH2C02H -CH3 -C(CH3)2(CH2)3CHs -(CH2)~GH3 i 4 -CH3 -CH2C02H -CHs -C(CH3)2CCH2)sGH3 -(GH2)7CHs 1, -CH3 -CH2C02H -CH3 -CH2-( H ) -(CH2)7CH3 i 5 -CH3 -CH2C02H -CN3 -~H2, ~ ~ , -(CH2)7GN3 i 1 5 -GH3 -GH2G02H -CH3 -NH(GH2)3GH5 -(GH2)5GH3 1 5 -GH3. -CH2C02H -CH3 -NH(GH2)3GH3 -(CH2)7GH3 1 5.4 -CH3 -CH2G02H -CHs -NH(CH2)sCHs -(CH2)sC~
w . -- CA 02233842 1998-04-02 i The 'H-NI~R above Examples values of 126-i54 the compounds of the are shown i~he in following.
Example 126 0.70-1.00 (3H, br-t), 1.10-1.70{8H, m), .35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, 2.~0-2.70(~H, m), s), 2.80-2.90 (2H, m), 3.68 (2H, 7.35 (1H,br), 9.50 br).
s), (2H, 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, 2.~0-2.70(4H, m), s), 2.80-2.90 (2H, m), 3.68 (2H, 7.35 (1H,br), 9.50 br).
s), (2H, 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, 2.~0-2.70(4H, m), s), 2.80-2.90 (2H, m), 3.68 (2H, 7.35 (1H,br), 9.50 br).
s), (2H, Example 129 0.80-1.70 (11H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.80-2.90(2H, m), 3.68(2H, s), 2.~0-2.70 (4H, m), 7.35 (1H, br), 9.50 (2H, br).
Example 130 0.70-1.00 (6H, br-t), i.10-1.70 35 (9H, s), (7H, m), 1.
1.80-2.10 (2H, m), 2.10 (6H, 2.~0-2.70(4H, m), s), 2.80-2.90 {2H, m), 3.68 {2H, 7.35 (1H,br), 9.50 br).
s), (2H, Example 131 0.70-1.10 (3H, br-t), 1.10-1.70 35 (9H, s), (~H, m), 1.
1.80-2.10 {2H, m), 2.10 (6H, 2.~0-2.70(4H, m), s), 2.80-2.90 (2H, m), 3.30-3.60 m), 3.68 (2H, s), 7.35(1H, br), (4H, 9. 50 (2H, lbr) .
Example 132 0.70-1.10 (3H, br-t), 1.10-1.70~4H, m), 35 (9H, s), ( 1.
1.80-2.10 (2H, m), 2.10 (6H, 2.~0-2.70(~4H, m), s), 2.80-2.90 (2H, m), 3.20-3.50 m), 3.68 (2H, s), 7.35(1H, br), (~.H, 9.50 (2H, br).
Example 133 7s 0.80-1.70 (13H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.~0-2.70 (~tH, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H., br).
Example 13~+
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 (~+H, 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 (~tH, m), 2.80-2.90 (2H, m), 3.30-3.60 (~H, 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), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (~H, 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 (3H, 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.~0-2.70 (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.~0 (2H, q), 2.~3 (2H, q), 2.40-2.70 (~H, 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.~0 (2H, q), 2.~3 (2H, q), 2.~0-2.70 (~H, 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.~0 (2H, q), 2.~3 (2H, q), 2.~0-2.70 (~H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 1~2 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 (~H, 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 1~3 0.70-1.10 (3H, br-t), 1.10-1.70 (12H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.~0-2.70 (~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 1~~
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 1~5 .
0.70-1.i0 (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.~0-2.70 (~H, m), 2.80-2.90 (2H, m), 4.65 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 1~6 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.u0-2.70 (~H, m), 2.80-2.90 (2H, m), 4.65 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 1~7 0.70-1.10 (3H, br-t), 1.10-i.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 (~H, m), 2.80-2.90 (2H, m), ~t.65 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 1 X48 0.70-1.00 (6H, br-t), 1.10-1.70 (18H, m), 1.35 (6H, s), ' CA 02233842 1998-04-02 1.80-2.10 (2H, m), 2.10 (6H, s), 2.~0-2.70 (~H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 1~9 .
0.70-1.00 (6H, br-t), 1.10-1.70 (22H, m), 1.35 (6H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.~0-2.70 (~H, 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 (~H, 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.~0-2.70 (4H, m), 2.80-2.90 (2H, m), 3.53 (2H, s), 3.68 (2H, s), 7.30 (5H, s), 7.35 (iH, 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 15~+
0.70-1.10 (6H, br-t), 1.10-1.70 (20H, m), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.~0-2.90 (8H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 155 N-(1-Octyl-5~ carboxy-6-methylindolin-7-yl)-2,2-dimethylpropanarnide (1) 5-Bromo-7-methyl-7-nitroindoline (3.6 g) was dissolved in N,N-dimethylformamide (36 ml), and sodium hydride (677 mg) was added, which was followed by stirring at room temperature for 0.5 hr. 1-Iodooctane (3.~ g) was added to the reaction mixture and the mixture was stirred at the same temperature for 24 hr. Ethyl acetate (200 ml) was added to the reaction mixture, and the mixture was washed with water and dried over anhydrous; sodium sulfate. Ethyl acetate was evaporated under reduced pressure. The residue was purified by gel column chromatography (eluent: ethyl acetate/n-hexane=1/100 - 1/50) to give ~.0 g of oily 1-octyl-5-bromo-6-methyl-7-nitroindoline.
IR (Nujol)cau' ; 1610, 1568.
'H-NMR (CDC13) 8 ;
0.88 (3H, br-~t, J=7Hz, -(CHz)7CHs), 1.00~1.70 (12H, m, -CHz(CHz)s-), 2.25 (3H, s, indoline C6-CH3), 2.93 (2H, t, J=BHz, indoline C3-Hz), 2.9~ (2H, t, J=7Hz, >NCHz-), 3.5'7 (2H, t, J=8Hz, indoline Cz-Hz), 7.19 (1H, s, indoline C~-H).
(2) 1-Octyl-5--bromo-6-methyl-7-nitroindoline (~.0 g) was dissolved in N-methylpyrrolidone (~0 ml), and copper cyanide (1.9 g) was added, which was followed by stirring at 190°C for 1 hr. Ethyl acetate (100 ml) and water (100 ml) were added to the reaction mixture. The insoluble matter was fi~.tered off. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5 - 1/3) to give 2.zE g of oily 1-oct3rl-5-cyano-6-methyl-7-nitroindoline.
IR (Nujol)cm-' ; 221, 1620.
' H-NMR (CDCl:~ ) 0.88 (3H, br--t, J=7Hz, -(CHz)7CHs), 1.00~1.70 (12H, m, -CHz(CHz)s-), 2.38 (3H, s,.indoline Cs-CHs), 3.03 (2H, t, J=8Hz, indoline C3-H2), 3.0~. (2H, t, J=7Hz, >NCHz-), 3.'73 (2H, t, J=8Hz, indoline Cz-Hz), 7.15 (1H, s, indoline C4-H).
s o ~
(3) 1-Octyl-5-~cyano-6-methyl-7-nitroindoline (2.~ g) was dissolved in n-propanol and a solution of NaOH (3.0 g) in water (10 ml) was added, which was followed by refluxing for 20 hr. n-Propanol was evaporated under reduced pressure and ethyl acetate (100 ml) was added to the residue. The mixture was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent:
ethyl acetate/benzene=1/5 - 1/1) to give 1.~ g of 1-octyl-5-carboxy-6-methyl-7-nitroindoline as crystals.
IR (Nujol)cm,-' ; 1679, 1620.
'H-NMR (CDCls) 8 ;
0.88 (3H, br-~t, J=7Hz, -(CH2)~CHs), 1.00~1.70 (12H, m, -CHZ(CH2)s-), 2.~7 (3H, s, indoline Cs-CH3), 3.02 (2H, t, J=8Hz, indoline Cs-HZ), 3.03 (2H, t, J=7Hz, >NCH2-), 3.69 (2H, t, J=8Hz, indoline Ca-Hi), 5.00 (1H, br, -COZH), 7.73 (1H, s, indoline C4-H).
1-Octyl-5-~carboxy-6-methyl-7-nitroindoline (1.~ g) was dissolved in methanol (30 ml), and conc, sulfuric acid (4.1 g) was added, which was followed by rE:fluxing for 4 hr. Methanol was evaporated under reduced pressure. Ethyl acetate (100 ml) was added to the residue. The mixture was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/
methanol=1/0 -- 10/1) to give 750 mg of 1-octyl-5-methoxycarbonyl-6-methyl-7-nitroindoline as crystals.
IR (Nu jol) crn-' ; 1679, 1620.
' H-NMR (CDCl:; ) 0.88 (3H, br--t, J=7Hz, -(CH2)ZCHs), 1.00~1.70 (12H, m, -CHZ(CHZ)6-), 2.43 (3H, s, indoline Cs-CIi3), 3.00 (2H, t, J=BHz, indoline C3-Hz), 3.02 (2H, t, J=7Hz, >NCH2-), 3.66 (2H, t, J=8Hz, indoline C2-H2), 3.82 (3H, s, -CO2CH3), 7.62 (1H, s, indoline Cr,-H).
(5) 1-Octyl-5-methoxycarbonyl-6-methyl-7-nitroindoline (750 mg) was dissolved in ethanol (50 ml), and 106 palladium-carbon (150 mg), which was followed 'by hydrogenation at 40°C for 15 hr. 10% Palladium-carbon s~
~
was filtered off and ethanol was evaporated under reduced pressure.
Chloroform (1C10 ml) was added to the residue. The mixture was washed with water andl dried over anhydrous sodium sulfate. Chloroform was evaporated undler reduced pressure. The obtained 1-octyl-7-amino--5-methoxycarbonyl-6-methylindoline was dissolved in chloroform (10 ml).
Pivaloyl chloride (310 mg) and triethylamine (286 mg) were added under ice-cooling, which was followed by stirring at room temperature for 1 hr. Chloroform (50 ml) was added to the reaction mixture. The mixture was washed successively with 5~ aqueous citric acid and water, and dried over anhydrou:> sodium sulfate. Chloroform was evaporated under reduced pressure. The: residue was purified by silica gel column chromatography (eluent: chloroform/methanol=1/0 - 20/1) to give 580 mg of oily N-(1-octyl-5-metho3~ycarbonyl-6-methylindolin-7-yl)-2,2-dimethylpropanamide.
IR (Nujol)cnn-' ; 1708, 1651.
'H-NMR (CDCls) 0.87 (3H, br--t, J=7Hz, -(CH2)7CHs), 1.00-x1.70 (12H, m, -CHZ(CHz)s-), 1.3~ (9H, s, -C(CH3)s), 2.39 (3H, s, indoline Cs-CHs), 2.93 (2H, t, J=8Hz, indoline Cs-Hi), 3.25 (2H, t, J=7Hz, >NCH2-), 3.51 (2H, t, J=8Hz, indoline CZ-Hi), 3.79 (3H, s, -C02CHs), 6.76 (1H, br, -CONH-), 7.55 (1H, s, indoline C4-H).
(6) N-(1-Octy:L-5-methoxycarbonyl-6-methylindolin-7-yl)-2,2-dimethylpropaaaamide (580 mg) was dissolved in methanol (10 ml) and a solution of N~aOH (290 mg) in water (5 ml) was added, which was followed by stirring at 60°C for ~ hr. Methanol was evaporated under reduced pressure. Water (50 ml) was added to the residue and the mixture was washed with ethyl acetate (20 ml). The aqueous layer was adjusted to pH
6-7 with 2N sulfuric acid and extracted with chloroform (100 ml). The chloroform layer was washed with water and dried over anhydrous sodium.
sulfate. Chloroform was evaporated under reduced pressure to give 380 mg of the title compound.
IR (Nujol)cm-' ; 1668, 1645, 1615.
'H-NMR (CDCls) 8 ;
0.79 (3H, br, -(CHZ)7CHs), 0.80~1.80 (12H, m, -CHZ(CHZ)6), az 1.3~ (9H, s, -C(CH3)s), 2.38 (3H, s, indoline C6-CHs), 2.9~+ (2H, t, J=8Hz, indoline Cs-HZ), 3.27 (2H, t, J=7Hz, >NCH~-), 3.5~ (2H, t, J=8Hz, indoline CZ-Hz), 6.80 (2H, br, -CONH-, -C02H), 7.67 (1H, s, indoline C.,-H).
Examples 156-160 The compounds of Table 13 were obtained according' to the method of the above Example 155.
Table 13 Ft~
Rs ~ N
R4 = -NHCOR~
~a~rpleR ~ R 2 R s R ~ R s 1 5 -H -C02H -CH3 -C(CH3)3 -(CH2)5CH3 1 5 -H -C02H -CH3 -C(CH3)3 -(CH2)9CH3 1 .5 -CHa -C02H -CHs -C(CHs)s -(CH2)sCl-l3 1 5 -CH3 -CO2H -CH3 -C(CH3)3 -(CH2)7CH3 1 6 -CH3 -C02H -CH3 -C(CH3)3 -(CH2)sCH3 The 'H-NfR values of the compounds of the above Examples 156-160 are shown in ~;he following.
Example 156 0.79 (3H, br-t), 0.80 ~-1.80 (8H, m), 1.3~ (9H, s), 2.38 (3H, s), 2.9~ (2H, t), 3.27 (2H, t), 3.5~ (2H, t), 6.80 (2H, br),7.67 (1H, s).
Example 157 0.79 (3H, br-t), 0.80 -~-1.80 (16H, m), 1.3~ (9H, s), 2.38 (3H, s), 2.9~ (2H, t), 3.27 (2H, t), 3.5~ (2H, t), 6.80 (2H, br), 7.67 (1H, s).
Example 0.79 (3H,br-t), 0.80 -~-1.80(8H, m), 1.33 (9H, 2.40 (3H, s), s), 2.~5 (3H,s), 2.95 (2H, 3.26 (2H,t), 3.5~ t), 6.80 (2H, t), (2H, br).
Example 0.79 (3H,br-t), 0.80 -~-1.80(12H, 1.33 (9H, 2.~0 (3H, s), m), s), 2.x+5 (3H,s), 2.95 (2H, 3.26 (2H,t), 3.5~+ t), 6.80 (2H, t), (2H, br).
Example 160 .
0.79 (3H,br-t), 0.80 ..1.80(16H, 1.33 (9H, 2.~0 (3H, s), m), s), 2.45 (3H,s), 2.95 (2H, 3.26 (2H,t), 3.5~t t), 6.80 (2H, t), (2H, br).
With the aim of demonstrating the superior properties of the compound of tree 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.
Experimental Example 1 . ACAT inhibitory activity 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 bar bleeding under anesthesia and small intestine was removed. The mucosal membrane of small intestine was peeled, co:Llected and homogenated. The homogenate was centrifuged at 4°C and 10,000 rpm for 15 min. '.Che obtained supernatant was further centrifuged at ~°C
and X41,000 rpm for 30 minutes to give microsomal fractions. The microsomal suspension as an enzyme sample, dimethyl sulfoxide (DMSO, 5 ~.1) or a test compound dissolved in DMSO (test compound solution 5 ul), and reaction substrate [1-"~C]-oleoyl CoA were added to 0.15 M phosphate buffer to the total amount of 500 ~tl. After incubation at 37°C for 7 minutes, a chloroform-methanol mixture was added to stop the reaction.
Water was add~sd thereto and mixed, and chloroform layer was separated.
The solvent w;3s evaporated to dryness, and the residue was re-dissolved in n-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 cholesteryl 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 ACAT
compound inhibition Example 1 9 9. 2 Example 3 9 2. 5 Example 4 9 3. 6 Example 36 9 4. 0 Example ~0 9 2. 7 Example ~6 9 4. 7 Example 116 9 2. 0 Example 120 9 2. 3 Example 121 9 2. 5 Example 122 9 2 0 .
Example 125 9 3. 0 .
YM-'T50 : 1-cycloheptyl-1-[(2-fluorenyl)methyl]-3-(2,x,6-trimethyl-phenyl) urea Experimental hxample 2 : serum total cholesterol reducing effect Male Winter 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 5~6 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 kit (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 (~) serum cholesterol of total Test 3 mg/kg/day 10 mg/kg/day compound Example 1 5 2 8 5 7. 1 .
Example 3 5 4 2 6 1 2 . .
Example ~ 5 8 8 5 7 5 . .
Example 18 4 5 1 5 6 6 . .
Example 25 4 5 0 5 2 3 . .
Example 36 6 0 0 5 8 9 . .
Example ~.0 5 1 3 5 6 2 . .
Example 71 2 6 5 5 2 3 . .
Example 81 3 1 7 5 3 8 . .
Example 116 2 6 5 5 0 9 . .
Example 120 4 5 8 4 4 6 . .
Example 121 3 7. 8 4 8 1 .
Example 122 3 8 2 5 0 0 . .
Example 125 3 0 2 4 7 9 . .
Example 155 5 5 2 5 8 5 . .
Example 159 5 3. 8 5 7. 5 YM-750 3 7. 7 4 6 4 .
YM-750 : 1-c:ycloheptyl-1-[(2-fluorenyl)methyl]-3-(2,4,6-trimethyl-phE~nyl) urea Experimental Example 3 : in vitro plasma lipoperoxidation inhibitory activity Under ether anesthesia, blood was taken from male blister rats weighing 160-'190 g that had been fasted for 16 hours, and heparinized plasma was se~~arated by conventional method. DMSO (10 ul) or a test compound (fin~~l concentration 10-5 M) dissolved in DMSO (test compound solution 10 ~t.l) was added to plasma (1.0 ml), and the mixture was incubated at 37°C for 5 minutes. Distilled water (10 ul) or aqueous solution (10 ;~tl) of copper sulfate (final concentration 1 M) was added, followed by incubation at 37°C for ~ 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 malondialdehydle. 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 Inhibition of plasma lipoperoxidation compound (~) Example 1 5 1. 7 Example 3 4 9. 2 Example ~ 5 1. 2 Example 11 4 4. 5 Example 18 4 4. 0 Example 25 6 3. 5 Example 36 4 1. 5 Example 71 4 8. 1 Example 76 5 1. 7 Example 81 4 7. 1 Example 116 4 5. 5 Example 121 4 1. 6 Example 125 4 8. 0 Example 155 4 7. 7 Example 159 4 8. 3 Experimental F~xample ~+ : ex vivo plasma lipoperoxidation inhibitory activity A test compound suspended in 5~6 gum arabic solution was forcibly administered orally to male Wister rats weighing 160-190 g that had been fasted for 16 hr. Only 5g~ gum arabic solution was administered to control animals. At 1 hour after administration, blood was taken under ether anesthe:~ia and heparinized plasma was separated by conventional method. The ~~lasma (1.0 ml) was processed in the same manner as in Experimental lrxample 3 and the amount of produced malondialdehyde was determined. The activity of the test compound was expressed as a proportion (yb') 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 Example 18 Example 36 Probucol ~4 mg/kg 3 9 . 0 2 7 . 1 4 1 . 6 100 mg/kg 1 5 . 4 Probucol : 4,4-isopropylidenedithiobis(2,6-di-t-butylphenol) Experimental Example 5 : solubility A pulverized test compound (10 mg) was added to buffer (1 ml, pH
6.8), and the mixture was shaken for 1 hr 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. 0 1 YM-750 : 1-c;ycloheptyl-1-[(2-fluorenyl)methyl]-3-(2,x,6-trimethyl-phE:nyl ) urea Experimental Example 6 : oral administration A test compound (30 mg/kg) suspended in 5~ gum arabic solution was forcibly administered orally to male blister rats weighing 200-250 g that had been fastErd for 16 hr. At 0.5, 1, 2, ~+ 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.
8s , Table 19 Test compound Highest concentration in plasma (ug/ml) Example ~4 1 . 4 Example 36 2. 2 Experimental Example 7 : oral administration 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 (ug/ml) Example 4 1 3. 6 Example 36 1 2. 2
20/1 - 5/1) t:o give 1.1. g of the title compound.
a IR (Nujol) cm-': 1730, 1620.
' H-NMR (CDCl;~ ) 0.70~1.00 (:;H, br-t, -(CHz)6CHs), 1.32 (9H, s, -C(CHs)3), 1.00-~-1.60 (12H, m, -(CHz)6CHs), 1.60~2.20 (2H, m, -CHzCH2COz-), 2.05, 2.18 (fiH, s x 2, -CHs x 2) , 2. 20-~-2. ~0 (2H, m, -CHZCHZCOzCH~ ) , 3.10-~-3.80 (5H, m, Indoline Cz-H, Cs-H, >NCHz-) , 3.6~+ (3H, s, -COzCH3), 6.~;8 (1H, s, Indoline Cs-H), 6.70 (1H, br, -CONH-).
Fv~mr, l 0 1 1 N-[(1-Octyl--3-(2-carboxyethyl)-~,6-dimethylindolin-7-yl)]-2,2-dimethyl-propanamide N-((1-tJci;yl-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 (49~ mg) in water (3 ml) was added, which was followed by stirring ai: room temperature for 30 min. EtOH was evaporated under reduced pressure and CHC13 (50 ml) was added. After washing successively caith 59~ aqueous citric acid and saturated brine, the mixture was dried over anhydrous sodium sulfate. CHCls was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHC13/MeOH=50/1 - 10/1) to give 800 mg of the title compound.
I R (Nujol) crn-' : 1700, 1680.
' H-NMR (CDCl :3 ) 0.70~1.00 (3H, br-t, -(CHz)7CHs), 1.38 (9H, s, -C(CHs)s), 1.00~1.60 (12H, m, -(Cl3z)sCHs), 1.60~2.20 (2H, m, -CHZCHZCOzH), 2.07, 2.16 (6H, s x 2, -t;Hs x 2) , 2. 20~2. X40 (2H, m, -CH2CHzCOzH) , 3.10-~-3. 80 (3H, m, Indo:line Cz-H, C3-H), 3.27 (2H, br-t, >NCHz-), 6.45 (1H, s, Indoline Cs-l~), 7.20 (1H, br, -CONH-), 7.60 (iH, br, -COzH).
Fxamnla 1~
N-(1-Octyl-!~-carboxymethyl-~,6-dimethylindol-7-yl)-2,2-dimethyl-propanamide (1) N-(5-ethosxycarbonylmethyl-~,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (1.0 g) was dissolved in xylene (75 ml), and 10~ Pd-C (250 mg) was added, which was followed by refluxing for 1 hr. Pd-C was filtered off and xylene was evaporated under,reduced pressure. The residue was purified by silica gel column chromatography (eluent:
benzene-CHCls) to give 0.9 g of N-(5-ethoxycarbonylmethyl-~,6-dimethylindol--7-yl)-2,2-dimethylpropanamide.
IR (Nujol) cnn-': 1732, 1629.
' H-NMR (CDCl:, ) 8 1.23 (3H, t, J=7.OHz, -CHZCH3), 1.~0 (9H, s, -C(CH3)s), 2.32 (3H, s, -CH3), 2.52 (3H, s, -CHs), 3.80 (2H, m, -CHZCOz-), X4.13 (2H, q, J=7.OHz, -CH_rCH3), 6.50 (1H, t, J=2.OHz, Indole Cs-H), 7.11 (lIi, t, J=2.OHz, Indole Cz-H), 7.35 (1H, br, -CONH-), 8.88 (1H, br, >NH ).
(2) N-(5-Ethos;ycarbonylmethyl-X4,6-dimethylindol-7-yl)-2,2-dimethylpropaulamide (1.~5 g) was dissolved in DMF (10 ml) and NaI~
(P=60%, 132 mg) was added under a nitrogen atanosphere, which was followed by shirring at room temperature for 1 hr. Then, 1-iodooctane (1.06 g) was added and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was poured into ice water. The mixture was extracted with AcOEt (100 ml), washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent:
benzene/AcOEt=1/0 - 1/1) to give 1.02 g of N-(1-octyl-5-ethoxycarbonylmethyl-~,6-dimethylindol-7-yl)-2,2-dimethylpropanamide.
IR (Nujol) cm-': 1735, 1651.
'H-NMR (CDCls) 0.70~1.10 (3H, br-t, -(CHz)TCHs), 1.10~1.70 (15H, m, -CHaCHs, -(CHz)sCHs), 1.38 (9H, s, -C(CHs)s), 2.21 (3H, s, -CHs), 2.47 (3H, s, -CHs), 3.79 (2H, m, -CHZCOz-), 3.90~ x.30 (4H, m, -CH_zCHs, >NCHz-), 6.42 (1H, t, J=3.5Hz, Indole Cs-H), 6.91 (1H, t, J=3.5Hz, Indole Cz-H), 7.12 (1H, br, -CONH-).
(3) N-(1-Octyl-5-ethoxycarbonylmethyl-X4,6-dimethylindol-7-yl)-2,2-dimethylpropanamide (3.5 g) was dissolved in EtOH (50 ml), and a solution of TfaOH (1.6 g) in water (20 ml) was added, which was followed by stirring apt 60°C for 1 hr. EtOH was evaporated under reduced pressure, and the residue was dissolved in water (20 ml), and washed with AcOEt (l0i ml). The aqueous layer was neutralized with 2N HCl and extracted with. AcOEt (50 ml). The AcOEt layer was washed successively with saturated. brine and dried over anhydrous sodium sulfate. AcOEt was evaporatedi under reduced pressure to give 2.0 g of the title compound.
IR (Nujol) cm-': 1705, 167.
' H-NMR (CDC13 ) ~S
0. 70-~-1 .10 (~iH, br, -(CHz ) 7CHs ) , 1.10-1 . 70 ( 12H, m, -CHz (CHz ) sCHs ) , 1.33 (9H, s, -C(CHs)s), 2.10 (3H, s, -CH3), 2.39 (3H, s, -CHs), 3.65 (1H, br, -COZH), x.07 (2H, br-t, >NCHz-), 4.15 (2H, s, -CHjCOz-), 6.38 (1H, t, J=3.5Hz, Indole C3-H), 6.89 (1H, t, J=3.5Hz, Indole Cz-H), 7.25 (1H, br,. -CONH-).
Examples 13-119 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 R4=-NHCOR' Ra. R°
sample R 1 R 2 R 3 R T R 6 -13 -CHs -CHaCOzH -CHs -C(C~I3}s-(CHz)4CHs 14 -CHs -CH2C02H -CHs -C(CHs)s I ~ -CHs -CHzCOzH -CHs -C(CHs}s-(CHz)zCH(CHs}a 16 -CHs 'CH2CO2II -CHs -C(CHs}s-CH2CH=C(CHs}2 t 7 -CHs -CH2C02H wCH3 -C(CHs)s-(CH2}20CH2CHs I8 -CHs -CH2C02H -CH3 -C(CHs)3-(CH2}SCHs I ~ -CHs -CH2C02H -CHs '-C(CH3)3--2 0 -CHs -CHzC02H -CHs -C(CHs)s-CH2-~H
2I -CHs -CH2COzH -CHs -C(CHs}s-(CHz)sCH(CHs)z 2 2 -CHa -CH2CO2H -CHs -C(CHs)s-CHzCH(CH2CHs}z 2 3 -CHs -CHzC02H -CHs -C(CHs)3-(CH2)2O(CH2}2CFis 2 4 -CH3 -CH2COzH -CHs -C(CHs)s-(CH2)sCHs 2 5 -CHs -CH2COzH -CH3 -C(CHs)s-CH2 2 6 -CHs -CH2COzH -CHs -C(CHs)s-(CHz)~CH(CH3)z Table 2 R~
R.2 /
;s ~ ~ ~ R4=-NHCORT
R ~ R
a R.2 R3 R7 Rs 2 7 -CHs -CH2CO2H -CH3 -C(CH3)~ -(CH2)2CH(CH2CHs)2 ~ 8 -CHa -CH2C02H -GH3 -C(CH3)s -(CH2)20(CH2)aCHa 2 9 -CHs -CH2CO2H -~H3 -C(CHs)s -(CH2)z-( g -CHs -CH2C0~2H -CHs -C(CHs)s -(CH2)sCH(CHs)2 31 -CHs -CHaCOaH -CH3 -C(CHs)s -tCH2)sCH(CHaCHs)2 3 2 -CHa -CH2C02H -CHa -C(CHs)s -(CHa)zO(CHZ)4CHs 3 3 -CHs -CHaCOzH -CHs -C(CH3)3~-(GHz)sC,Hs 3 4 -CH3 -CH2C02H -CHs -C~CH3~3~-(CH2)sCH(CHs)2 .
3 5 -CHs -CH2CO2H~ -CH3 -C(CHs)s -(CHa)4CH(CHaCHs)a 3 6 -CHs -CH2COZH -CHs -C(CHs)s -(CH2)~CH3 3 7 -CH3 -CH2CO2H -CHs -C(CHs)s -(CH2)~CH(CH3)2 3 8 -CHs -CH2CO2H -CHs -C(CHs)s -(CH2)loCHs 3 9~ -CHs -CH2CO2H =CH3 -C(CHs)s -(CH2)sCH(CHs)2 -CHs -CH2COZH -CHs -C(CHa)3 -(CHz)lCHs 4 1 -CHs -CH2C02H -CHs -C(CHs)s -(CH2)9CH(CH3)2~
~
Table 3 Rs \ ~~ R4=-NHCOR' R4 Rs ~p~ R1 R2 R3 R7 R6 4 2 -CH3 -CHzCO2H -CH3 -C(CHs)aC4H9-(CHz)SCHs 4 3 -CH3 -CH2CO2~T -CH3 -C(CH3)2C:~Hs-(CHz)sCHs -CHs rC.H2CO2H .-CHa. -CfCH3~C~Hs-(CHa)7CHs , 4 5 -CHs -CH2C.O2H -CH3 -C(CHs)2CsHn-(CH2)SCHs 4 6 -CHs -CH2C02H -CH3 -C(CHs)2CsH13-(CH2)sCHs 4 7 -CHs -CHzCOaH -CH3 -C(CH~)zCsHi3-(CH2)?CH3 4 $ -CH3 -CHaCOaH -CH3 -C(CH3~C8H1?-(CHa)sCHa -CHs -GHaC02H -CHs -C(CHs)aCBHm. -(CHz)sCHs -CH3 -CH2CO2H -CHs -C(CHa)2CsIii7-(CH2)7CH3 1 -CHzCHs -CHaCOzH -CHzCHs -C(CHs)s . -(CHa)sCHs .
5 2 "~~~H3 -CHaCOzH -CHzCHa -C(CHs)s -(CHz)sCHs 5 3 -CH2CHs -CH2C02H -CH2CHs -C(CHs)s -(CH2)7CH3 5 4 -CHzCHs -CH2CO2H -CHaCHs -C(CHa)s -(CH2)aCH3 ~ ~
5 5 -CHaCHs -CHzCO2H -CH2CHa -C(CHs)s -(CH2)sCHs 5 6 -OCHs -CHzC02H -OCHa -C(CHa)s -(CHZ)sCHs 5 7 -OCHs -CH2C02H -OCHs -C(CHa)s -(CH2)sCHa .
5 $ -OCHs -CH2C02H -OCHs -C(CHs)s -(CH2~rCH3 5 9 -OCHs -GH2C02H -OCHs -C(CHs)3 =(CH2)BCHs 6 0 -OCHs -CH2CO2H -OCH3 -G(CHs)a -(CH2)sCH3 6 1 -GHQ -GHZOH . -CHs -C(CHs)s -(CH2)SCHs 6 2 ' -CHs -CH~OH -CHs -C(CHs)s -(CH2)sCHs Table ~
R~=-,~1~HC0R' RZ. R3. R7. Rs 6 3 -CHs -CH2~H -CH3 -C(CHs)s -(CHa)sCHa 6 4 -CHa -CHzOH -CH3 -C(CHs)s -(CHZ)sCHa 6 5 .-CHs -CHaN(CHs)z-CHs -C(CH8)s -(CHz)sCHa 6 6 ~-CH3 -CH2N(CHs)2-CHs -C(CHs)3 -(CH2)sCHs ~
~ 7 -CH3 -CH2N(CHs)2-CHa ~C(CH3)3 -(CHz)sCH3 g $ -CHs ~ -CH2N(CH3~ ~ =GHs ~: C(CHa)s -(CHa)sCHs .
6 9 -Hv vCIi.~CC2H -CHs' -C(CHs)s -(CH2)sCH3 7 0 .-H -CH2CO2H -CHs -C(CHs)s -(CH2)sCHs 7 1 ' -H -CH2C~2H -CHs -C(CHs)s -(CH2)~CH3.
7 2 -H -CH2C02H -CH3 -C(CHa)s -(CH2)BCHa -H =CHaC02H -CHs -C(CHs)s -(CH2~CHs.
~
7 4 -H -CH2~H ' -CHa -C(CH3)s -(CH2)sCH3 7 ~- -H' ' -CH2CH =CH3 -C(CHs)a -(CHz)sCHs .
7 6~ -H -CH2~H -CHs -C(CH3)s -(CH2)7CH3 -H .-CH2~H -CHs -C(CHs)s -(CH2)aCHs , 7 8 ~ ' -H -CH2CH -CHs -C(CHs)s -(CH2)sCHs . 7 -H -CH2N(CH3)2-CHs -C(CHs)s -(CH2)5CH3~
g , $ ~ -H -CH2N(CHa)2-CHs -C(CHs)s -(CH2)sCHs $ 1 , -H . -CHZN(CHs)2-CHs -C(CHs)s -(CHz)7CHs $ 2 -H -CHaN(CHs)z-GHs -C(CH3)s -(CHz)sCHs $ 3 . -H -CH2N(CHs)z-CHs -C(CH3)s -(CHz)sCHs Table 5 R1 R$
~2 R4=-NHCOR' Rs ExampleR I R 2 ' R 3 R.7 ~ R~ R s $ 4 -C:EIs -H -CH3 -C(CH3)s-(CH2)2CO2H -(CH2)SCHs $ 5 -CFi3 -H -CHs -C(CHs)3-(CH2)2C02H -(CH2)sGH3 $ 6 -CHa -H -CHa -C(CHs)s(CH2)zOH -(CH2)sCHs -$ 7 -CFi3 -H, -CHs -C(CH3)3-(CH2)20H -(CH2)sCH3 $ $ -C.Fi3 -H -CHs -C(CHs)s-(CHa)aN(CHs)a-(CH2)sCHa .
$ 9 -CHs -H. -CH$ -C(CH3)~-(CH2)21V(CH3)2-(CH2)6CH3 9 0 -CHs -H -CH3 -C(CH3)s-(CH2)2N(CHs)2-(CH2)7CHs y Table 6 R4=-NHCONHR'~
R4 R°
Example R 1 R 2 R 3 R 7~ R s -CH3 -CH2CO2H -CHs -(CHz)sCHa -(CH2)~CH3 g 2 -CFi3 -CHaCOaH -CHa -(CH2)sCH.~ -(CH2)sGH~~
9 3 -CHs -CH2C02H -CH3 -(CH2)3CH3 -(CH2)sCHs g 4 -CHzCHs -CH2C02H -CH2CHa -(CHz)aCH3 =(CH2)~CH3 .
9 5 -CH2CH3 -CH2CO2H -CH2CHs -(CHa)sCHs -(CHz)sCHs ~
9 6 -CHaCH3 -CH2COaH -CH2CHs -(CH2)sCHa -(CH~)sCHs ~ 7 -OCH3 -CH2C02H -OCH3 -(CHa)sCHs -(CH2)~CH3 g $ -OnHs ~ -CH2C02H -OCHs -(CH2)3CH3 -(CH2)BCHs g g -O'CH3 -CH2C02H -OCH3 -(CHz)aCH3 -(CHz)9CHs Table 7 R~
R3 \ N~ R~=-NHCOR' R4 Rs Ri R2 R3 R7 R6 1 0 0 -C;Hs -CH2CO2H -CHs -C(CHs)a -(CH2)$CHs 1 ~ 1 -C:Hs -CH2C02H, -CHa -C(CH3)3 -(CH2)sCHs 1 ~ 2 -CH2CHs -CH2C02H -CH2CHs -C(CHs)s -(CH2)~CHa I 0 3 -GH2CHs -CH2C02H -CH2CHs -G(CHs)s -(CH2)aCHs 1 ~ 4 -CH:2CHs -CH2C.02H -CHaCHs -C(CHa)s -(CH2)sCH3 1 0 5 -~CH3 -CH2C02H -~CH3 -C(CHa)s -(CH2)7CH3 1 d 6 -OCHs -CH2C02H -OCH3 -C(CH3)3 -(CH2)sCHs 1 0 7 -OCH3 -CH2CO2H -OCH3 -C(CHa)s -(CH2)sCHa _ CA 02233842 1998-04-02 Table $
R4 Rb R~=-NHCOR' R1 Rz Rs Rr Rs 1 ~ -CHs =CIi2CO2H-CH3 -(CH2)2OCH3=(CH2~tCH3 8 ~
1 0 -CHs -CH2CO2H~ -CHs-(CH2)2$CH~-(GH2nCH3 1 1.0 -CHa -CH2C02H. -CHs~ -(CH2ytCHa.
1 1 -CHs -CH2CO2H-CH3 _~2~ -{CH2yrCHa 1 .
1 ~ -CH3 -CH2C02H-CHs -~ ~-(CH2nCH3 1 '2 1 1 -CHs -CH2CO2H-CHs -~2 ~ -(CH2nCHa:
~3 .
I i -CHs -CH2CO2H-CHa -C(CH3)s "-(CH2~2S(CH2)3CH3 1 I -CHa -CH2C02H' -CH3-C{CHs)a I 1 =H ~-G~C02Ft-CHs -C(CHs)3 -(CH2y~CH~:
Table 9 R 3=-N. H C 0 R' 'N
.R4 Rs Examp R i . R z. RQ-. . R z R s 1 7 -CH2C02H -CH3 -CHs -C(CH~3)3 -(CH2)SCHs-1 1 $ -CH2CO2H -CHs -CHs -C(CI-i3)& -(CH2)aCHa 1 1 9 'CH2!CO2H -CHs -CHa -C(CHs)s -(CH2)~.OCH3 The 'H-NMR values of the compound of the above Examples 13-119 are shown in the following.
Examp le 13 : 0 . 7 -~-1.1 ( 3H, br-t ) , 1 .1 -~-1. 7 ( 6H, m ) , 1. 33 ( 9H, s ) , 2. O1 (3H, s) , 2.15 (3H, s) , 2.70---3.10 (~4H, m) , 3. ~+1 (2H, t) , 3. 56 (2H, s) , 7. 6 -~-8.1 (2H, br) .
Example 1~ : 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), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (~4H, m), 3.~1 (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 (~H, m), 3.~1 (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 (~H, m), 3.3 - 3.6 (6H, m), 3.56 (2H, s), 7.6 - 8.1 (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 (~tH, m), 3.~1 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br).
Example 19 : 0.7 - 1.70 (IOH, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.'70 - 3.10 (3H, m), 3.~t1 (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.~1 (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 (~H, 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.~1 (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 (uH, m), 3.3 - 3.6 (6H, m), 3.56 (2H, s), 7.6 - 8.1 (2H, br).
Example 2~ : 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 (~H, m), 3..41 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (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), 2.70 - 3.10 (4H, m), 3.~1 (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 (~H, m), 3.~1 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br).
Example 28 : 1.59 (3H, br-t), 1.0 - 1.7 (~tH, 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 29 : 0.7 - 1.70 (13H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (~H, m), 3.~1 (2H, t), 3.56 (2H,s), 7.6 8.1 (2H,br).
-Example30 : (6H,d), 1.1 1.8 (9H,m), 3H, s), 0.87 - 1.33 (9H, s), 2.01 ( 2.15 (3H,s), 2.70 - 0 , 3.~1 (2H, t), 3.1 (4H, m) 3.56 (2H,s), 7.6 8.1 (2H,br).
-Example31 : (6H,br-t), 0 .Z 9H, ), 1.33 (9H, s), 1.59 1. - ( m 2.01 (3H,s), 2.15 (3H,s), 2.703.10 (4H, m), 3.~1 (2H,t), 3.56 (2H,s), 7.6 8.1 (2H, br).
-Example32 : (3H,br-t), 0 .7 6H, ), 1.33 (9H, s), 1.59 1. - ( m 2.01 (3H,s), 2.15 (3H,s), 2.70- 3.10 (~H, m), 3.3 - 3.6 (6H,m), 3.56(2H,s), 7.6 - 8.1 (2H, br).
Example33 : 1.10 .1 1.7 (1~H, m), 1.33 s), 0.7 (3H, - (9H, - br-t), 2.01 (3H,s), 2.15 (3H,s), 2.70- 3.10 (4H, m), 3.~1 (2H,t), 3.56 (2H,s), 7.6 8.1 (2H, br).
-Example3~ : (6H,d), 1.1 1.8 (11H, 1.33 (9H, s), 0.87 - 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).
-Example35 : (6H,br-t), 0 m), 1.33 (9H, s), i"59 1. -1.7 (11H, 2,.01 (3H,s), 2.15 (3H,s), 2.70- 3.10 (~H, m), 3"~1 (2H,t), 3.56 (2H,s), 7.6 8.i (2H, br).
-Example36 : 1.10 1.7 (16H, m), 1.33 s), 0"~ (3H, (9H, - br-t), 1.1 -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).
-Example37 : (6H,d), 1.1 - (13H, 1.33 (9H, s), 0.87 1.8 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).
-Example38 : - 0 1.1 - (18H, m), 1.33 s), 0.7 1.1 (3H, 1.7 (9H, br-t), 2.01 (3H,s), 2.15 (3H,s), 2.70- 3.10 (~H, m), 3.~1 (2H,t), 3.56 (2H,s), 7.6 - 8.1 (2H, br).
Example39 : (6H,d), 1.1 - (15H, 0.87 1.8 m), 1.33 (9H, s), 2.01 (3H,s), 2.i5 (3H,s), 2.70- 3.10 (4H, m), 3.41 (2H,t), 3.56 (2H,s), 7.6 - 8.1 (2H, br).
Example~0 : - 0 -t),1.1 - (20H, m), 1.33 s), 0.7 1.1 (3H, 1.7 (9H, br 2.01 (3H,s), 2.15 (3H,s), 2.70- 3.10 (~H, m), 3.~1 (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), 2.70 - 3.10 (~H, m), 3.u1 (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), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (~H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br).
Example ~3 : 0.7 - 1.10 (6H, br-t), 1.0 - 2.0 (22H, m), 2.01 (3H, s), 2..15 (3H, s), 2.70 - 3.10 (~H, m), 3.~1 (2H, t), 3..56 (2H, s), 7.6 - 8.1 (2H, br).
Example ~4~.: 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 (~H, m), 3.~1 (2H, t), 3..56 (2H, s), 7.6 - 8.1 (2H, br).
Example ~5 : 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 (~H, m), 3.41 (2H, t), 3..56 (2H, s), 7.6 - 8.1 (2H, br).
Example ~6 : 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 (~H, m), 3.41 (2H, t), 3..56 (2H, s), 7.6 - 8.1 (2H, br).
Example ~7 : 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.~1 (2H, t), v 3.56 (2H, s), 7.6 - 8.1 (2H, br).
Example ~8 : 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 (~H, m), 3.~t1 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br).
Example ~9 : 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.~1 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (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 (~tH, 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 (1~H, m), 1.33 (9H, s), 2.~2 (2H, q), 2.46 (2H, q), 2.7 - 3.1 (~H, 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.~2 (2H, q), 2.46 (2H, q), 2.7 - 3.1 (~H, m), 3.~1 (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.~2 (2H, q), 2.~6 (2H, q), 2.7 - 3.1 (~4H, m), 3.~1 (2H, t), 3.56 (2H, t), 7.6 - 8.1 (2H, br).
Example 5~ : 0.7 - i.1 (3H, br-t), 1.0 - 1.7 (20H, m), 1.33 (9H, s), 2.~2 (2H, q), 2.46 (2H, q), 2.7 - 3.1 (~H, m), 3.~1 (2H, t), 3.56 (2H, t), 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.~2 (2H, q), 2.46 (2H, q), 2.7 - 3.1 (~H, m), 3.~t1 (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 (~+H, m), 3.32 (2H, t), 3.~5 (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 (IOH, m), 1.33 (9H, s), 2..50 - 3.10 (~H,im), 3.32 (2H, t), 3.~5 (2H, s),T
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 - i.7 (12H, m), 1.33 (9H, s), .2.50 - 3.10 (4H, m), 3.32 (2H, t), 3.~5 (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), 1.0 - 1.7 (1~4H, m), 1.33 (9H, s), 2..50 - 3.10 (~tH, m), 3.32 (2H, t), 3.45 (2H, s), 3.73 (3H, s), 3.77 (3H, s), 7.6 - 8.1 (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.~5 (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), l.i - 1.7 (8H, m), 1.33 (9H, s), 2.1~t (3H, s), 2.22 (3H, s), 2.70 - 3.10 (~H, m), 3.~1 (2H, t), x.62 (2H, s), 6.86 (2H, br).
Example 62 : 0.7 - 1.1 (3H, br-t), 1.1 - 1.7 (IOH, m), 1.33 (9H, s), 2.14 (3H, s), 2.22 (3H, s), 2.70 - 3.10 (4H, m), ~
3.~1 (2H, t), x.62 (2H, s), 6.86 (2H, br).
Example63 : 1.1 (3H, br-t), 1.1 - 1.7 (1~.H, m), 1.33 (9H, s), 0.7 -2.14 (3H, s), 2.22 (3H, s), 2.70 - 3.10 (~H, m), 3.41 (2H, t), 4.62 (2H, s), 6.86 (2H, br).
Example64 : 1.1 (3H, br-t), 1.1 -.1.7 (16H, m), 1.33 (9H, s), 0.7 -2.1~ (3H, s), 2.22 (3H, s), 2.70 - 3.10 (4H, m), 3.~1 (2H, t), x.62 (2H, s), 6.86 (2H, br).
Example65 : 1.1 (3H, br-t), 1.1 - 1.7 (8H, m), 1.33 (9H, s), 0.7 -2.00 (6H, s), 2.09 (3H, s), 2.23 (3H, s), 2.70 -3.20 (~H, m), 3.31 (2H, s), 3.38 (2H, t), 6. 8~4 ( br) .
H, Example66 : 1.1 (3H, br-t), 1.1 - 1.7 (10H, m), 1.33 (9H, s), 0.7 ~
-2.00 (6H, s), 2.23 (3H, s), s), 2.09 (3H, 2.70 -3.20 (~H, m), 3.31 (2H, s), 3.38 (2H, t), 6.84 (1H, br).
Example67 : 1.1 (3H, br-t), i.1 - 1.7 (1~4H, m), 1.33 (9H, s), 0.7 -2,.00 (6H, s), 2.09 (3H, s), 2.23 (3H, s), 2"70 -3.20 (~tH, m), 3.31 (2H, s), 3.38 (2H, t), 6"8~ (1H, br).
Example68 : 1.1 (3H, br-t), 1.1 - 1.7 (16H, m), 1.33 (9H, s), 0"7 -2"00 (6H, s), 2.09 (3H, s), 2.23 (3H, s), 2..70 -3.20~(~H, m), 3.31 (2H, s), 3.38 (2H, t), 6.. 84 ( br) .
H, Example69 : - (3H, br), 1.0 - 1.7 (8H, m), 1.33 (9H, s), 0..7 1.0 ~
1.97 (3H, , 2.7 - 3.1 (~H, m), 3.35 (2H, t), s) 3.~7 (2H, s), 6.90 (1H, s), 7.6 - 8.1 (2H, br).
Example70 : - (3H, br), 1.0 - 1.7 (10H, m), 1.33 (9H, s), 0.7 1.0 1.97 (3H, s), 2.7 - 3.i (~H, m), 3.35 (2H, t), 3.~7 (2H, s), 6.90 (1H, s), 7.6 - 8.1 (2H, br).
Example71 : - (3H, br), 1.0 - 1.7 (12H, m), 1.33 (9H, s), 0.7 1.0 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).
Example72 : - (3H, br), 1.0 - 1.7 (14H, m), 1.33 (9H, s), 0.7 1.0 1.97 (3H, s),2.7 3.1 (~H, m), 3.35 (2H, t), -3.~7 (2H, s),6.90 (1H,s), 7.6 - 8.1 (2H, br).
Example73 : 1.0 (3H,br), 1.0 1.7 (16H, m), 1.33 (9H, s), 0.7 -1.97 (3H, s),2.7 3.1 (~H, m), 3.35 (2H, t), -3.~7 (2H, s),6.90 (1H,s), 7.6 - 8.1 (2H, br).
Example7~ : 1.0 (3H,br), 1.0 - 1.7 (8H, m), 1.33 (9H, s), 0.7 -2.07 (3H, s),2.89 (2H,t), 3.09 (2H, t), 3.~0 (2H, t), x.51 (2H, s),6.90 (1H,s), 7.0 - 7.~ (2H, br).
Example75 : 1.0 (3H,br), 1.0 - 1.7 (10H, m), 1.33 (9H, s), 0.7 -2.07 (3H, s),2.89 (2H,t), 3.09 (2H, t), 3.~0 (2H, t), x.51 (2H, s),6.90 (1H,s), 7.0 - 7.~ (2H, br).
Example76 : 1.0 (3H,br), 1.0 - 1.7 (12H, m), 1.33 (9H, s), 0.7 -2.07 (3H, s),2.89 (2H,t), 3.09 (2H, t), 3.40 (2H, t), x.51 (2H, s),6.90 (1H,s), 7.0 - 7.4 (2H, br).
Example77 : 1.0 (3H, 1.0 - 1.7 (1~H, m), 1.33 (9H, s), 0.7 br), -2.07 (3H, s),2.89 (2H,t), 3.09 (2H, t), 3.~0 (2H, t), 4.51 (2H, s),6.90 (1H,s), 7.0 - 7.~ (2H, br).
Example78 : 1.0 (3H, 1.0 - 1.7 (16H, m), 1.33 (9H, s), 0.7 br), -2.07 (3H, s),2.89 (2H,t), 3.09 (2H, t), 3.~0 (2H, t), x..51 (2H, s),6.90 (1H,s), 7.0 - 7.~ (2H, br).
Example79 : 1.0 (3H, 1.0 - 1.7 (8H, m), 1.33 (9H, s), 0.7 br), -2.,08 (3H, s),2.23 (6H,s), 2.89 (2H, t), 3.1~ (2H, t), 3..30 (2H, s),3.38 (2H,t), 6.84 (1H, s), 6.90 (1H, br).
Example80 : 1.0 (3H, 1.0 - 1.7 (10H, m), 1.33 (9H, s), 0,.7 br), -2,.08 (3H, s),2.23 (6H,s), 2.89 (2H, t), 3.1~ (2H, t), 3.30 (2H, s),3.38 (2H,t), 6.8~ (1H, s), 6.90 (1H, br).
Example81 : - (3H, - 1.7 (12H, m), 1.33 (9H, s), 0.7 1.0 br), 1.0 2.08 (3H, s),2.23 (6H,s), 2.89 (2H, t), 3.1~ (2H, t), 3.30 (2H, s),3.38 (2H,t), 6.8~ (1H, s), 6.90 (1H, br).
Example82 : - (3H, - 1.7 (1~H, m), 1.33 (9H, s), 0.7 1.0 br), 1.0 2.08 (3H, s),2.23 (6H,s), 2.89 (2H, t), 3.1~ (2H, t), 3.30 (2H, s),3.38 (2H,t), 6.8~ (1H, s), 6.90 (1H, br).
Example83 : - , - 1.7 (16H, m), 1.33 (9H, s), 0.7 1.0 1.0 (3H, br) 2.08 (3H, s), 2.23 (6H, s), 2.89 (2H, t), 3.1.4 (2H, t), 3.30 (2H, s), 3.38 (2H, t), 6.8~ (iH, s), 6.90 (1H, br).
Example 8~t: 0.7 - i.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.i6 (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 (IOH, m), 1.38 (9H, s), 1.60 - 2.20 (2H, m), 2.07 (3H, s), 2.16 (3H, s), 2.20 - 2.~0 (2H, m), 3.10 - 3.80 (3H, m), 3.27 (2H, br-t), 6.~5 (1H, s), 7.20 - 7.60 (2H, br).
Example 86 : 0.7 - 1.0 (3H, br-t), 1.0 - 2.0 (iOH, m), 1.33 (9H, s), 2.07 (3H, s), 2.16 (3H, s), 2.60 - 3.60 (7H, m), 6.~~ (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.~~ (1H, s), 6.78 (2H, br).
Example 88 : 0.7 - 1.0 (3H, br-t), 1.0 - 2.0 (IOH, 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.~5 (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 (5H, m), 6.~5 (1H, s), 7.2 (1H, br).
Example 90 : 0,.7 - 1.0 (3H, br-t), 1.0 - 2.0 (1~H, 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 -~~..00 (6H, m), 3.55 (2H, s), ~+. 80 ( 1 H, br) , 5. 50 ( 1 H, br) , 6. X40 ( 1 H, br) .
Example 92 : 0.70 - 1.10 (6H, m), 1.10 - 1.90 (18H, m), 2.10 (6H, s), i.80 - 2.00 (2H, br-t), 2.00 - x..00 (6H, m), 3.55 (2H, s), 4.80 (1H, br), 5.50 (1H, br), 6.~0 (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 - x.00 (6H, m), 3.55 (2H, s), ~. ( 1 H, br) , 5. 50 ( 1 H, br) , 6. ~0 ( 1 H, br) 80 .
Example 0.70- 1.10 (6H, m), 1.10 - 1.90 (22H, m), 2.09 (4H, 9~ : br-t), 1.80- 2.00 (2H, br-t), 2.00 - x.00 (6H, m), 3.55 (2H, s), ~. ( 1 H, br) , 5. 50 ( 1 H, br) , 6. ~+0 ( 1 H, br) 80 .
Example 0.70- 1.10 (6H, m), 1.10 - 1.90 (2~H, m), 95 :
2.09(~H, br-t), 1.80 - 2.00 (2H, br-t), 2.00- 4.00 (6H, m), 3.55 (2H, s), X4.80 (1H, br), 5.50(1H, br), 6.40 (1H, br).
Example 0.70- 1.10 (6H, m), 1.10 - 1.90 {26H, m), 96 :
2.09(~H, br-t), 1.80 - 2.00 (2H, br-t), 2.00- 4.00 (6H, m), 3.55 (2H, s), x+.80 (1H, br), 5..50(1H, br), 6.~0 (1H, br).
Example 0..70- 1.10 (6H, m), 1.10 - 1.90 (16H, m), 97 :
1"80- 2.00 (2H, br-t), 2.00 - x.00 (6H, m), 3..35(2H, s), 3.7~ (3H, s), 3.78 (3H, s), X4.80 (1H, br), 5.50(1H, br), 6.40 (1H, br).
Example 0.70- 1.10 (6H, m), 1.10 - 1.90 (18H, m), 98 :
1.80- 2.00 (2H, br-t), 2.00 - 4.00 (6H, m), 3.35(2H, s), 3.7~ (3H, s), 3.78 (3H, s), 4.80 (1H, br), 5.50(1H, br), 6.~0 (1H, br).
Example 0.70- 1.10 (6H, m), 1.10 - 1.90 (20H, m), 99 :
1.80- 2.00 (2H, br-t), 2.00 - 4.00 (6H, m), 3.35(2H, s), 3.7~t (3H, s), 3.78 (3H, s), x.80 (1H, br), 5.50(1H, br), 6.~0 (1H, br).
Example 70 - 1.10 (3H, br-t), 1.10 - 1.70 (1~H, m), 100 : 0.
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 : 70 - 1.10 (3H, br-t), 1.10 - 1.70 (IOH, m), 101 0.
1. 33 (9H, s), 2.10 (3H, s), 2.39 (3H, s), 3.71 (2H, br), 3. 99 (2H, br-t), x.15 (2H, s), 6.38 (1H, d), 6.89 (1H, d).
Example 70 - 1.10 (3H, br-t), 1.10 - 1.70 (18H, m), 102 : 0.
1.33 (gH, s), 2.08 (2H, q), 2.~6 (2H, q), 3.71 (2H, br), 3.99 (2H, br-t), x.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.~6 (2H, q), 3.71 (2H, br), 3.99 (2H, br-t), 4.15 (2H, s), 6.38 (1H, d), 6.89 (1H, d).
Example 10~.; - 1.10 (3H, br-t), 1.10 - 1.70 (22H, m), 0.70 1.33 (9H, s), 2.~2 (2H, q)., 2.~6 (2H, q), 3.71 (2H, br), 3.99 (2H, br-t), x.15 (2H, s), 6.38 (1H, d), 6.89 (1H, d).
Example 105 : - 1.10 (3H, br-t), 1.10 - 1.'70 (12H, m), 0.70 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 : - 1.10 (3H, br-t), 1.10 - 1.70 (1~4H, m), 0.70 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 : - 1.10 (3H, br-t), 1.10 - 1.70 (16H, m), 0.70 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 : - 1.10 (3H, br-t), 1.10 - 2.00 (15H, m), 0.70 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (~tH, m), 3.37 (3H, s), 3.~0 (2H, t), 3.41 (2H, t), 3.56 (2H, s), 7.60 - 8.10 (2H, br).
Example 109 : - 1.10 (3H, br-t), 1.10 - 2.00 (15H, m), 0.70 2.01 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.~5 (2H, s), 2.70 - 3.10 (~H, m), 3.~1 (2H, t), 3.56 (2H, s), 7.60 - 8.10 (2H, br).
Example li0 ; - 1.10 (3H, br-t), 1.10 - 2.00 (23H, m), 0.70 T
=
2.01 (2H, t), 3.10 (~H, m), 3.~1 (3H, s), 2.70 -3.56 (2H, s), 7.60 - 8.10 (2H, br).
Example 111 : - 1.10 (3H, br-t), 1.10 - 2.00 (25H, m), 0.70 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.60 - 8.10 (2H, br).
Example 112 ;; - 1.10 (3H, br-t), 1.10 - 1.70 (12H, m), 0.70 2.Oi (3H, s), 2.15 (3H, s), 2.70 - 3.10 (~H, m), 3.~1 (2H, t), 3.56 (2H, s), 7.30 - 7.80 (3H, m), 7.60 - 8.10 (2H, br), 8.12 (2H, d).
Example 113 :~~.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.~1 (2H, t), 3.53 (2H, s), 3.56 (2H, s), '7.30 (5H, s), 7.60 - 8.10 (2H, br).
Example 11~ :_1.59 (3H, br-t), 1.10 - 1..70 (~H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.10 - 2.50 (~H, m), 2.70 - 3.10 (~H, m) , 3. ~1 (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), x.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), 1.3~ (9H, s), 2.02 (3H, s), 2.90 (2H, t), 3.13 (2H, t), 3.38 (2H, t), 3.50 (2H, s), ~t.12 (2H, q), 6.80 (1H, br), 6.85 (1H, s).
Example 117 : 0.70 - 1.10 (3H, br-t), 1.10 - 2.00 (8H, m), 1.23 (9H, s), 2.07 (3H, s), 2.24 (3H, s), 2.70- 3.10 (~+H, 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 (~H, 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 (~tH, m), 3.39 (2H, t), 3.35 (2H, s), 6.60 - 7.50 (2H, br).
Example 120 N-(1-Octyl-5. carboxyethyl-~,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (1) N-(1-Octyl-5-chloroethyl-~,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (3.0 g) was dissolved in CH3CN (30 ml), and NaCH (3.7 g) and 18-crown-6 (0.1 g) were added, which was followed by refluxing for 17 hr under a nitrogen atmosphere. CHsCN was evaporated under reduced pressure, and water (100 ml) was added to the obtained residue. The mixture was extracted twice with AcOEt (100 ml). The AcOEt layer was washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate, and AcOEt was evaporated under reduced pressure. The obtained residue was purified by silica geI column chromatography (eluent: AcOEt/benzene=1/i0 - 1/5) to give l.i~ g of N-(1-octyl-5-cyanoethyl-~,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
IR (Nujol)cm -' : 2243, 1647, 1601.
'H-NMR (CDCls) Q
0.88 (3H, br-t, J=6.OHz, -(CHz)~CHs), 1.10-.-1.90 (12H, m, -CHz(CHz)sCHs), 1.33 (9H, s, -C(CHs)3), 2.05, 2.15 (3H x 2, s x 2, indoline C4,6 -CH3), 2.38 (2H, t, J=7Hz, -CHZCN), 2.70-3.30 (6Ei, m, indoline C3-Hz, >NCHz-, -CHZCHaCN), 3.~1 (2H, t, .J=9Hz, indoline Cz-Hz), 6.81 (1H, br, -CONH-).
(2) N-(1-Octyl-5-cyanoethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (1.1~ g) was dissolved in EtOH (26 ml), and a solution of NaOH (1.1 g) i:n water (7.5 ml) was added, which was followed by refluxing for 1~ hr under a nitrogen atmosphere. EtOH was evaporated under reduced ;pressure. The obtained residue was dissolved in warm water (30 ml) .and washed with AcOEt (30 ml). The aqueous layer was neutralized with 2N HC1 and extracted with CHC13 (50 ml). CHC13 layer was evaporated under reduced pressure to give 830 mg of the title compound.
IR (Nujol)cm -': 172, 1655, 1618.
'H-NMR (CDCls) Q
0.86 (3H, br-t, J=5.OHz, -(CHz)~CH3 ), 1.10~ 2.10 (12H, m, ' CA 02233842 1998-04-02 -CHz(CHz)sCH3), 1.42 (9H, s, -C(CHs)3), 2.12, 2.26 {3Hx 2, s x 2, indoline Ca , s -CH3 ) , 2. 30-~-r2.60 (2H, m, -CHZCOz-) , 2. 90-~-3. ~t0 (E~H, m, indoline C3-H2, >NCHz-, -CH2CHzCOz-) , 3.78 (1H, br, indoline Cz-Hz), 7.70 (1H, br -COzH), 9.91 (1H, br, -CONH-).
Examples 121-123 The compounds of Table 10 were obtained according to the method of the above Exacruple 120.
Table 10 R~
/w R4 = -Nt-(COR7 ~R R
. ExampleE2' R 2 R 3 R 7 ft s 1 2 1 -CHa -CH2C02H -CHs -C{CHs}~ -(Cti2)sS(CHZ)3C(-I~
1 2 2 -GH3 -CHzG02H -GHQ -C(GHs}s -tEH2}3S(CH2)3G.H3 ~ .
1 2 3 -CH3 -{CH2}3C02H -CH3 -C(CH3)3 -{Ct-f2}7CH3 The 'H-NI~iR values of the compounds of the above Examples 121-123 are shown in t;he following.
Example 121 : 0. 91 (3H, br-t) , 1. 00 -~-1.80 ( 12H, m) , 1.3'7 (9H, s) , 1.93 (3H, s), 2.06 (3H, s), 2.~7 (~H, 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.~8 (4H, br-t), 2.90 ~-3.~0 (4H, m), 3.~0---3.80 (2H, m), 3.61 (2H, s), 7.34 (1H, br), 8.~8 (1H, br).
Example 123 : 0.86 (3H, br-t), 1.00 -~-1.50 (12H, m), 1.42 (9H, s), 2.00-~-2.90 (6H, m), 2.11 (3H, s), 2.23 (3H, s), 2.90-3.30 (4H, m), 3.~0 (2H, br), 6.10 (1H, br), 9. 21 ( 1 H, br) .
Example 12~+
N-(1-Octyl-Ei-ethoxycarbonylmethyl-5,'7-dimethyl-1,2,3,x-tetrahydro-quinolin-8-yl~i-2,2-dimethylpropanamide (1) 3,5-Xylidine (5.0 g) and acrylonitrile (2.3 g) were dissolved in acetic acid (~'_ ml) , and the mixture was stirred at 60°C for 20 lv~.
Ethyl acetate (200 ml) was added to the reaction mixture and neutralized with saturated aqueous solution of sodium hydrogencarbonate.
The mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/benzene=1/10 - 1/3) to give 4.5 g of oily j3-(3,5-dimethyl-anilino)propionitrile.
IR (Nujol) cm-' ; 2248, 1602.
' H-NMR (CDC1:; ) 8 ;
2.2~ (6H, s, Cs.S-CH3), 2.60 (2H, t, J=7.5Hz, -CHzCHzCN), 3.48 (2H, t, J=7.5Hz, -CHZCH2CN), 3.90 (1H, br, >NH), 6.2~ (2H, s, C2,s-H), 6.~3 (1H, s, Co-H).
(2) ~3-(3,5-Dicnethylanilino)propionitrile (~..5 g) was dissolved in ethanol (50 m:1), and a solution of NaOH (5.1 g) in water (25 ml) was added, which was followed by refluxing for ~ hr. The solvent was evaporated under reduced pressure. 2N Hydrochloric acid was added to adjust the residue acidic, and the mixture was washed with chloroform (100 ml). The aqueous layer was concentrated to about 20 ml and allowed to stand. The precipitated crystals were collected by filtration and dried to give ~.0 g of j3-(3,5-dimethylanilino)propionic acid.
IR (Nujol) cm-' ; 1560.
'H-NMR (DMSO-ds) 2.29 (6H, s, Cs.s-CHs), 2.73 (2H, t, J=7.5Hz, -CHZCHZCO-), 3.~~ (2H, t, J=7.5Hz, -CHzCH2C0-), 7.0 (3H, s, C2.a.s-H), 9.80 (2H, br, -COZH, >NH).
(3) j3-(3,5-Dimethylanilino)propionic acid (1.2 g) was added by portions to sulfuric acid (60°C, 12 ml), and the mixture was stirred at the same temperature for 0.5 hr. The reaction mixture was poured ini:o ice water (100 ml) and extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/benzene=1/5 - 1/1) to give 750 mg of 5,7-dimethylquinolone as crystals.
IR (Nujol) cm-' ; 165, 1614.
' H-NMR (CDC1:, ) 8 ;
2.19 (3H, s, C5-CH3), 2.57 (3H, s, C~-CHs), 2.63 (2H, t, J=7.5Hz, C3-Hi), 3.~9 (2H, t, J=7.5Hz, C2-Hz), x.39 (1H, br, >NH), 6.32 (2H, s, C6.a-H).
Lithium a7Luminum hydride (687 mg) was suspended in ether (16 ml), and aluminum chloride (~+.2 g) was added. A solution of 5,7-dimethylquinolone (1.6 g) in ether (16 ml) was dropwise added and the mixture was refluxed for 0.5 hr. The reaction mixture was poured into ice water (100 ml) and extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfates. The solvent was evaporated under reduced pressure.
The obtained 5,7-dimethyl-1,2,3,4-tetrahydroquinoline was dissolved in chloroform (30 ml), and acetic anhydride (929 mg) was added, which was followed by stirring at room temperature for 1 hr. Chloroform (100 ml) was added to the reaction mixture, and the mixture was washed successively caith saturated aqueous solution of sodium hydrogencarbonate and water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/benzene=1/5 - 1/1) to give 1.5 g of oily 1-acetyl°5,7-dimethyl-1,2,3,x-tetrahydroquino7.ine.
IR (Nujol) cm-' ; 1625, 1614.
'H-NMR (CDC13) ~ ;
1.70-2.10 (2H, m, Cs-Hi), 2.21 (6H, s x 2, -COCHs, Ar-CHs), 2.29 (3H, s, Ar-CH3), 2.5~t (2H, t, J=7.lHz, C4-HZ), 3.77 (2H, t, J=7.lHz, C2-H2), 6.83 (2H, s, CG,8-H).
(5) 1-Acetyl-5,7-dimethyl-1,2,3,x-tetrahydroquinoline (3.0 g) was dissolved in c;onc. hydrochloric acid (6 ml), and 35~ formaldehyde solution (2.5 g) and zinc chloride 0400 mg) were added. The mixture was stirred at 40--50°C for 2 hr while blowing hydrogen chloride. The reaction mixture was poured into ice water (100 ml) and extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over° anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained 1-acetyl-6-chloromethyl-5,7-dimethyl-1,2,;3,x-tetrahydroquinoline was dissolved in acetonitrile (30 ml), and sodiiun cyanide (3.6 g) and 18-crown-6 (780 mg) were added, which was fol:Lowed by refluxing for 5 hr. The solvent was evaporated under reduced pressure, and the residue was extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform - chloroform/methanol=10/1) to give~2.~ g of oily 1-acetyl-6-cyanomethyl-5,7-dimethyl-1,2,3,x-tetrahydroquinoline.
IR (Nujol) cm-' ; 228, 1650.
'H-NMR (CDCls) cs ;
1. 80-2. 20 (2:H, m, C3-H2 ) , 2. 21 , 2. 29 (3H x 2, s x 2, Cs. T-CH3 ) , 2.37 (3H, s, -COCHs), 2.68 (2H, t, J=7.5Hz, C4-HZ), 3.66 (2H, s, -CH2CN), 3.'76 (2H, t, J=7.5Hz, C2-Hi), 7.00 (1H, s, Ca-H).
. ' CA 02233842 1998-04-02 (6) 1-Acetyl-6-cyanomethyl-5,7-dimethyl-1,2,3,~+-tetrahydroquinoline (2.7 g) was dissolved in ethanol (30 ml), and a solution of NaOH (~.~4 g) in water (10 ml) was added, which was followed by refluxing for 10 hr under nitrogen. The. solvent was evaporated under reduced pressure, and the residue was extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate.
The solvent wa.s evaporated under reduced pressure. The obtained 6-carbamoylmethyl-5,7-dimethyl-1,2,3,x-tetrahydroquinoline was dissolved in N,N-dimethylformamide (10 ml), and octyl bromide (1.6 g), potassium carbonate (1.c'. g) and potassium iodide (166 mg) were added, which was followed by stirring at ~0°C far 10 hr in nitrogen. The reaction mixture was extracted with ethyl acetate (100 ml). After washing with water, the ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/
methanol=50/1 - 10/1) to give 600 mg of 1-octyl-6-carbamoylmethyl-5,7-dimethyl-1,2,5,4-tetrahydroquinoline as crystals.
IR (Nujol) cm-' ; 165, 162.
' H-NMR (CDC13~ ) 0.60-1.10 (3Ft, br-t, -(CH2)7CHs), 1.10-1.80 (12H, m, -(CHZ)eCHs), 1. 80-2.10 (2Fi, m, Cs-H2 ) , 2.16, 2. 2~ (3H x 2, s x 2, Cs, 7-CH3 ) , 2.63 (2H, t, J=7.5Hz, C4-Hi), 3.00-3.50 (~H, m, C2-Hi, >NCH2-), 3.57 (2H, s, -CH2C0-), 3.~~ (2H, br, -CONH2), 6.35 (1H, s, Ca-H).
(7) 1-Octyl-6--carbamoylmethyl-5,7-dimethyl-1,2,3,x-tetrahydroquinoline (2.5 g) was dLssolved in n-propanol (50 ml) and a solution of NaOH (3.0 g) in water (30 ml) was added, which was followed by stirring at 130°C
for 20 hr under nitrogen. The organic layer of the reaction mixture was separated and the solvent was evaporated under reduced pressure. The residue was dissolved in water (300 ml) and washed with ethyl acetate (100 ml). The aqueous layer was adjusted to pH 1-2 with 6N hydrochloric acid and extr<3cted with chloroform (200 ml). The chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained 1-octyl-6-carboxymethyl-5,7-dimethyl-1,2,3,4-tetrah.ydroquinoline was dissolved in ethanol (50 ml), and conc.
hydrochloric acid (4 ml) was added, which was followed by stirring at 70°C for 1 hr. The solvent was evaporated under reduced pressure.
The residue was neutralized with saturated aqueous solution of sodium hydrogencarbon.ate and extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography {eluent:
benzene) to give 1.0 g of oily 1-octyl-b-ethoxycarbonylmethyl-5,7-dimethyl-1,2,3.,4-tetrahydroquinoline.
IR (Nujol) cm-' ; i732, 1599.
'H-NMR (CDCIs) 8 ;
0.70-1.00 {3Hf, br-t, -(CHZ)~CHs), 1.10-1.80 (15H, m, -(CHa)sCHs, -COCH2CHs), 1.80-2.10 (2H, m, Cs-Hz), 2.12, 2.26 (3H x 2, s x 2, C5,7-CH3), 2.62 (2H, t, J=7.5Hz, C4-Hi), 3.00-3.30 (4H, m, C2-Hi, >NCHz-), 3.59 (2H, s, -CH2C0-), 4.13 (2H, q, J=7.OHz, -COCHZ-), 6.33 (1H, s, Cs-H).
(8) 1-Octyl-6-ethoxyca.rbonylmethyl-5,7-dimethyl-1,2,3,x-tetrahydro-quinoline (1.0 g) was dissolved in acetic anhydride (5 ml), and a solution of 7C)% nitric acid (517 mg) in acetic anhydride {3 ml) was dropwise added, which was followed by stirring at the same temperature for 0.5 hr. The reaction mixture was poured into ice water (50 ml), neutralized w9_th saturated aqueous solution of sodium hydrogencarbonate, and extracted with chloroform (50 ml). After washing with water, the chloroform la5rer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate/n-hexane=1/5) to give 700 mg of oily 1-octyl-6-ethoxycarbonylmethyl-5,7-dimethyl-8-nii:ro-1,2,3,4-tetrahydroquinoline.
IR (Nujol) cm-' ; 1732, 1527.
'H-NMR (CDCls) 8 0.70-1.00 (3H, br-t, -(CHZ)7CHs), 1.10-1.70 (15H, m, -(CHZ)sCHs, -COCH2CHs), 'i1.80-2.10 (2H, m, Cs-Hz), 2.16 (6H, s, Cs,~-CH3), > CA 02233842 1998-04-02 2.6~ (2H, t, J=7.5Hz, C4-H2), 2.70-3.20 (~H, m, C2-Hi, >NCHz-), 3.65 (2H, s, -CH2C0-), x.13 (2H, q, J=7.OHz, -COCH2-).
(9) 1-Octyl-6--ethoxycarbonylmethyl-5,7-dimethyl-8-nitro-1,2,3,4-tetra-hydroquinoline: (700 mg) was dissolved in ethanol (500 ml), and 10~
palladium-carton (200 mg) was added. The mixture was subjected to hydrogenation at room temperature under atmospheric pressure. 10~
Palladium-carbon was filtered off and the solvent was evaporated under reduced pressure. The obtained 1-octyl-6-ethoxycarbonylmethyl-5,7-dimethyl-8-ampno-1,2,3,4-tetrahydroquinoline was dissolved in chloroform {50 ml). Pivaloyl chloride (207 mg) and triethylamine (192 mg) were added under ice-cooling, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was washed successively with 596 aqueous citric acid and water, and dried over anhydrous sod:~Lum sulfate. The solvent was evaporated under reduced pressure. The: residue was purified by silica gel column chromatography (eluent: chlo»form - chloroform/methanol=10/1) to give 230 mg of oily title compound.
IR (Nujol) cm-' ; 1732, 1483.
' H-NMR (CDCl:a ) S ;
0.70-1.00 (3H, br-t, -(CH2)~CHs), 1.10-1.70 (15H, m, -(CHz)6CHs, -COCHZCHs), '1.35 (9H, s, -C(CH3)s), 1.80-2.10 (2H, m, Cs-Hi), 2.05, 2.11 {;3Hx 2, s x 2, Cs, z-CHs ) , 2. ~0-2.70 (~4H, m, C4-Hi, >NCH2-) , 2.80-2.90 (2H, m, C2-H2), 3.68 (2H, s, -CH2C0-), ~.1~. (2H, q, J=7.OHz, -COCH2-), 7.35 (1H, br, -CONH-).
Example 125 N-(1-Octyl-i5-carboxymethyl-5,7-dimethyl-1,2,3,x-tetrahydroquinolin-8-yl)-2,2-dimetllylpropanamide N-{1-Oct;yl-6-ethoxycarbonylmethyl-5,7-dimethyl-1,2,3,x-tetrahydro-quinolin-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 arid 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 60F25~ Art. 5714 (Merck), CHC13-MeOH (10:1), Rf value 0.5.
IR (Nujol) cm-' ; 1732, 1722.
' H-NMR (CDCls ) cs ;
0.70-1.00 (3H, br-t, -(CHa)~CH3), 1.10-1.70 (12H, m, -(CHz)sCHs), 1.35 (9H, s, -C(CHs)3), 1.80-2.10 (2H, m, Cs-Hz), 2.10 (6H, s, Cs,7-CHs), 2.~0-2.70 (~tH, m, C~-Hz, >NCHz-), 2.80-2.90 (2H, m, Cx-Hx), 3.68 (2H, s, -CH2C0-), 7.35 (1H, br, -CONH-), 9.50 (2H, br, 1/2H2S04, -COzH).
Examples 126-154 The compounds of Tables 11 and 12 were obtained according to the method of the above Example 12~..
Table 11 . Rj R2.
/.
R$ ~ ~N
R4 R6 R4 = -NHCOR~.
E~amPleR ~ R 2 R 3 R 7 . R -1 2 -GH3 -CH2CO2H -CH3 -C(CH3)3-(CH2)5CH3 1 2 -CH3 -CH2C0.2H -CH3 -C(CH3)3-CH2CH(CH2CH3)2 1 2 -CH.3 -CH2C02H -CH3 -C(CH3)3-(CH2)sCH3 1 2 -CHs -CH2G02H -CH3 -C(CHs)s-CH2 9 .
1. 3 -CH3 -CH2C02H -CH3w C(CH3)3 -(GH2)2CH(CH2CH3)2 7 ' -CH3 -CH2C02H -.GH3 -G(GH3)s'-(GH2)20(GH2~sGH3 3 ~
1 3 -CH3 -CH2C02H -CH3 -C(CH3)s-(CH2)2S(CH2)3CH3 -cHs -cr~co2H -cHs -c(GHs?s -CH2C:H 2-~~
1 S -GH3 -GH2G02H -CH3 -G(GH~)3-(~H2~3GH(GH2GH3)2 1 3 -CH3 -GH2CO2N -GH3 -C(CH3)3-(CH2)30(GH2)3CH3 1 3 -CHs -CH2C02H -CHs -C(CHs)s-(CH2)3S(CH2)3CH3 '~ 3 -GH3 -H2fl2H -y-f3 -(~GH3)3-(GH23sH3 1 3 -CH3 -CH2C02H -GH3 -C(CH3)3-{CH2)9CH3 1 3 -CH2C:H3 -CH2CO2H -CH2CH3 -C(CH3)3.- -(CH2)5GH3 i 4 -CH2~:1-is-GH2CO2H -CH2GH3 -C(CH3)3-(Gf-i2)7GH3 1 4 -CH2C;H3 wGH2C02H -CH2cH3 -C(CH3~3.-(GH2)sCHs Table 12 R3 w R4 _ -NHCOR~
R2 Rs R7 Rs i 4 -OCH3 -CH2C02H -OCH3 -CtCH3)3 =(CH2)5CH3 7 4 -OCH3 -GH2G02H -OCH3 -G(GH3)3 -(CH2)7GH3 1 4 -OCH3 -CH2C02H -OCH3 -C(CH3)3 -(CH2)9CH3 7 4 -CH3 -GH2OH -CH3 -C(CH3)3 -(CH2)5CH3 .
1 4 -CH3 -CH20H -CH3 -C(,GH3)3' -(CH2)7CH3 6 ~
i 4 -CH3 -GHZOH -CH3 -C(GH3)3 -(GH2)gCH3 7 4.8 -CH3 -CH2C02H -CH3 -C(CH3)2(CH2)3CHs -(CH2)~GH3 i 4 -CH3 -CH2C02H -CHs -C(CH3)2CCH2)sGH3 -(GH2)7CHs 1, -CH3 -CH2C02H -CH3 -CH2-( H ) -(CH2)7CH3 i 5 -CH3 -CH2C02H -CN3 -~H2, ~ ~ , -(CH2)7GN3 i 1 5 -GH3 -GH2G02H -CH3 -NH(GH2)3GH5 -(GH2)5GH3 1 5 -GH3. -CH2C02H -CH3 -NH(GH2)3GH3 -(CH2)7GH3 1 5.4 -CH3 -CH2G02H -CHs -NH(CH2)sCHs -(CH2)sC~
w . -- CA 02233842 1998-04-02 i The 'H-NI~R above Examples values of 126-i54 the compounds of the are shown i~he in following.
Example 126 0.70-1.00 (3H, br-t), 1.10-1.70{8H, m), .35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, 2.~0-2.70(~H, m), s), 2.80-2.90 (2H, m), 3.68 (2H, 7.35 (1H,br), 9.50 br).
s), (2H, 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, 2.~0-2.70(4H, m), s), 2.80-2.90 (2H, m), 3.68 (2H, 7.35 (1H,br), 9.50 br).
s), (2H, 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, 2.~0-2.70(4H, m), s), 2.80-2.90 (2H, m), 3.68 (2H, 7.35 (1H,br), 9.50 br).
s), (2H, Example 129 0.80-1.70 (11H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.80-2.90(2H, m), 3.68(2H, s), 2.~0-2.70 (4H, m), 7.35 (1H, br), 9.50 (2H, br).
Example 130 0.70-1.00 (6H, br-t), i.10-1.70 35 (9H, s), (7H, m), 1.
1.80-2.10 (2H, m), 2.10 (6H, 2.~0-2.70(4H, m), s), 2.80-2.90 {2H, m), 3.68 {2H, 7.35 (1H,br), 9.50 br).
s), (2H, Example 131 0.70-1.10 (3H, br-t), 1.10-1.70 35 (9H, s), (~H, m), 1.
1.80-2.10 {2H, m), 2.10 (6H, 2.~0-2.70(4H, m), s), 2.80-2.90 (2H, m), 3.30-3.60 m), 3.68 (2H, s), 7.35(1H, br), (4H, 9. 50 (2H, lbr) .
Example 132 0.70-1.10 (3H, br-t), 1.10-1.70~4H, m), 35 (9H, s), ( 1.
1.80-2.10 (2H, m), 2.10 (6H, 2.~0-2.70(~4H, m), s), 2.80-2.90 (2H, m), 3.20-3.50 m), 3.68 (2H, s), 7.35(1H, br), (~.H, 9.50 (2H, br).
Example 133 7s 0.80-1.70 (13H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.~0-2.70 (~tH, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H., br).
Example 13~+
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 (~+H, 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 (~tH, m), 2.80-2.90 (2H, m), 3.30-3.60 (~H, 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), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (~H, 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 (3H, 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.~0-2.70 (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.~0 (2H, q), 2.~3 (2H, q), 2.40-2.70 (~H, 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.~0 (2H, q), 2.~3 (2H, q), 2.~0-2.70 (~H, 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.~0 (2H, q), 2.~3 (2H, q), 2.~0-2.70 (~H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 1~2 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 (~H, 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 1~3 0.70-1.10 (3H, br-t), 1.10-1.70 (12H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.~0-2.70 (~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 1~~
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 1~5 .
0.70-1.i0 (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.~0-2.70 (~H, m), 2.80-2.90 (2H, m), 4.65 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 1~6 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.u0-2.70 (~H, m), 2.80-2.90 (2H, m), 4.65 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 1~7 0.70-1.10 (3H, br-t), 1.10-i.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 (~H, m), 2.80-2.90 (2H, m), ~t.65 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 1 X48 0.70-1.00 (6H, br-t), 1.10-1.70 (18H, m), 1.35 (6H, s), ' CA 02233842 1998-04-02 1.80-2.10 (2H, m), 2.10 (6H, s), 2.~0-2.70 (~H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 1~9 .
0.70-1.00 (6H, br-t), 1.10-1.70 (22H, m), 1.35 (6H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.~0-2.70 (~H, 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 (~H, 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.~0-2.70 (4H, m), 2.80-2.90 (2H, m), 3.53 (2H, s), 3.68 (2H, s), 7.30 (5H, s), 7.35 (iH, 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 15~+
0.70-1.10 (6H, br-t), 1.10-1.70 (20H, m), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.~0-2.90 (8H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).
Example 155 N-(1-Octyl-5~ carboxy-6-methylindolin-7-yl)-2,2-dimethylpropanarnide (1) 5-Bromo-7-methyl-7-nitroindoline (3.6 g) was dissolved in N,N-dimethylformamide (36 ml), and sodium hydride (677 mg) was added, which was followed by stirring at room temperature for 0.5 hr. 1-Iodooctane (3.~ g) was added to the reaction mixture and the mixture was stirred at the same temperature for 24 hr. Ethyl acetate (200 ml) was added to the reaction mixture, and the mixture was washed with water and dried over anhydrous; sodium sulfate. Ethyl acetate was evaporated under reduced pressure. The residue was purified by gel column chromatography (eluent: ethyl acetate/n-hexane=1/100 - 1/50) to give ~.0 g of oily 1-octyl-5-bromo-6-methyl-7-nitroindoline.
IR (Nujol)cau' ; 1610, 1568.
'H-NMR (CDC13) 8 ;
0.88 (3H, br-~t, J=7Hz, -(CHz)7CHs), 1.00~1.70 (12H, m, -CHz(CHz)s-), 2.25 (3H, s, indoline C6-CH3), 2.93 (2H, t, J=BHz, indoline C3-Hz), 2.9~ (2H, t, J=7Hz, >NCHz-), 3.5'7 (2H, t, J=8Hz, indoline Cz-Hz), 7.19 (1H, s, indoline C~-H).
(2) 1-Octyl-5--bromo-6-methyl-7-nitroindoline (~.0 g) was dissolved in N-methylpyrrolidone (~0 ml), and copper cyanide (1.9 g) was added, which was followed by stirring at 190°C for 1 hr. Ethyl acetate (100 ml) and water (100 ml) were added to the reaction mixture. The insoluble matter was fi~.tered off. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5 - 1/3) to give 2.zE g of oily 1-oct3rl-5-cyano-6-methyl-7-nitroindoline.
IR (Nujol)cm-' ; 221, 1620.
' H-NMR (CDCl:~ ) 0.88 (3H, br--t, J=7Hz, -(CHz)7CHs), 1.00~1.70 (12H, m, -CHz(CHz)s-), 2.38 (3H, s,.indoline Cs-CHs), 3.03 (2H, t, J=8Hz, indoline C3-H2), 3.0~. (2H, t, J=7Hz, >NCHz-), 3.'73 (2H, t, J=8Hz, indoline Cz-Hz), 7.15 (1H, s, indoline C4-H).
s o ~
(3) 1-Octyl-5-~cyano-6-methyl-7-nitroindoline (2.~ g) was dissolved in n-propanol and a solution of NaOH (3.0 g) in water (10 ml) was added, which was followed by refluxing for 20 hr. n-Propanol was evaporated under reduced pressure and ethyl acetate (100 ml) was added to the residue. The mixture was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent:
ethyl acetate/benzene=1/5 - 1/1) to give 1.~ g of 1-octyl-5-carboxy-6-methyl-7-nitroindoline as crystals.
IR (Nujol)cm,-' ; 1679, 1620.
'H-NMR (CDCls) 8 ;
0.88 (3H, br-~t, J=7Hz, -(CH2)~CHs), 1.00~1.70 (12H, m, -CHZ(CH2)s-), 2.~7 (3H, s, indoline Cs-CH3), 3.02 (2H, t, J=8Hz, indoline Cs-HZ), 3.03 (2H, t, J=7Hz, >NCH2-), 3.69 (2H, t, J=8Hz, indoline Ca-Hi), 5.00 (1H, br, -COZH), 7.73 (1H, s, indoline C4-H).
1-Octyl-5-~carboxy-6-methyl-7-nitroindoline (1.~ g) was dissolved in methanol (30 ml), and conc, sulfuric acid (4.1 g) was added, which was followed by rE:fluxing for 4 hr. Methanol was evaporated under reduced pressure. Ethyl acetate (100 ml) was added to the residue. The mixture was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/
methanol=1/0 -- 10/1) to give 750 mg of 1-octyl-5-methoxycarbonyl-6-methyl-7-nitroindoline as crystals.
IR (Nu jol) crn-' ; 1679, 1620.
' H-NMR (CDCl:; ) 0.88 (3H, br--t, J=7Hz, -(CH2)ZCHs), 1.00~1.70 (12H, m, -CHZ(CHZ)6-), 2.43 (3H, s, indoline Cs-CIi3), 3.00 (2H, t, J=BHz, indoline C3-Hz), 3.02 (2H, t, J=7Hz, >NCH2-), 3.66 (2H, t, J=8Hz, indoline C2-H2), 3.82 (3H, s, -CO2CH3), 7.62 (1H, s, indoline Cr,-H).
(5) 1-Octyl-5-methoxycarbonyl-6-methyl-7-nitroindoline (750 mg) was dissolved in ethanol (50 ml), and 106 palladium-carbon (150 mg), which was followed 'by hydrogenation at 40°C for 15 hr. 10% Palladium-carbon s~
~
was filtered off and ethanol was evaporated under reduced pressure.
Chloroform (1C10 ml) was added to the residue. The mixture was washed with water andl dried over anhydrous sodium sulfate. Chloroform was evaporated undler reduced pressure. The obtained 1-octyl-7-amino--5-methoxycarbonyl-6-methylindoline was dissolved in chloroform (10 ml).
Pivaloyl chloride (310 mg) and triethylamine (286 mg) were added under ice-cooling, which was followed by stirring at room temperature for 1 hr. Chloroform (50 ml) was added to the reaction mixture. The mixture was washed successively with 5~ aqueous citric acid and water, and dried over anhydrou:> sodium sulfate. Chloroform was evaporated under reduced pressure. The: residue was purified by silica gel column chromatography (eluent: chloroform/methanol=1/0 - 20/1) to give 580 mg of oily N-(1-octyl-5-metho3~ycarbonyl-6-methylindolin-7-yl)-2,2-dimethylpropanamide.
IR (Nujol)cnn-' ; 1708, 1651.
'H-NMR (CDCls) 0.87 (3H, br--t, J=7Hz, -(CH2)7CHs), 1.00-x1.70 (12H, m, -CHZ(CHz)s-), 1.3~ (9H, s, -C(CH3)s), 2.39 (3H, s, indoline Cs-CHs), 2.93 (2H, t, J=8Hz, indoline Cs-Hi), 3.25 (2H, t, J=7Hz, >NCH2-), 3.51 (2H, t, J=8Hz, indoline CZ-Hi), 3.79 (3H, s, -C02CHs), 6.76 (1H, br, -CONH-), 7.55 (1H, s, indoline C4-H).
(6) N-(1-Octy:L-5-methoxycarbonyl-6-methylindolin-7-yl)-2,2-dimethylpropaaaamide (580 mg) was dissolved in methanol (10 ml) and a solution of N~aOH (290 mg) in water (5 ml) was added, which was followed by stirring at 60°C for ~ hr. Methanol was evaporated under reduced pressure. Water (50 ml) was added to the residue and the mixture was washed with ethyl acetate (20 ml). The aqueous layer was adjusted to pH
6-7 with 2N sulfuric acid and extracted with chloroform (100 ml). The chloroform layer was washed with water and dried over anhydrous sodium.
sulfate. Chloroform was evaporated under reduced pressure to give 380 mg of the title compound.
IR (Nujol)cm-' ; 1668, 1645, 1615.
'H-NMR (CDCls) 8 ;
0.79 (3H, br, -(CHZ)7CHs), 0.80~1.80 (12H, m, -CHZ(CHZ)6), az 1.3~ (9H, s, -C(CH3)s), 2.38 (3H, s, indoline C6-CHs), 2.9~+ (2H, t, J=8Hz, indoline Cs-HZ), 3.27 (2H, t, J=7Hz, >NCH~-), 3.5~ (2H, t, J=8Hz, indoline CZ-Hz), 6.80 (2H, br, -CONH-, -C02H), 7.67 (1H, s, indoline C.,-H).
Examples 156-160 The compounds of Table 13 were obtained according' to the method of the above Example 155.
Table 13 Ft~
Rs ~ N
R4 = -NHCOR~
~a~rpleR ~ R 2 R s R ~ R s 1 5 -H -C02H -CH3 -C(CH3)3 -(CH2)5CH3 1 5 -H -C02H -CH3 -C(CH3)3 -(CH2)9CH3 1 .5 -CHa -C02H -CHs -C(CHs)s -(CH2)sCl-l3 1 5 -CH3 -CO2H -CH3 -C(CH3)3 -(CH2)7CH3 1 6 -CH3 -C02H -CH3 -C(CH3)3 -(CH2)sCH3 The 'H-NfR values of the compounds of the above Examples 156-160 are shown in ~;he following.
Example 156 0.79 (3H, br-t), 0.80 ~-1.80 (8H, m), 1.3~ (9H, s), 2.38 (3H, s), 2.9~ (2H, t), 3.27 (2H, t), 3.5~ (2H, t), 6.80 (2H, br),7.67 (1H, s).
Example 157 0.79 (3H, br-t), 0.80 -~-1.80 (16H, m), 1.3~ (9H, s), 2.38 (3H, s), 2.9~ (2H, t), 3.27 (2H, t), 3.5~ (2H, t), 6.80 (2H, br), 7.67 (1H, s).
Example 0.79 (3H,br-t), 0.80 -~-1.80(8H, m), 1.33 (9H, 2.40 (3H, s), s), 2.~5 (3H,s), 2.95 (2H, 3.26 (2H,t), 3.5~ t), 6.80 (2H, t), (2H, br).
Example 0.79 (3H,br-t), 0.80 -~-1.80(12H, 1.33 (9H, 2.~0 (3H, s), m), s), 2.x+5 (3H,s), 2.95 (2H, 3.26 (2H,t), 3.5~+ t), 6.80 (2H, t), (2H, br).
Example 160 .
0.79 (3H,br-t), 0.80 ..1.80(16H, 1.33 (9H, 2.~0 (3H, s), m), s), 2.45 (3H,s), 2.95 (2H, 3.26 (2H,t), 3.5~t t), 6.80 (2H, t), (2H, br).
With the aim of demonstrating the superior properties of the compound of tree 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.
Experimental Example 1 . ACAT inhibitory activity 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 bar bleeding under anesthesia and small intestine was removed. The mucosal membrane of small intestine was peeled, co:Llected and homogenated. The homogenate was centrifuged at 4°C and 10,000 rpm for 15 min. '.Che obtained supernatant was further centrifuged at ~°C
and X41,000 rpm for 30 minutes to give microsomal fractions. The microsomal suspension as an enzyme sample, dimethyl sulfoxide (DMSO, 5 ~.1) or a test compound dissolved in DMSO (test compound solution 5 ul), and reaction substrate [1-"~C]-oleoyl CoA were added to 0.15 M phosphate buffer to the total amount of 500 ~tl. After incubation at 37°C for 7 minutes, a chloroform-methanol mixture was added to stop the reaction.
Water was add~sd thereto and mixed, and chloroform layer was separated.
The solvent w;3s evaporated to dryness, and the residue was re-dissolved in n-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 cholesteryl 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 ACAT
compound inhibition Example 1 9 9. 2 Example 3 9 2. 5 Example 4 9 3. 6 Example 36 9 4. 0 Example ~0 9 2. 7 Example ~6 9 4. 7 Example 116 9 2. 0 Example 120 9 2. 3 Example 121 9 2. 5 Example 122 9 2 0 .
Example 125 9 3. 0 .
YM-'T50 : 1-cycloheptyl-1-[(2-fluorenyl)methyl]-3-(2,x,6-trimethyl-phenyl) urea Experimental hxample 2 : serum total cholesterol reducing effect Male Winter 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 5~6 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 kit (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 (~) serum cholesterol of total Test 3 mg/kg/day 10 mg/kg/day compound Example 1 5 2 8 5 7. 1 .
Example 3 5 4 2 6 1 2 . .
Example ~ 5 8 8 5 7 5 . .
Example 18 4 5 1 5 6 6 . .
Example 25 4 5 0 5 2 3 . .
Example 36 6 0 0 5 8 9 . .
Example ~.0 5 1 3 5 6 2 . .
Example 71 2 6 5 5 2 3 . .
Example 81 3 1 7 5 3 8 . .
Example 116 2 6 5 5 0 9 . .
Example 120 4 5 8 4 4 6 . .
Example 121 3 7. 8 4 8 1 .
Example 122 3 8 2 5 0 0 . .
Example 125 3 0 2 4 7 9 . .
Example 155 5 5 2 5 8 5 . .
Example 159 5 3. 8 5 7. 5 YM-750 3 7. 7 4 6 4 .
YM-750 : 1-c:ycloheptyl-1-[(2-fluorenyl)methyl]-3-(2,4,6-trimethyl-phE~nyl) urea Experimental Example 3 : in vitro plasma lipoperoxidation inhibitory activity Under ether anesthesia, blood was taken from male blister rats weighing 160-'190 g that had been fasted for 16 hours, and heparinized plasma was se~~arated by conventional method. DMSO (10 ul) or a test compound (fin~~l concentration 10-5 M) dissolved in DMSO (test compound solution 10 ~t.l) was added to plasma (1.0 ml), and the mixture was incubated at 37°C for 5 minutes. Distilled water (10 ul) or aqueous solution (10 ;~tl) of copper sulfate (final concentration 1 M) was added, followed by incubation at 37°C for ~ 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 malondialdehydle. 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 Inhibition of plasma lipoperoxidation compound (~) Example 1 5 1. 7 Example 3 4 9. 2 Example ~ 5 1. 2 Example 11 4 4. 5 Example 18 4 4. 0 Example 25 6 3. 5 Example 36 4 1. 5 Example 71 4 8. 1 Example 76 5 1. 7 Example 81 4 7. 1 Example 116 4 5. 5 Example 121 4 1. 6 Example 125 4 8. 0 Example 155 4 7. 7 Example 159 4 8. 3 Experimental F~xample ~+ : ex vivo plasma lipoperoxidation inhibitory activity A test compound suspended in 5~6 gum arabic solution was forcibly administered orally to male Wister rats weighing 160-190 g that had been fasted for 16 hr. Only 5g~ gum arabic solution was administered to control animals. At 1 hour after administration, blood was taken under ether anesthe:~ia and heparinized plasma was separated by conventional method. The ~~lasma (1.0 ml) was processed in the same manner as in Experimental lrxample 3 and the amount of produced malondialdehyde was determined. The activity of the test compound was expressed as a proportion (yb') 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 Example 18 Example 36 Probucol ~4 mg/kg 3 9 . 0 2 7 . 1 4 1 . 6 100 mg/kg 1 5 . 4 Probucol : 4,4-isopropylidenedithiobis(2,6-di-t-butylphenol) Experimental Example 5 : solubility A pulverized test compound (10 mg) was added to buffer (1 ml, pH
6.8), and the mixture was shaken for 1 hr 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. 0 1 YM-750 : 1-c;ycloheptyl-1-[(2-fluorenyl)methyl]-3-(2,x,6-trimethyl-phE:nyl ) urea Experimental Example 6 : oral administration A test compound (30 mg/kg) suspended in 5~ gum arabic solution was forcibly administered orally to male blister rats weighing 200-250 g that had been fastErd for 16 hr. At 0.5, 1, 2, ~+ 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.
8s , Table 19 Test compound Highest concentration in plasma (ug/ml) Example ~4 1 . 4 Example 36 2. 2 Experimental Example 7 : oral administration 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 (ug/ml) Example 4 1 3. 6 Example 36 1 2. 2
Claims (51)
1. A heterocyclic derivative of formula (I):
wherein:
one of R1, R2 and R5 is (i) hydroxyl , (ii) carboxyl, (iii) alkoxycarbonyl, (iv) a group of the formula:
-NR9R10 (wherein R9 and R10 are each independently hydrogen or C1-6alkyl), or (v) C1-8alkyl or C2-8alkenyl, each substituted by hydroxyl, an acidic group, alkoxycarbonyl or a group of the formula: -NR9R10 (wherein R9 and R10 are each independently hydrogen or C1-6alkyl), and the other two are each independently hydrogen, C1-6alkyl or C1-6alkoxy;
one of R3 and R4 is a group of the formula:
-NHCOR7 (wherein R7 is C1-20alkyl, C1-6alkoxy-C1-6alkyl, C1-6alkylthio-C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl, aryl, arylalkyl or a group of the formula: -NHR8 (wherein R8 is C1-20alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl, aryl or arylalkyl)), and the other is hydrogen, C1-6alkyl or C1-6alkoxy;
R6 is C1-20alkyl, C3-12alkenyl, C1-6alkoxy-C1-6alkyl, C1-6alkylthio-C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl or arylalkyl;
Z is a binding group of the formula:
the alkoxycarbonyl has a C1-4alkoxy moiety;
the acidic group is a carboxyl group, a sulfonic acid group or a phosphoric acid group;
the aryl is phenyl or naphthyl;
the arylalkyl is an aryl-C1-4alkyl in which the aryl is as defined above, or a pharmaceutically acceptable salt thereof, provided that when one of R1, R2 and R5 is hydroxyl, carboxyl or the alkoxylcarbonyl, then Z is:
wherein:
one of R1, R2 and R5 is (i) hydroxyl , (ii) carboxyl, (iii) alkoxycarbonyl, (iv) a group of the formula:
-NR9R10 (wherein R9 and R10 are each independently hydrogen or C1-6alkyl), or (v) C1-8alkyl or C2-8alkenyl, each substituted by hydroxyl, an acidic group, alkoxycarbonyl or a group of the formula: -NR9R10 (wherein R9 and R10 are each independently hydrogen or C1-6alkyl), and the other two are each independently hydrogen, C1-6alkyl or C1-6alkoxy;
one of R3 and R4 is a group of the formula:
-NHCOR7 (wherein R7 is C1-20alkyl, C1-6alkoxy-C1-6alkyl, C1-6alkylthio-C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl, aryl, arylalkyl or a group of the formula: -NHR8 (wherein R8 is C1-20alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl, aryl or arylalkyl)), and the other is hydrogen, C1-6alkyl or C1-6alkoxy;
R6 is C1-20alkyl, C3-12alkenyl, C1-6alkoxy-C1-6alkyl, C1-6alkylthio-C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl or arylalkyl;
Z is a binding group of the formula:
the alkoxycarbonyl has a C1-4alkoxy moiety;
the acidic group is a carboxyl group, a sulfonic acid group or a phosphoric acid group;
the aryl is phenyl or naphthyl;
the arylalkyl is an aryl-C1-4alkyl in which the aryl is as defined above, or a pharmaceutically acceptable salt thereof, provided that when one of R1, R2 and R5 is hydroxyl, carboxyl or the alkoxylcarbonyl, then Z is:
2. The heterocyclic derivative or salt of claim 1, wherein one of R1, R2 and R5 is C1-8alkyl or C2-8alkenyl, each substituted by hydroxyl, the acidic group, the alkoxycarbonyl or a group of the formula -NR9R10 (in which R9 and R10 are each independently hydrogen or C1-6alkyl), and the other two are each independently hydrogen, C1-6alkyl or C1-6alkoxy.
3. The heterocyclic derivative or salt of claim 2, wherein Z is
4. The heterocyclic derivative or salt of claim 3, wherein:
one of R1, R2 and R5 is C1-8alkyl substituted by hydroxyl, carboxyl, the alkoxycarbonyl or a group of the formula -NR9R10 (in which R9 and R10 are each independently C1-6alkyl), and the other two are each independently hydrogen, C1-6alkyl or C1-6alkoxy; and one of R3 and R4 is a group of the formula -NHCOR7 (in which R7 is C1-20alkyl, C1-6alkoxy-C1-6alkyl, C1-6alkylthio-C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl, phenyl, naphthyl, aryl-C1-4alkyl (in which the aryl is phenyl or naphthyl) or a group of the formula -NHR8 (in which R8 is C1-20alkyl)), and the other is hydrogen, C1-6alkyl or C1-6alkoxy.
one of R1, R2 and R5 is C1-8alkyl substituted by hydroxyl, carboxyl, the alkoxycarbonyl or a group of the formula -NR9R10 (in which R9 and R10 are each independently C1-6alkyl), and the other two are each independently hydrogen, C1-6alkyl or C1-6alkoxy; and one of R3 and R4 is a group of the formula -NHCOR7 (in which R7 is C1-20alkyl, C1-6alkoxy-C1-6alkyl, C1-6alkylthio-C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl, phenyl, naphthyl, aryl-C1-4alkyl (in which the aryl is phenyl or naphthyl) or a group of the formula -NHR8 (in which R8 is C1-20alkyl)), and the other is hydrogen, C1-6alkyl or C1-6alkoxy.
5. The heterocyclic derivative or salt of claim 4, wherein:
R1 and R3 are each independently hydrogen, C1-6alkyl or C1-6alkoxy;
one of R2 and R5 is C1-8alkyl substituted by hydroxyl, carboxyl, the alkoxycarbonyl or a group of the formula -NR9R10 (in which R9 and R10 are each independently C1-6alkyl), and the other is hydrogen, C1-6alkyl or C1-6alkoxy;
and R4 is a group of the formula -NHCOR7 in which R7 is as defined in claim 4.
R1 and R3 are each independently hydrogen, C1-6alkyl or C1-6alkoxy;
one of R2 and R5 is C1-8alkyl substituted by hydroxyl, carboxyl, the alkoxycarbonyl or a group of the formula -NR9R10 (in which R9 and R10 are each independently C1-6alkyl), and the other is hydrogen, C1-6alkyl or C1-6alkoxy;
and R4 is a group of the formula -NHCOR7 in which R7 is as defined in claim 4.
6. The heterocyclic derivative or salt of claim 5, wherein, one of R2 and R5 is C1-8alkyl substituted by hydroxyl, carboxyl, the alkoxycarbonyl or a group of the formula -NR9R10 in which R9 and R10 are each independently C1-6alkyl, and the other is hydrogen.
7. The heterocyclic derivative or salt of claim 6, wherein:
R1 and R3 are each independently hydrogen or C1-6alkyl;
one of R2 and R5 is C1-8alkyl substituted by hydroxyl, carboxyl, the alkoxycarbonyl or a group of the formula -NR9R10 in which R9 and R10 are each independently C1-6alkyl, and the other is hydrogen;
R4 is a group of the formula -NHCOR7 wherein R7 is C1-20alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-3alkyl; and R6 is C1-20alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-3alkyl.
R1 and R3 are each independently hydrogen or C1-6alkyl;
one of R2 and R5 is C1-8alkyl substituted by hydroxyl, carboxyl, the alkoxycarbonyl or a group of the formula -NR9R10 in which R9 and R10 are each independently C1-6alkyl, and the other is hydrogen;
R4 is a group of the formula -NHCOR7 wherein R7 is C1-20alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-3alkyl; and R6 is C1-20alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-3alkyl.
8. The heterocyclic derivative or salt of claim 7, wherein:
R2 is C1-8alkyl substituted by hydroxyl, carboxyl, the alkoxycarbonyl or a group of the formula -NR9R10 wherein R9 and R10 are each independently C1-6alkyl, and R5 is hydrogen.
R2 is C1-8alkyl substituted by hydroxyl, carboxyl, the alkoxycarbonyl or a group of the formula -NR9R10 wherein R9 and R10 are each independently C1-6alkyl, and R5 is hydrogen.
9. The heterocyclic derivative or salt of claim 1, wherein the heterocyclic derivative is represented by the formula (IIa):
wherein:
R1a is hydrogen or C1-6alkyl;
R3a is C1-6alkyl;
R2a is C1-8alkyl substituted by hydroxyl or carboxyl;
R4a is a group of the formula -NHCOR7a in which R7a is C1-20alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-3alkyl; and R6a is C1-20alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-3alkyl.
wherein:
R1a is hydrogen or C1-6alkyl;
R3a is C1-6alkyl;
R2a is C1-8alkyl substituted by hydroxyl or carboxyl;
R4a is a group of the formula -NHCOR7a in which R7a is C1-20alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-3alkyl; and R6a is C1-20alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-3alkyl.
10. The heterocyclic derivative or salt of claim 9, wherein:
R1a is hydrogen or C1-6alkyl;
R3a is C1-6alkyl;
R2a is C1-8alkyl substituted by hydroxyl or carboxyl;
R4a is a group of the formula -NHCOR7a wherein R7a is C1-20alkyl; and R6A is C1-20alkyl.
R1a is hydrogen or C1-6alkyl;
R3a is C1-6alkyl;
R2a is C1-8alkyl substituted by hydroxyl or carboxyl;
R4a is a group of the formula -NHCOR7a wherein R7a is C1-20alkyl; and R6A is C1-20alkyl.
11. The heterocyclic derivative or salt of claim 10, wherein the heterocyclic derivative is N-(1-hexyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide.
12. The heterocyclic derivative or salt of claim 10, wherein the heterocyclic derivative is N-(1-heptyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide.
13. The heterocyclic derivative or salt of claim 10, wherein the heterocyclic derivative is N-(1-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide.
14. The heterocyclic derivative or salt of claim 10, wherein the heterocyclic derivative is N-(1-nonyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide.
15. The heterocyclic derivative or salt of claim 10, wherein the heterocyclic derivative is N-(1-decyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide.
16. The heterocyclic derivative or salt of claim 10, wherein the heterocyclic derivative is N-(1-undecyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide.
17. The heterocyclic derivative or salt of claim 10, wherein the heterocyclic derivative is N-(1-dodecyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide.
18. The heterocyclic derivative or salt of claim 10, wherein the heterocyclic derivative is N-(1-hexyl-5-hydroxymethyl-6-methylindolin-7-yl)-2,2-dimethyl-propanamide.
19. The heterocyclic derivative or salt of claim 10, wherein the heterocyclic derivative is N-(1-hexyl-5-hydroxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide.
20. The heterocyclic derivative or salt of claim 10, wherein the heterocyclic derivative is N-(1-heptyl-5-hydroxymethyl-6-methylindolin-7-yl)-2,2-dimethyl-propanamide.
21. The heterocyclic derivative or salt of claim 10, wherein the heterocyclic derivative is N-(1-heptyl-5-hydroxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide.
22. The heterocyclic derivative or salt of claim 10, wherein the heterocyclic derivative is N-(1-octyl-5-hydroxymethyl-6-methylindolin-7-yl)-2,2-dimethyl-propanamide.
23. The heterocyclic derivative or salt of claim 10, wherein the heterocyclic derivative is N-(1-octyl-5-hydroxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide.
24. The heterocyclic derivative or salt of claim 2, wherein Z is
25. The heterocyclic derivative or salt of claim 24, wherein the heterocyclic derivative is represented by the formula (IIb):
wherein:
R1b and R3b are each independently hydrogen, C1-6alkyl or C1-6alkoxy;
R2b is C1-8alkyl substituted by hydroxyl, carboxyl or the alkoxycarbonyl;
R4b is a group of the formula -NHCOR7b wherein R7b is C1-C20alkyl, C1-6alkoxy-C1-6alkyl, C1-6alkylthio-C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl, phenyl, naphthyl, aryl-C1-4alkyl (in which the aryl is phenyl or naphthyl) or a group of the formula -NHR8b wherein R8b is C1-C20alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl, phenyl, naphthyl or aryl-C1-4alkyl in which the aryl is as defined above; and R6b is C1-C20alkyl, C3-12alkenyl, C1-6alkoxy-C1-6alkyl, C1-6alkylthio-C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl or aryl-C1-4alkyl in which the aryl is as defined above.
wherein:
R1b and R3b are each independently hydrogen, C1-6alkyl or C1-6alkoxy;
R2b is C1-8alkyl substituted by hydroxyl, carboxyl or the alkoxycarbonyl;
R4b is a group of the formula -NHCOR7b wherein R7b is C1-C20alkyl, C1-6alkoxy-C1-6alkyl, C1-6alkylthio-C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl, phenyl, naphthyl, aryl-C1-4alkyl (in which the aryl is phenyl or naphthyl) or a group of the formula -NHR8b wherein R8b is C1-C20alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl, phenyl, naphthyl or aryl-C1-4alkyl in which the aryl is as defined above; and R6b is C1-C20alkyl, C3-12alkenyl, C1-6alkoxy-C1-6alkyl, C1-6alkylthio-C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl or aryl-C1-4alkyl in which the aryl is as defined above.
26. The heterocyclic derivative or salt of claim 25, wherein:
R1b and R3b are each independently C1-6alkyl or C1-6alkoxy;
R2b is C1-8alkyl substituted by hydroxyl, carboxyl or the alkoxycarbonyl;
R4b is a group of the formula -NHCOR7b wherein R7b is C1-C20alkyl, C3-8cycloalkyl-C1-3alkyl, aryl-C1-4alkyl (in which the aryl is phenyl or naphthyl) or a group of the formula -NHR8b wherein R8b is C1-C20alkyl; and R6b is C1-C20alkyl, C1-6alkoxy-C1-6alkyl, C1-6alkylthio-C1-6alkyl or C3-8cycloalkyl-C1-3alkyl.
R1b and R3b are each independently C1-6alkyl or C1-6alkoxy;
R2b is C1-8alkyl substituted by hydroxyl, carboxyl or the alkoxycarbonyl;
R4b is a group of the formula -NHCOR7b wherein R7b is C1-C20alkyl, C3-8cycloalkyl-C1-3alkyl, aryl-C1-4alkyl (in which the aryl is phenyl or naphthyl) or a group of the formula -NHR8b wherein R8b is C1-C20alkyl; and R6b is C1-C20alkyl, C1-6alkoxy-C1-6alkyl, C1-6alkylthio-C1-6alkyl or C3-8cycloalkyl-C1-3alkyl.
27. The heterocyclic derivative or salt of claim 26, wherein R1b and R3b are each independently C1-6alkyl, R2b is C1-8alkyl substituted by hydroxy or carboxy, R4b is a group of the formula -NHCOR7b wherein R7b is C1-20alkyl, and R6b is C1-20alkyl.
28. The heterocyclic derivative or salt of claim 27, wherein the heterocyclic derivative is N-(1-hexyl-6-carboxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide.
29. The heterocyclic derivative or salt of claim 27, wherein the heterocyclic derivative is N-(1-heptyl-6-carboxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide.
30. The heterocyclic derivative or salt of claim 27, wherein the heterocyclic derivative is N-(1-octyl-6-carboxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide.
31. The heterocyclic derivative or salt of claim 27, wherein the heterocyclic derivative is N-(1-nonyl-6-carboxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide.
32. The heterocyclic derivative or salt of claim 27, wherein the heterocyclic derivative is N-(1-decyl-6-carboxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide.
33. The heterocyclic derivative or salt of claim 27, wherein the heterocyclic derivative is N-(1-hexyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide.
34. The heterocyclic derivative or salt of claim 27, wherein the heterocyclic derivative is N-(1-heptyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide.
35. The heterocyclic derivative or salt of claim 27, wherein the heterocyclic derivative is N-(1-octyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide.
36. The heterocyclic derivative or salt of claim 27, wherein the heterocyclic derivative is N-(1-nonyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide.
37. The heterocyclic derivative or salt of claim 27, wherein the heterocyclic derivative is N-(1-decyl-6-hydroxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)-2,2-dimethylpropanamide.
38. The heterocyclic derivative or salt of claim 1, wherein:
one of R1, R2 and R5 i s hydroxyl , carboxyl , the alkoxycarbonyl or a group of the formula -NR9R10 (wherein R9 and R10 are each independently hydrogen or C1-6alkyl) , and the other two are each independently hydrogen, C1-6alkyl or C1-6alkoxy, provided that when one of R1, R2 and R5 is hydroxyl, carboxyl or the alkoxylcarbonyl, then Z is
one of R1, R2 and R5 i s hydroxyl , carboxyl , the alkoxycarbonyl or a group of the formula -NR9R10 (wherein R9 and R10 are each independently hydrogen or C1-6alkyl) , and the other two are each independently hydrogen, C1-6alkyl or C1-6alkoxy, provided that when one of R1, R2 and R5 is hydroxyl, carboxyl or the alkoxylcarbonyl, then Z is
39. The heterocyclic derivative or salt of claim 38, which is represented by the formula (IIc) wherein:
one of R1c, R2c and R5c is hydroxyl, carboxyl, the alkoxycarbonyl or a group of the formula -NR9cR10c wherein R9c and R10c are each independently hydrogen or C1-6alkyl and the other two are each independently hydrogen, C1-6alkyl or C1-6alkoxy;
one of R3c and R4c is a group of the formula:
-NHCOR7c wherein R7c is C1-20alkyl , C1-6alkoxy-C1-6alkyl , C1-6alkylthio-C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl, phenyl, naphthyl, aryl-C1-4alkyl (in which the aryl is phenyl or naphthyl) or a group of the formula -NHR8c wherein R8c is C1-20alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl, phenyl, naphthyl or aryl-C1-4alkyl (in which the aryl is phenyl or naphthyl) and the other is hydrogen, C1-6alkyl or C1-6alkoxy;
and R6c is C1-20alkyl, C3-12alkenyl, C1-6alkoxy-C1-6alkyl, C1-6alkylthio-C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl or aryl-C1-4alkyl (in which the aryl is phenyl or naphthyl).
one of R1c, R2c and R5c is hydroxyl, carboxyl, the alkoxycarbonyl or a group of the formula -NR9cR10c wherein R9c and R10c are each independently hydrogen or C1-6alkyl and the other two are each independently hydrogen, C1-6alkyl or C1-6alkoxy;
one of R3c and R4c is a group of the formula:
-NHCOR7c wherein R7c is C1-20alkyl , C1-6alkoxy-C1-6alkyl , C1-6alkylthio-C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl, phenyl, naphthyl, aryl-C1-4alkyl (in which the aryl is phenyl or naphthyl) or a group of the formula -NHR8c wherein R8c is C1-20alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl, phenyl, naphthyl or aryl-C1-4alkyl (in which the aryl is phenyl or naphthyl) and the other is hydrogen, C1-6alkyl or C1-6alkoxy;
and R6c is C1-20alkyl, C3-12alkenyl, C1-6alkoxy-C1-6alkyl, C1-6alkylthio-C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl or aryl-C1-4alkyl (in which the aryl is phenyl or naphthyl).
40. The heterocyclic derivative or salt of claim 39, wherein:
R1c and R3c are each independently hydrogen, C1-6alkyl or C1-6alkoxy;
R2c is carboxyl;
R4c is a group of the formula -NHCOR7c wherein R7c is C1-20alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-3alkyl;
R5c is hydrogen; and R6c is C1-20alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-3alkyl.
R1c and R3c are each independently hydrogen, C1-6alkyl or C1-6alkoxy;
R2c is carboxyl;
R4c is a group of the formula -NHCOR7c wherein R7c is C1-20alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-3alkyl;
R5c is hydrogen; and R6c is C1-20alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-3alkyl.
41. The heterocyclic derivative or salt of claim 40, wherein:
R1c is hydrogen or C1-6alkyl;
R3c is C1-6alkyl;
R2c is carboxyl;
R4c is a group of the formula -NHCOR7c wherein R7c is C1-20alkyl;
R5c is hydrogen; and R6c is C1-20alkyl.
R1c is hydrogen or C1-6alkyl;
R3c is C1-6alkyl;
R2c is carboxyl;
R4c is a group of the formula -NHCOR7c wherein R7c is C1-20alkyl;
R5c is hydrogen; and R6c is C1-20alkyl.
42. The heterocyclic derivative or salt of claim 41, wherein the heterocyclic derivative is N-(1-hexyl-5-carboxy-6-methylindolin-7-yl)-2,2-dimethylpropanamide.
43. The heterocyclic derivative or salt of claim 41, wherein the heterocyclic derivative is N-(1-octyl-5-carboxy-6-methylindolin-7-yl)-2,2-dimethylpropanamide.
44. The heterocyclic derivative or salt of claim 41, wherein the heterocyclic derivative is N-(1-decyl-5-carboxy-6-methylindolin-7-yl)-2,2-dimethylpropanamide.
45. The heterocyclic derivative or salt of claim 41, wherein the heterocyclic derivative is N-(1-hexyl-5-carboxy-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
46. The heterocyclic derivative or salt of claim 41, wherein the heterocyclic derivative is N-(1-octyl-5-carboxy-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
47. The heterocyclic derivative or salt of claim 41, wherein the heterocyclic derivative is N-(1-decyl-5-carboxy-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
48. A pharmaceutical composition, comprising:
the heterocyclic derivative or salt of any one of claims 1-47, and a pharmaceutically acceptable additive.
the heterocyclic derivative or salt of any one of claims 1-47, and a pharmaceutically acceptable additive.
49. The pharmaceutical composition of claim 48, which is an acyl-CoA : cholesterol acyltransferase inhibitor.
50. The pharmaceutical composition of claim 48, which is a lipoperoxidation inhibitor.
51. The pharmaceutical composition of claim 48, which is for prophylaxis or treatment of arteriosclerosis, hyperlipemia, arteriosclerosis in diabetes, cerebrovascular ischemic disease or cardiovascular ischemic disease.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP259082/1995 | 1995-10-05 | ||
| JP25908295 | 1995-10-05 | ||
| JP5801896 | 1996-03-14 | ||
| JP58018/1996 | 1996-03-14 | ||
| JP19433196 | 1996-07-24 | ||
| JP194331/1996 | 1996-07-24 | ||
| PCT/JP1996/002852 WO1997012860A1 (en) | 1995-10-05 | 1996-09-30 | Novel heterocyclic derivatives and medicinal use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2233842A1 CA2233842A1 (en) | 1997-04-10 |
| CA2233842C true CA2233842C (en) | 2006-04-11 |
Family
ID=36178155
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002233842A Expired - Fee Related CA2233842C (en) | 1995-10-05 | 1996-09-30 | Novel heterocyclic derivatives having indoline, indole or tetrahydroquinoline ring and pharmaceutical use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2233842C (en) |
-
1996
- 1996-09-30 CA CA002233842A patent/CA2233842C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2233842A1 (en) | 1997-04-10 |
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