1,3-Di-oxo-indene derivative, pharmaceutically acceptable salt or optical isomer thereof, preparation method thereof, and pharmaceutical composition containing same as an antiviral, active ingredient
09833423 · 2017-12-05
Assignee
- KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY (Daejeon-Si, KR)
- KATHOLIEKE UNIVERSITEIT LEUVEN K.U. LEUVEN R & D (Belgium, BE)
Inventors
- Young Sik Jung (Daejeon, KR)
- Chong Kgo Lee (Daejeon, KR)
- Ihl Young Choi (Daejeon, KR)
- Hae Soo KIM (Daejeon, KR)
- Phil Ho Kim (Daejeon, KR)
- Soo Bong Han (Daejeon, KR)
- Johan Neyts (Belgium, BE)
- Hendrik Jan Thibaut (Belgium, BE)
Cpc classification
A61P29/00
HUMAN NECESSITIES
C07C69/736
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A61P31/00
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C07C205/45
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C07C233/43
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C07C271/24
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C07C271/64
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C07C69/22
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C07C49/755
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C07C69/618
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C07C233/32
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A61K31/435
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C07C69/54
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C07C231/02
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C07C247/14
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C07C275/64
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C07C233/76
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C07C323/22
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C07C269/00
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C07C271/12
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C07C45/00
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A61K31/122
HUMAN NECESSITIES
Y02A50/30
GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
C07C233/41
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A61P21/00
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C07C275/26
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C07C225/22
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C07C271/44
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C07C67/08
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C07C69/738
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C07C225/20
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C07C233/33
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C07C49/753
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International classification
A61K31/122
HUMAN NECESSITIES
C07C271/44
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C07C69/738
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C07C49/753
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C07C45/00
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C07C69/22
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C07C69/736
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C07C269/00
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C07C49/755
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C07C67/08
CHEMISTRY; METALLURGY
C07C231/02
CHEMISTRY; METALLURGY
C07C271/12
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A61K31/435
HUMAN NECESSITIES
C07C271/24
CHEMISTRY; METALLURGY
C07C271/64
CHEMISTRY; METALLURGY
C07C275/26
CHEMISTRY; METALLURGY
C07C275/64
CHEMISTRY; METALLURGY
C07C69/54
CHEMISTRY; METALLURGY
C07C69/618
CHEMISTRY; METALLURGY
C07C205/45
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C07C323/22
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C07C225/20
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C07C225/22
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C07C233/32
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C07C233/33
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C07C233/41
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C07C233/43
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C07C233/61
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C07C233/76
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Abstract
Disclosed are 1,3-Dioxoindene derivatives, pharmaceutically acceptable salts thereof or enantiomers, a preparation method thereof, and a pharmaceutical composition for the prevention or treatment of viral diseases, comprising the same as an active ingredient. The 1,3-Dioxoindene derivatives have excellent inhibitory activity against picornaviruses including coxsackie-, entero-, echo-, Polio-, and rhinoviruses, as well as exhibiting low cytotoxicity, so that they can be useful as an active ingredient of a pharmaceutical composition for the prevention or treatment of viral diseases including poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, cold, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis or otitis media.
Claims
1. A compound of Formula 1, or a pharmaceutically-acceptable salt or optical isomer thereof: ##STR00115## where, A.sup.1 is —NH.sub.2; A.sup.2, A.sup.3 and A.sup.4 are, independently any one selected from a group consisting of —H, halogen, —OH, —CN, —N.sub.3, C.sub.1-C.sub.10 alkoxy, C.sub.1-C.sub.10 straight- or branched-chain alkyl, C.sub.6-C.sub.12 aryl, —O(C═O)R.sup.1, —(C═O)R.sup.1, —(C═O)OR.sup.1, —O(C═O)OR.sup.1, —O(C═O)NR.sup.1R.sup.2, —NO.sub.2, —NR.sup.1R.sup.2, —NR.sup.1(C═O)R.sup.2, —NR.sup.1(C═S)R.sup.2, —NR.sup.1(C═O)OR.sup.2, —NR.sup.1(C═O)—NR.sup.2R.sup.3 and —NR.sup.1(C═S)—NR.sup.2R.sup.3, or two or more neighboring substituents A.sup.2, A.sup.3 and A.sup.4 may form a ring together, wherein a ring formed by two or more neighboring substituents A.sup.2, A.sup.3 and A.sup.4 may include one or more hetero atom, and the hetero atom is N, O or S; G is halogen, —OH, —CN, —N.sub.3, C.sub.1-C.sub.10 alkoxy, —O(C═O)R.sup.1, —(C═O)R.sup.1, —(C═O)OR.sup.1, —O(C═O)OR.sup.1, —O(C═O)NR.sup.1R.sup.2, —NO.sub.2, —NR.sup.1R.sup.2, —NR.sup.1(C═O)R.sup.2, —NR.sup.1(C═S)R.sup.2, —NR.sup.1(C═O)OR.sup.2, —NR.sup.1(C═O)—NR.sup.2R.sup.3, —NR.sup.1(C═S)—NR.sup.2R.sup.3 or ##STR00116## D.sup.1, D.sup.2, D.sup.3 and D.sup.4 are independently selected from a group consisting of —H, halogen, —OH, —CN, C.sub.1-C.sub.10 alkoxy, C.sub.1-C.sub.10 straight- or branched-chain alkyl, C.sub.6-C.sub.12 aryl, —(CH.sub.2).sub.n—(C═O)OR.sup.1, —O(C═O)R.sup.1, —(C═O)R.sup.1, —(C═O)OR.sup.1, —O(C═O)OR.sup.1, —O(C═O)NR.sup.1R.sup.2, —NO.sub.2, —NR.sup.1R.sup.2, —NR.sup.1(C═O)R.sup.2, —NR.sup.1(C═S)R.sup.2, —NR.sup.1(C═O)OR.sup.2, —NR.sup.1(C═O)—NR.sup.2R.sup.3, —SR.sup.1 and —NR.sup.1(C═S)—NR.sup.2R.sup.3, or two or more neighboring substituents D.sup.1, D.sup.2, D.sup.3 and D.sup.4 may form a ring together, a ring formed by two or more neighboring substituent D.sup.1, D.sup.2, D.sup.3 and D.sup.4 may include one or more hetero atom, and the hetero atom is N, O or S; E is —H, —OH, —OR.sup.1, —O(C═O)R.sup.1, —(C═O)R.sup.1, —(C═O)OR.sup.1, —O(C═O)OR.sup.1, —O(C═O)NR.sup.1R.sup.2, —NO.sub.2, —NR.sup.1R.sup.2, —NR.sup.1(C═O)R.sup.2, —SR.sup.1, —NR.sup.1(C═S)R.sup.2, —NR.sup.1(C═O)OR.sup.2, —NR.sup.1(C═O)—NR.sup.2R.sup.3 or —NR.sup.1(C═S)—NR.sup.2R.sup.3; R.sup.1, R.sup.2 and R.sup.3 are, each independently, hydrogen, nonsubstituted or phenyl-substituted C.sub.1-C.sub.10 straight- or branched-chain alkyl, C.sub.1-C.sub.10 alkoxy, nonsubstituted or phenyl-substituted C.sub.1-C.sub.10 straight- or branched-chain alkenyl, C.sub.3-C.sub.7 cycloalkyl or nonsubstituted or phenyl-substituted C.sub.6-C.sub.12 aryl; X and Y are, each independently, hydrogen, oxygen, hydroxy or sulfur; Z.sup.1, Z.sup.2 and Z.sup.3 are carbon or nitrogen; n is integer between 1-10; and ‘’ denotes single or double bond.
2. The compound of claim 1, or a pharmaceutically-acceptable salt or optical isomer thereof where, A.sup.2, A.sup.3 and A.sup.4 are independently any one selected from a group consisting of —H, halogen, —OH, —CN, —N.sub.3, C.sub.1-C.sub.10 alkoxy, C.sub.1-C.sub.10 straight- or branched-chain alkyl, C.sub.6-C.sub.12 aryl, —O(C═O)R.sup.1, —(C═O)R.sup.1, —(C═O)OR.sup.1, —O(C═O)OR.sup.1, —O(C═O)NR.sup.1R.sup.2, —NO.sub.2, —NR.sup.1R.sup.2, —NR.sup.1(C═O)R.sup.2, —NR.sup.1(C═S)R.sup.2, —NR.sup.1(C═O)OR.sup.2, —NR.sup.1(C═O)—NR.sup.2R.sup.3 and —NR.sup.1(C═S)—NR.sup.2R.sup.3; G is halogen, —OH, —CN, —N.sub.3, C.sub.1-C.sub.10 alkoxy, —O(C═O)R.sup.1, —O(C═O)OR.sup.1, —O(C═O)NR.sup.1R.sup.2, —NR.sup.1(C═O)R.sup.2, —NR.sup.1(C═O)OR.sup.2, —NR.sup.1(C═O)—NR.sup.2R.sup.3, or ##STR00117## D.sup.1, D.sup.2, D.sup.3 and D.sup.4 are independently selected from a group consisting of —H, halogen, —OH, —CN, C.sub.1-C.sub.10 alkoxy, C.sub.1-C.sub.10 straight- or branched-chain alkyl, C.sub.6-C.sub.12 aryl, —(CH.sub.2).sub.n—(C═O)OR.sup.1, —O(C═O)R.sup.1, —(C═O)R.sup.1, —(C═O)OR.sup.1, —O(C═O)OR.sup.1, —O(C═O)NR.sup.1R.sup.2, —NO.sub.2, —NR.sup.1R.sup.2, —NR.sup.1(C═O)R.sup.2, —NR.sup.1(C═S)R.sup.2, —NR.sup.1(C═O)OR.sup.2, —NR.sup.1(C═O)—NR.sup.2R.sup.3, —SR.sup.1 and —NR.sup.1(C═S)—NR.sup.2R.sup.3; E is —OH, —OR.sup.1, —O(C═O)R.sup.1, —O(C═O)OR.sup.1, or —O(C═O)NR.sup.1R.sup.2; X and Y are, each oxygen; Z.sup.1, Z.sup.2 and Z.sup.3 are carbon; n is an integer between 1-10; and ‘’ denotes a double bond.
3. The compound of claim 1, or a pharmaceutically-acceptable salt or optical isomer thereof, wherein, A.sup.2, A.sup.3 and A.sup.4 are selected from a group consisting of —H, halogen, C.sub.1-C.sub.10 straight- or branched-chain alkyl, —NR.sup.1R.sup.2, and —NR.sup.1(C═O)R.sup.2: G is —OH, —O(C═O)R.sup.1, —O(C═O)OR.sup.1, —NR.sup.1(C═O)R.sup.2, —NR.sup.1(C═O)OR.sup.2 or ##STR00118## D.sup.1, D.sup.2, D.sup.3 and D.sup.4 are independently selected from a group consisting of halogen, C.sub.1-C.sub.10 straight- or branched-chain alkyl, —NR.sup.1(C═O)R.sup.2, —NR.sup.1(C═O)OR.sup.2 and —NR.sup.1(C═O)—NR.sup.2R.sup.3; E is —OH, —OR.sup.1, —O(C═O)R.sup.1, —O(C═O)OR.sup.1, or —O(C═O)NR.sup.1R.sup.2; R.sup.1, R.sup.2 and R.sup.3 are, each independently, hydrogen, nonsubstituted or phenyl-substituted C.sub.1-C.sub.9 straight- or branched-chain alkyl, nonsubstituted or phenyl-substituted C.sub.1-C.sub.5 straight- or branched-chain alkenyl or C.sub.6-C.sub.10 aryl; and n is an integer between 1-5.
4. The compound of claim 1, or a pharmaceutically-acceptable salt or optical isomer thereof, wherein A.sup.2, A.sup.3 and A.sup.4 are independently selected from a group consisting of —H, halogen, and —NR.sup.1R.sup.2; G is —OH, —NR.sup.1(C═O)R.sup.2, or —NR.sup.1(C═O)OR.sup.2; D.sup.1, D.sup.2, D.sup.3 and D.sup.4 are independently selected from the group consisting of halogen, C.sub.1-C.sub.10 straight- or branched-chain alkyl, and —NR.sup.1(C═O)R.sup.2; E is —OH, —OR.sup.1, —O(C═O)R.sup.1, —O(C═O)OR.sup.1 or —O(C═O)NR.sup.1R.sup.2; R.sup.1, R.sup.2 and R.sup.3 are, each independently, hydrogen, nonsubstituted or phenyl-substituted C.sub.1-C.sub.8 straight- or branched-chain alkyl, nonsubstituted or phenyl-substituted C.sub.1-C.sub.4 straight- or branched-chain alkenyl or C.sub.6-C.sub.10 aryl; and n is an integer between 1-3.
5. The compound of claim 1, or a pharmaceutically-acceptable salt or optical isomer thereof, wherein, A.sup.2, A.sup.3 and A.sup.4 are independently selected from a group consisting of —H and —NR.sup.1R.sup.2; G is —NR.sup.1(C═O)R.sup.2; D.sup.1, D.sup.2, D.sup.3 and D.sup.4 are hydrogen, C.sub.1-C.sub.10 straight- or branched-chain alkyl; E is —O(C═O)R.sup.1; R.sup.1, R.sup.2 and R.sup.3 are, each independently, hydrogen, or C.sub.1-C.sub.7 straight- or branched-chain alkyl; and n is an integer between 1˜3.
6. The compound, pharmaceutically acceptable salt, or optical isomer of claim 1, wherein the compound is selected from the group consisting of: Acetic acid 2-(2-acetoxy-4-isopropyl-phenyl)-4-amino-1,3-dioxo-indan-2-yl ester; 4-Amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione; N-(7-Amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide; 4,7-Diamino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione; 4,5-Diamino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione; 2-(4-Amino-1,3-dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl pentanoate; 2-(4-Amino-2-hexanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl hexanoate; 2-(4-Amino-2-heptanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl heptanoate; 2-(4-Amino-1,3-dioxo-2-propionamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl propionate; 2-(4-Amino-2-butyramido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyrate; 2-(4-Amino-2-octanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl octanoate; 2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyl carbonate2-(2-acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyl carbonate; 2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl dimethylcarbamate; 2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl ethylcarbamate; and N-[2-(4-Amino-2-hydroxy-1,3-dioxo-indan-2-yl)-4,5-dimethoxy-phenyl]-isobutyramide.
7. The compound, pharmaceutically acceptable salt, or optical isomer of claim 1, wherein the compound is selected from the group consisting of: Acetic acid 2-(2-acetoxy-4-isopropyl-phenyl)-4-amino-1,3-dioxo-indan-2-yl ester; 2-(4-Amino-1,3-dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl pentanoate; 2-(4-Amino-2-hexanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl hexanoate; 2-(4-Amino-2-heptanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl heptanoate; 2-(4-Amino-1,3-dioxo-2-propionamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl propionate; 2-(4-Amino-2-butyramido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyrate; 2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyl carbonate2-(2-acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyl carbonate; 2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl dimethylcarbamate; and 2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl ethylcarbamate.
8. A method for preparing a compound of formula 1a: ##STR00119## or a pharmaceutically-acceptable salt or optical isomer thereof, wherein A.sup.1, A.sup.2, A.sup.3, A.sup.4, D.sup.1, D.sup.2, D.sup.3, D.sup.4, Z.sup.1, Z.sup.2 and Z.sup.3 are as defined in claim 1, and J and L are, independently, identical to A.sup.1, A.sup.2, A.sup.3, A.sup.4, D.sup.1, D.sup.2, D.sup.3 or D.sup.4; comprising acylating or alkylating a compound of formula 2: ##STR00120## in the presence of a base and a solvent to afford the compound of formula 1a.
9. A method for preparing a compound of formula 1b: ##STR00121## or a pharmaceutically acceptable salt or optical isomer thereof, wherein A.sup.1, A.sup.2, A.sup.3, A.sup.4, D.sup.1, D.sup.2, D.sup.3, D.sup.4, Z.sup.1, Z.sup.2 and Z.sup.3 are as defined in Formula 1 of claim 1, and J and L are, independently, identical to A.sup.1, A.sup.2, A.sup.3, A.sup.4, D.sup.1, D.sup.2, D.sup.3 or D.sup.4; comprising: treating a compound of Formula 2: ##STR00122## with thionyl chloride or oxalic chloride in the presence of a reacting base and a solvent, and then treating the resulting mixture with ammonia to afford a compound of formula 3: ##STR00123## and acylating or alkylating the compound of formula 3 in the presence of a base and a solvent to afford the compound of formula 1b.
10. A pharmaceutical composition comprising the compound, pharmaceutically acceptable salt, or optical isomer of claim 1 and a pharmaceutically acceptable diluent or excipient.
11. A method for preventing or treating a viral disease in a patient, wherein the viral disease is caused by a Coxsackie virus, a polio virus, an echovirus, an enterovirus, a rhinovirus, or a picornavirus comprising a ministering a therapeutically effective amount of the compound, pharmaceutically acceptable salt, or optical isomer of claim 1 to the patient.
12. The method of claim 11, wherein the viral disease is caused by a Coxsackie virus.
13. The method of claim 11, wherein the viral disease is caused by a polio virus.
14. The method of claim 11, wherein the viral disease is caused by an echovirus.
15. The method of claim 11, wherein the viral disease is caused by an enterovirus.
16. The method of claim 11, wherein the viral disease is caused by a rhinovirus.
17. The method of claim 11, wherein the viral disease is caused by a picornavirus.
18. The method of claim 11, wherein the viral disease comprises: polio, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot and mouth disease, swine vesicular disease (SVD), hepatitis A, myositis, viral myocarditis, viral pancreatitis, flu, herpangina, or foot and mouth disease.
Description
BEST MODE
(1) Below, a detailed description will be given of the present invention.
(2) According to one aspect thereof, the present invention addresses 1,3-Dioxoindene derivatives expressed by Formula 1, pharmaceutically-acceptable salt thereof or optical isomer thereof:
(3) ##STR00002##
(4) wherein,
(5) A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are, either independently or optionally, any one selected from a group consisting of —H, halogen, —OH, —CN, —N.sub.3, C.sub.1˜C.sub.10 alkoxy, C.sub.1˜C.sub.10 straight- or branched-chain alkyl, C.sub.6˜C.sub.12 aryl, —O(C═O)R.sup.1, —(C═O)R.sup.1, —(C═O)OR.sup.1, —O(C═O)OR.sup.1, —O(C═O)NR.sup.1R.sup.2, —NO.sub.2, —NR.sup.1R.sup.2, —NR.sup.1(C═O)R.sup.2, —NR.sup.1(C═S)R.sup.2, —NR.sup.1(C═O) OR.sup.2, —NR.sup.1(C═O)—NR.sup.2R.sup.3 and —NR.sup.1(C═S)—NR.sup.2R.sup.3, or two or more neighboring substituents A, A2, A.sup.3 and A.sup.4 may form a ring together, wherein a ring formed by two or more neighboring substituents A.sup.1, A.sup.2, A.sup.3 and A.sup.4 may include one or more hetero atom, and the hetero atom is N, O or S; G is —H, halogen, —OH, —CN, —N.sub.3, C.sub.1˜C.sub.10 alkoxy, —O(C═O)R, —(C═O)R, —(C═O)OR.sup.1, —O(C═O)OR.sup.1, —O(C═O)NR.sup.1R.sup.2, —NO.sub.2, —NR.sup.1R.sup.2, —NR.sup.1(C═O)R.sup.2, —NR.sup.1(C═S)R.sup.2, —NR.sup.1(C═O) OR.sup.2, —NR.sup.1(C═O)—NR.sup.2R.sup.3, —NR.sup.1(C═S)—NR.sup.2R.sup.3 or
(6) ##STR00003##
(7) D.sup.1, D.sup.2, D.sup.3 and D.sup.4 are, either independently or optionally, any one selected from a group consisting of —H, halogen, —OH, —CN, C.sub.1˜C.sub.10 alkoxy, C.sub.1˜C.sub.10 straight- or branched-chain alkyl, C.sub.6˜C.sub.12 aryl, —(CH.sub.2).sub.n—(C═O) OR.sup.1, —O(C═O)R, —(C═O)R, —(C═O)OR, —O(C═O)OR, —O(C═O)NR.sup.1R.sup.2, —NO.sub.2, —NR.sup.1R.sup.2, —NR.sup.1(C═O)R.sup.2, —NR.sup.1(C═S)R.sup.2, —NR.sup.1(C═O) OR.sup.2, —NR.sup.1(C═O)—NR.sup.2R.sup.3, —SR.sup.1 and —NR.sup.1(C═S)—NR.sup.2R.sup.3, or two or more neighboring substituents D.sup.1, D.sup.2, D.sup.3 and D.sup.4 may form a ring together, a ring formed by two or more neighboring substituent D.sup.1, D.sup.2, D.sup.3 and D.sup.4 may include one or more hetero atom, and the hetero atom is N, O or S;
(8) E is —H, —OH, —OR.sup.1, —O(C═O)R.sup.1, —(C═O)R.sup.1, —(C═O)OR.sup.1, —O(C═O)OR, —O(C═O)NR.sup.1R.sup.2, —NO.sub.2, —NR.sup.1R.sup.2, —NR.sup.1(C═O)R.sup.2, —SR, —NR.sup.1(C═S)R.sup.2, —NR.sup.1(C═O) OR.sup.2, —NR.sup.1(C═O)—NR.sup.2R.sup.3 or —NR.sup.1(C═S)—NR.sup.2R;
(9) R.sup.1, R.sup.2 and R.sup.3 are, each independently, hydrogen, nonsubstituted or phenyl-substituted C.sub.1˜C.sub.10 straight- or branched-chain alkyl, C.sub.1˜C.sub.10 alkoxy, nonsubstituted or phenyl-substituted C.sub.1˜C.sub.10 straight- or branched-chain alkenyl, C.sub.3˜C.sub.7 cycloalkyl or nonsubstituted or phenyl-substituted C.sub.6˜C.sub.12 aryl;
(10) X and Y are, each independently, hydrogen, oxygen, hydroxy or sulfur;
(11) Z.sup.1, Z.sup.2 and Z.sup.3 are carbon or nitrogen;
(12) n is integer between 1˜10; and
(13) ‘’ denotes single or double bond.
(14) In a preferred embodiment,
(15) A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are, either independently or optionally, any one selected from a group consisting of —H, halogen, C.sub.1˜C.sub.10 straight- or branched-chain alkyl, —NR.sup.1R.sup.2, —NR.sup.1(C═O)R.sup.2, or two or more neighboring substituents A.sup.1, A.sup.2, A.sup.3 and A.sup.4 may form a ring together, wherein a ring formed by two or more neighboring substituents A.sup.1, A.sup.2, A.sup.3 and A.sup.4 may include one or more hetero atom, and the hetero atom is N, O or S;
(16) G is —OH, —O(C═O)R.sup.1, —O(C═O) OR.sup.1, —NR.sup.1(C═O)R.sup.2, —NR.sup.1(C═O) OR.sup.2 or
(17) ##STR00004##
(18) D.sup.1, D.sup.2, D.sup.3 and D.sup.4 are, either independently or optionally, any one selected from a group consisting of halogen, C.sub.1˜C.sub.10 straight- or branched-chain alkyl, —NR.sup.1(C═O)R.sup.2, —NR.sup.1(C═O) OR.sup.2 and —NR.sup.1(C═O)—NR.sup.2R.sup.3, or two or more neighboring substituents D.sup.1, D.sup.2, D.sup.3 and D.sup.4 may form a ring together, wherein a ring formed by two or more neighboring substituents D.sup.1, D.sup.2, D.sup.3 and D.sup.4 may include one or more hetero atom, and the hetero atom is N, O or S;
(19) E is —H, —OH, —OR.sup.1, —O(C═O)R.sup.1, —O(C═O) OR.sup.1, —O(C═O)NR.sup.1R.sup.2, —NR.sup.1(C═O)R.sup.2 or —NR.sup.1(C═O)OR.sup.2;
(20) R.sup.1, R.sup.2 and R.sup.3 are, each independently, hydrogen, nonsubstituted or phenyl-substituted C.sub.1˜C.sub.9 straight- or branched-chain alkyl, nonsubstituted or phenyl-substituted C.sub.1˜C.sub.5 straight- or branched-chain alkenyl or C.sub.6˜C.sub.10 aryl;
(21) X and Y are, each independently, oxygen or hydroxy;
(22) Z.sup.1, Z.sup.2 and Z.sup.3 are carbon;
(23) n is integer between 15; and
(24) ‘’ denotes single or double bond.
(25) In a more preferred embodiment,
(26) A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are, either independently or optionally, any one selected from a group consisting of —H, halogen and —NR.sup.1R.sup.2;
(27) G is —OH, —NR.sup.1(C═O)R.sup.2 or —NR.sup.1(C═O)OR.sup.2;
(28) D.sup.1, D.sup.2, D.sup.3 and D.sup.4 are, either independently or optionally, any one selected from a group consisting of halogen, C.sub.1˜C.sub.10 straight- or branched-chain alkyl and —NR.sup.1(C═O)R.sup.2;
(29) E is —H, —OH, —OR.sup.1, —O(C═O)R.sup.1, —O(C═O) OR.sup.1 or —O(C═O)NR.sup.1R.sup.2;
(30) R.sup.1, R.sup.2 and R.sup.3 are, each independently, hydrogen, nonsubstituted or phenyl-substituted C.sub.1˜C.sub.8 straight- or branched-chain alkyl, nonsubstituted or phenyl-substituted C.sub.1˜C.sub.4 straight- or branched-chain alkenyl or C.sub.6˜C.sub.10 aryl;
(31) X and Y are oxygen;
(32) Z.sup.1, Z.sup.2 and Z.sup.3 are carbon;
(33) n is integer between 13; and
(34) ‘’ denotes double bond.
(35) In a further more preferred embodiment,
(36) A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are, either independently or optionally, any one selected from a group consisting of —H and —NR.sup.1R.sup.2;
(37) G is —NR.sup.1(C═O)R.sup.2;
(38) D.sup.1, D.sup.2, D.sup.3 and D.sup.4 are C.sub.1˜C.sub.10 straight- or branched-chain alkyl;
(39) E is —O(C═O)R.sup.1;
(40) R.sup.1, R.sup.2 and R.sup.3 are, each independently, hydrogen or C.sub.1˜C.sub.7 straight- or branched-chain alkyl;
(41) X and Y are oxygen;
(42) Z.sup.1, Z.sup.2 and Z.sup.3 are carbon;
(43) n is integer between 13; and
(44) ‘’ denotes double bond.
(45) Concrete examples of the compound represented by Chemical Formula 1 include: 1) Ethyl 2-(4-acetoxy-3-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-methoxyphenyl)acetate; 2) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl acetate; 3) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-chlorophenyl acetate; 4) 6-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-2,3-dichlorophenyl acetate; 5) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,6-dichlorophenyl acetate; 6) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-ethylphenyl acetate; 7) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-methoxyphenyl acetate; 8) 4-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)biphenyl-3-yl acetate; 9) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-nitrophenyl acetate; 10) 3-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)biphenyl-4-yl acetate; 11) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-propylphenyl acetate; 12) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-ethylphenyl acetate; 13) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-sec-butylphenyl acetate; 14) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-tert-butylphenyl acetate; 15) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-tert-butylphenyl acetate; 16) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-3,4,5-trimethylphenyl acetate; 17) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-tert-pentylphenyl acetate; 18) Acetic acid 2-(2,3-diacetoxy-5-methyl-phenyl)-1,3-dioxo-indan-2-yl ester; 19) Acetic acid 2-(2-acetoxy-4-isopropyl-phenyl)-1,3-dioxo-indan-2-yl ester; 20) 2-(4-Acetyl-2-hydroxy-phenyl)-2-hydroxy-indan-1,3-dione; 21) 2-(1,3-Dioxo-2-(propionyloxy)-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl propionate; 22) 2-(2-(Butyryloxy)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyrate; 23) 2-(2-Hydroxy-4-isopropylphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl benzoate; 24) 2-(2-Benzyloxy-4-isopropyl-phenyl)-2-hydroxy-indan-1,3-dione; 25) 2-(2-Benzyloxy-4-isopropyl-phenyl)-2-methoxy-indan-1,3-dione; 26) 2-Hydroxy-2-(4-hydroxy-3,5-dimethyl-phenyl)-indan-1,3-dione; 27) 2-(2-Acetoxy-4-isopropylphenyl)-5-methoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl acetate; 28) 2-(2-Hydroxy-4-isopropylphenyl)-2-methoxy-1H-inden-1,3(2H)-dione; 29) 2-(1,3-Dioxo-2-(pivaloyloxy)-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl pivalate; 30) 2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl cinnamate; 31) Dimethyl-carbamic acid 2-(2-dimethylcarbamoyloxy-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester; 32) 2-(2-(Acryloyloxy)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl acrylate; 33) Diethyl-carbamic acid 2-(2-diethylcarbamoyloxy-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester; 34) 2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl diethylcarbamate; 35) 2-Hydroxy-2-(4-hydroxy-2,5-dimethylphenyl)-1H-inden-1,3(2H)-dione; 36) Acetic acid 2-(2-acetoxy-4-isopropyl-phenyl)-4-amino-1,3-dioxo-indan-2-yl ester; 37) Acetic acid 2-(2-acetoxy-4-isopropyl-phenyl)-4-nitro-1,3-dioxo-indan-2-yl ester; 38) 2-Hydroxy-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione; 39) 2-Chloro-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione; 40) 2-Azido-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione; 41) 4-Amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione; 42) N-(2-Hydroxy-2-(4-isopropyl-2-methoxyphenyl)-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide; 43) N-(2-Hydroxy-2-(4-isopropyl-2-methoxyphenyl)-5-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide; 44) N-(7-Amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide; 45) N-(5-Amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide; 46) 4,7-Diamino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione; 47) 4,5-Diamino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione; 48) Methyl 2-(4-isopropyl-2(methoxycarbonyloxy)phenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl carbamate; 49) 2-(1,3-Dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl pentanoate; 50) 2-(2-Isobutylamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl isobutyrate; 51) 2-Hydroxy-2-(2-hydroxy-4-isopropylphenyl)-2,3-dihydro-1H-inden-1-one; 52) 2-Azido-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione; 53) 2-Amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione; 54) N-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)acetamide; 55) N-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)benzamide; 56) N-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl) cyclopropancarboxamide; 57) 2-(2-(Methylthio)phenyl)-2H-inden-1,3-dione; 58) 2-(4-(Methylthio)phenyl)-2H-inden-1,3-dione; 59) Methyl 2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ylcarbamate; 60) 1-Ethyl-3-(2,3-dihydro-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-1H-inden-2-yl)urea; 61) 1-(2,3-Dihydro-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-1H-inden-2-yl)urea; 62) Isopropyl 2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ylcarbamate; 63) 1-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-3-methoxy urea; 64) Ethyl 2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ylcarbamate; 65) N-(2-Bromo-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide; 66) N-(2-Amino-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide; 67) N,N′-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2,4-diyl)diacetamide; 68) 2-(1,3-Dioxo-2-propionamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl propionate; 69) 2-(1,3-Dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl pentanoate; 70) 2-(2-Benzamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl benzoate; 71) 2-(2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-6-methylpyridin-3-yl acetate; 72) 2-Hydroxy-2-(4-hydroxy-5-methylpyridin-3-yl)-1H-inden-1,3(2H)-dione; 73) 2-(5-Chloro-3-hydroxypyridin-2-yl)-2-hydroxy-1H-inden-1,3(2H)-dione; 74) 2-2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl; 75) 2-Hydroxy-2-(6-hydroxyquinolin-7-yl)-1H-inden-1,3(2H)-dione; 76) Butyric acid 2-(2-butyrylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester; 77) Octanoic acid 7-isopropyl-9b-octanoylamino-10-oxo-9b,10-dihydro-5-oxa-indeno[2,1-a]inden-4b-yl ester; 78) Hexanoic acid 2-(2-hexanoylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester; 79) Heptanoic acid 2-(2-heptanoylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester; 80) 2,2-Dimethyl-propionic acid 2-(1,3-dioxo-2-pentanoylamino-indan-2-yl)-5-isopropyl-phenyl ester; 81) 2-(4-Amino-1,3-dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl pentanoate; 82) 2-(4-Amino-2-hexanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl hexanoate; 83) 2-(4-Amino-2-heptanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl heptanoate; 84) 2-(4-Amino-1,3-dioxo-2-propionamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl propionate; 85) 2-(4-Amino-2-butyramido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyrate; 86) N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)acetamide; 87) N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)propionamide; 88) N-(5-Ethyl-2-(2-hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)phenyl)acetamide; 89) N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)butyramide; 90) N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)isobutyramide; 91) 2-(4-Amino-2-octanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl octanoate; 92) 2-(2-Acetamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl methyl carbonate; 93) 2-(2-Acetamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl pentanoate; 94) N-(2-(4-Acetamido-2-hydroxy-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)isobutyramide; 95) N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl)isobutyramide; 96) 2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyl carbonate2-(2-acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyl carbonate; 97) 2-(2-Acetamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl methylcarbamate; 98) Dimethyl-carbamic acid 2-(2-acetylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester; 99) Carbonic acid 2-(2-acetylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester phenyl ester; 100) 2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl dimethylcarbamate; 101) 2-(2-Acetamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl ethyl carbonate; 102) Ethyl acetyl(2-(2-hydroxy-4-isopropylphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)carbamate; 103) 2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl ethylcarbamate; 104) 2-(3-Methoxyphenyl)-2H-inden-1,3-dione; 105) Ethyl (6-(2-((ethoxycarbonyl)oxy)-4-isopropylphenyl)-5,7-dioxo-6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)carbonate; 106) N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethoxyphenyl)isobutyramide; 107) N-[2-(4-Amino-2-hydroxy-1,3-dioxo-indan-2-yl)-4,5-dimethoxy-phenyl]-isobutyramide; and 108) N-[2-(2-Hydroxy-5,6-dimethoxy-1,3-dioxo-indan-2-yl)-4,5-dimethoxy-phenyl]-isobutyramide.
(46) Preferred examples of the 1,3-Dioxoindene derivative represented by Chemical Formula 1 are as follows:
(47) Compounds 27), 36)˜48), 53)˜56), 59)˜70), and 76)˜108).
(48) More preferred examples of the 1,3-Dioxoindene derivative represented by Chemical Formula include:
(49) Compounds 6), 19), 21)˜23), 30), 32), 36), 48), 49), 68)˜70), 76), 78)˜85), 92)˜97), and 99)˜103).
(50) The 1,3-Dioxoindene derivatives, represented by Chemical Formula 1, according to the present invention may be used in the form of pharmaceutical acceptable salts. Useful are acid addition salts formed with pharmaceutically acceptable free acids. As used herein, the term “pharmaceutically acceptable salt” refers to any organic or inorganic salt of the base compounds of Chemical Formula 1, not exhibiting a side effect in which the beneficial activity of the base compounds of Chemical Formula 1 is degraded when it is present at a concentration causing no toxicity and harm in the body. The free acids may be inorganic or organic. examples of useful inorganic free acids include hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid and phosphoric acid. As organic acids, citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methane sulfonic acid, gluconic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D)- or (L)-malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, 4-toluenesulfonic acid, salicylic acid, benzoic acid, or malonic acid may be used. The pharmaceutically acceptable salts may include alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salts (calcium salt, magnesium salt, etc.). Acid addition salts useful in the present invention include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, alamine, potassium, sodium, tromethamine, and zinc salt, with hydrochloride or trifluoroacetate being preferred. Addition salts according to the present invention may be prepared by typical methods. For example, they may be prepared by dissolving the compound of Chemical Formula 1 in an organic solvent, such as methanol, ethanol, acetone, methylene chloride, or acetonitrile, and adding an excess of organic acids or an excess of aqueous inorganic acid solutions so as to precipitate or crystallize salts. These addition salts may be obtained by precipitation or crystallization, or by evaporating the solvent or excess acid and drying or suction-filtering the precipitated salt.
(51) Also, pharmaceutically acceptable metal salts formed with bases may fall within the range of pharmaceutically acceptable salts of the compound of the present invention. Examples of the metal salts useful in the present invention include alkali metal salts and alkaline earth metal salts. By way of example, the compound of the present invention may be dissolved in excess alkali metal hydroxide or alkaline earth metal hydroxide in water, and, after the filtration of the solution to remove non-dissolved compound salts, the filtrate may be dried to afford the pharmaceutically acceptable salts of the compound of the present invention. Suitable for use in pharmaceutics are sodium, potassium or calcium salts. Corresponding silver salts may be obtained by reacting the alkali metal or alkaline earth metal salts with suitable silver salt (e.g., silver nitrate).
(52) Not only the 1,3-Dioxoindene derivatives of compound of Chemical Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, hydrates and isomers prepared therefrom, if having the same effect, are within the scope of the present invention.
(53) Also, the present invention is concerned with a method for the preparation of the 1,3-Dioxoindene derivative according to the present invention. In one embodiment, the method comprises acylating or alkylating the compound of Chemical Formula 2 with a base in a solvent to afford a compound of Chemical Formula 1a (step 1), as illustrated in the following Reaction Scheme 1:
(54) ##STR00005##
(55) wherein,
(56) the compound of Chemical Formula 1a is a derivative of the compound of Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an enantiomer thereof,
(57) A.sup.1, A.sup.2, A.sup.3, A.sup.4, D.sup.1, D.sup.2, D.sup.3, D.sup.4, Z.sup.1, Z.sup.2, and Z.sup.3 are as defined in Chemical Formula 1, respectively,
(58) J and L are, independently or optionally, the same as A.sup.1, A.sup.2, A.sup.3, A.sup.4, D.sup.1, D.sup.2, D.sup.3, or D.sup.4
(59) As the solvent useful in Reaction Scheme 1, diisopropylether, diethylether, dioxane, tetrahydrofurane (THF), dimethylformamide(DMF), dimethylacetamide(DMA), dimethylsulfoxide(DMSO), methylene chloride(MC), chlorobenzene, toluene, or benzene may be employed.
(60) The base used in this reaction may be pyridine (PPTs), 4-dimethyl aminopyridine, trimethylamine, or ethylamine.
(61) In another embodiment, the method comprises:
(62) reacting the compound of Chemical Formula 2 with thionyl chloride or oxalic chloride in the presence of a base in a solvent and then with ammonia to give a compound of Chemical Formula 3 (step 1); and
(63) acylating or alkylating the compound of Chemical Formula 3 in the presence of a base in a solvent to afford a compound of Chemical Formula 1b (step 2), as illustrated in the following Reaction Scheme 2:
(64) ##STR00006##
(65) wherein,
(66) the compound of Chemical Formula 1b is a derivative of the compound of Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an enantiomer thereof,
(67) A.sup.1, A.sup.2, A.sup.3, A.sup.4, D.sup.1, D.sup.2, D.sup.3, D.sup.4, Z.sup.1, Z.sup.2, and Z.sup.3 are as defined in Chemical Formula 1, respectively,
(68) J and L are, independently or optionally, the same as A.sup.1, A.sup.2, A.sup.3, A.sup.4, D.sup.1, D.sup.2, D.sup.3, or D.sup.4
(69) The solvents used in steps 1 and 2 in Reaction Scheme 2 of this method may be, independently, selected from the group consisting of diisopropylether, diethylether, dioxane, tetrahydrofurane(THF), dimethylformamide(DMF), dimethylacetamide(DMA), dimethylsulfoxide(DMSO), methylene chloride(MC), chlorobenzene, toluene, and benzene.
(70) As the base for the acylating or alkylating reaction in this method, pyridine (PPTs), trimethylamine, ethylamine, or triphosgene may be used.
(71) Also contemplated in accordance with an aspect of the present invention is a pharmaceutical composition of the prevention or treatment of a viral disease, comprising an 1,3-Dioxoindene derivative represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an enantiomer thereof as an active ingredient.
(72) The viral disease that the pharmaceutical composition of the present invention targets is a disease caused by picornaviruses including coxsackie-, entero-, polio-, and rhinoviruses. Examples of the viral disease include poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, epidemic myalgia, encephalitis, cold, herpangina, and foot-and-mouth disease.
(73) Having excellent antiviral activity against picornaviruses such as coxsackie-, entero-, echo-, polio- and rhinoviruses as well as exhibiting low cytotoxicity, the 1,3-Dioxoindene derivative of Chemical Formula 1 can be useful as an active ingredient of a pharmaceutical composition for the prevention or treatment of various viral diseases including poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, cold, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, and otitis media.
(74) Clinically, the compound of the present invention may be administered in the form of various formulations. For this, the compound is usually formulated in combination with a diluent or excipient, such as a filler, a thickening agent, a binder, a wetting agent, a disintegrant, a surfactant, etc.
(75) Solid preparations intended for oral administration of the compound of the present invention may take the form of tablets, pills, powders, granules, capsules, troches, and the like. These solid preparations are formulated in combination with at least one excipient such as starch, calcium carbonate, sucrose, lactose, or gelatine. In addition to a simple excipient, a lubricant such as magnesium stearate, talc, or the like may also be added. Liquid preparations intended for oral administration include suspensions, internal use solutions, emulsion, syrups, and the like. In addition to a simple diluent such as water or liquid paraffin, various excipients, such as wetting agents, sweetening agents, aromatics, preservatives, and the like may be contained in the liquid preparations for the oral administration of the compound of the present invention.
(76) Also, the compound of the present invention may be in a parenteral dosage form such as sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilizates, suppositories, and the like. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and esters such as ethyl oleate may be suitable for the non-aqueous solvents and suspensions. The basic materials of suppositories include Witepsol, macrogol, Tween 61, cacao butter, laurin butter, and glycerogelatin.
(77) The compound of the present invention is administered in a therapeutically effective amount. The effective dose of the compound of the present invention varies depending on various factors including a patient's age, weight, sex, and health condition, the route of administration, and the severity of disease. Typically, the compound of the present invention may be administered at a daily dose of from 0.001 to 100 mg/kg, and preferably at a daily dose of from 0.01 to 35 mg/kg. For an adult with a weight of 70 kg, the dose of the compound of the present invention may typically range from 0.07 to 7,000 mg/day, and preferably from 0.7 to 2,500 mg/day. The formulations of the compound may be administered in a single dose or may be divided into multiple doses at regular intervals of time according to the instructions of a physician or pharmacist who is responsible for monitoring or observing the administration of the drug.
MODE FOR INVENTION
(78) A better understanding of the present invention may be obtained through the following examples which are set forth to illustrate, but are not to be construed as limiting the present invention.
(79) Ethyl 2-(4b,9b-dihydroxy-6-methoxy-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-8-yl)acetate (0.50 g, 1.4 mmol) was completely dissolved in anhydrous dichloromethane (30 ml). This solution was added with anhydrous acetic acid (0.37 ml, 3.9 mmol), pyridine (0.11 ml, 1.4 mmol), and 4-dimethyl aminopyridine (0.05 g), and stirred at room temperature for 3 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.03 g, 4%).
(80) mp: 102-107° C.
(81) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.25 (t, J=7.2 Hz, 3H, CH3) 1.98 (s, 3H, OAc) 2.19 (s, 3H, OAc) 3.60 (s, 2H, CH2) 3.73 (s, 3H OCH3) 4.12-4.19 (q, J=7.2, 14.4 Hz, 2H, CH2) 6.93 (s, 1H, ArH) 7.23 (s, 1H, ArH) 7.85-8.00 (m, 4H, ArH). MS(EI): 454.
(82) 4b,9b-Dihydroxy-7,8-dimethyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (1.00 g, 3.5 mmol) was dissolved in anhydrous THF (50 ml). This solution was added with anhydrous acetic acid (0.67 ml, 7.1 mmol), pyridine (0.30 ml, 3.5 mmol), and 4-dimethyl aminopyridine (0.1 g), and stirred at room temperature for 3 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.55 g, 42%).
(83) mp: 206-207° C.
(84) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 2.05 (s, 3H, CH.sub.3) 2.19 (s, 3H, OAc) 2.23 (s, 3H, OAc) 6.74 (s, 1H, ArH) 7.44 (s, 1H, ArH) 7.83-8.00 (m, 4H, ArH). MS(EI): 366.
(85) 7-Chloro-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (2.00 g, 6.9 mmol) was completely dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (1.41 ml, 13.8 mmol), pyridine (0.55 ml, 6.9 mmol), and 4-dimethyl aminopyridine (0.2 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:3) to afford the title compound (0.51 g, 19%).
(86) mp: 148-150° C.
(87) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 2.04 (s, 3H, OAc) 2.20 (s, 3H, OAc) 7.04 (d, J=2.1 Hz, 1H, ArH) 7.30 (d, J=1.8 Hz, 1H, ArH) 7.68 (d, J=9.0 Hz, 1H, ArH) 7.89-7.93 (m, 2H, ArH) 7.99-8.03 (m, 2H, ArH). MS(EI): 372.
(88) 2-(3,4-Dichloro-2-hydroxyphenyl)-2-hydroyx-1H-inden-1,3(2H)-dione (2.00 g, 6.9 mmol) was completely dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (1.41 ml, 13.8 mmol), pyridine (0.55 ml, 6.9 mmol), and 4-dimethyl aminopyridine (0.2 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4 to 1:2.5) to afford the title compound (0.037 g, 1.5%).
(89) mp: 129-136° C.
(90) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 2.07 (s, 3H, OAc) 2.19 (s, 3H, OAc) 7.42 (d, J=8.8 Hz, 1H, ArH) 7.64 (d, J=8.7 Hz, 1H, ArH) 7.89-8.03 (m, 4H, ArH). MS(EI): 407.
(91) 2-(3,5-Dichloro-2-hycroxyphenyl)-2-hydroxy-1H-inden-1,3(2H)-dione (1.50 g, 4.6 mmol) was completely dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (0.95 ml, 9.28 mmol), pyridine (0.37 ml, 4.6 mmol), and 4-dimethyl aminopyridine (0.15 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (80 g, 4.2%).
(92) mp: 178-180° C.
(93) .sup.1H-NMR (200 MHz, CDCl.sub.3) δ 2.07 (s, 3H, OAc) 2.20 (s, 3H, OAc) 7.48 (d, J=3.6 Hz, 1H, ArH) 7.72 (d, J=3.3 Hz, 1H, ArH) 7.92-8.08 (m, 4H, ArH). MS(EI): 407.
(94) 7-Ethyl-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (2.00 g, 7.0 mmol) was completely dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (1.44 ml, 14.1 mmol), pyridine (0.56 ml, 7.0 mmol), and 4-dimethyl aminopyridine (0.2 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (2.28 g, 88%).
(95) mp: 136-137° C.
(96) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.19 (t, J=7.6 Hz, 3H, CH.sub.3) 2.08 (s, 3H, OAc) 2.19 (s, 3H, OAc) 2.57-2.64 (q, J=15.3 Hz, J=7.8 Hz, 2H, CH.sub.2) 6.81 (s, 1H, ArH) 7.11 (d, J=9.0 Hz, 1H, ArH) 7.59 (d, J=8.4 Hz, 1H, ArH) 7.86-7.90 (m, 2H, ArH) 7.97-8.01 (m, 2H, ArH). MS(EI): 366.
(97) 4b,9b-Dihydroxy-8-methyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (3.03 g, 10.6 mmol) was dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (2.01 g, 21.3 mmol), pyridine (0.84 ml, 10.6 mmol), and 4-dimethyl aminopyridine (0.3 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:3 to 1:2.5) to afford the title compound (0.44 g, 11%).
(98) mp: 184-186° C.
(99) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 2.15 (s, 3H, OAc) 2.17 (s, 3H, OAc) 3.78 (s, 3H, OCH.sub.3) 6.78 (d, J=8.7 Hz, 1H, ArH) 6.91 (dd, J=2.7, 9.0 Hz, 1H, ArH) 7.12 (d, J=2.7 Hz, 1H, ArH) 7.60 (t, J=7.5 Hz, 1H, ArH) 7.76-7.85 (m, 2H, ArH) 8.14 (d, J=7.8 Hz, 1H, ArH). MS(EI): 368.
(100) 4b,9b-Dihydroxy-7-phenyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (2.00 g, 6.0 mmol) was dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (1.24 ml, 12.1 mmol), pyridine (0.48 ml, 6.0 mmol), and 4-dimethyl aminopyridine (0.2 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.41 g, 11%).
(101) mp: 165-167° C.
(102) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 2.05 (s, 3H, OAc) 2.22 (s, 3H, OAc) 7.20 (s, 1H, ArH) 7.33-7.43 (m, 3H, ArH) 7.51 (d, J=6.0 Hz, 3H, ArH) 7.78 (dd, J=8.4 Hz, J=1.8 Hz, 1H, ArH) 7.88-7.92 (m, 2H, ArH) 8.01-8.05 (m, 2H, ArH). MS(EI): 414.
(103) 4b,9b-Dihydroxy-8-nitro-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (0.80 g, 2.6 mmol) was dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (0.54 ml, 5.3 mmol), pyridine (0.21 ml, 2.6 mmol), and 4-dimethyl aminopyridine (0.08 g), and stirred at room temperature for 30 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:2 to 1:1) to afford the title compound (0.44 g, 11%).
(104) mp: 163-167° C.
(105) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.92 (s, 3H, OAc) 2.24 (s, 3H, OAc) 7.22 (d, J=9.0 Hz, 1H, ArH) 7.93-7.97 (m, 2H, ArH) 8.03-8.08 (m, 2H, ArH) 8.24 (dd, J=8.4 Hz, J=3.0 Hz, 1H, ArH) 8.72 (d, J=2.7 Hz, 1H, ArH). MS(EI): 383.
(106) 4b,9b-Dihydroxy-8-phenyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (1.00 g, 3.0 mmol) was dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (0.62 ml, 6.0 mmol), pyridine (0.25 ml, 3.0 mmol), and 4-dimethyl aminopyridine (0.1 g), and stirred at room temperature for 30 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.12 g, 6%).
(107) mp: 196-198° C.
(108) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 2.08 (s, 3H, OAc) 2.22 (s, 3H, OAc) 7.06 (d, J=8.4 Hz, 1H, ArH) 7.35-7.48 (m, 3H, ArH) 7.54-7.58 (m, 3H, ArH) 7.88-7.92 (m, 3H, ArH) 8.00-8.04 (m, 2H, ArH). MS(EI): 414.
(109) 4b,9b-Dihydroxy-8-propyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (0.80 g, 2.70 mmol) was dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (0.55 ml, 5.40 mmol), pyridine (0.21 ml, 2.7 mmol), and 4-dimethyl aminopyridine (0.08 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.85 g, 56%)
(110) mp: 108-111° C.
(111) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.96 (t, J=8.0 Hz, 3H, CH.sub.3) 1.55-1.70 (m, 2H, CH.sub.2) 2.08 (s, 3H, OAc) 2.24 (s, 3H, OAc) 2.61 (t, J=8.4 Hz, 2H, CH.sub.2) 6.92 (d, J=8.2 Hz, 1H, ArH) 7.28 (s, 1H, ArH) 7.55 (m, 1H, ArH) 7.78-8.07 (m, 4H, ArH). MS(EI): 380.
(112) 8-Ethyl-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (0.80 g, 2.70 mmol) was completely dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (0.57 ml, 5.66 mmol), pyridine (0.22 ml, 2.83 mmol), and 4-dimethyl aminopyridine (0.08 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (0.56 g, 27%).
(113) mp: 153-154° C.
(114) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.25 (t, J=7.2 Hz, 3H, CH.sub.3) 2.16 (s, 3H, OAc) 2.20 (s, 3H, OAc) 2.61-2.69 (q, J=15.0, 7.5 Hz, 2H, CH.sub.2) 6.89 (d, J=8.4 Hz, 1H, ArH) 7.20 (d, J=8.4 Hz, 1H, ArH) 7.53 (s, 1H, ArH) 7.86-7.90 (m, 2H, ArH) 7.98-8.02 (m, 2H, ArH). MS(EI): 366.
(115) 8-sec-Butyl-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (0.58 g, 1.8 mmol) was completely dissolved in anhydrous THF (10 ml). This solution was added with anhydrous acetic acid (0.39 ml, 3.7 mmol), pyridine (0.15 ml, 1.8 mmol), and 4-dimethyl aminopyridine (0.06 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (0.70 g, 48%).
(116) mp: 118-120° C.
(117) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.82 (t, J=9.0 Hz, 3H, CH.sub.3) 1.21 (d, J=6.9 Hz, 3H, CH.sub.3) 1.52-1.61 (m, 2H, CH.sub.2) 2.06 (s, 3H, OAc) 2.21 (s, 3H, OAc) 2.59-2.66 (m, 1H, CH) 6.90 (d, J=8.4 Hz, 1H, ArH) 7.20 (dd, J=2.1, 8.4 Hz, 1H, ArH) 7.50 (d, J=1.8 Hz, 1H, ArH) 7.87-7.91 (m, 2H, ArH) 7.98-8.03 (m, 2H, ArH). MS(EI): 394.
(118) 8-tert-Butyl-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (0.50 g, 1.6 mmol) was completely dissolved in anhydrous THF (10 ml). This solution was added with anhydrous acetic acid (0.32 ml, 3.7 mmol), pyridine (0.13 ml, 1.8 mmol), and 4-dimethyl aminopyridine (0.05 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (0.44 g, 36%).
(119) mp: 195-196° C.
(120) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.29 (s, 9H, CH.sub.3) 2.14 (s, 3H, OAc) 2.18 (s, 3H, OAc) 6.80 (d, J=8.7 Hz, 1H, ArH) 7.37-7.40 (dd, J=2.1, 8.7 Hz, 1H, ArH) 7.52-7.61 (m, 2H, ArH) 7.75-7.85 (m, 2H, ArH) 8.16 (d, J=8.1 Hz, 1H, ArH). MS(EI): 394.
(121) 7-sec-Butyl-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (0.52 g, 1.67 mmol) was completely dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (0.34 g, 3.3 mmol), pyridine (0.13 g, 1.6 mmol), and 4-dimethyl aminopyridine (0.05 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (0.53 g, 42%).
(122) mp: 119-120° C.
(123) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.25 (s, 9H, CH.sub.3) 2.04 (s, 3H, OAc) 2.10 (s, 3H, OAc) 6.95 (d, J=2.1 Hz, 1H, ArH) 7.29 (dd, J=8.4, 2.1 Hz, 1H, ArH) 7.60 (d, J=8.4 Hz, 1H, ArH) 7.84-7.90 (m, 2H, ArH) 7.97-8.02 (m, 2H, ArH). MS(EI): 394.
(124) 4b,9b-Dihydroxy-8-propyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (0.69 g, 2.33 mmol) was dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (0.48 ml, 4.66 mmol), pyridine (0.18 g, 2.33 mmol), and 4-dimethyl aminopyridine (0.07 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4 to 1:1) to afford the title compound (0.016 g, 2%).
(125) mp: 238-242° C.
(126) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 2.05 (s, 6H, CH.sub.3) 2.22 (s, 6H, OAc) 2.59 (s, 3H, CH.sub.3) 6.54 (s, 1H, ArH) 7.56 (t, J=7.5 Hz, 1H, ArH) 7.78 (t, J=7.5 Hz, 2H, ArH) 7.94 (d, J=6.6 Hz, 1H, ArH). MS(EI): 380.
(127) 4b,9b-Dihydroxy-8-tert-pentyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (0.80 g, 2.46 mmol) was dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (0.50 g, 4.93 mmol), pyridine (0.19 ml, 2.46 mmol), and 4-dimethyl aminopyridine (0.08 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:3) to afford the title compound (0.71 g, 38%).
(128) mp: 146-151° C.
(129) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.68 (t, J=7.5 Hz, 3H, CH.sub.3) 1.26 (s, 6H, CH.sub.3) 1.56-1.66 (m, 2H, CH.sub.2) 2.06 (s, 3H, OAc) 2.20 (s, 3H, OAc) 6.90 (d, J=8.7 Hz, 1H, ArH) 7.31 (dd, J=8.7 Hz, 2.7 Hz, 1H, ArH) 7.64 (d, J=2.4 Hz, 1H, ArH) 7.86-7.91 (m, 2H, ArH) 7.98-8.02 (m, 2H, ArH). MS(EI)=408.
(130) 4b,6,9b-Trihydroxy-8-methyl-4b,9b-dihydro-5-oxa-indeno[1,2-a]-inden-10-one (0.50 g, 1.70 mmol) was dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (0.36 g, 3.5 mmol), pyridine (0.14 ml, 1.7 mmol), and 4-dimethyl aminopyridine (0.05 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.47 g, 65%).
(131) mp: 192-194° C.
(132) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 2.08 (s, 3H, OAc) 2.17 (s, 3H, OAc) 2.19 (s, 3H, OAc) 2.35 (s, 3H, CH.sub.3) 7.06 (s, 1H, ArH) 7.35 (s, 1H, ArH) 7.86-7.89 (m, 2H, ArH) 7.98-8.01 (m, 2H, ArH). MS(EI): 410.
(133) 4b,9b-Dihydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]-inden-10-one (0.80 g, 2.70 mmol) was dissolved in anhydrous THF (100 ml). This solution was added with anhydrous acetic acid (11.46 g, 121.4 mmol), pyridine (4.9 g, 60.7 mmol), and 4-dimethyl aminopyridine (1.8 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (19.0 g, 82%).
(134) mp: 136-137° C.
(135) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.18 (d, J=6.9 Hz, 6H, CH.sub.3) 2.09 (s, 3H, OAc) 2.20 (s, 3H, OAc) 2.83-2.88 (q, J=6.9 Hz, 1H, CH) 6.83 (d, J=1.6 Hz, 1H, ArH) 7.14 (dd, J=8.4 Hz, J=1.8 Hz, 1H, ArH) 7.59 (d, J=8.4 Hz, 1H, ArH) 7.77-7.88 (m, 2H, ArH) 7.97-8.01 (m, 2H, ArH). MS(EI): 380.
(136) To a solution of ninhydrin (1.00 g, 5.61 mmol) in acetic acid (20 ml) was added 1-(3-hydroxy-phenyl)-ethanone (0.76 g, 5.61 mmol), followed by heating for 3 hrs at 110° C. The reaction mixture was diluted with methylene chloride, extracted with 2N NaOH aqueous solution, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (White, 1.32 g, 79%).
(137) mp: 177-180° C.
(138) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 3.87 (s, 3H, CH.sub.3) 7.07 (d, J=7.0 Hz, 1H, ArH) 7.32 (d, J=7.9 Hz, 1H, ArH) 7.43 (d, J=8.1 Hz, 1H, ArH) 7.91-7.94 (q, J=5.7, 3.0 Hz, 2H, ArH) 8.06-8.08 (q, J=5.7, 3.0 Hz, 2H, ArH). MS(EI): 296.
(139) 2-hydroxy-2-(2-hydroxy-4-isopropyl-phenyl)-indan-1,3-dione (1.00 g, 3.37 mmol) was completely dissolved in anhydrous THF (20 ml). This solution was added with propionyl chloride (0.62 g, 6.74 mmol), and triethylamine (0.41 g, 4.04 mmol), followed by heating 12 hrs under reflux. After the reaction mixture was concentrated, extracted with dichloromethane, and the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (White, 0.23 g, 17%).
(140) mp: 123-125° C.
(141) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.10-1.19 (m, 12H, CH.sub.3) 2.31-2.39 (q, J=15.0, 7.5 Hz, 2H, CH.sub.2) 2.46-2.54 (q, J=15.0, 7.5 Hz, 2H, CH.sub.2) 2.80-2.89 (m, 1H, CH) 6.82 (s, 1H, ArH) 7.14 (d, J=8.4 Hz, 1H, ArH) 7.61 (d, J=8.1 Hz, 1H, ArH) 7.83-7.86 (m, 2H, ArH) 7.95-7.99 (m, 2H, ArH). MS(EI)=408.
(142) 2-hydroxy-2-(2-hydroxy-4-isopropyl-phenyl)-indan-1,3-dione (1.00 g, 3.37 mmol) was completely dissolved in anhydrous methylene chloride (20 ml). This solution was added with butyryl chloride (0.72 g, 6.74 mmol), and triethylamine (0.41 g, 4.04 mmol), followed by heating 24 hrs under reflux. After the reaction mixture was concentrated, extracted with dichloromethane, and the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (White, 0.20 g, 14%).
(143) mp: 98-102° C.
(144) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.94-1.02 (m, 6H, CH.sub.3) 1.17 (s, 3H, CH.sub.3) 1.20 (s, 3H, CH.sub.3) 1.59-1.73 (m, 4H, CH.sub.2) 2.29 (t, J=7.2 Hz, 2H, CH.sub.2) 2.45 (t, J=7.5 Hz, 2H, CH.sub.2) 2.81-2.90 (m, 1H, CH) 6.80 (s, 1H, ArH) 7.13 (dd, J=8.4 Hz, 1.4H, 1H, ArH) 7.60 (d, J=8.4 Hz, 1H, ArH) 7.85-7.89 (m, 2H, ArH) 7.96-8.01 (m, 2H, ArH). MS(EI): 436.
(145) 2-hydroxy-2-(2-hydroxy-4-isopropyl-phenyl)-indan-1,3-dione (1.00 g, 3.37 mmol) was completely dissolved in anhydrous methylene chloride (20 ml). This solution was added with benzoyl chloride (0.94 g, 6.74 mmol), triethylamine (0.41 g, 4.04 mmol), and DMPA (0.01 g), followed by heating 24 hrs under reflux. After the reaction mixture was concentrated, extracted with dichloromethane, and the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.81 g, 14%)
(146) mp: 117-119° C.
(147) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.19-1.28 (m, 6H, CH.sub.3) 2.84-2.97 (m, 1H, CH) 6.91-8.09 (m, 12H, ArH). MS(EI): 400.
(148) 4b,9b-dihydroxy-7-isopropyl-4b,9b-dihydroxy-5-oxa-indeno[2,1-a]inden-10-one (0.50 g, 1.68 mmol) was completely dissolved in anhydrous DMF (10 ml). This solution was added with potassium carbonate (0.46 g, 3.26 mmol) and benzyl bromide (0.26 g, 1.51 mmol), and stirred at room temperature for 13 hrs. The reaction mixture was washed with 1N NaOH, extracted with dichloromethane, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.40 g, 61%).
(149) mp: 197-199° C.
(150) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.21 (d, J=6.9 Hz, 6H, CH.sub.3) 2.83-2.93 (m, 1H, CH) 3.04 (s, 1H, OH) 4.67 (s, 2H, OCH.sub.2) 6.69 (s, 1H, ArH) 6.91 (d, J=7.5 Hz, 2H, ArH) 6.99 (d, J=8.1 Hz, 1H, ArH) 7.11-7.23 (m, 3H, ArH) 7.57-7.60 (m, 2H, ArH) 7.61-7.71 (m, 3H, ArH). MS(EI): 386.
(151) 2-(2-benzyloxy-4-isopropyl-phenyl)-2-hydroxy-indan-1,3-dione (0.10 g, 0.25 mmol) was completely dissolved in anhydrous DMF (2 ml). This solution was added with sodium hydride (0.007 g, 0.31 mmol) and methyl iodide (0.04 g, 0.28 mmol), and stirred at room temperature for 13 hrs. The reaction mixture was extracted with dichloromethane, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (12 mg, 12%).
(152) mp: 140-144° C.
(153) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.21 (d, J=6.9 Hz, 6H, CH.sub.3) 2.82-2.92 (m, 1H, CH) 3.44 (s, 1H, OCH.sub.3) 4.63 (s, 2H, OCH.sub.2) 6.68 (s, 1H, ArH) 6.88 (d, J=7.8 Hz, 2H, ArH) 6.99 (d, J=8.1 Hz, 1H, ArH) 7.09-7.21 (m, 3H, ArH) 7.54-7.58 (m, 2H, ArH) 7.63-7.70 (m, 3H, ArH). MS(EI): 400.
(154) Ninhydrin (1.00 g, 5.61 mmol) was dissolved in acetic acid (15 ml), and this solution was heated for 13 hrs. The reaction mixture was concentrated, and extracted with dichloromethane, and then concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.31 g, 20%).
(155) mp: 210-213° C.
(156) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 2.16 (s, 6H, CH.sub.3) 3.27 (s, 1H, OH) 4.81 (s, 1H, OH) 7.02 (s, 2H, ArH) 7.90-7.92 (m, 2H, ArH) 8.04-8.07 (m, 2H, ArH). MS(EI): 282.
(157) 4b,9b-dihydroxy-7-isopropyl-2-methoxy-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (0.30 g, 0.91 mmol) was completely dissolved in anhydrous THF (10 ml). This solution was added with anhydrous acetic acid (0.18 g, 1.82 mmol), pyridine (0.07 g, 0.91 mmol) and DMAP (0.03 g), and stirred at room temperature. The reaction mixture was concentrated, and extracted with ethylacetate, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:3) to afford the title compound (0.19 g, 51%).
(158) mp: 146-148° C.
(159) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.19 (dd, J=2.1, 6.9 Hz, 6H, CH.sub.3) 2.13 (s, 3H, OAc) 2.18 (s, 3H, OAc) 2.81-2.90 (m, 1H, CH) 3.93 (s, 3H, OCH.sub.3) 6.84 (s, 1H, ArH) 7.13 (d, J=1.2 Hz, 8.4 Hz, 1H, ArH) 7.33-7.36 (m, 2H, ArH) 7.57 (d, J=8.4 Hz, 1H, ArH) 7.91 (d, J=6.0 Hz, 1H, ArH). MS(EI): 410.
(160) 2-(2-(tert-butyldimethylsilyloxy)-4-isopropylphenyl)-2-methoxy-1H-indene-1,3(2H)-dione (0.2 g, 0.47 mmol) was completely dissolved in anhydrous THF (10 ml). This solution was added with quaternary ammonium fluoride (0.27 g, 1.04 mmol), and stirred at room temperature for 1 hr. The reaction mixture was concentrated, and extracted with ethylacetate, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (38 mg, 27%).
(161) mp: 272-274° C.
(162) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.20 (d, J=7.2 Hz, 6H, CH.sub.3) 2.82-2.91 (m, 1H, CH) 3.36 (s, 3H, OCH.sub.3) 3.47 (s, 1H, OH) 6.59 (s, 1H, ArH) 6.94 (d, J=8.1 Hz, 1H, ArH) 7.62 (d, J=8.1 Hz, 1H, ArH) 7.87-8.05 (m, 4H, ArH). MS(EI)=310.
(163) To a solution of 4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indeno[2,1-a]inden-10-one (1.00 g, 3.3 mmol) in anhydrous THF were added 2,2-dimethyl-propionyl chloride (0.81 g, 6.7 mmol), trimethylamine (0.40 g, 4.0 mmol), and DMAP (0.1 g), followed by heating for 24 hrs under reflux. The reaction mixture was concentrated in a vacuum, and extracted with ethylaceteta. The extracted organic layer was purified using column chromatography (ethylacetate:hexane=1:6) to afford the title compound (0.38 g, 24%).
(164) mp: 121-124° C.
(165) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.18 (d, J=8.7 Hz, 6H, CH.sub.3) 1.26 (s, 9H, CH.sub.3) 1.35 (s, 9H, CH.sub.3) 6.67 (s, 1H, ArH) 7.07 (d, J=8.4 Hz, 1H, ArH) 7.42 (d, J=8.4 Hz, 1H, ArH) 7.79-7.83 (m, 2H, ArH) 7.93-7.97 (m, 2H, ArH). MS(EI): 464.
(166) To a solution of 4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indeno[2,1-a]inden-10-one (1.00 g, 3.3 mmol) in anhydrous THF (10 ml) were added 3-phenyl-acyloyl chloride (1.12 g, 6.7 mmol), trimethylamine (0.40 g, 4.0 mmol), and DMAP (0.1 g), followed by heating for 24 hrs under reflux. The reaction mixture was concentrated in a vacuum, and extracted with ethylacetate. The extracted organic layer was purified using column chromatography (ethylacetate:hexane=1:8 to 1:4) to afford the title compound (0.05 g, 3.5%).
(167) mp: 95-97° C.
(168) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.20 (dd, J=2.7 Hz, 6.8 Hz, 6H, CH.sub.3) 2.86-2.91 (m, 1H, CH) 4.20 (m, 1H, OH) 6.24 (d, J=16.0 Hz, 1H, CH) 6.49 (d, J=16.0 Hz, 1H, CH) 6.93 (s, 1H, ArH) 7.20 (d, J=8.3 Hz, 1H, ArH) 7.35-7.59 (m, 6H, ArH) 7.67-7.76 (m, 3H, ArH) 7.67-7.98 (m, 1H, ArH). MS(EI)=426.
(169) To a solution of 4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indeno[2,1-a]inden-10-one (1.00 g, 3.3 mmol) in anhydrous THF (10 ml) were added dimethylcarbamoyl chloride (0.72 g, 6.7 mmol), trimethylamine (0.41 g, 4.0 mmol), and DMAP (0.1 g), followed by heating for 24 hrs under reflux. The reaction mixture was concentrated in a vacuum, and extracted with ethylacetate. The extracted organic layer was purified using column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (0.20 g, 13%).
(170) mp: 203-205° C.
(171) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.19 (d, J=6.8 Hz, 6H, CH.sub.3) 2.73 (s, 3H, NCH.sub.3) 2.83 (s, 3H, NCH.sub.3) 2.93 (s, 3H, NCH.sub.3) 3.08 (s, 3H, NCH.sub.3) 6.78 (s, 1H, ArH) 7.12 (d, J=8.0 Hz, 1H, ArH) 7.59 (d, J=8.0 Hz, 1H, ArH) 7.79-7.82 (m, 2H, ArH) 7.95-7.98 (m, 2H, ArH). MS(EI): 438.
(172) To a solution of 4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indeno[2,1-a]inden-10-one (1.00 g, 3.37 mmol) in anhydrous THF (10 ml) were added acyloyl chloride (0.61 g, 6.74 mmol), trimethylamine (0.41 g, 4.0 mmol), and DMAP (0.1 g), followed by heating for 24 hrs under reflux. The reaction mixture was concentrated in a vacuum, and extracted with ethylacetate. The extracted organic layer was purified using column chromatography (ethylacetate:hexane=1:2 to 1:1) to afford the title compound (0.26 g, 19%).
(173) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.18 (d, J=2.1 Hz, 7.2 Hz, 6H, CH.sub.3) 2.81-2.87 (m, 1H, CH) 5.94-6.24 (m, 4H, CH.sub.2) 6.44-6.47 (m, 2H, CH) 6.87 (s, 1H, ArH) 7.15 (d, J=8.1 Hz, 1H, ArH) 7.58 (d, J=8.1 Hz, 1H, ArH) 7.83-7.86 (m, 2H, ArH) 7.96-7.99 (m, 2H, ArH). MS(EI): 404
(174) To a solution of 4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indeno[2,1-a]inden-10-one (1.00 g, 3.3 mmol) in anhydrous THF were added trimethylamine (0.40 g, 4.0 mmol), diethylcarbamoyl chloride (0.91 g, 6.7 mmol), and DMAP (0.1 g), followed by heating for 24 hrs under reflux. The reaction mixture was concentrated in a vacuum, and extracted with ethylacetate. The extracted organic layer was purified using column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (0.54 g, 32%).
(175) mp: 103-105° C.
(176) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.02-1.28 (m, 18H, CH.sub.3) 2.82-2.86 (m, 1H, CH) 3.10-3.26 (m, 6H, NCH.sub.2) 3.40 (q, J=14.2 Hz, 7.1 Hz, 2H, NCH.sub.2) 6.73 (s, 1H, ArH) 7.10 (d, J=8.3 Hz, 1H, ArH) 7.60 (d, J=8.3 Hz, 1H, ArH) 7.76-7.79 (m, 2H, ArH) 7.93-7.96 (m, 2H, ArH). MS(EI): 494.
(177) To a solution of 4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indeno[2,1-a]inden-10-one (1.00 g, 3.3 mmol) in anhydrous THF were added trimethylamine (0.40 g, 4.0 mmol), diethylcarbamoyl chloride (0.91 g, 6.7 mmol), and DMAP (0.1 g), followed by heating for 24 hrs under reflux. The reaction mixture was concentrated in a vacuum, and extracted with ethylacetate. The extracted organic layer was purified using column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (0.06 g, 5%).
(178) mp: 103-106° C.
(179) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.94-1.04 (m, 6H, CH.sub.3) 1.20 (d, J=6.9 Hz, 6H, CH.sub.3) 2.81-2.89 (m, 3H, CH, NCH.sub.2) 3.08 (q, J=14.2 Hz, 7.1 Hz, 2H, NCH.sub.2) 4.03 (s, 1H, OH) 6.74 (s, 1H, ArH) 7.14 (d, J=8.1 Hz, 1H, ArH) 7.70 (d, J=7.8 Hz, 1H, ArH) 7.84-7.89 (m, 2H, ArH) 7.99-8.03 (m, 2H, ArH). MS(EI): 395
(180) To a solution of ninhydrin (1.00 g, 5.6 mmol) in glacial acetic acid (20 ml) was added 2,5-dimethyl phenol (0.68 g, 5.6 mmol), followed by heating for 24 hrs under reflux. The reaction mixture was concentrated in a vacuum, and extracted with ethylacetate. The concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:6 to 1:4) to afford the title compound (0.13 g, 8%).
(181) mp: 228-230° C.
(182) .sup.1H-NMR (300 MHz, CDCl.sub.3+CD.sub.3OD) δ 2.12 (s, 3H, CH.sub.3) 2.24 (s, 3H, CH.sub.3) 3.39 (s, 1H, OH) 5.59 (s, 1H, OH) 6.54 (s, 1H, ArH) 7.02 (s, 1H, ArH) 7.90-7.93 (m, 2H, ArH) 8.03-8.06 (m, 2H, ArH). MS(EI)=282.
(183) Triethylamine (0.10 g, 0.6 mmol) was added to a solution of 1-amino-4b,9b-dihydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one (0.20 g, 0.6 mmol) in methylene chloride (5 ml) at room temperature. To this reaction mixture, a dilution of 10% acetyl chloride (1 ml) in methylene chloride was slowly added at 0° C. and stirred at room temperature 1 hr. The reaction mixture was concentrated in a vacuum, and extracted with ethylacetate. The concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (100 mg, 40%).
(184) mp: 148-151° C.
(185) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.19 (d, J=6.9 Hz, 6H, CH.sub.3) 2.07 (s, 3H, OAc) 2.18 (s, 3H, OAc) 2.83-2.88 (m, 1H, CH) 5.67 (s, 2H, NH.sub.2) 6.83 (d, J=1.8 Hz, 1H, ArH) 6.88 (d, J=8.4 Hz, 1H, ArH) 7.14 (dd, J=8.4 Hz, 2.1 Hz, 1H, ArH) 7.22 (d, J=7.2 Hz, 1H, ArH) 7.53 (t, J=7.2 Hz, 1H, ArH) 7.59 (d, J=8.4 Hz, 1H, ArH). 13C-NMR (300 MHz, DMSO) δ 19.86, 20.83, 23.98, 34.89, 82.49, 111.47, 122.19, 122.52, 123.17, 123.91, 125.54, 130.59, 138.55, 141.87, 148.87, 149.94, 153.17, 17.077, 171.10, 195.88, 196.68. MS(EI): 395.
(186) Triethylamine (0.11 g, 1.16 mmol) was added to a solution of 4b,9b-dihydroxy-7-isopropyl-1-nitro-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one (0.20 g, 0.58 mmol) in anhydrous chloroform (10 ml) at room temperature. To this reaction mixture, acetyl chloride (1 ml) was slowly added at 0° C. and stirred at room temperature 1 hr. The reaction mixture was concentrated in a vacuum, and extracted with ethylacetate. The concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (30 mg, 12%).
(187) mp: 94-98° C.
(188) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.20 (dd, J=6.9 Hz, 6H, CH.sub.3) 2.19 (s, 3H, OAc) 2.27 (s, 3H, OAc) 2.83-2.92 (m, 1H, CH) 6.91 (s, 1H, ArH) 7.15 (dd, J=8.2 Hz, 1.7 Hz, 1H, ArH) 7.53 (d, J=8.2 Hz, 1H, ArH) 7.99 (t, J=7.8 Hz, 1H, ArH) 8.23 (dd, J=3.0 Hz, 7.8 Hz, 2H, ArH). .sup.13C-NMR (300 MHz, CDCl.sub.3) δ 19.72, 20.92, 23.45, 33.71, 82.07, 119.57, 12.83, 125.03, 127.88, 129.86, 130.24, 131.48, 136.49, 141.09, 145.18, 148.77, 153.02, 168.90, 169.92, 187.91, 190.47. MS(EI): 425.
(189) A solution of 4-nitro-2,3-dihydro-1H-inden-1-one (4.00 g, 20.9 mmol) in 1,4-dioxane (40 ml) and glacial acetic acid (4 ml) was added with selenium dioxide (5.10 g, 46.03 mmol), and refluxed for 3 hrs. After filtration at high temperature, the filtrate was concentrated to afford 2,2-dihydroxy-4-nitro-2H-inden-1,3-dione (4.67 g, 100%). To a solution of 2,2-dihydoxy-4-nitro-2H-inden-1,3-dione (4.67 g, 20.9 mmol) in TFA (10 ml) was added isopropyl anisole (3.14 g, 20.9 mmol), followed by stirring at 60° C. for 6 hrs. The reaction mixture was concentrated in a vacuum, and extracted with aq. sodium bicarbonate and ethylacetate. The concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (1.19 mg, 16%).
(190) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.21 (d, J=6.9 Hz, 6H, CH.sub.3) 2.82-2.92 (m, H, CH) 3.05 (s, 3H, OCH.sub.3) 3.75 (s, 3H, OH) 6.60 (s, 1H, ArH) 6.96 (dd, J=7.8 Hz, 1H, ArH) 7.65 (d, J=8.1 Hz, 1H, ArH) 8.01 (t, J=7.8 Hz, 1H, ArH) 8.20-8.26 (m, 2H, ArH). MS(EI): 355.3.
(191) 2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione (1.00 g, 2.8 mmol) was dissolved in excess of thionyl chloride (10 ml), stirred at room temperature for 2 hrs. The reaction mixture was concentrated in a vacuum, and extracted with aq. sodium bicarbonate and ethylacetate. The organic layer was concentrated to afford the title compound (1.05 g, 77%).
(192) mp: 81-84° C.
(193) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.25 (d, J=6.9 Hz, 6H, CH.sub.3) 2.87-2.96 (m, 1H, CH) 3.44 (s, 3H, OCH.sub.3) 6.65 (s, 1H, ArH) 7.02 (dd, J=1.2 Hz, 7.8 Hz, 1H, ArH) 8.05-8.12 (m, 1H, ArH) 8.22 (dd, J=1.2 Hz, 7.8 Hz, 1H, ArH) 8.28-8.35 (m, 2H, ArH). MS(EI): 373.
(194) 2-chloro-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione (1.23 g, 3.2 mmol) was completely dissolved in acetone (30 ml). This solution was added with sodium azide (0.47 g, 7.2 mmol), sodium iodide (0.59 g, 3.9 mmol), water (6 ml), followed by heating 12 hrs under reflux. The reaction mixture was concentrated, and extracted with ethylacetate, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (Brown syrup, 600 mg, 48%).
(195) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.23 (d, J=6.9 Hz, 6H, CH.sub.3) 2.28-2.94 (m, 1H, CH) 3.40 (s, 3H, OCH.sub.3) 6.63 (d, J=1.5 Hz, 1H, ArH) 7.01 (dd, J=1.5 Hz, 8.1 Hz, 1H, ArH) 7.56-7.60 (m, 2H, ArH) 7.78-7.90 (m, 2H, ArH). MS(EI): 380.
(196) 2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione (52 mg, 1.4 mmol) was completely dissolved in anhydrous ethanol (10 ml). This solution was added with iron (0.59 g, 10.6 mmol), conc. HCl (0.01 ml) and water (1 ml). The reaction mixture was heated for 3 hrs under reflux. After filtration at high temperature to remove iron, the filtrate was concentrated in a vacuum and purified using column chromatography(ethylacetate:hexane=1:2) to afford the title compound (0.32 g, 68%).
(197) mp: 219-220° C.
(198) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.21 (d, J=6.9 Hz, 6H, CH.sub.3) 2.82-2.91 (m, 1H, CH) 3.41-3.45 (s, 3H, OCH.sub.3) 6.60 (d, J=1.2 Hz, 1H, ArH) 6.89-6.98 (m, 2H, ArH) 7.21-7.27 (m, 1H, ArH) 7.56-7.66 (m, 2H, ArH). MS(EI): 325.
(199) N-(2,2-dihydroxy-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (1.50 g, 6.4 mmol) was completely dissolved in anhydrous dioxane (15 ml). This solution was added with selenium oxide (1.56 g, 14.0 mmol) and AcOH (1.5 ml). The reaction mixture was heated for 12 hrs under reflux. After filtration at high temperature, the filtrate was concentrated to afford 1.79 g (100%). The resulting product was extracted with ethyl acetate, and concentrated organic layer was purified using column chromatography(ethylacetate:hexane=1:1) to afford the title compound (0.52 g, 20%).
(200) mp: 110-115° C.
(201) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.23 (d, J=6.9 Hz, 6H, CH.sub.3) 2.29 (s, 3H, CH.sub.3), 2.84-2.93 (m, 1H, CH) 3.57 (s, 3H, OCH.sub.3), 3.78 (s, 1H, OH), 6.63 (s, 1H, ArH) 7.00 (dd, J=1.5, 8.1 Hz, 1H, ArH) 7.68 (d, J=8.1 Hz, 1H, ArH) 8.28 (d, J=8.7 Hz, 1H, ArH) 9.04 (d, J=2.4, 9.0 Hz, 1H, ArH) 10.54 (s, 1H, NH). MS(EI): 412.39.
(202) N-(2,2-dihydroxy-5-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (2.60 g, 11.1 mmol) was completely dissolved in anhydrous dioxane (20 ml). This solution was added with selenium oxide (2.70 g, 24.4 mmol) and AcOH (1.5 ml). The reaction mixture was heated for 7 hrs under reflux. After filtration at high temperature, the filtrate was concentrated to afford 1.79 g (100%). Trifluoroacetic solution of the resulting product was added with isopropyl-3-methoxybenzene (1.66 g, 11.1 mmol), followed by stirring for 12 hrs. The remainder was extracted with ethyl acetate, and concentrated organic layer was purified using column chromatography(ethylacetate 100%) to afford the title compound (0.64 g, 14%).
(203) mp: 199-201° C.
(204) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.23 (d, J=6.9 Hz, 6H, CH.sub.3) 2.28 (s, 3H, CH.sub.3), 2.84-2.91 (m, 1H, CH) 3.42 (s, 3H, OCH.sub.3), 3.77 (s, 1H, OH), 6.65 (s, 1H, ArH) 7.00 (dd, J=1.4, 7.9 Hz, 1H, ArH) 7.63 (d, J=7.9 Hz, 1H, ArH) 7.85 (d, J=8.1 Hz, 1H, ArH) 8.35 (d, J=8.1 Hz, 1H, ArH) 9.79 (s, 1H, NH). MS(EI): 412.
(205) N-(2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (0.10 g, 0.24 mmol) was completely dissolved in anhydrous ethanol (3 ml). This solution was added with iron (0.098 g), conc. HCl (0.05 ml) and water (0.3 ml). The reaction mixture was heated for 2 hrs under reflux. After filtration at high temperature to remove iron, the filtrate was concentrated in a vacuum and purified using column chromatography(ethylacetate:hexane=1:2) to afford the title compound (65 mg, 71%).
(206) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.22 (s, 6H, CH.sub.3) 2.20 (s, 3H, CH.sub.3) 2.83-2.92 (m, 1H, CH) 3.50 (s, 3H, OCH.sub.3) 3.78 (s, 1H, OH) 5.54 (s, 2H, NH.sub.2) 6.66 (d, J=2.7 Hz, 1H, ArH) 6.91-7.07 (m, 2H, ArH) 7.56 (d, J=7.8 Hz, 1H, ArH) 8.76 (d, J=3.3, 9.0 Hz, 1H, ArH) 9.81 (s, 1H, NH). MS(EI): 382.
(207) N-(2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-5-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (0.10 g, 0.24 mmol) was completely dissolved in anhydrous ethanol (3 ml). This solution was added with iron (0.098 g), conc. HCl (0.05 ml) and water (0.3 ml). The reaction mixture was heated for 2 hrs under reflux. After filtration at high temperature to remove iron, the filtrate was concentrated in a vacuum and purified using column chromatography(ethylacetate 100%) to afford the title compound (90 mg, 98%).
(208) mp: 124-131° C.
(209) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.21 (d, J=6.9 Hz, 6H, CH.sub.3) 2.30 (s, 3H, CH.sub.3) 2.83-2.92 (m, CH) 3.46 (s, 3H, OCH.sub.3) 3.78 (s, 1H, OH) 5.36 (s, 2H, NH.sub.2) 6.62 (s, 1H, ArH) 6.93 (d, J=8.1 Hz, 1H, ArH) 7.14 (d, J=8.4 Hz, 1H, ArH) 7.56 (d, J=8.1 Hz, 1H, ArH) 7.70 (d, J=8.1 Hz, 1H, ArH) 9.56 (s, 1H, NH). MS(EI): 382.
(210) N-(7-amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (45 mg, 0.10 mmol) was completely dissolved in 6M HCl (1.4 ml) and methanol (0.1 ml), followed by heating for 90 min at 80 D. The reaction mixture was diluted with methylene chloride, extracted with 2N NaOH aqueous solution, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:1) to afford the title compound (80 mg, 200%).
(211) mp: 243-247° C.
(212) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.21 (d, J=6.9 Hz, 6H, CH.sub.3) 2.84-2.88 (m, 1H, CH) 3.55 (s, 3H, OCH.sub.3) 3.78 (s, 1H, OH) 5.20 (s, 2H, NH.sub.2) 6.64 (s, 1H, ArH) 6.90 (s, 3H, ArH) 7.52 (d, J=7.8 Hz, 1H, ArH). MS(EI): 340.
(213) N-(5-amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (85 mg, 0.19 mmol) was completely dissolved in 6M HCl (1.4 ml) and methanol (0.1 ml), followed by heating for 40 min at 80□. The reaction mixture was diluted with methylene chloride, extracted with 2N NaOH aqueous solution, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:1) to afford the title compound (30 mg, 44%).
(214) mp: 272-274° C.
(215) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.21 (d, J=6.9 Hz, 6H, CH.sub.3) 2.83-2.92 (m, 1H, CH) 3.33 (s, 3H, OCH.sub.3) 3.76 (s, 1H, OH) 4.13 (s, 2H, NH.sub.2) 6.63 (s, 1H, ArH) 6.96 (d, J=7.8 Hz, 1H, ArH) 7.68 (d, J=7.8 Hz, 1H, ArH) 7.83 (d, J=8.1 Hz, 1H, ArH) 8.08 (d, J=8.4 Hz, 1H, ArH). MS(EI): 340.
(216) 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one (0.30 g, 1.01 mmol) was completely dissolved in THF (10 ml). This solution was added with triethylamine (0.17 ml, 1.21 mmol) and methylchloroformate (0.07 ml, 1.01 mmol), followed by heating for 3 hrs under room temperature. After the reaction mixture was concentrated in a vacuum, extracted with water and methylene chloride, and purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.30 g, 72%).
(217) mp: 105-107° C.
(218) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.18 (d, J=6.9 Hz, 6H), 2.85 (q, J=7.1 Hz, 1H), 3.61 (s, 3H), 3.89 (s, 3H), 5.97 (s, 1H), 6.91 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.82-7.87 (m, 2H), 7.97-8.03 (m, 2H).
(219) 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one (0.30 g, 1.01 mmol) was dissolved in THF (10 ml). This solution was added with valeryl chloride (0.12 ml, 1.01 mmol), followed by heating for 1 hr under room temperature. After the reaction mixture was concentrated in a vacuum, extracted with water and methylene chloride, and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.10 g, 20%).
(220) mp: 117-118° C.
(221) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.89 (t, J=7.8 Hz, 3H), 1.00 (t, J=8.1 Hz, 3H), 1.17 (d, J=6.8 Hz, 6H), 1.29-1.40 (m, 2H), 1.42-1.62 (m, 4H), 1.77 (q, J=8.8 Hz, 2H), 2.24 (t, J=8.3 Hz, 2H), 2.65 (t, J=9.4 Hz, 2H), 2.84 (q, J=7.8 Hz, 1H), 6.67 (s, 1H), 6.85 (s, 1H), 7.05 (dd, J=1.4 Hz, 8.3 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.79-7.84 (m, 2H), 7.93-7.99 (m, 2H).
(222) 9b-Amino-4b-hydro-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]-inden-10-one (0.30 g, 1.01 mmol) was dissolved in THF (10 ml). This solution was added with triethylamine (0.17 ml, 1.21 mmol), isobutyryl chloride (0.10 ml, 1.01 mmol), and stirred at room temperature for 1 hrs. The reaction mixture was concentrated in a vacuum, and extracted with water and methylene chloride. The extracted organic layer was purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.10 g, 23%).
(223) mp: 195-197° C.
(224) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.15 (d, J=6.9 Hz, 6H), 1.17 (d, J=6.9 Hz, 6H), 1.38 (d, J=7.0 Hz, 6H), 2.45 (q, J=7.3 Hz, 1H), 2.77-3.00 (m, 2H), 6.70 (s, 1H), 6.82 (d, J=1.7 Hz, 1H), 7.04 (dd, J=1.7 Hz, 8.2 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.77-7.84 (m, 2H), 7.93-7.99 (m, 2H).
(225) To a solution of 4b,9b-dihydroxy-7-isopropyl-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (1.0 g, 3.3 mmol) in diethylene glycol (10 ml) were added with hydrazine hydrate (80%, 0.36 g, 9.6 mmol), followed by stirring at 150° C. for 15 min. The reaction mixture was added potassium hydroxide (360 mg, 6.4 mmol), and stirred at 165-170° C. for 1 hrs. The reaction mixture was extracted with ethylacetate, and purified using column chromatography (20% ethylacetate in hexane) to afford the title compound (60 g, 6.5%).
(226) mp: 144-146° C.
(227) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.17 (d, J=7 Hz, 6H, CH.sub.3) 2.75-2.79 (septet, 1H, CH) 3.52-3.69 (m, 2H, CH.sub.2) 6.57 (d, J=8.0 Hz, 1H, ArH) 6.70 (d, J=8.0 Hz, 1H, ArH) 6.79 (s, 1H, ArH) 7.41 (t, J=6.8 Hz, 2H, ArH) 7.65 (t, J=7.1 Hz, 1H, ArH) 7.82 (d, J=7.7 Hz, 1H, ArH). MS(EI): 282.
(228) To a solution of 2-chloro-2-(4-isopropyl-2-methoxyphenyl)-1H-inden-1,3(2H)-dione (0.10 g, 0.3 mmol) in acetone (5 ml) were added with sodium iodide (54 mg, 0.36 mmol) and sodium azide (50 mg, 0.76 mmol) and distilled water (1 ml), followed by stirring at 80° C. for 6 hrs. The reaction mixture was added water, and extracted diethyl ether, and washed with water and brine in that order. The washed organic layer was concentrated to afford the title compound (100 g, 98%).
(229) mp: 175-177° C.
(230) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.24 (d, J=6.9 Hz, 6H, CH.sub.3) 2.89 (septet, J=6.9 Hz, 1H, CH) 3.43 (s, 3H, OCH.sub.3) 6.62 (d, J=1.2 Hz, 1H, ArH) 7.02 (dd, J=7.8 Hz, J=1.2 Hz, 1H, ArH) 7.61 (d, J=8.1 Hz, 1H, ArH) 7.89-7.95 (m, 2H, ArH) 8.03-8.09 (m, 2H, ArH). MS(EI): 335.
(231) To a solution of 2-azido-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (50 mg, 0.15 mmol) in methanol (10 ml) were added with triphenylphosphine (47 mg, 0.18 mmol), followed by stirring at 60° C. for 4 hrs. The concentrated reaction mixture was purified using silica column chromatography (25% ethylacetate in hexane) to afford the title compound (25 g, 54%).
(232) mp: 164-166° C.
(233) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.22 (d, J=6.9 Hz, 6H, CH.sub.3) 2.88 (septet, J=6.9 Hz, 1H, CH) 3.30 (s, 3H, OCH.sub.3) 6.57 (d, J=1.2 Hz, 1H, ArH) 6.97 (dd, J=7.8 Hz, J=1.5 Hz, 1H, ArH) 7.60 (d, J=7.8 Hz, 1H, ArH) 7.86-7.90 (m, 2H, ArH) 8.00-8.04 (m, 2H, ArH). MS(EI): 309.
(234) 2-Amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.10 g, 0.32 mmol) was dissolved in methylene chloride (4 ml). This solution was added with acetyl chloride (0.05 ml, 0.70 mmol), followed by stirring at room temperature for 15 min, and added with triethylamine (0.12 ml, 0.86 mmol), and stirred for 6 hrs. After the reaction mixture was extracted with methylene chloride (50 ml×3), the organic layer was purified using column chromatography (45% ethylacetate in hexane) to afford the title compound (70 g, 62%).
(235) mp: 222-224° C.
(236) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.18 (d, J=6.9 Hz, 6H, CH.sub.3) 1.95 (s, 3H, OAc) 2.82 (septet, J=6.9 Hz, 1H, CH) 3.51 (s, 3H, OCH3) 6.63 (d, J=1.5 Hz, 1H, ArH) 6.85-6.90 (m, 2H, NH, ArH) 7.41 (d, J=8.4 Hz, 1H, ArH) 7.76-7.82 (m, 2H, ArH) 7.93-7.97 (m, 2H, ArH). MS(EI): 351.
(237) A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (200 mg, 0.60 mmol) in dichloromethane (10 ml) was stirred overnight together with benzoyl chloride (0.09 mL, 0.77 mmol) and triethylamine (0.27 mL, 1.9 mmol) at room temperature. The reaction mixture was extracted with dichloromethane, and purified by silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (250 mg, 97%).
(238) mp: 106-108° C.
(239) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.21 (d, J=6.9 Hz, 6H, CH.sub.3) 2.86 (septet, J=6.9 Hz, 1H, CH) 3.64 (s, 3H, OCH.sub.3) 6.72 (s, 1H, ArH) 6.90 (d, J=8.1 Hz, 1H, ArH) 7.40-7.45 (m, 3H, ArH) 7.50-7.55 (m, 2H, ArH) 7.80-7.87 (m, 4H, ArH) 8.01-8.06 (m, 2H, ArH). MS(EI): 413.
(240) A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (200 mg, 0.60 mmol) in dichloromethane (10 ml) was stirred overnight together with cyclopropyl carbonyl chloride (0.07 mL, 0.77 mmol) and triethylamine (0.27 mL, 1.9 mmol) at room temperature. The reaction mixture was extracted with dichloromethane, and purified by silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (235 mg, 96%).
(241) mp: 145-147° C.
(242) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.22 (d, J=6.9 Hz, 6H, CH.sub.3) 2.88 (septet, J=6.9 Hz, 1H, CH) 3.30 (s, 3H, OCH.sub.3) 6.57 (d, J=1.2 Hz, 1H, ArH) 6.97 (dd, J=7.8 Hz, J=1.5 Hz, 1H, ArH) 7.60 (d, J=7.8 Hz, 1H, ArH) 7.86-7.90 (m, 2H, ArH) 8.00-8.04 (m, 2H, ArH). MS(EI): 377.
(243) Ninhydrin (0.10 g, 0.56 mmols) and thioanisole (0.07 mL, 0.56 mmols) were dissolved in trifluoroacetic acid (3 mL) and was stirred for 90 min at room temperature. The reaction mixture was neutralization with an aqueous sodium bicarbonate solution and was extracted with ethylacetate and was purified by silica gel column chromatography to afford the title compound (20 mg, 13%).
(244) mp: 191-193° C.
(245) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 2.11 (s, 3H, SMe) 3.70 (b, 1H, OH) 7.34-7.42 (m, 3H, ArH) 7.82 (m, 1H, ArH) 7.87-7.96 (m, 2H, ArH) 8.01-8.05 (m, 2H, ArH). MS(EI): 284.
(246) The title compound (115 mg, 77%) was obtained in a similar manner as described in EXAMPLE 70.
(247) mp: 153-155° C.
(248) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 2.14 (s, 3H, SMe) 3.74 (b, 1H, OH) 7.13-7.17 (m, 2H, ArH) 7.26-7.31 (m, 2H, ArH) 7.90-7.95 (m, 2H, ArH) 8.03-8.06 (m, 2H, ArH). MS(EI): 284.
(249) A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.50 g, 1.62 mmol) in anhydrous THF (10 ml) was added triphosgene (0.21 g, 0.71 mmol) and stirred for 30 min. The reaction mixture was concentrated and was dissolved in methanol (6 mL) and was stirred for 2 hrs and was concentrated to afford the title compound (220 mg, 93%).
(250) mp: 153-155° C.
(251) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.18 (d, J=6.9 Hz, 6H, CH.sub.3) 2.83 (septet, J=6.9 Hz, 1H, CH) 3.50 (s, 3H, OCH.sub.3) 3.65 (s, 3H, OCH.sub.3) 5.94 (br, 1H, NH) 6.63 (d, J=1.5 Hz, 1H, ArH) 6.89 (dd, J=8.1 Hz, J=1.5 Hz, 1H, ArH) 7.44 (d, J=8.1 Hz, 1H, ArH) 7.79-7.85 (m, 2H, ArH) 7.97-8.03 (m, 2H, ArH). MS(EI): 367.
(252) A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.50 g, 1.62 mmol) in anhydrous THF (10 ml) was added triphosgene (0.52 g, 1.77 mmol) and stirred for 15 min. The reaction mixture was concentrated and was dissolved in anhydrous THF (10 ml) and was added ethylamine (2.0M in methanol, 2 mL, 400 mmol) and was stirred for 2 hrs. Concentrated reaction mixture was added dichloromethane to afford the title compound (450 mg, 74%).
(253) mp: 267-269° C.
(254) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.17.1.23 (m, 9H, CH.sub.3) 2.72 (br, 1H, NH) 2.89 (septet, J=6.9 Hz, 1H, CH) 3.30-3.44 (m, 4H, CH.sub.3 and CH.sub.2) 3.50-3.62 (m, 1H, CH2) 5.33 (s, 1H, NH) 6.70 (s, 1H, ArH) 6.96 (dd, J=8.1 Hz, J=1.2 Hz, 1H, ArH) 7.51 (d, J=8.1 Hz, 1H, ArH) 7.59-7.64 (m, 1H, ArH) 7.75-7.83 (m, 2H, ArH) 7.94 (d, J=7.8 Hz, 1H, ArH). MS(EI): 380.
(255) A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.50 g, 1.62 mmol) in anhydrous THF (10 ml) was added triphosgene (0.52 g, 1.77 mmol) and stirred for 15 min. The reaction mixture was concentrated and was dissolved in anhydrous THF (10 ml) and was added ammonia ((2.0M in IPA, 1.6 mL, 3.23 mmol) was stirred for 2 hrs. The reaction mixture was concentrated and was purified using silica gel column chromatography to afford the title compound (150 mg, 29%).
(256) mp: 272-274° C.
(257) .sup.1H-NMR (300 MHz, Acetone-D.sub.6) δ 1.24 (d, J=6.9 Hz, 6H, CH.sub.3) 2.84-2.96 (m, 3H, CH, NH.sub.2) 3.30 (s, 3H, OMe) 6.81 (d, J=1.5 Hz, 1H, ArH) 6.91-6.95 (m, 1.7H, ArH and NH) 7.18 (br, 0.63H, NH) 7.51 (d, J=7.8 Hz, 1H, ArH) 7.59-7.64 (m, 1H, ArH) 7.79-7.86 (m, 3H, ArH). MS(EI): 352.
(258) The title compound (150 mg, 23%) was obtained in a similar manner as described in EXAMPLE 75.
(259) mp: 159-161° C.
(260) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.10-1.17 (m, 12H, CH.sub.3) 2.82 (septet, J=6.9 Hz, 1H, CH) 3.48 (s, 3H, OMe) 4.76 (m, 1H, CH) 5.83 (s, 1H, NH) 6.62 (d, J=1.5 Hz, 1H, ArH) 6.88-6.93 (m, 1H, ArH) 7.45-7.49 (m, 1H, ArH) 7.80-7.84 (m, 2H, ArH) 7.97-8.01 (m, 2H, ArH). MS(EI): 395.
(261) A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.50 g, 1.61 mmol) in anhydrous THF (20 ml) was added triphosgene (0.528 g, 1.77 mmol) and stirred for 15 min. The reaction mixture was concentrated and was dissolved in anhydrous THF (20 ml) and was added hydroxylamine hydrochloride(0.28 g, 4.04 mmol) was stirred for 2 hrs at room temperature. The reaction mixture was concentrated and was purified using silica gel column chromatography(1:1=ethylacetate:hexane) to afford the title compound (420 mg, 69%).
(262) mp: 153-155° C.
(263) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.25 (dd, J=1.5 Hz, J=6.9 Hz, 6H, CH.sub.3) 2.91 (septet, J=6.9 Hz, 1H, CH) 2.97 (s, 1H, NH) 3.45 (s, 3H, OCH.sub.3) 4.02 (s, 3H, OCH.sub.3) 5.51 (br, 1H, NH) 6.76 (d, J=1.5 Hz, 1H, ArH) 7.00 (dd, J=1.5 Hz, J=7.8 Hz, 1H, ArH) 7.47 (d, J=7.8 Hz, 1H, ArH) 7.60-7.65 (m, 1H, ArH) 7.76-7.81 (m, 1H, ArH) 7.89-7.95 (t, J=8.4 Hz, 2H, ArH). MS(EI): 382.
(264) A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.80 g, 2.58 mmol) in anhydrous THF (20 ml) was added triphosgene (0.84 g, 2.84 mmol) and stirred for 15 min. The reaction mixture was concentrated and was dissolved in ethanol (20 ml) was stirred for 2 hrs at room temperature to afford the title compound (0.95 g, 96%).
(265) mp: 149-150° C.
(266) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.17-1.24 (m, 9H, CH.sub.3) 2.83 (septet, J=6.9 Hz, 1H, CH) 3.49 (s, 3H, OCH.sub.3) 4.02 (q, 2H, CH.sub.2) 5.89 (br, 1H, NH) 6.62 (s, 1H, ArH) 6.89 (d, J=8.1 Hz, 1H, ArH) 7.46 (d, J=8.1 Hz, 1H, ArH) 7.80-7.83 (m, 2H, ArH) 7.98-8.01 (m, 2H, ArH). MS(EI): 381.
(267) A solution of N-(2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-2,3-dihydro-1H-inden-4-yl)acetamide (0.25 g, 0.68 mmol) in dichloromethane (10 ml) and was added thionyl bromide (0.08 mL, 1.02 mmol) and DMF (2 drops) was stirred for 2 hrs at room temperature. The reaction mixture was extracted with dichloromethane and was purified using silica gel column chromatography (20% ethylacetate in hexane) to afford the title compound (0.22 g, 75%).
(268) mp: 143-145° C.
(269) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.24 (d, J=6.9 Hz, 6H, CH.sub.3) 2.63 (s, 3H, NAc) 2.91 (septet, J=6.9 Hz, 1H, CH) 3.41 (s, 3H, OCH3) 6.61 (d, J=1.2 Hz, 1H, ArH) 6.98 (dd, J=8.1 Hz, J=1.2 Hz, 1H, ArH) 7.70 (d, J=8.1 Hz, 1H, ArH) 7.81 (d, J=7.8 Hz, 1H, ArH) 7.86-7.91 (m, 1H, ArH) 9.00 (d, J=8.4 Hz, 1H, ArH) 10.31 (br, 1H, NH). MS(EI): 430.2.
(270) A solution of N-(2-azido-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-2,3-dihydro-1H-inden-4-yl)acetamide (115 mg, 0.29 mmol) in methanol (5 ml) and was added triphenylphosphine (92 mg, 0.35 mmol) and water (1 mL) was stirred for 2.5 hrs at 50° C. The reaction mixture was concentrated and purified using silica gel column chromatography(30% ethylacetate in hexane, 1% triethylamine) to afford the title compound (75 mg, 70%).
(271) mp: 183-185° C.
(272) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.23 (d, J=6.9 Hz, 6H, CH.sub.3) 1.99 (br, 2H, NH.sub.2) 2.24 (s, 3H, NAc) 2.88 (septet, J=6.9 Hz, 1H, CH) 3.35 (s, 3H, OCH.sub.3) 6.59 (d, J=1.5 Hz, 1H, ArH) 6.98 (dd, J=7.8 Hz, J=1.5 Hz, 1H, ArH) 7.60 (d, J=7.8 Hz, 1H, ArH) 7.66 (d, J=7.2 Hz, 1H, ArH) 7.84 (t, J=7.8 Hz, 1H, ArH) 8.93 (d, J=8.1 Hz, 1H, ArH) 10.2 (br, 1H, NH). MS(EI): 366.
(273) A solution of N-(2-amino-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-2,3-dihydro-1H-inden-4-yl)acetamide (0.20 g, 0.54 mmol) in dichloromethane (10 mL) and was added triethylamine (0.23 mL, 1.6 mmol) and then stirred for overnight. The reaction mixture was extracted with dichloromethane and purified using silica gel column chromatography(50% ethylacetate in hexane) to afford the title compound (210 mg, 95%).
(274) mp: 241-243° C.
(275) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.19 (d, J=6.9 Hz, 6H, CH.sub.3) 2.05 (s, 3H, NAc) 2.23 (s, 3H, NAc) 2.85 (septet, J=6.9 Hz, 1H, CH) 3.55 (s, 3H, OCH3) 6.65-6.74 (m, 2H, ArH and NH) 6.91 (dd, J=8.1 Hz, J=1.5 Hz, 1H, ArH) 7.39 (d, J=8.1 Hz, 1H, ArH) 7.62 (d, J=7.5 Hz, 1H, ArH) 7.78 (t, J=8.1 Hz, 1H, ArH) 8.86 (d, J=8.4 Hz, 1H, ArH) 10.1 (br, 1H, NH). MS(EI): 408.
(276) A solution of 9b-amino-4b-hydroxy-7-isopropyl-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (0.10 g, 0.34 mmol) in dichloromethane (5 ml) was added triethylamine (0.14 mL, 1.02 mmol) and propionyl chloride(32.5 μL, 0.37 mmol) at 0° C. and then stirred for 4 hrs at room temperature. The reaction mixture was extracted with dichloromethane and purified using silica gel column chromatography(40% ethylacetate in hexane) to afford the title compound (116 mg, 85%).
(277) mp: 173-175° C.
(278) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.07-1.19 (m, 9H, CH.sub.3) 1.23-1.33 (m, 3H, CH.sub.3) 2.27 (q, J=7.5 Hz, 2H, CH.sub.2) 2.68 (q, J=7.5 Hz, 2H, CH.sub.2) 2.84 (septet, J=6.9 Hz, 1H, CH) 6.69 (s, 1H, NH) 6.86 (d, J=1.5 Hz, 1H, ArH) 7.06 (dd, J=1.5 Hz, J=8.1 Hz, 1H, ArH) 7.35 (d, J=8.1 Hz, 1H, ArH) 7.80-7.83 (m, 2H, ArH) 7.95-7.98 (m, 2H, ArH). MS(EI): 407.
(279) A solution of 9b-amino-4b-hydroxy-7-isopropyl-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (0.15 g, 0.50 mmol) in dichloromethane (5 ml) was added triethylamine (0.21 mL, 1.52 mmol) and valeroyl chloride(74 μL, 0.61 mmol) at 0° C. and then stirred for overnight at room temperature. The reaction mixture was extracted with dichloromethane and purified using silica gel column chromatography(30% ethylacetate in hexane) to afford the title compound (150 mg, 68%).
(280) mp: 128-130° C.
(281) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.89 (t, J=7.2 Hz, 3H, CH.sub.3) 0.99 (t, J=7.2 Hz, 3H, CH.sub.3) 1.18 (d, J=6.9 Hz, 6H, CH.sub.3) 1.23-1.40 (m, 2H, CH.sub.2) 1.42-1.62 (m, 4H, CH.sub.2) 1.72-1.82 (m, 2H, CH.sub.2) 2.43 (t, J=7.5 Hz, 2H, CH.sub.2) 2.65 (t, J=7.8 Hz, 2H, CH.sub.2) 2.84 (septet, J=6.9 Hz, 1H, CH) 6.67 (s, 1H, NH) 6.85 (d, J=1.5 Hz, 1H, ArH) 7.06 (dd, J=1.5 Hz, J=8.4 Hz, 1H, ArH) 7.34 (d, J=8.4 Hz, 1H, ArH) 7.79-7.84 (m, 2H, ArH) 7.93-7.97 (m, 2H, ArH). MS(EI): 463.
(282) A solution of 9b-amino-4b-hydroxy-7-isopropyl-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (0.25 g, 0.85 mmol) in dichloromethane (15 ml) was added diisopropylethylamine (0.73 mL, 4.22 mmol) and benzoyl chloride(0.29 mL, 2.54 mmol) at 0° C. and then stirred for overnight at room temperature. The reaction mixture was extracted with dichloromethane and purified using silica gel column chromatography (20% ethylacetate in hexane) to afford the title compound (280 mg, 66%).
(283) mp: 138-140° C.
(284) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.22 (d, J=6.9 Hz, 6H, CH.sub.3) 2.90 (septet, J=6.9 Hz, 1H, CH) 7.00 (d, J=1.5 Hz, 1H, ArH) 7.16 (dd, J=1.5 Hz, J=8.1 Hz, 1H, ArH) 7.34-7.61 (m, 9H, ArH) 7.73-7.76 (m, 4H, ArH) 7.77-7.86 (m, 2H, ArH) 8.10-8.12 (m, 2H, ArH). MS(EI): 503.
(285) The title compound was obtained in a similar manner as described in EXAMPLE 2.
(286) .sup.1H-NMR (200 MHz, CDCl.sub.3): δ 8.33 (d, J=7.7 Hz, 1H), 7.80 (t, J=7.7 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.52-7.44 (m, 2H), 7.26 (d, J=8.0 Hz, 1H), 2.59 (s, 3H), 2.35 (s, 3H), 2.30 (s, 3H).
(287) The title compound was obtained in a similar manner as described in EXAMPLE 24.
(288) .sup.1H-NMR (200 MHz, DMSO-d.sub.6) δ 10.5 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.90 (m, 2H), 7.65 (m, 2H), 7.52 (d, J=8.5 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 2.51 (s, 3H).
(289) The title compound was obtained in a similar manner as described in EXAMPLE 24.
(290) .sup.1H-NMR (200 MHz, CDCl.sub.3): δ 8.32 (d, J=7.9 Hz, 1H), 8.08 (m, 1H), 7.89 (td, J=8.2, 1.2 Hz, 1H), 7.65 (t, J=7.0 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.32 (d, J=1.4 Hz, 1H).
(291) A solution of 4b,9b-dihyroxy-7-methyl-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (0.25 g, 0.85 mmol) in anhydrous dichloromethane (50 ml) was added anhydrous acetic acid (0.7 ml, 7.4 mmol), pyridine (0.3 ml, 3.7 mmol), 4-dimethylaminopyridine (0.1 g) and then stirred for 3 hrs at room temperature. The reaction mixture was extracted with dichloromethane, the concentrated organic layer was purified using silica gel column chromatography (ethylacetate:hexane=1:8) to afford the title compound (1.1 g, 84%).
(292) m.p: 145-147° C.
(293) .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 2.07 (s, 3H, OAc), 2.19 (s, 3H, OAc), 2.31 (s, 3H, CH.sub.3), 6.80 (s, 1H, ArH), 7.08 (d, J=8.1 Hz, 1H, ArH), 7.57 (d, J=8.1 Hz, 1H, ArH), 7.86-8.02 (m, 4H, ArH). MS(EI): 352.
(294) The title compound was obtained in a similar manner as described in EXAMPLE 24.
(295) .sup.1H-NMR (200 MHz, CDCl.sub.3): δ 8.86 (d, J=8.5 Hz, 1H), 8.75 (m, 1H), 8.35 (s, 1H), 8.05-7.88 (m, 3H), 7.75-7.55 (m, 3H), 7.36 (d, J=9.1 Hz, 1H), 6.87 (s, 1H).
(296) A solution of 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one (0.20 g, 0.67 mmol) in anhydrous methylene chloride(10 ml) was added triethylamine (0.20 g, 2.01 mmol) and butyryl chloride (0.18 g, 1.69 mmol) at room temperature and then stirred for 3 hrs. The reaction mixture was diluted in ethylacetate, and washed with water several time. The organic layer was dried, filtered, and purified using silica gel column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (230 mg, 79%).
(297) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.95 (t, J=7.5 Hz, 3H, CH.sub.3) 1.08 (t, J=7.5 Hz, 3H, CH.sub.3) 1.18 (d, J=6.9 Hz, 6H, CH.sub.3) 1.57-1.67 (m, 2H, CH.sub.2) 1.78-1.86 (m, 2H, CH.sub.2) 2.23 (t, J=7.5 Hz, 2H, CH.sub.2) 2.64 (t, J=7.5 Hz, 2H, CH.sub.2) 2.82-2.86 (m, 1H, CH) 6.61 (s, 1H, NH) 6.85 (d, J=1.5 Hz, 1H, ArH) 7.06 (dd, J=1.5, 8.1 Hz, 1H, ArH) 7.33 (d, J=8.1 Hz, 1H, ArH) 7.80-7.85 (m, 2H, ArH) 7.94-7.98 (m, 2H, ArH).
(298) A solution of 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one (0.20 g, 0.67 mmol) in anhydrous methylene chloride(10 ml) was added triethylamine (0.20 g, 2.01 mmol) and octanoyl chloride (0.27 g, 1.67 mmol) and then stirred for 28 hrs. The reaction mixture was concentrated and extracted with ethylacetate. The concentrated organic layer was purified using silica gel column chromatography (ethylacetate:hexane=1:6 to 1:4) to afford the title compound as a syrup (55 mg, 15%).
(299) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.88 (t, J=7.5 Hz, 3H, CH.sub.3) 1.18 (d, J=6.9 Hz, 6H, CH.sub.3) 1.26-1.45 (m, 12H, CH.sub.2) 1.54-1.65 (m, 4H, CH.sub.2) 1.73-1.83 (m, 2H, CH.sub.2) 2.24 (t, J=7.8 Hz, 2H, CH.sub.2) 2.34 (t, J=7.5 Hz, 2H, CH.sub.2) 2.65 (t, J=7.5 Hz, 2H, CH.sub.2) 2.80-2.89 (m, 1H, CH) 6.61 (s, 1H, NH) 6.85 (d, J=1.5 Hz, 1H, ArH) 7.06 (dd, J=1.8, 8.4 Hz, 1H, ArH) 7.33 (d, J=8.4 Hz, 1H, ArH) 7.79-7.84 (m, 2H, ArH) 7.94-7.99 (m, 2H, ArH).
(300) A solution of 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one (0.20 g, 0.67 mmol) in anhydrous methylene chloride(10 ml) was added triethylamine (0.20 g, 2.01 mmol) and hexanoyl chloride(0.22 g, 1.69 mmol) and then stirred for 5 hrs. The reaction mixture was concentrated and extracted with ethylacetate. The concentrated organic layer was purified using silica gel column chromatography (ethylacetate:hexane=1:6 to 1:4) to afford the title compound as a syrup (0.14 g, 46%).
(301) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.88 (t, J=6.9 Hz, 3H, CH.sub.3) 0.95 (t, J=6.9 Hz, 3H, CH.sub.3) 1.18 (d, J=6.9 Hz, 6H, CH.sub.3) 1.25-1.37 (m, 6H, CH.sub.2) 1.40-1.47 (m, 2H, CH.sub.2) 1.55-1.65 (m, 2H, CH.sub.2) 1.74-1.84 (m, 2H, CH.sub.2) 2.24 (t, J=7.5 Hz, 2H, CH.sub.2) 2.65 (t, J=7.5 Hz, 2H, CH.sub.2) 280-2.89 (m, 1H, CH) 6.60 (s, 1H, NH) 6.85 (d, J=1.8 Hz, 1H, ArH) 7.05 (dd, J=1.8, 8.1 Hz, 1H, ArH) 7.33 (d, J=8.4 Hz, 1H, ArH) 7.80-7.84 (m, 2H, ArH) 7.93-7.98 (m, 2H, ArH).
(302) A solution of 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one (0.20 g, 0.67 mmol) in anhydrous methylene chloride(10 ml) was added triethylamine (0.20 g, 2.01 mmol) and heptanoyl chloride(0.25 g, 1.69 mmol) and then stirred for 3 hrs. The reaction mixture was concentrated and extracted with ethylacetate. The concentrated organic layer was purified using silica gel column chromatography (ethylacetate:hexane=1:6 to 1:4) to afford the title compound as a syrup (0.21 g, 60%).
(303) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.85-0.94 (m, 6H, CH.sub.3) 1.18 (d, J=7.2 Hz, 6H, CH.sub.3) 1.25-1.37 (m, 10H, CH.sub.2) 1.54-1.63 (m, 4H, CH.sub.2) 1.73-1.80 (m, 2H, CH.sub.2) 2.24 (t, J=7.5 Hz, 2H, CH.sub.2) 2.65 (t, J=7.5 Hz, 2H, CH.sub.2) 2.82-2.86 (m, 1H, CH) 6.60 (s, 1H, NH) 6.85 (d, J=1.5 Hz, 1H, ArH) 7.05 (dd, J=1.5, 8.4 Hz, 1H, ArH) 7.33 (d, J=8.1 Hz, 1H, ArH) 7.80-7.83 (m, 2H, ArH) 7.95-7.98 (m, 2H, ArH).
(304) A solution of pentanoic acid [2-(2-hydroxy-4-isopropyl-phenyl)-1,3-dioxo-indan-2-yl]-amide (0.10 g, 0.26 mmol) in anhydrous methylene chloride(10 ml) was added triethylamine (0.03 g, 0.31 mmol) and pivaloyl chloride(0.047 g, 0.39 mmol) and then stirred for 2 hrs. The reaction mixture was concentrated and extracted with ethylacetate. The concentrated organic layer was purified using silica gel column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.11 g, 91%).
(305) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.88 (t, J=7.2 Hz, 3H, CH.sub.3) 1.17 (d, J=6.9 Hz, 6H, CH.sub.3) 1.44-1.25 (m, 2H, CH.sub.2) 1.50 (s, 9H, CH.sub.3) 1.53-1.61 (m, 2H, CH.sub.2) 2.23 (t, J=7.2 Hz, 2H, ArH) 2.78-2.88 (m, 1H, CH) 6.77-6.79 (m, 2H, NH, ArH) 6.97 (d, J=1.2, 8.1 Hz, 1H, ArH) 7.08 (d, J=1.2, 8.1 Hz, 1H, ArH) 7.79-7.82 (m, 2H, ArH) 7.95-7.98 (m, 2H, ArH).
(306) Iron powder (0.03 g, 0.6 mmol), conc. HCl (0.05 ml), and water (0.5 ml) were added in that order to a solution of 5-isopropyl-2-(4-nitro-1,3-dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl) phenyl pentanoate (43 mg, 0.08 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 hrs under reflux. The reaction mixture was hot filtered off, the filtrate was concentrated in a vacuum and purified by column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (22 mg, 55%).
(307) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.90 (t, J=7.2 Hz, 3H, CH.sub.3) 0.98 (t, J=7.2 Hz, 3H, CH.sub.3) 1.16-1.61 (m, 12H, CH.sub.2, CH.sub.3) 1.73 (t, J=7.5 Hz, 2H, CH.sub.2) 2.25 (t, J=7.5 Hz, 2H, CH.sub.2) 2.63 (t, J=8.1 Hz, 2H, CH.sub.2) 2.80-2.89 (m, 1H, CH) 5.69 (s, 2H, NH.sub.2) 6.62 (s, 1H, NH) 6.77 (d, J=8.1 Hz, 1H, ArH) 6.85 (s, 1H, ArH) 7.05 (d, J=6.9 Hz, 1H, ArH) 7.13 (d, J=6.9 Hz, 1H, ArH) 7.30 (d, J=8.1 Hz, 1H, ArH) 7.40 (t, J=7.8 Hz, 1H, ArH).
(308) Iron powder (0.03 g, 0.5 mmol), conc. HCl (0.05 ml), and water (0.5 ml) were added in that order to a solution of 2-(2-hexanamido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl hexanoate (40 mg, 0.07 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 hrs under reflux. The reaction mixture was hot filtered off, the filtrate was concentrated in a vacuum and purified by column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (21 mg, 57%).
(309) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.79-0.96 (m, 6H, CH.sub.3) 1.18 (dd, J=6.9 Hz, 6H, CH.sub.3) 1.22-1.32 (m, 6H, CH.sub.3) 1.36-1.41 (m, 2H, CH.sub.2) 1.47-1.63 (m, 3H, CH.sub.2) 1.73-1.82 (m, 1H, CH.sub.2) 2.24 (t, J=7.5 Hz, 2H, CH.sub.2) 2.65 (t, J=7.8 Hz, 2H, CH.sub.2) 2.80-2.89 (m, 1H, CH) 5.66 (s, 2H, NH2) 6.59 (s, 1H, NH) 6.80 (d, J=8.1 Hz, 1H, ArH) 6.86 (d, J=1.8 Hz, 1H, ArH) 7.05 (dd, J=1.8, 8.1 Hz, 1H, ArH) 7.15 (d, J=7.2 Hz, 1H, ArH) 7.30 (d, J=8.4 Hz, 1H, ArH) 7.44 (d, J=7.8 Hz, 1H, ArH).
(310) Iron powder (0.03 g, 0.5 mmol), conc. HCl (0.05 ml), and water (0.5 ml) were added in that order to a solution of 2-(2-heptanamido-4nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl heptanoate (60 mg, 0.10 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 hrs under reflux. The reaction mixture was hot filtered off, the filtrate was concentrated in a vacuum and purified by column chromatography (ethylacetate:hexane=1:6 to 1:4) to afford the title compound (20 mg, 36%).
(311) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.79-0.97 (m, 6H, CH.sub.3) 1.18 (dd, J=6.9 Hz, 6H, CH.sub.3) 1.25-1.49 (m, 12H, CH.sub.2) 1.58 (t, J=7.2 Hz, 2H, CH.sub.2) 1.82 (t, J=7.2 Hz, 2H, CH.sub.2) 2.22 (t, J=7.5 Hz, 2H, CH.sub.2) 2.65 (t, J=7.5 Hz, 2H, CH.sub.2) 2.80-2.89 (m, 1H, CH) 5.66 (s, 2H, NH.sub.2) 6.59 (s, 1H, NH) 6.79 (d, J=8.1 Hz, 1H, ArH) 6.85 (d, J=1.5 Hz, 1H, ArH) 7.05 (dd, J=1.8, 8.4 Hz, 1H, ArH) 7.15 (d, J=7.2 Hz, 1H, ArH) 7.29 (d, J=8.1 Hz, 1H, ArH) 7.42 (t, J=8.1 Hz, 1H, ArH).
(312) Iron powder (0.03 g, 0.5 mmol), conc. HCl (0.05 ml), and water (0.5 ml) were added in that order to a solution of 5-isopropyl-2-(4-nitro-1,3-dioxo-2-propionamido-2,3-dihydro-1H-inden-2-yl)phenyl propionate (40 mg, 0.08 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 hrs under reflux. The reaction mixture was hot filtered off, the filtrate was concentrated in a vacuum and purified by column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (28 mg, 75%).
(313) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.18 (dd, J=6.9 Hz, 6H, CH.sub.3) 1.27 (dd, J=3.3, 7.5 Hz, 6H, CH.sub.3) 2.29 (q, J=7.5 Hz, 2H, CH.sub.2) 2.70 (q, J=7.5 Hz, 2H, CH.sub.2) 2.80-2.89 (m, 1H, CH) 5.67 (s, 2H, NH.sub.2) 6.60 (s, 1H, NH) 6.80 (d, J=8.1 Hz, 1H, ArH) 6.87 (d, J=1.5 Hz, 1H, ArH) 7.06 (dd, J=1.5, 6.9 Hz, 1H, ArH) 7.16 (d, J=7.2 Hz, 1H, ArH) 7.32 (t, J=8.1 Hz, 1H, ArH) 7.43 (t, J=7.5 Hz, 1H, ArH).
(314) Iron powder (0.07 g, 1.3 mmol), conc. HCl (0.05 ml), and water (1 ml) were added in that order to a solution of 2-(2-butyramido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyrate (90 mg, 0.18 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 hrs under reflux. After filtration at high temperature, the filtrate was concentrated in a vacuum and purified using column chromatography(ethylacetate:hexane=1:4 to 1:2) to afford the title compound (70 mg, 83%).
(315) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.95 (t, J=7.5 Hz, 3H, CH.sub.3) 1.07 (t, J=7.5 Hz, 3H, CH.sub.3) 1.18 (d, J=6.9 Hz, 6H, CH.sub.3) 1.64 (q, J=7.5, 14.7 Hz, 2H, CH.sub.2) 1.80 (q, J=7.5, 14.7 Hz, 2H, CH.sub.2) 2.23 (t, J=7.5 Hz, 2H, CH.sub.2) 2.64 (t, J=7.5 Hz, 2H, CH.sub.2) 2.80-2.89 (m, 1H, CH) 5.70 (s, 2H, NH.sub.2) 6.62 (s, 1H, NH) 6.74 (d, J=8.4 Hz, 1H, ArH) 6.86 (d, J=1.5 Hz, 1H, ArH) 7.05 (dd, J=1.5, 8.4 Hz, 1H, ArH) 7.12 (d, J=7.2 Hz, 1H, ArH) 7.28 (t, J=7.5 Hz, 1H, ArH) 7.38 (t, J=7.5 Hz, 1H, ArH).
(316) N-(3,4-dimethylphenyl)acetamide (915 mg, 5.62 mmol) and ninhydrin (1.00 g, 5.62 mmol) were dissolved in conc. sulfuric acid (20 mL) and stirred at room temperature for 1.5 hrs. The reaction was stopped by slowing pouring the solution to 150 g of ice and stirring. The reaction mixture was extracted with ethylacetate and water, washed with brine. The washed organic layer was dried over sodium sulfate, concentrated in a vacuum, and purified through column chromatography (30% ethylacetate in hexane) to afford the title compound (yellow solid, 800 mg, 44%).
(317) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 2.02 (s, 3H, NAc) 2.20 (s, 3H, CH.sub.3) 2.22 (s, 3H, CH.sub.3) 6.11 (s, 1H, ArH) 7.03 (s, 1H, ArH) 7.99-8.02 (m, 2H, ArH) 8.13-8.16 (m, 2H, ArH).
(318) N-(3,4-dimethylphenyl)propion amide (500 mg, 2.82 mmol) and ninhydrin (500 mg, 2.82 mmol) were dissolved in conc. sulfuric acid (10 mL) and stirred at room temperature for 1.5 hrs. The reaction was stopped by slowing pouring the solution to 150 g of ice and stirring. The reaction mixture was extracted with ethylacetate and water, washed with brine. The washed organic layer was dried over sodium sulfate, concentrated in a vacuum, and purified through silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (yellow solid, 430 mg, 45%).
(319) .sup.1H-NMR (300 MHz, DMSO) δ 1.26 (t, J=7.5 Hz, 3H, CH.sub.3) 2.14 (s, 6H, CH.sub.3) 3.06-3.58 (m, 2H, CH.sub.2) 6.84 (s, 1H, ArH/OH) 7.16 (s, 1H, ArH/OH) 7.48 (s, 1H, ArH/OH) 7.56-7.61 (m, 1H, ArH) 7.70 (d, J=7.8 Hz, 1H, ArH) 7.80-7.86 (m, 2H, ArH) 7.95-8.01 (m, 1H, ArH).
(320) N-(3-ethylphenyl)acetamide (500 mg, 3.06 mmol) and ninhydrin (546 mg, 3.06 mmol) were dissolved in conc. sulfuric acid (10 mL) and stirred at room temperature for 3 hrs. The reaction was stopped by slowing pouring the solution to 150 g of ice and stirring. The reaction mixture was extracted with ethylacetate and water, washed with brine. The washed organic layer was dried over sodium sulfate, concentrated in a vacuum, and purified through silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (90 mg, 9%).
(321) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.17 (t, J=7.5 Hz, 3H, CH.sub.3) 2.45 (s, 3H, NAc) 2.57 (q, J=7.5 Hz, 2H, CH.sub.2) 6.30 (d, J=7.5 Hz, 1H, ArH) 6.81 (dd, J=7.5 Hz, J=1.5 Hz, 1H, ArH) 7.09 (d, J=1.5 Hz, 1H, ArH) 7.98-8.03 (m, 2H, ArH) 8.11-8.15 (m, 2H, ArH).
(322) N-(3,4-dimethylphenyl)butyramide (1.00 mg, 5.61 mmol) and ninhydrin (1.07 mg, 5.61 mmol) were dissolved in conc. sulfuric acid (15 mL) and stirred at room temperature for 5 hrs. The reaction was stopped by slowing pouring the solution to 150 g of ice and stirring. The reaction mixture was extracted with ethylacetate and water, washed with brine. The washed organic layer was dried over sodium sulfate, concentrated in a vacuum, and purified through silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (yellow solid, 1.10 g, 56%).
(323) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.028 (t, J=7.5 Hz, 3H, CH.sub.3) 1.69-1.79 (m, 2H, CH.sub.2) 2.01 (s, 3H, CH.sub.3) 2.17 (s, 3H, CH.sub.3) 2.43 (t, J=7.5 Hz, 2H, CH.sub.2) 6.11 (s, 1H, ArH) 7.05 (s, 1H, ArH) 7.99-8.03 (m, 2H, ArH) 8.11-8.16 (m, 2H, ArH).
(324) N-(3,4-dimethylphenyl)isobutyramide (1.00 mg, 5.61 mmol) and ninhydrin (1.07 mg, 5.61 mmol) were dissolved in conc. sulfuric acid (15 mL) and stirred at room temperature for 5 hrs. The reaction was stopped by slowing pouring the solution to 200 g of ice and stirring. The reaction mixture was extracted with ethylacetate and water, washed with brine. The washed organic layer was dried over sodium sulfate, concentrated in a vacuum, and purified through silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (yellow solid, 1.85 g, 94%).
(325) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.26 (d, J=6.9 Hz, 6H, CH.sub.3) 2.01 (s, 3H, CH.sub.3) 2.18 (s, 3H, CH.sub.3) 2.68 (sept, J=6.9 Hz, 1H, CH) 6.11 (s, 1H, ArH) 7.08 (s, 1H, ArH) 7.99-8.03 (m, 2H, ArH) 8.11-8.16 (m, 2H, ArH).
(326) Iron powder (58 mg, 1.03 mmol) and conc. HCl (3 drops) were added in that order to a solution of 5-isopropyl-2-(4-nitro-2-octanamino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)phenyl octanoate (80 mg, 0.14 mmol) in ethanol:water (9:1, 7 ml). The reaction mixture was heated for 3 hrs under reflux. After filtration at high temperature, the filtrate was concentrated in a vacuum and purified using silica gel column chromatography(20% ethylacetate in hexane, 1% triethylamine) to afford the title compound (45 mg, 59%).
(327) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.84-0.88 (m, 6H, CH.sub.3) 1.16-1.28 (m, 16H+6H, CH.sub.2+CH.sub.3) 1.51-1.64 (m, 4H, CH.sub.2) 2.10-2.46 (m, 4H, CH.sub.2) 2.85 (sept, J=6.9 Hz, 1H, CH) 4.40 (br, 2H, NH.sub.2) 5.98 (s, 1H, ArH/NH) 6.72 (s, 1H, ArH/NH) 6.89-6.96 (m, 2H, ArH) 7.22-7.34 (m, 2H, ArH) 7.40-7.43 (m, 1H, ArH).
(328) Triethylamine (0.24 ml, 1.77 mmol) and methylchloroformate (0.11 ml, 1.48 mmol) were added to N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-9b-yl)acetamide (0.50 g, 1.48 mmol) in THF (5 ml). The reaction mixture was stirred at room temperature for 12 hrs, concentrated in a vacuum to remove solvent. The reaction mixture was extracted with water and methylene chloride, and purified through silica gel column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.10 g, 14%).
(329) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.17 (d, J=6.8 Hz, 6H), 1.89 (s, 3H), 2.84 (q, J=7.8 Hz, 1H), 3.89 (s, 3H), 6.90 (s, 1H), 7.01 (s, 1H), 7.10 (d, J=7.7 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.77-7.83 (m, 2H), 7.92-7.96 (m, 2H).
(330) Triethylamine (0.24 ml, 1.77 mmol) and Valeroyl chloride (0.18 ml, 1.48 mmol) were added to N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-9b-yl)acetamide (0.50 g, 1.48 mmol) in THF (10 ml). The reaction mixture was stirred at room temperature for 12 hrs, concentrated in a vacuum to remove solvent. The reaction mixture was extracted with water and methylene chloride, and purified through silica gel column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.20 g, 32%).
(331) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.99 (t, J=8.9 Hz, 3H), 1.17 (d, J=7.0 Hz, 6H), 1.44-1.52 (m, 2H), 1.75 (q, J=8.3 Hz, 2H), 2.62 (t, J=8.9 Hz, 2H), 2.83 (q, J=7.7 Hz, 1H), 6.81-6.87 (m, 2H), 7.06 (dd, J=1.3 Hz, 8.3 Hz, 1H), 7.38 (d, J=7.7 Hz, 1H), 7.79-7.85 (m, 2H), 7.92-7.98 (m, 2H).
(332) N-(2,2-dihydroxy-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (0.20 g, 0.71 mmol) and N-(3,4-dimethylphenyl)isobutyramide (136 mg, 0.71 mmol) were dissolved in conc. sulfuric acid (5 mL) and stirred at room temperature for 3 hrs. The reaction mixture was extracted with ethylacetate and ice-water, washed with brine. The washed organic layer dried over sodium sulfate, concentrated in a vacuum, and purified through silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (30 mg, 10%).
(333) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.27 (d, J=6.9 Hz, 6H, CH.sub.3) 2.08 (s, 3H, NAc) 2.19 (s, 6H, CH.sub.3) 2.69 (sept, J=6.9 Hz, 1H, CH) 6.30 (s, 1H, ArH), 7.02 (d, J=9 Hz, 1H, ArH) 7.08 (s, 1H, ArH) 8.22 (d, J=9 Hz, 1H, ArH).
(334) Ninhydrin (0.5 g, 2.80 mmol) and N-(4-isopropylphenyl)acetamide (575 mg, 2.80 mmol) were dissolved in conc. sulfuric acid (5-6 mL) and stirred at room temperature for 15 hrs. The reaction mixture was extracted with ethylacetate and ice-water, washed with brine. The washed organic layer was dried over sodium sulfate, concentrated in a vacuum, and purified through silica gel column chromatography (20% ethylacetate in hexane) to afford the title compound (320 mg, 31%).
(335) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.19 (d, J=6.9 Hz, 6H, CH.sub.3) 1.29 (d, J=6.9 Hz, 6H, CH.sub.3) 2.71 (sept, J=6.9 Hz, 1H, CH) 2.81 (sept, J=6.9 Hz, 1H, CH) 6.31 (d, J=7.8 Hz, 1H, ArH) 6.83 (dd, J=1.5 Hz, J=7.8 Hz, 1H, ArH) 7.17 (d, J=1.5 Hz, 1H, ArH) 7.98-8.02 (m, 2H, ArH) 8.11-8.15 (m, 2H, ArH).
(336) 9b-acetamido-7-isopropyl-1-nitro-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-4b-yl butylcarbonate (0.11 g, 0.22 mmol) was completely dissolved in anhydrous ethanol (5 ml). This solution was added with iron (0.09 g, 1.66 mmol), conc. HCl (0.05 ml) and water (0.5 ml). The reaction mixture was heated for 1.5 hrs under reflux. After filtration at high temperature to remove iron, the filtrate was concentrated in a vacuum and purified using column chromatography(ethylacetate:hexane=1:2) to afford the title compound (50 mg, 50%).
(337) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.91 (t, J=7.2 Hz, 3H, CH.sub.3) 1.22 (dd, J=7.2 Hz, 16.8 Hz, 6H, CH.sub.3) 1.33-1.44 (m, 2H, CH.sub.2) 1.59-1.73 (m, 2H, CH.sub.2) 1.95 (s, 3H, CH.sub.3) 2.04-2.90 (m, 1H, CH) 4.07-4.46 (m, 2H, OCH.sub.2) 5.59 (s, 1H, NH) 6.10 (s, 1H, ArH) 6.60 (d, J=8.1 Hz, 1H, ArH) 6.75 (s, 1H, ArH) 6.91 (dd, J=1.5, 7.8 Hz, 1H, ArH) 7.12 (d, J=7.2 Hz, 1H, ArH) 7.39-7.48 (m, 1H, ArH).
(338) 9b-chloro-4b-hydroxy-7-isopropyl-1-nitro-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (0.50 g, 1.48 mmol) was dissolved in anhydrous THF (15 ml). This solution was added with methyl isocyanate (0.12 g, 2.22 mmol), trimethylamine (0.18 g, 1.77 mmol). The reaction mixture was heated for 5 hrs under reflux. After concentrating in a vacuum to remove THF, and the remainder was diluted with methylene chloride and washed with water many times. After drying and filtrating, the organic layer was purified using column chromatography(ethylacetate:hexane=1:2) to afford the title compound (0.25 g, 44%).
(339) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.17 (d, J=6.9 Hz, 6H, CH.sub.3) 2.01 (s, 3H, CH.sub.3) 2.79-2.91 (m, 4H, CH, CH.sub.3) 5.22 (s, 1H, NH) 6.86 (s, 1H, NH) 6.95 (s, 1H, ArH) 7.04 (d, J=7.8 Hz, 1H, ArH) 7.32 (d, J=8.4 Hz, 1H, ArH) 7.80-7.83 (m, 2H, ArH) 7.94-7.97 (m, 2H, ArH).
(340) N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-5-oxa-indeno[2,1-a]inden-9b-yl)-acetamide (0.50 g, 1.48 mmol) was dissolved in anhydrous THF (15 ml). This solution was added with Dimethyl-carbamylchrolide (0.23 g, 2.22 mmol), Trimethylamine (0.17 g, 1.77 mmol). The reaction mixture was heated for 24 hrs under reflux. After concentrating in a vacuum to remove THF, and the remainder was diluted with Ethylacetate and washed with Bicarbonate sodium aqueous solution many times. After drying and filtrating, the organic layer was purified using column chromatography(ethylacetate:hexane=1:1) to afford the title compound (0.26 g, 43%).
(341) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.17 (d, J=6.9 Hz, 6H, CH.sub.3) 1.98 (s, 3H, CH.sub.3) 2.80-2.88 (sept, 1H, CH) 3.04 (s, 3H, CH.sub.3) 3.23 (s, 3H, CH.sub.3) 6.88 (s, 1H, ArH) 7.01 (d, J=8.1 Hz, 1H, ArH) 7.16 (s, 1H, ArH) 7.23 (d, J=8.4 Hz, 1H, ArH) 7.79-7.82 (m, 2H, ArH) 7.94-7.97 (m, 2H, ArH).
(342) N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-5-oxa-indeno[2,1-a]inden-9b-yl)-acetamide (0.50 g, 1.48 mmol) was dissolved in anhydrous THF (15 ml). This solution was added with Phenyl chroloformate (0.35 g, 2.22 mmol), Trimethylamine (0.18 g, 1.77 mmol). The reaction mixture was heated for 24 hrs under reflux. After concentrating in a vacuum to remove THF, and the remainder was diluted with Ethylacetate and washed with Bicarbonate sodium aqueous solution many times. After drying and filtrating, the organic layer was purified using column chromatography(ethylacetate:hexane=1:1) to afford the title compound (0.18 g, 26%).
(343) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.19 (d, J=6.9 Hz, 6H, CH.sub.3) 2.04 (s, 3H, CH.sub.3) 2.82-2.91 (sept, 1H, CH) 6.67 (s, 1H, NH) 7.03 (s, 1H, ArH) 7.15 (d, J=8.4 Hz, 1H, ArH) 7.30-7.34 (m, 1H, ArH) 7.45-7.47 (m, 5H, ArH) 7.81-7.84 (m, 2H, ArH) 8.00-8.02 (m, 2H, ArH).
(344) 2-(2-acetamido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl dimethylcarbamate (0.20 g, 0.4 mmol) was dissolved in anhydrous ethanol (10 ml) and water (1 ml). This solution was added with iron (0.18 g, 3.2 mmol) and conc. HCl (0.03 ml). The reaction mixture was heated for 2 hrs under reflux. After filtrating and washing with MeOH, the remainder was concentrated in a vacuum and purified using column chromatography(ethylacetate:hexane=1:2) to afford the title compound (90 mg, 50%).
(345) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.18 (d, J=6.9 Hz, 6H, CH.sub.3) 1.98 (s, 3H, CH.sub.3) 2.97 (s, 3H, CH.sub.3) 2.79-2.89 (m, 1H, CH) 3.05 (s, 3H, CH.sub.3) 3.23 (s, 3H, CH.sub.3) 5.67 (s, 2H, NH.sub.2) 6.81 (d, J=8.1 Hz, 1H, ArH) 6.85 (s, 1H, NH) 7.01 (d, J=8.4 Hz, 1H, ArH) 7.08 (s, 1H, ArH) 7.13-7.21 (m, 2H, ArH) 7.44 (t, J=8.1 Hz, 1H, ArH).
(346) 9b-chrolo-4b-hydroxy-7-isopropyl-1-nitro-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (0.70 g, 2.07 mmol) was dissolved in anhydrous THF (15 ml). This solution was added with Ethyl chroloformate (0.32 g, 3.11 mmol) and Trimethylamine (0.25 g, 2.48 mmol). The reaction mixture was stirred for 4 hrs. After concentrating in a vacuum to remove THF, and the remainder was diluted with Methylene chloride and washed with water many times. After drying and filtrating, the organic layer was purified using column chromatography(ethylacetate:hexane=1:4) to afford the title compound (30 mg, 3.6%).
(347) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.16-1.28 (m, 9H, CH.sub.3) 2.33 (s, 3H, CH.sub.3) 2.79-2.88 (m, 1H, CH) 4.02-4.15 (m, 2H, OCH.sub.2) 5.90 (s, 1H, NH) 6.68 (s, 1H, ArH) 7.07 (dd, J=1.5, 8.3 Hz, 1H, ArH) 7.42 (d, J=8.3 Hz, 1H, ArH) 7.81-7.90 (m, 2H, ArH) 7.96-8.02 (m, 2H, ArH).
(348) 9b-chrolo-4b-hydroxy-7-isopropyl-1-nitro-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (0.70 g, 2.07 mmol) was dissolved in anhydrous THF (15 ml). This solution was added with Ethyl chroloformate (0.32 g, 3.11 mmol) and Trimethylamine (0.25 g, 2.48 mmol). The reaction mixture was stirred for 4 hrs. After concentrating in a vacuum to remove THF, and the remainder was diluted with Methylene chloride and washed with water many times. After drying and filtrating, the organic layer was purified using column chromatography(ethylacetate:hexane=1:4) to afford the title compound (0.64 g, 71%).
(349) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.18 (d, J=6.9 Hz, 6H, CH.sub.3) 1.46 (t, J=7.1 Hz, 3H, CH.sub.3) 2.03 (s, 3H, CH.sub.3) 2.83-2.88 (m, 1H, CH) 4.31-4.38 (q, J=7.1 Hz, 2H, OCH.sub.2) 6.67 (s, 1H, NH) 6.92 (s, 1H, ArH) 7.12 (dd, J=1.2, 8.2 Hz, 1H, ArH) 7.43 (d, J=8.2 Hz, 1H, ArH) 7.81-7.84 (m, 2H, ArH) 7.96-7.99 (m, 2H, ArH).
(350) 2-(2-acetamido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl ethylcarbamate (0.27 g, 0.59 mmol) was dissolved in Ethanol (10 ml) and water (1 ml). This solution was added with iron (0.24 g, 4.3 mmol) and conc. HCl (0.03 ml). The reaction mixture was heated for 2 hrs under reflux. After filtrating and washing with MeOH, the remainder was concentrated in a vacuum and purified using column chromatography(ethylacetate:hexane=1:1) to afford the title compound (90 mg, 36%).
(351) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.11-1.92 (d, J=6.9 Hz, 6H, CH.sub.3) 1.95 (s, 3H, CH.sub.3) 2.79-2.88 (m, 1H, CH) 3.10-3.26 (m, 2H, CH.sub.3) 5.24 (s, 1H, NCH) 5.56 (s, 2H, NH.sub.2) 6.21 (s, 1H, NH) 6.60 (d, J=8.4 Hz, 1H, ArH) 6.71 (s, 1H, ArH) 6.88 (d, J=7.8 Hz, 1H, ArH) 7.06 (d, J=7.5 Hz, 1H, ArH) 7.42 (t, J=7.8 Hz, 2H, ArH).
(352) Sodium (1.1 g) was dissolved in anhydrous Ethanol (90 ml). This solution was added with Phthalide (4.43 g, 33.04 mmol) and m-Methoxy benzaldehyde (3.00 g, 22.03 mmol). The reaction mixture was heated for 3 hrs under reflux. The reaction mixture was concentrated in a vacuum. White solid was obtained by adding conc. HCl. And then the white solid was recrystallized in ethylacetate:hexane (=1:2) to afford the title compound (2.45 g, 44%).
(353) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 3.78 (s, 3H, OCH.sub.3) 6.73-6.76 (m, 2H, ArH) 6.85 (d, J=7.2 Hz, 1H, ArH) 7.26 (t, J=7.8 Hz, 1H, ArH) 7.89-7.93 (m, 2H, ArH) 8.06-8.09 (m, 2H, ArH).
(354) 4b,9b-dihydroxy-7-isopropyl-4bH-benzofuro[2′,3′:3,4]cyclopenta[1,2-b]pyridin-10(9bH)-one (0.50 g, 1.68 mmol) was dissolved in THF (10 ml) and Et.sub.3N (0.70 ml, 5.04 mmol). This solution was added with Ethyl chroloformate (0.40 ml, 4.20 mmol). The reaction mixture was stirred for 2 hrs. After concentrating in a vacuum, and the remainder was purified using column chromatography(ethylacetate:hexane=1:2) to afford the title compound (0.20 g, 27%).
(355) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.19 (d, J=6.8 Hz, 6H), 1.28 (t, J=7.2 Hz, 3H), 1.32 (t, J=7.6 Hz, 3H), 2.87 (q, J=7.1 Hz, 1H), 4.10-4.18 (m, 4H), 6.92 (s, 1H), 6.20 (dd, J=1.1 Hz, 8.4 Hz, 1H), 7.73-7.79 (m, 2H), 8.33 (d, J=7.9 Hz, 1H), 9.16 (d, J=4.7 Hz, 1H).
(356) Ninhydrin (1.00 g, 5.6 mmol) was dissolved in conc. H.sub.2SO.sub.4(10 ml). This solution was added with N-(3,4-dimethoxyphenyl)isobutyramide (1.25 g, 5.62 mmol) at 0° C. and stirred for 30 min under room temperature. Ice water was added with the reaction mixture, and then washed with ice water and ethylacetate. After drying and filtrating, the ethylacetate layer was purified using column chromatography(ethylacetate:hexane=1:4) to afford the title compound (1.37 g, 63%).
(357) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.28 (d, J=6.9 Hz, 6H, CH.sub.3) 2.63-2.72 (m, 1H, CH) 3.56 (s, 3H, OCH.sub.3) 3.86 (s, 3H, OCH.sub.3) 5.84 (s, 1H, ArH) 6.87 (s, 1H, ArH) 7.99-8.04 (m, 2H, ArH) 8.13-8.18 (m, 2H, ArH).
(358) N-[2-(2-hydroxy-4-nitro-1,3-dioxo-indan-2-yl)-4,5-dimethoxy-phenyl]-isobutyramide (150 mg, 0.35 mmol) was dissolved in ethanol (3 ml) and water (0.3 ml). This solution was added with iron (Fe) (0.14 g, 2.55 mmol) and conc. HCl (0.03 ml), followed by heating for 3 hrs under reflux. The reaction mixture was filtrated with MeOH washing via celite pad, and the filtrate was concentrated in a vacuum. The concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (17 mg, 12%).
(359) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 0.77 (d, J=6.9 Hz, 3H, CH.sub.3) 1.19 (d, J=6.9 Hz, 3H, CH.sub.3) 2.01-2.10 (m, 1H, CH), 3.91 (s, 3H, OMe) 4.07 (s, 3H, OMe) 5.36 (s, 2H, NH.sub.2) 6.49 (d, J=7.2 Hz, 1H, ArH) 6.74 (d, J=8.1 Hz, 1H, ArH) 7.15 (s, 1H, ArH) 7.37 (t, J=7.5 Hz, 1H, ArH) 8.35 (s, 1H, ArH).
(360) 5,6-dimethoxy-indan-1-one (3.0 g, 15.6 mmol) was dissolved in anhydrous dioxane (30 ml). This solution was added with SeO2 (3.80 g, 34.3 mmol) and acetic acid (3 ml), followed by heating for 5 hrs under reflux. The reaction mixture was filtrated with MeOH washing via celite pad, and the filtrate was concentrated in a vacuum to remove solvent. The remainder (2.13 g, 8.95 mmol) was dissolved in conc. H2SO4(20 ml), and added with isobutyramide (3.50 g, 15.6 mmol), followed by stirring for 2 hrs under room temperature. After stirring, the reaction mixture was washed with ethylacetate and water in several times. The obtained organic layer was dried, filtrated and concentrated in a vacuum. The concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (218 mg, 3%).
(361) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 1.36 (d, J=6.6 Hz, 6H, CH.sub.3) 2.67-2.76 (m, 1H, CH) 3.63 (s, 3H, OMe) 3.85 (s, 3H, OMe) 4.06 (s, 6H, OMe) 6.24 (s, 1H, ArH) 7.15 (s, 1H, ArH) 7.99 (s, 1H, ArH) 9.70 (s, 1H, ArH).
(362) In Table 1, chemical formulas of compounds of examples 1 to 108 are shown.
(363) TABLE-US-00001 TABLE 1 Ex. Chemical structure 1
(364) In the assay, HeLa (human cervical cancer cells), MRC-5 (human fetal lung fibroblast cells), and RD cells (derived from human rhabdomyosarcoma) were employed. For comparison, ribavirin (Riv), pleconaril (pleco), and BTA-798 (BTA) were used as controls. Reagents were dissolved at a concentration of 10˜40 mg/ml in 100% dimethylsulfoxide (DMSO). Water-soluble reagents were dissolved in PBS (−) solution and stored at −20° C. On the day of the experiment, they were used in 3× to 5× concentrations in such a manner that the concentration of dimethylsulfoxide in each well was between 0.5% and 1.
(365) Pharmaceutical effects were determined using a virus-induced cytopathic effect (CPE) inhibition assay. In this regard, after cells suitable for viruses were grown in 96-well plates, dilutions of viruses in DME supplemented with 2% FBS (DME/2% FBS) or MEM supplemented with 2% FBS (MEM/2% FBS) were inoculated in an amount of 100 μl with a concentration corresponding to 100 CCID.sub.50(50% cell culture infective dose) into each well of the plates, and incubated for 30 min˜1 hrs at 33° C. or 37° C. to allow the viruses to adosorb to the cells. The culture medium was removed before aliquots of drug dilutions with various concentrations were added in an amount of 100 μl to each well. While HRV was grown at 33° C., the other viruses were incubated in a 37° C. CO.sub.2 incubator for 2˜3 days. Alternatively, the cells were cultured for 2˜3 days without removal of the medium after they were added with 50 μl of each drug dilution having a 2-fold higher concentration and then with 50 μl of the virus dilution.
(366) Test conditions for each virus are summarized in Table 2, below.
(367) TABLE-US-00002 TABLE 2 Host Incubation Incubation Virus Note cell Temp. Term Medium Coxsackie — RD 37° C. 2 days MEM/2% A9 FBS Coxsackie — MRC-5 37° C. 2 days MEM/2% A24 FBS Coxsackie Isolated MRC-5 37° C. 2 days MEM/2% A24 from FBS patients Coxsackie — HeLa 37° C. 2 days DME/2% B1 FBS Coxsackie — HeLa 37° C. 2 days DME/2% B3 FBS Coxsackie — HeLa 37° C. 2 days DME/2% B4 FBS Entero 70 — MRC-5 37° C. 2 days MEM/2% FBS Poliovirus3 — HeLa 37° C. 2 days DME/2% FBS Rhinovirus — HeLa 33° C. 3 days MEM/2% FBS
(368) For HeLa cells, the drugs were measured for EC.sub.50 (50% maximal effective concentration), which is the concentration of a drug inducing a response halfway between the baseline and maximun, using an MTT assay. With regard to RD and MRC-5 cells, CPE was determined using FDA (Fluorescein diacetate). In order for the evaluation results of drug potency to reflect the toxic effect of the drug, mock-infected cells which were prepared by adding a virus-free medium to a cell culture were treated in the same manner. That is, the medium was removed after one hour of incubation, and dilutions of drugs in the medium were added once more. Following incubation for 2 3 days, the cells were observed under a microscope and the drugs were determined for CC.sub.50(50% cytotoxic concentration), using an MTT assay in which counts of viable cells in mock-infected wells containing drugs were compared to those of viable cells in control wells containing no drugs. In an FDA hydrolysis assay, FDA was added to each well after removal of the medium, and incubated for 20˜30 min before fluorescence intensity was measured using a spectrofluorometer to determine CPE in the same manner as in MTT.
(369) Survival rate (% survival) of mock-infected cells was calculated using the following Mathmatic Formula 1:
(370)
(371) While 100% cell survival means no cytotoxicity of the drug, the highest cytotoxicity is reflected by 0% cell survival. The 50% cytotoxic concentration (CC.sub.50) was defined as the concentration required to reduce the cell number by 50% compared to that for the untreated controls. Higher CC.sub.50 values mean lower cytotoxicity.
(372) In addition, antiviral effects can be calculated using the following Mathmatic Formula 2:
(373)
(374) A survival rate of 100% means a perfect antiviral effect (100%) whereas the drugs are regarded to be devoid of antiviral effects at a survival rate of 0%. The viral cytopathic effect (CPE) was recorded, and the 50% effective concentration (EC.sub.50) was defined as the compound concentration required to reduce the viral CPE by 50% compared to that for the untreated control. Lower EC.sub.50 values mean higher antiviral activities.
(375) CC.sub.50 and EC.sub.50 values of the compounds which account cytotoxicity and antivival activity against picornaviruses, respectively, are given in Tables 3 and 4.
(376) TABLE-US-00003 TABLE 3 EC.sub.50 (μg/mL) Coxsackie- Coxsackie- Polio- Polio- Entero- Ex. CC.sub.50 Coxsackie- Coxsackie- Coxsackie- virus virus virus virus virus No. (μg/mL) virus B1 virus B3 virus B4 A24 (DN) A24 (HG) 3 2 70 1 >100 — — — — — — — — 2 >100 — — — — — — — <1.0 3 50.7 — — — — — — — 0.013 4 50.4 — — — — — — — — 5 26 — — — — — — — — 6 23.5 <0.01 0.035 — — — — — <0.01 7 >100 — — — — — — — — 8 7.91 — — — — — — — — 9 >100 — — — — — — — — 10 7.85 — — — — — — — — 11 8.42 — — — — — — — — 12 74.12 — — — — — — — — 13 7.93 — — — — — — — — 14 8.26 — — — — — — — — 15 8.26 0.015 — — — — — — — 16 8.87 — — — — — — — — 17 9.3 — — — — — — — — 18 >100 — — — — — — — — 19 17.7 <0.01 <0.01 — — <1.0 <1.0 — <0.01 20 >100 — — — — — — — — 21 16 <0.01 — — — — — — — 22 33.8 <0.01 — — — — — — — 23 44.3 <0.01 — — — — — — — 24 >100 — — — — — — — — 25 >100 — — — — — — — — 26 >100 — — — — — — — — 27 9.5 — — — — — — — — 28 9.2 — — — — — — — — 29 >100 — — — — — — — — 30 >100 <0.01 — — — — — — — 31 >100 — — — — — — — — 32 28.69 <0.01 — — — — — — — 33 >100 — — — — — — — — 34 46.25 — — — — — — — — 35 59.8 — — — — — — — — 36 9.42 <0.01 <0.01 — <0.1 <0.01 <0.01 — — 37 62.72 — — — — — — — — 38 >100 — — — — — — — — 39 6.67 — — — — — — — — 40 53.25 — — — — — — — — 41 — — — — — — — — — 42 71.06 — — — — — — — — 43 61.7 — — — — — — — — 44 >117 — — — — — — — — 45 >117 — — — — — — — — 46 63.98 — — — — — — — — 47 50.92 — — — — — — — — 48 46.74 <0.01 <0.01 — — — — — — 49 >100 <0.01 <0.01 <0.01 <1.0 <1.0 <1.0 <1.0 — 50 44.32 0.0112 — — — — — — — 51 9.34 — — — — — — — — 52 27.67 — — — — — — — — 53 10.2 — — — — — — — — 54 >117 0.0198 — — — — — — — 55 >117 — — — — — — — — 56 87.77 — — — — — — — — 57 48.21 — — — — — — — — 58 47.79 — — — — — — — — 59 53.67 — — — — — — — — 60 68.93 — — — — — — — — 61 >117 — — — — — — — — 62 11.26 — — — — — — — — 63 >117 — — — — — — — — 64 87.77 — — — — — — — — 65 11.16 — — — — — — — — 66 26.69 — — — — — — — — 67 54.59 — — — — — — — — 68 65.95 <0.01 <0.01 — — <1.0 — — — 69 >117 <0.01 <0.01 — <1.0 <1.0 <1.0 — — 70 >117 <0.01 <0.01 — — <1.0 — — — 71 >100 — — — — — — — — 72 >100 — — — — — — — — 73 >100 — — — — — — — — 74 — — — — — — — — — 75 >100 — — — — — — — —
(377) TABLE-US-00004 TABLE 4 Coxsackie-virus Coxsackie-virus Picorna-virus B1 B3 Polio-virus 3 Ex. CC.sub.50 EC.sub.50 EC.sub.50 EC.sub.50 No. (μg/mL) (μg/mL) (μg/mL) (μg/mL) 76 45.11 <0.01 <0.04 — 77 77.77 0.014 0.018 — 78 68.17 <0.01 <0.01 — 79 8.94 <0.01 <0.01 — 80 >100 <0.01 <0.01 — 81 41.26 <0.01 <0.01 0.012 82 >100 <0.01 <0.02 0.015 83 >100 <0.01 <0.01 — 84 >100 <0.01 <0.01 — 85 45.85 <0.01 <0.03 0.015 86 4.63 — — — 87 8.31 0.019 — — 88 4.49 — — — 89 10.7 — — — 90 38.26 — — — 91 40.02 0.015 — — 92 43.58 <0.01 <0.01 — 93 35.21 <0.01 <0.01 — 94 39.17 <0.01 <0.01 — 95 27.45 <0.01 <0.01 — 96 48.85 <0.01 <0.01 0.03 97 45.09 <0.01 <0.01 — 98 >100 0.013 — — 99 38.07 <0.01 <0.01 — 100 >100 <0.01 <0.01 — 101 45.95 <0.01 <0.01 — 102 42.5 <0.01 <0.01 — 103 26.27 <0.01 <0.01 0.013 104 >100 — — — 105 >100 — — — 106 >100 — — — 107 >100 — — — 108 >100 — — —
(378) As is understood from data of Tables 3 and 4, most of the 1,3-Dioxoindene derivatives of the present invention exhibited low cytotoxicity because they had high CC.sub.50 values. In addition, most of the 1,3-Dioxoindene derivatives of the present invention were found to be highly inhibitory of coxsackie-, polio-, rhino-, and entero-viruses because their EC.sub.50 values were 0.01 μg/mL or less.
(379) Accordingly, the 1,3-Dioxoindene derivatives represented by Chemical Formula 1 in accordance with the present invention exhibit low cytotoxicity and high inhibitory activity against a broad spectrum of picornaviruses, and thus may be usefully applied to a pharmaceutical composition for preventing or treating picornavirus-caused diseases.
(380) The test compounds were evaluated for anti-picornavirus activity by a multicycle cytopathic effect (CPE) reduction assay. The antiviral activity was initially determined using an MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium]-based CPE reduction assay.
(381) In this regard, cells grown to confluence in 96-well plates were infected with 100 50% cell culture infective doses (CCID.sub.50) of virus. After an adsorption period of 2 hrs at 37° C., virus was removed and serial dilutions of the compounds were added. The cultures were further incubated at 37° C. for 3 days, until complete CPE was observed in the infected and untreated virus control (VC). After removal of the medium, 90 μl of a culture medium and 10 μl of MTS-phenazine methosulfate (Promega, Leiden, The Netherlands) were added to each well. After an incubation period of 2 hrs at 37° C., the optical density (OD) of each well was read at 498 nm in a microplate reader.
(382) CPE values for evaluating antiviral activity were calculated using the following Mathmatic Formula 3:
(383)
(384) CPE values for evaluating cytotoxicity were calculated using the following Mathmatic Formula 4:
(385)
(386) In Formulas 3 and 4,
(387) OD.sub.CC corresponds to the OD of the uninfected and untreated, background cell cultures,
(388) OD.sub.VC represents the OD of the infected and untreated control cell cultures,
(389) OD.sub.virus+Compound represents the OD of the virus-infected cell cultures treated with a given concentration of compound, and
(390) ODBlank represents the OD of the well added with the cell culture medium alone.
(391) The 50% effective concentration (EC.sub.50) and the 50 cytotoxic concentration (CC.sub.50) were defined as the concentrations of compound that offered 50% protection against virus-induced CPE and that killed cells by 50%, respectively, and were calculated using logarithmic interpolation.
(392) CC.sub.50 and EC.sub.50 against various viruses of some compounds are given in Table 3, below.
(393) TABLE-US-00005 TABLE 5 Ex. 19 Ex. 36 Ex. 74 CC.sub.50 [μM] >100 >50 >100 Coxsackie B3.sup.c EC.sub.50 <0.01 <0.01 — [μM] Coxsackie A16.sup.d 0.064 ± 0.010 — 13 ± 0.32 EC.sub.50 [μM] Coxsackie A9.sup.f EC.sub.50 — 0.0070 ± 0.00018 — [μM] Coxsackie A21.sup.d 0.67 ± 0.13 — 26 ± 0.34 EC.sub.50 [μM] Entero 71.sup.e EC.sub.50 0.10 ± 0.0018 0.0067 ± 0.00078 3.3 ± 1.6 [μM] Echo 9.sup.d EC.sub.50 [μM] 0.017 ± 0.0067 0.011 ± 0.0032 0.61 ± 0.038 Echo 11.sup.f EC.sub.50 [μM] 0.017 ± 0.0078 0.0082 ± 0.0019 0.70 ± 0.24 Polio 1.sup.f EC.sub.50 [μM] 0.79 ± 0.36 0.22 ± 0.050 20 ± 14 Polio 2.sup.f EC.sub.50 [μM] — — — Polio 3.sup.f EC.sub.50 [μM] <1.0 <0.01 — Rhino 2.sup.g EC.sub.50 [μM] >50 7.8 ± 0.57 >50 Rhino 9.sup.g EC.sub.50 [μM] >50 1.2 ± 0.12 >50 Rhino 15.sup.g EC.sub.50 >50 1.5 ± 0.24 >50 [μM] Rhino 29.sup.g EC.sub.50 >50 5.5 ± 0.72 >50 [μM] Rhino 39.sup.g EC.sub.50 >50 1.4 ± 0.20 >50 [μM] Rhino 41.sup.g EC.sub.50 >50 0.54 ± 0.0030 >50 [μM] Rhino 45.sup.g EC.sub.50 4.6 ± 0.0083 <0.078.sup.i >50 [μM] Rhino 59.sup.g EC.sub.50 — — >50 [μM] Rhino 63.sup.g EC.sub.50 >50 >10 >50 [μM] Rhino 85.sup.g EC.sub.50 >50 7.5 ± 1.2 >50 [μM] Rhino 89.sup.g EC.sub.50 >50 0.49 ± 0.038 >50 [μM] Rhino 14.sup.g EC.sub.50 0.45 ± 0.41 0.35 ± 0.32 >50 [μM] Rhino 42.sup.g EC.sub.50 >50 — >50 [μM] Rhino 70.sup.g EC.sub.50 2.0 ± 0.12 >0.078.sup.i >50 [μM] Rhino 72.sup.g EC.sub.50 4.6 ± 0.092 — >50 [μM] Rhino 86.sup.g EC.sub.50 26 ± 18 — 26 ± 18 [μM]
(394) In Table 5, the superscript c represents incubation at 37° C. in Vero cells, the superscript d represents incubation at 37° C. in MRC-5 cells, the superscript e represents incubation at 37° C. in RD cells, the superscript f represents incubation at 37° C. in BGM cells, the superscript g represents incubation at 37° C. in HeLa cells, and the superscript i represents 100% inhibition of viral replication with compounds of 0.078 μM or higher.
(395) As can be seen in Table 5, the 1,3-Dioxoindene derivatives according to the present invention are low in cytotoxicity because their CC.sub.50 was measured at 50 μM or higher, especially the compound of EXAMPLE 19 and EXAMPLE 74 are low in cytotoxicity because their CC.sub.50 was measured at 100 μM or higher. In addition, the 1,3-Dioxoindene derivatives were observed to have an EC.sub.50 of 26 μM or less against coxsackieviruses B3, A16, A9, and A21. Particularly high antiviral activity was detected in the compound of EXAMPLE 19 and EXAMPLE 36 with an EC.sub.50 of as low as 0.01 μM.
(396) With regard to enterovirus 71, the 1,3-Dioxoindene derivatives according to the present invention showed an EC.sub.50 of 3.3 μM or less. Particularly high antiviral activity was detected in the compound of EXAMPLE 36 with an EC.sub.50 of as low as 0.0067 μM.
(397) The 1,3-Dioxoindene derivatives according to the invention showed an EC.sub.50 of 0.70 μM or less against echovirus 9 and echovirus 11, while the highest antiviral activity was detected in the compound of EXAMPLE 36 as demonstrated by the EC.sub.50 of 0.0082 μM.
(398) In the case of polioviruses 1, 2 and 3, EC.sub.50 values of the 1,3-Dioxoindene derivatives according to present invention were measured to be 20 μM or less. Particularly high antiviral activity was detected in the compound of EXAMPLE 36 with an EC.sub.50 of as low as 0.01 μM.
(399) Also, the 1,3-Dioxoindene derivatives according to the invention were highly inhibitory of rhinoviruses. For example, EC.sub.50 of 50 μM or more was detected against rhinoviruses 2, 9, 15, 29, 39, 41, 45, 59, 63, 85, 89, 14, 42, 70, 72, and 86. Particularly high antiviral activity was detected in the compound of EXAMPLE 36 with an EC.sub.50 of 0.078 μM or less against rhinoviruses 45 and 70.
(400) Consequently, the 1,3-Dioxoindene derivatives of the present invention are of low cytotoxicity and exhibit excellent antiviral activity against picornaviruses including coxsackie-, entero-, echo-, polio- and rhinoviruses, so that they can be usefully applied to the prevention or treatment of picornavirus-caused respiratory, cardiocirculatory, and nervous system diseases, including poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, cold, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis and otitis media.
(401) <1-1> Preparation of Powder
(402) TABLE-US-00006 1,3-Dioxoindene derivative: 2 g Lactose: 1 g
(403) The above ingredients were mixed and loaded into an airtight sac to produce a powder agent.
(404) <1-2> Preparation of Tablet
(405) TABLE-US-00007 1,3-Dioxoindene derivative: 100 mg Corn starch: 100 mg Lactose: 100 mg Mg stearate: 2 mg
(406) These ingredients were mixed and prepared into tablets using a typical tabletting method.
(407) <1-3> Preparation of Capsule
(408) TABLE-US-00008 1,3-Dioxoindene derivative: 100 mg Corn starch: 100 mg Lactose: 100 mg Mg stearate: 2 mg
(409) These ingredients were mixed and loaded into gelatin capsules according to a typical method to produce capsules.
(410) <1-4> Preparation of Injection
(411) TABLE-US-00009 1,3-Dioxoindene derivative: 10 μg/ml Diluted Hydrochloric acid BP: to be pH 3.5 Sodium chloride BP for injection: maximum 1 ml
(412) The 1,3-Dioxoindene derivative of the present invention was dissolved in a appropriate volume of sodium chloride BP for injection. The pH of the resultant solution was regulated to be pH 3.5 with dil.HCl BP, and then its volume was regulated with sodium chloride BP for Injection and the solution was mixed completely. The solution was then filled in 5-ml type 1 ample that is made of transparent glass. The air was sealed in upper lattice by melting the glass. The solution contained in ample was autoclaved at 120° C. for 15 min or more to be sterilized and thereby to obtain an injection.
INDUSTRIAL APPLICABILITY
(413) Having excellent inhibitory activity against picornaviruses including coxsackie-, entero-, echo-, Polio-, and rhinoviruses, as well as exhibiting low cytotoxicity, as described hitherto, the 1,3-Dioxoindene derivative of Chemical Formula 1 can be useful as an active ingredient of a pharmaceutical composition for the prevention or treatment of viral diseases including poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, cold, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis or otitis media.