CA2101335A1 - Reissert compounds as anti-hiv agents - Google Patents
Reissert compounds as anti-hiv agentsInfo
- Publication number
- CA2101335A1 CA2101335A1 CA002101335A CA2101335A CA2101335A1 CA 2101335 A1 CA2101335 A1 CA 2101335A1 CA 002101335 A CA002101335 A CA 002101335A CA 2101335 A CA2101335 A CA 2101335A CA 2101335 A1 CA2101335 A1 CA 2101335A1
- Authority
- CA
- Canada
- Prior art keywords
- hydrogen
- dihydroquinoline
- cyano
- oxo
- propenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Immunology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
Abstract
Disclosed are heterocyclic compounds of formula (I). The compounds of the invention are useful in the treatment of AIDS and AIDS
related complex. The compounds of the invention are generally synthesized by following the reactions and conditions used to make Reissert compounds. Compounds included within the scope of formula (I) are 1,2-dihydroquinolines, 1,4-dihydroquinolines, 1,2,3,4-tetrahydroquinolines, 1,2-dihydroquinazolines, and the 1,2-dihydroquinoxalines. Representative compounds include 1-(4-bromobenzoyl)-2-cyano-1,2-dihydroquinoline, 1-(4-chlorobenzoyl)-2-cyano-5-fluoro-1,2-dihydroquinoline, 1-(4-chlorobenzoyl)-2-cyano-6-fluoro-1,4-dihydroquinoline, 1-(4-chlorobenzoyl)-2-cyano-1,2,3,4-tetrahydroquinoline, 1-(4-chlorobenzoyl)-2-carboximidamide-8-fluoro-1,2-dihydroquinoline, 1-(4-chlorobenzoyl)-2-cyano-1,4-dihydroquinoxaline, 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, and 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinol_ ine. Also included within the scope of the invention is a method of treating a human having AIDS or ARC with an effective amount of a compound of the invention.
related complex. The compounds of the invention are generally synthesized by following the reactions and conditions used to make Reissert compounds. Compounds included within the scope of formula (I) are 1,2-dihydroquinolines, 1,4-dihydroquinolines, 1,2,3,4-tetrahydroquinolines, 1,2-dihydroquinazolines, and the 1,2-dihydroquinoxalines. Representative compounds include 1-(4-bromobenzoyl)-2-cyano-1,2-dihydroquinoline, 1-(4-chlorobenzoyl)-2-cyano-5-fluoro-1,2-dihydroquinoline, 1-(4-chlorobenzoyl)-2-cyano-6-fluoro-1,4-dihydroquinoline, 1-(4-chlorobenzoyl)-2-cyano-1,2,3,4-tetrahydroquinoline, 1-(4-chlorobenzoyl)-2-carboximidamide-8-fluoro-1,2-dihydroquinoline, 1-(4-chlorobenzoyl)-2-cyano-1,4-dihydroquinoxaline, 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, and 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinol_ ine. Also included within the scope of the invention is a method of treating a human having AIDS or ARC with an effective amount of a compound of the invention.
Description
2~ PC1/l'S92tO1~6 "~
t" - ` !
REISSERT COMPOUNP~S ANTI-HIV AGE~
Field of the Invention This invention provides novel 1,2-dihydroquinolines, 1,4-dihydroquinolines, 1,2,3,4-tetrahydroquinolines, 1,2-dihydroquinazoliDes, and 1,2-dihydroquinoxalines, as well as known compounds of these classes, which are useful as anti-AlDS drugs.
Baçkeround o~f~ Qc An estimated one to one and one-half million people in the United S~ales are infected with a human retrovirus, the human immunodeficiency virus type I (HIV-I) which is the etiologicaJ agent of acquired imrnunodeficiency syndrome, AIDS, see Science, 661~62 (1986).
Of those infected, an estimated two hundred and fifty thousand people will develop AlDS in the next five years, see Science, 1352-1357 (1985). OD March 20, 1987, the FDA approved the use of the çompound, AZT (zidovudine), to treat AIDS patients with a reçent initial episode of pneumocystis carinii pneumonia, AIDS patients with conditions other than pneumocystis çarinii pneumonja or patients infeçted with the virus with an absolute CD4 Iymphocyte çount of less than 200/mm3 jD tbe peripheral blood. AZT is a known inhibitor of viral reverse transcriptase, an enzyme necessary for human immunodeficiency virus replication.
U,S. Patent 4,724,232 claims a method of treating bumans baving acquired immunodeficiency syndrome utiliziog 3'-azido-3'-deoxy-thymidine (a~idothymidine, AZT).
It is known in the art that certain antibiot;cs and polyanionic dyes inhibit retrovirus reverse transcriptase. It has also been reported that various sulfated compounds inhibit virus replication, including HIV.
Information Disclosute F.D. Popp, ~Reissert Compounds and Related N-acyldihydroquinolines~ in Quholines, Part 11, Ed. C. Jones, (1982) p. 353-372, is a general review covering the synthesis and reactions of Reissert compounds. This review also specifically describes the synthesis of 1-(4-chlorobenzoyl)-2-cyano-1,2~ihydroquinoline, 1-(1 fluorobenzoyl)-2-cyano-1,2-dihydroquinoline, l~methoxybeyl)-2~yano-1,2-dihydroquinoline, 1-(4-toluoyl~2-cyano-1,2~ihydroquinoline, I-(~nitrobenzoyl)-2~yano-1,2-dihydroquinoline, 1-(2-naphthoyl)-2-cyano- 1,2-dihydroquinoline, and I -(I -oxo-3-phenyl-2-propenyl)-2-cyano-1,2~ihydroquinoline.
F.D. Popp, W. Blount and P. Melvin, 1 Org. Chem., 26, 4930 (1961), describes themethylene chloride/water method for synthesizing Reissert Compounds.
S. Ruchirawat, N. Phadu~glcul, M. Chuankamnerdl~arn, and C. Thebtaranonth, ~eterocycles, 6, No. 1, 43 ~1977), describes the trimethylsilyl cyanide med~od of synthesiziDg Reissert compounds.
M. Rozwadowska, Roczniki Chemii. 51, 2321 (1977), describes hydrogenation of - SUBSTITUTE SHEET
~: .- ~ . ~ : . :
, . . . .. . . . .
, . . . .
~vo 92J16508 PC-r/US92/017~6 2~ ~133~ 2- ~
dihydroquinoline Reissert compounds to tetrahydroquinolines.
L. Wal~ers, M. Siegel, and R. Cook, I HeterQcyclic ~ , 5,577 ~1968), describes synthesis of amidoximes via addition of hydroxylamine to a Reissert compound.
H. Bartsch, O. Schwan, and G. Neubauer, Heterocycle~, 24, 3483 (1986), describesthe synthesis of a benzoxazine Reissert compound.
F. Elroy and R. Lenaers, ~The Chemistry of Amidoximes and Related Compounds,~
~h~. ~. 155 (1962), describes synthesis and reactions of amidoximes.
Uff, B C., Budhram, R.S., Consterdine, M.P., Hicks, J.K., and Slingsby, B.P., J. Chem Soc., ~Ç~ ~ 1 (18): 2018-22 (1977), describes synthesis of 2-cyano-1-(4-methoxybenzoyl) 4 methyl-1,2-dihydroquinoline.
F.D. Popp and A. Soto, I ~ oc., 1760 (1963), describes the synthesis of 1-(4-fluorobenzoyl)-2-cyano- 1,2-dihydroquinoline.
~apanese Patent Applicatioo JO 2049-782-A, discloses quinolidine compounds which are stated as useful n treating AlDS. lbese quinolidines are not structurally related to the compounds of the present invention.
SUMMARY OF THE INVENTION
This invention provides compounds of formula I whereîn R2 is -CN, -N3, -SCN, and the E or Z isomers of -C(=NORlo)NH2, -C(-NRlo)H, -C(=NNRSo)NH2, -C(=NRlo)NH2, -C(=NORlo)H, and -C(=NOH)N(RIo)H;
Rlo is hydrogen, Cl-C4 alhyl, -Ac, -C(O)OCH3, -C(O)OC2Hs, -phenyl, -P02-0-cation+, -CO-CH(M)NH2, -CO-C6H6-NRI IRl2, and -CO-C6H6-CH2-NRI IRl2;
AA is-CH3, -CH(CH3)2, -CH2CH(CH3)2,-CH2OH, -CH(OH)CH3, -CH2CO2H, -cH2cH2co2H~ -(CH2)4NH2. and -(CH2)3-NH2;
R~l and R12 may be the same or different and are hydrogen and C1-C4 allcyl;
Rl l and R12 taken together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and N-(CI-C4 allcyl)piperazinyl;
R3, present when the connection between positions 2 and 3 is a single bond, is hydrogen, Cl-C4 all~yl, -(CH2)"CN, and -(CH2)bR~3;
R13 is -N(CH3)2, -OH, -OPO3H, -OCH2CH(-OH)CH2OH, -OCH2CO2H, -O2C(CH2)2CO2H,-OR14, and -NR14;
R14 is a N-terrninal arnino acid;
a is zero to six;
b is one to five;
A is CH, CH2, N, and CHN(CH3)2;
X is CH, CH2, NH, O, and C-R4;
R4 is-CH3 -OCH3, and -OAc;
SUBSTITUTE SHEET
~' . ~
: ~, WO 9~/16508 2 1 0 1 3 ~ 5 PCr/US92/ol746
t" - ` !
REISSERT COMPOUNP~S ANTI-HIV AGE~
Field of the Invention This invention provides novel 1,2-dihydroquinolines, 1,4-dihydroquinolines, 1,2,3,4-tetrahydroquinolines, 1,2-dihydroquinazoliDes, and 1,2-dihydroquinoxalines, as well as known compounds of these classes, which are useful as anti-AlDS drugs.
Baçkeround o~f~ Qc An estimated one to one and one-half million people in the United S~ales are infected with a human retrovirus, the human immunodeficiency virus type I (HIV-I) which is the etiologicaJ agent of acquired imrnunodeficiency syndrome, AIDS, see Science, 661~62 (1986).
Of those infected, an estimated two hundred and fifty thousand people will develop AlDS in the next five years, see Science, 1352-1357 (1985). OD March 20, 1987, the FDA approved the use of the çompound, AZT (zidovudine), to treat AIDS patients with a reçent initial episode of pneumocystis carinii pneumonia, AIDS patients with conditions other than pneumocystis çarinii pneumonja or patients infeçted with the virus with an absolute CD4 Iymphocyte çount of less than 200/mm3 jD tbe peripheral blood. AZT is a known inhibitor of viral reverse transcriptase, an enzyme necessary for human immunodeficiency virus replication.
U,S. Patent 4,724,232 claims a method of treating bumans baving acquired immunodeficiency syndrome utiliziog 3'-azido-3'-deoxy-thymidine (a~idothymidine, AZT).
It is known in the art that certain antibiot;cs and polyanionic dyes inhibit retrovirus reverse transcriptase. It has also been reported that various sulfated compounds inhibit virus replication, including HIV.
Information Disclosute F.D. Popp, ~Reissert Compounds and Related N-acyldihydroquinolines~ in Quholines, Part 11, Ed. C. Jones, (1982) p. 353-372, is a general review covering the synthesis and reactions of Reissert compounds. This review also specifically describes the synthesis of 1-(4-chlorobenzoyl)-2-cyano-1,2~ihydroquinoline, 1-(1 fluorobenzoyl)-2-cyano-1,2-dihydroquinoline, l~methoxybeyl)-2~yano-1,2-dihydroquinoline, 1-(4-toluoyl~2-cyano-1,2~ihydroquinoline, I-(~nitrobenzoyl)-2~yano-1,2-dihydroquinoline, 1-(2-naphthoyl)-2-cyano- 1,2-dihydroquinoline, and I -(I -oxo-3-phenyl-2-propenyl)-2-cyano-1,2~ihydroquinoline.
F.D. Popp, W. Blount and P. Melvin, 1 Org. Chem., 26, 4930 (1961), describes themethylene chloride/water method for synthesizing Reissert Compounds.
S. Ruchirawat, N. Phadu~glcul, M. Chuankamnerdl~arn, and C. Thebtaranonth, ~eterocycles, 6, No. 1, 43 ~1977), describes the trimethylsilyl cyanide med~od of synthesiziDg Reissert compounds.
M. Rozwadowska, Roczniki Chemii. 51, 2321 (1977), describes hydrogenation of - SUBSTITUTE SHEET
~: .- ~ . ~ : . :
, . . . .. . . . .
, . . . .
~vo 92J16508 PC-r/US92/017~6 2~ ~133~ 2- ~
dihydroquinoline Reissert compounds to tetrahydroquinolines.
L. Wal~ers, M. Siegel, and R. Cook, I HeterQcyclic ~ , 5,577 ~1968), describes synthesis of amidoximes via addition of hydroxylamine to a Reissert compound.
H. Bartsch, O. Schwan, and G. Neubauer, Heterocycle~, 24, 3483 (1986), describesthe synthesis of a benzoxazine Reissert compound.
F. Elroy and R. Lenaers, ~The Chemistry of Amidoximes and Related Compounds,~
~h~. ~. 155 (1962), describes synthesis and reactions of amidoximes.
Uff, B C., Budhram, R.S., Consterdine, M.P., Hicks, J.K., and Slingsby, B.P., J. Chem Soc., ~Ç~ ~ 1 (18): 2018-22 (1977), describes synthesis of 2-cyano-1-(4-methoxybenzoyl) 4 methyl-1,2-dihydroquinoline.
F.D. Popp and A. Soto, I ~ oc., 1760 (1963), describes the synthesis of 1-(4-fluorobenzoyl)-2-cyano- 1,2-dihydroquinoline.
~apanese Patent Applicatioo JO 2049-782-A, discloses quinolidine compounds which are stated as useful n treating AlDS. lbese quinolidines are not structurally related to the compounds of the present invention.
SUMMARY OF THE INVENTION
This invention provides compounds of formula I whereîn R2 is -CN, -N3, -SCN, and the E or Z isomers of -C(=NORlo)NH2, -C(-NRlo)H, -C(=NNRSo)NH2, -C(=NRlo)NH2, -C(=NORlo)H, and -C(=NOH)N(RIo)H;
Rlo is hydrogen, Cl-C4 alhyl, -Ac, -C(O)OCH3, -C(O)OC2Hs, -phenyl, -P02-0-cation+, -CO-CH(M)NH2, -CO-C6H6-NRI IRl2, and -CO-C6H6-CH2-NRI IRl2;
AA is-CH3, -CH(CH3)2, -CH2CH(CH3)2,-CH2OH, -CH(OH)CH3, -CH2CO2H, -cH2cH2co2H~ -(CH2)4NH2. and -(CH2)3-NH2;
R~l and R12 may be the same or different and are hydrogen and C1-C4 allcyl;
Rl l and R12 taken together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and N-(CI-C4 allcyl)piperazinyl;
R3, present when the connection between positions 2 and 3 is a single bond, is hydrogen, Cl-C4 all~yl, -(CH2)"CN, and -(CH2)bR~3;
R13 is -N(CH3)2, -OH, -OPO3H, -OCH2CH(-OH)CH2OH, -OCH2CO2H, -O2C(CH2)2CO2H,-OR14, and -NR14;
R14 is a N-terrninal arnino acid;
a is zero to six;
b is one to five;
A is CH, CH2, N, and CHN(CH3)2;
X is CH, CH2, NH, O, and C-R4;
R4 is-CH3 -OCH3, and -OAc;
SUBSTITUTE SHEET
~' . ~
: ~, WO 9~/16508 2 1 0 1 3 ~ 5 PCr/US92/ol746
3-R5, R6, R7, and R8 may be the sarne or different and are hydrogen and nuorine;
W is o~ygen and sulfur;
Z is a dire bond or a linker selected from the group consisting of -(CO)-, -CH=CH-CH=CH- (all E), -CR~5=CR16- (E or Z), and -CH=C=CH-;
RlS and R16 may be the sarne or different and are hydrogen and fluorine;
Yl is hydrogen, -Cl, -F, -Br, -CH3, -CF3, -(CH2)CRl7, -CHO, -CO2CH3, -OH, -OCH3 -OAc, -CN,-NO2, -SH, and-SCH3;
c is zero to five;
R17 is-CH2N(CH3)2, -OH, -OPO3H, -CH2N(C2H5)2~ -O-sugar, -OCH2CH(OH)CH2OH, -OCH2CO2H, -O2CCH2CH2CO2H, -CH2N = CHN(CH3)2, -ORI 8~ or -NR~8;
R18 is an N-terminal a nino acid;
Y2 is hydrogeD, -F, -Cl, -OCH3, and -CF3;
Yl and Y2 talcen together can form -OCH20-, -OC(CH3)20-, -OCH2NH-, -NHCH2O-, -OCH2S-, -SCH2O-, and -CH = CR19-CH = CH-;
Rlg is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CH3, -OH, -CN, and -OAc;
provided, however, when Z is a direct bond and A and X are each CH, and R5, R6, R~, and R8 are each hydrogen, and R2 is -CN, Yl is not -Cl, -F, or -CH3 and Rl9 is not hydrogen, when Z is a direct bond and R2 is -C(=NOH)N(RIo)H and Rlo is hydrogen, R19 is not hydrogen, when Z is a direct bond, Yl is not hydrogen, when Z is ~R~5=CR~6- (E), and Y2, R15, and R16 are each hydrogen, Yl is not hydrogen, when Yl is -OCH3 ~nd Z is a direct bond, at least one of Rs, R6, R7 or R8 is fluorine, when Yl is -CF3 and Z is direct bond, the connection between positions 3 and 4 is a double bond, when Z is a direct bond, X is not O, when Z is a direct bond, R2 is not -N3, when Z is a direct bond, Y2 is hydrogen, when A is N, X is C-R4 and R4 is -OCH3, or -OAc and the coMection between position 3 and 4 is a double bond, when A is CHN(CH~)2, X is CH2 when R4 is -CH3, R3 is hydrogen, when R4 is-CH3, Yl is -Cl, -F, -Br, -CF3, ~N, or -NO2, when R5 is fluorine, R6, R~ and R8 are each hydrogen, SUBSTITUTE SHEET
3: ' . '- . .
-,~ ~ . , , ' ' ' ' ' ' . ' '' ~, ' ,' . . :
~vo 92/16508 2 1 ~ 1 3 3 5 PCr/US92/ol746
W is o~ygen and sulfur;
Z is a dire bond or a linker selected from the group consisting of -(CO)-, -CH=CH-CH=CH- (all E), -CR~5=CR16- (E or Z), and -CH=C=CH-;
RlS and R16 may be the sarne or different and are hydrogen and fluorine;
Yl is hydrogen, -Cl, -F, -Br, -CH3, -CF3, -(CH2)CRl7, -CHO, -CO2CH3, -OH, -OCH3 -OAc, -CN,-NO2, -SH, and-SCH3;
c is zero to five;
R17 is-CH2N(CH3)2, -OH, -OPO3H, -CH2N(C2H5)2~ -O-sugar, -OCH2CH(OH)CH2OH, -OCH2CO2H, -O2CCH2CH2CO2H, -CH2N = CHN(CH3)2, -ORI 8~ or -NR~8;
R18 is an N-terminal a nino acid;
Y2 is hydrogeD, -F, -Cl, -OCH3, and -CF3;
Yl and Y2 talcen together can form -OCH20-, -OC(CH3)20-, -OCH2NH-, -NHCH2O-, -OCH2S-, -SCH2O-, and -CH = CR19-CH = CH-;
Rlg is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CH3, -OH, -CN, and -OAc;
provided, however, when Z is a direct bond and A and X are each CH, and R5, R6, R~, and R8 are each hydrogen, and R2 is -CN, Yl is not -Cl, -F, or -CH3 and Rl9 is not hydrogen, when Z is a direct bond and R2 is -C(=NOH)N(RIo)H and Rlo is hydrogen, R19 is not hydrogen, when Z is a direct bond, Yl is not hydrogen, when Z is ~R~5=CR~6- (E), and Y2, R15, and R16 are each hydrogen, Yl is not hydrogen, when Yl is -OCH3 ~nd Z is a direct bond, at least one of Rs, R6, R7 or R8 is fluorine, when Yl is -CF3 and Z is direct bond, the connection between positions 3 and 4 is a double bond, when Z is a direct bond, X is not O, when Z is a direct bond, R2 is not -N3, when Z is a direct bond, Y2 is hydrogen, when A is N, X is C-R4 and R4 is -OCH3, or -OAc and the coMection between position 3 and 4 is a double bond, when A is CHN(CH~)2, X is CH2 when R4 is -CH3, R3 is hydrogen, when R4 is-CH3, Yl is -Cl, -F, -Br, -CF3, ~N, or -NO2, when R5 is fluorine, R6, R~ and R8 are each hydrogen, SUBSTITUTE SHEET
3: ' . '- . .
-,~ ~ . , , ' ' ' ' ' ' . ' '' ~, ' ,' . . :
~vo 92/16508 2 1 ~ 1 3 3 5 PCr/US92/ol746
-4-when Yl and Y2 taken toge~her are {:H=CR19-CH=CH-, Z is a direct bond, and when Yl and Y2 taken togelher can form -OCH20-, -OC(CH3)20-, -0CH2NH-, -NHCH20-, -OCH2S-, and -SCH20-, Z is a linker;
or the pharmaceuticaJly acceptable sal~s thereof.
S nle preferred compound is l-E-(3-(4-chlorophenyl)-1-o~o-2-propenyl)-2-cyano-1,2-d ihydroqu inol ine.
The invention further provides compounds of formula n wherein R2 is -CN, -SCN, and the E or Z isomers of -C(-NORI~)NH2, -C(=NRlo)H, -C(= NNRlo)NH2, -C(= NRlo)NH2, -C(= NORIo)H, and -C(= NOH)N(RIo)H;
Rlo is hydrogen, Cl-C4 alkyl, -Ac, -C(O)OCH3, -C(O)OC2HS, -pbenyl, -PO2-O-cation+, -CO-CH(AA)NH2, -CO-C6H6-NRlIR~2, and -CO-C6H6-CH2-NRIIR12;
AA is-CH3, -CH(CH3)2,-CH2CH(CH3)2.-CH2OH, -CH(OH)CH3, -CH2CO2H, -cH2cH2co2H~ -(CH2)4NH2. and -(CH2)3-NH2;
Rll and R12 may be the sarne or differen~ and are hydrogen and Cl-C4 alkyl;
Rl I and R12 taken together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and N-(CI-C4 alkyl)piperazinyl;
R3, present when the conne tion between positions 2 and 3 is a single bond, is hydrogen, Cl-C4 alkyl, -(CH2),CN, and -(CH2)bR13;
R13 is-N(CH3)2, -OH, -OPO3H, ~CH2CH(OH)CH2OH, -OCH2CO2H, -02C(CH2)2C02H, -OR14, and ~ 4;
R14 is a N-terminal amino acid;
a is zero to six;
b is one to five;
A is CH, CH2, and CHN(CH3)2;
X is CH, CH2, and C-R4;
R4 is -CH3, -OCH3, and ~Ac;
R5, R6, R7, R8 may be the same or different and are hydrogen and fluorine;
W is o~tygen and sulfur;
Yl is-CI,-F, -Br,-CH3,-CF3,-(CH2)cRl7,-CHO,-CO2CH3,-OH,-OCH3 -OAc, -CN, -NO2, -SH, and -SCH3;
c is zero to four;
R17 is-CH2N(CH3)2, -OH, -OPO3H, -CH2N(C2H5)2, -O-sugar, -OCH2CH(OH~CH20H,-OCH2C02H,-02CCH2CH2C02H,-CH2N=CHN(CH3)2,-OR~8, asld -NR~8;
R18 is a N-terrninal amino acid;
Y2 is hydrogen;
SUBSTITUTE SHEET
...
- :~
.
wo 92/16508 2 1 ~ 1 3 3 5 ` PCT/I IS92/01746 f, '.' . -S~
Yl and Y2 ta~en together are -CH=CRI9-CH=CH-;
Rl9 is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CM3, -OH, -CN, and -OAc;
provided, however, when A and X are each CH, and R5, R6, R7, and R8 are each hydrogen, and R2 is -CN, Y~ is not ~1, -F, or -CH3 and R19 is not hydrogen, S when R2 is -C(=NOH)N(RIo)H and Rlo is hydrogen, Rl9 is not hydrogen, when Yl is ~CH3, at least one of R5, R6, R7 or R8 is fluorine, when Yl is -CF3, the connection between positions 3 and 4 is a dauble bond, when R4 is -CH3, R3 is hydrogen, when R4 is -CH3, Yl is -Cl, -F, -Br, -CF3, -CN, or -NO2, and î0 when R5 is fluorine, R6, R7 and R8 are each hydrogen, or the phannaceutically acceptable salts thereof.
Further provided is a compound of forrnula 11 wherein R2 is -CN, -SCN, and the E or Z isomers of -C(=NORlo)NH2, -C(=NRlo)H, -C(= NNRlo)NH2, -C(= NRlo)NH2, (:(= NORIo)H, and -C(= NOH)N(Rlo)H;
Rlo is hydrogen, Cl-C4 alkyl, -Ac, ~(O)OCH3, -C(O)OC2H5, -phenyl, -PO2-O-cation+, ~CO-CH(AA)NH2, -CO-C6H6-NRI IR12, and -CO-C6H6-CH2-NRI ~R12;
AA is-CH3, ~H(CH3)2, -CH2CH(CH3)2,-CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H, -(CH2)4NH2. and -(CH2)3-NH2;
R1~ and R12 may be the sarne or diffe-enl and are hydrogen and Cl-C4 aJkyl;
Rll and R12 taken together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and N-(CI-C4 alkyl)piperazinyl;
A is CH, CH2, and N;
X is C-R4, and NH;
R4 is -CH3 ~CH3, and -OAc;
R3, preseDt when the connection between positions 2 and 3 is a single bond, is hydrogen;
R5, R6, R7, R8 may be the sa ne or different and are hydrogen and fluorine;
W is oxygen;
Yl is-CI, -F, -Br, -CH3, -CF3, -CHO, -C02CH3,-OH, -OCH3 ~Ac, -CN, -NO2, -SH, and-SCH3;
Y2 is hydrogen;
Yl and Y2 taken together are -CH=CRI9-CH=CH-;
Rl9 is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CH3, -OH, -CN, and -OAc;
provided, however, when Yl is -OCH3, at least one of Rs, R6, R7 or R8 is fluorine, when Yl is -CF3, the connection between positions 3 and ~ is a double bond, when A is N, X is C-R4 and R4 is -OCH3 or -OAc and the connection between position - SUBSTITUTE SHEET
.. . . .... .... . . . . .
.. . ..
- . ... - .. ` . . : ~ -. . : -.
: ~ :. . .. ..
-`: ~ : ~ . . ~ . . ..
WO 92/16508 21 D 1 ~ 3 ~ PCr/US92/01746 3 and 4 is a double bond, when R4 is -CH3, R3 is hydrogen, when R4 is -CH3, Yl is-CI, -F, -Br, -CF3, -CN, or -NO2, and when R5 is fluorine, R6, R7 and R8 are each hydrogen;
S or the pharrnaceutically acceptable salts thereof.
llle invention further provides compourds of formula I wherein ~2 is -CN, -N3, -SCN, and the E or Z isomers of -C(=NORlo)NH2, -C(=NRlo)H, -C~=NNRlo)NH2, -C(=NRIo)NH2, -C(=NORlo)H, and -C(=NOH)NtRlo)H;
Rlo is hydrogen, Cl-C4 alkyl, -Ac, -C(O)OCH3, -C(O)OC2H5, -phenyl, -PO2-O-cation+, -CO-CH(AA)NH2, -CO-C6H6-NR~ ~R~2, and -CO-C6H6-CH2-NRI ~R~2;
AA is-CH3, -CH(CH3)2, -CH2CH(CH3)2,-CH2OH, ~H(OH)CH3, -CH2CO2H, -CH2CH2C02H. -(CH2)4NH2. and-(CH2)3-NH2;
Rl I and R12 may be the sarne or different and are hydrogen and Cl-C4 alkyl;
Rll and R12 talceD together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and N-(CI-C4 allcyl)piperazinyl;
R3, present when the connection between positions 2 and 3 is a single bond, is hydrogen, Cl-C4 allcyl, -(CH2),CN, and -(CH2)bR~3;
R~3 is-N(CH3)2, -OH, -OPO3H, -OCH2CH(OH)CH2OH, -OCH2CO2H, -O2C(CH2)2CO2H, 4R14, and-NRl4;
R14 is a N-termina~ arnino acid;
a is zero to six;
b is one to five;
A is CH, CH2, and CHNtCH3)2;
X is CH, CH2, and C-R4;
R4 is -CH3, -OCH3, and -OAc;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen and sulfur;
Z is a linker selected from the group consisting of -(CO)-, -CH=CH-CH=CH- (all E), -CR15=CRl6- (E or Z), or -CH=C=CH-;
R15 and R16 may be the same or different and are hydrogen and fluorine;
Yl is hydrogen, -I~l, -F, -Br, -CH3, -CF3, -~CH2)CR17, -CHO, -C02CH3, -OH, -OCH3 -OAc, -CN, -NO2, -SH, and -SCH3;
c is zero to five;
R17 is-CH2N(CH3)2, -OH, -OPO3H, -CH2N(C2Hs)2, -O-sugar, -OCH2CH(OH)CH2OH, -OCH2CO2H, -O2CCH2CH2CO2H, -CH2N= CHN(CH3)2, -OR18, and -NR18;
- SUBSTITUl'E SHEET
. . .
. . , , . . ~ :
- . ., :: -WO 92/16508 2 ~ 013 3 S PCI/-rS92/01746 R18 is a N-terminal arnino acid;
Y2 is hydrogen, -Cl. -F, -OCH3, and -CF3;
Yl and Y2 taken together are -OCH20-, -OC(CH3);!0-, -OCH2NH-, -NHCH2~, -OCH2S, or-SCH20-;
S provided, however, when Z is -CR15=CR16- (E), and Y2, R15, and R16 are each hydrogen, Yl is not hydrogen, when R4 is -CH3, R3 is hydrogen, when R4 is -CH3, Yl is -Cl, -F, -Br, -CF3, -CN, or -N02, and wben R5 is fluorine, R6, R7 and R8 are each hydrogen;
or the pharrnaceutically acceptable salts thereof.
The invention aJso provides a method for treating a human infected wi~ one or more than one strain of a human immunodeficiency virus (HIV) which comprises administering an effective amount of a compound of formula I wherein R2 is -CN, -N3, -SCN, and the E or Z isomers of -C(=NORlo)NH2, -C(=NRlo)H, -C(=NNR1o)NH2, -C(=NRlo)NH2, -C(=NORIo)H, and -C(=NOH)N(Rlo)H;
Rlo is hydrogen, Cl-C4 alkyl, -Ac, -C02CH3, -C02C2H5, -phenyl, -P02-0- cation+, -CO-CH(AA)NH2, -CO-C6H6-NRI ~R12, and -CO-C6H6-CH2-NR1 IR12;
M is-CH3, -CH(CH3)2, -CH2CH(CH3)2,-CH20H, -CH(OH)CH3, -CH2C02H, -CH2CH2C02H, -(CH2)4NH2. and-(CH2)3-NH2;
R11 and R12 may be the sarne or different and are hydrogen and Cl-C4 alkyl;
Rll and R12 tal~en together are morpholinyl, piperazinyJ, pyrrolidinyl, piperadinyl, and N-(CI-C4 allcyl)pipera~inyl;
R3, present when the connection between positions 2 and 3 is a single bond, is hydrogen, Cl-C4 allcyl, -(CH2)"CN, and -(CH2)bR~3;
R13 is-N(CH3)2, -OH, -OP03H, -OCH2CH(-OH)CH20H, -OCH2C02H, -02C(cH2)2co2H~ -ORI4, and -NRI4;
R14 is a N-terminal arnino acid;
a is zero ~o s~x;
b is one to five;
A is CH, CH2, N, and CHN(CH3)2;
X is CH, CH2, NH, O, and C-R4;
R4 is -CH3 ~CH3, and -OAc;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen and sulfur;
Z is a direct ~ond or a linker selected from the group consisting of -(CO)-, -CH=CH-CH=CH- (all E), -CR15=CRl6- (E or Z), and -CH=C=CH-;
SUBSTITUTE SHEET
- . ' . . ' , . ' ' . . .
., . - . , . `, ` . .. .
. . . -. . . . :.
. . .
-. . , - - , , .
. . . .. . . . .. . ..
~vo 92/16508 2 1 ~ ~ 3 3 ~ -8- PCI/US92/01746 R15 and R16 may be Lhe same or different and are hydrogen and fluorine;
Yl is hydrogen, -Cl, -F, -Br, -CH3, -CF3, -(CH2)cRl7, ~HO, -C02CH3. -OH, -OCH3 -OAc, ~N, -N02, -SH, and -SCH3;
c is zero ~o five;
R17 is ~H2N(CH3)2, -OH, -OP03H, -CH2N(C2Hs)2, -O-sugar~
-OCH2CH(OH)CH20H, -OCH2CO2H, -02CCH2CH2C02H, -CH2N=CHN(CH3)2, -OR~8, or -NR18;
R18 is an N-terminal amino acid;
Y2 is hydrogen, -Cl, -F, -OCH3, and -CF3;
Yl and Y2 taken together can forrn -OCH20-, -OC(CH3)20-, -OCH2NH-, -NHCH20-, ~CH2S-, -SCH20-, and-CH=CRIg-CH=CH-;
R19 is hydrogen, -Cl, -Br, -N02, ~F3, -C02CH3, -OH, -CN, and -OAc;
provided, however, when Z is a direct bond and R2 is ~(=NOH)N(RIo)H and Rlo is hydrogen, Rl9 is not hydrogen, when Z is a direct bond, Yl is not hydrogen, when Yl is -OCH3 and Z is a direct bond, at least one of Rs, R6, R7 or R8 is fluorine, when Y1 is -CF3 and Z is direct bond, the coMection between positions 3 and 4 is a double bond, when Z is a direct bond, X is not 0, when Z is a direct bond, R2 is not -N3, when Z is a direct bond, Y2 is hydrogen or -F, when A is N, X is C-R4 and R4 is -OCH3 or -OAc and the connection between position 3 and 4 is a double bond, when A is CHN(cH3)2~ X is CH
when R4 is -CH3, R3 is hydrogen, when R4 is -CH3, Yl is -Cl, -F, -Br, -CF3, -CN, or -N02, when R5 is fluorine, R6, R7 and R8 are each hydrogen, when Yl and Y2 taken together are -CH=CRI9-CH=CH-, Z is a direct bond, and when Yl and Y2 taken together can forrn -OCH20-, -OC(CH3)2~, -OCH2NH-, 30 -NHCH20-, -OCH2S-, and -SCH20-, Z is a linker; to a human patient.
The preferred compound for this method is l-E-(3-(4-chlorophenyl)-1-o~o-2-propenyl)-2-cyano-1 ,2-dihydroquinoline.
The invention further provides the use of the compounds of the invention and/or their pharmaceutically acceptable salts, hydrates, and solvates for the preparation of pharmaceutical 35 formulations. These formulations are useful to practice the method claimed in this invention.
DETAILED DESCRIPllON OF THE INVENTION
SUBSTITVTE SHEET
- - - - . , ` . - - .
.~: . . :
-. ` ' - ~
wo 92/16508 21 a 13 3 ~ . PCl/US92/01746 r 9 Generally, the compounds of forrnula I are preferred.
Particularly preferred are the compounds of the invention wherein there is a double bond berween A and X, and A is CH. It is preferred that X is CH. It is preferred that Z is ~R15=CR16- (E), and that R15 and R16 are hydrogen. It is preferred that W is O. It is
or the pharmaceuticaJly acceptable sal~s thereof.
S nle preferred compound is l-E-(3-(4-chlorophenyl)-1-o~o-2-propenyl)-2-cyano-1,2-d ihydroqu inol ine.
The invention further provides compounds of formula n wherein R2 is -CN, -SCN, and the E or Z isomers of -C(-NORI~)NH2, -C(=NRlo)H, -C(= NNRlo)NH2, -C(= NRlo)NH2, -C(= NORIo)H, and -C(= NOH)N(RIo)H;
Rlo is hydrogen, Cl-C4 alkyl, -Ac, -C(O)OCH3, -C(O)OC2HS, -pbenyl, -PO2-O-cation+, -CO-CH(AA)NH2, -CO-C6H6-NRlIR~2, and -CO-C6H6-CH2-NRIIR12;
AA is-CH3, -CH(CH3)2,-CH2CH(CH3)2.-CH2OH, -CH(OH)CH3, -CH2CO2H, -cH2cH2co2H~ -(CH2)4NH2. and -(CH2)3-NH2;
Rll and R12 may be the sarne or differen~ and are hydrogen and Cl-C4 alkyl;
Rl I and R12 taken together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and N-(CI-C4 alkyl)piperazinyl;
R3, present when the conne tion between positions 2 and 3 is a single bond, is hydrogen, Cl-C4 alkyl, -(CH2),CN, and -(CH2)bR13;
R13 is-N(CH3)2, -OH, -OPO3H, ~CH2CH(OH)CH2OH, -OCH2CO2H, -02C(CH2)2C02H, -OR14, and ~ 4;
R14 is a N-terminal amino acid;
a is zero to six;
b is one to five;
A is CH, CH2, and CHN(CH3)2;
X is CH, CH2, and C-R4;
R4 is -CH3, -OCH3, and ~Ac;
R5, R6, R7, R8 may be the same or different and are hydrogen and fluorine;
W is o~tygen and sulfur;
Yl is-CI,-F, -Br,-CH3,-CF3,-(CH2)cRl7,-CHO,-CO2CH3,-OH,-OCH3 -OAc, -CN, -NO2, -SH, and -SCH3;
c is zero to four;
R17 is-CH2N(CH3)2, -OH, -OPO3H, -CH2N(C2H5)2, -O-sugar, -OCH2CH(OH~CH20H,-OCH2C02H,-02CCH2CH2C02H,-CH2N=CHN(CH3)2,-OR~8, asld -NR~8;
R18 is a N-terrninal amino acid;
Y2 is hydrogen;
SUBSTITUTE SHEET
...
- :~
.
wo 92/16508 2 1 ~ 1 3 3 5 ` PCT/I IS92/01746 f, '.' . -S~
Yl and Y2 ta~en together are -CH=CRI9-CH=CH-;
Rl9 is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CM3, -OH, -CN, and -OAc;
provided, however, when A and X are each CH, and R5, R6, R7, and R8 are each hydrogen, and R2 is -CN, Y~ is not ~1, -F, or -CH3 and R19 is not hydrogen, S when R2 is -C(=NOH)N(RIo)H and Rlo is hydrogen, Rl9 is not hydrogen, when Yl is ~CH3, at least one of R5, R6, R7 or R8 is fluorine, when Yl is -CF3, the connection between positions 3 and 4 is a dauble bond, when R4 is -CH3, R3 is hydrogen, when R4 is -CH3, Yl is -Cl, -F, -Br, -CF3, -CN, or -NO2, and î0 when R5 is fluorine, R6, R7 and R8 are each hydrogen, or the phannaceutically acceptable salts thereof.
Further provided is a compound of forrnula 11 wherein R2 is -CN, -SCN, and the E or Z isomers of -C(=NORlo)NH2, -C(=NRlo)H, -C(= NNRlo)NH2, -C(= NRlo)NH2, (:(= NORIo)H, and -C(= NOH)N(Rlo)H;
Rlo is hydrogen, Cl-C4 alkyl, -Ac, ~(O)OCH3, -C(O)OC2H5, -phenyl, -PO2-O-cation+, ~CO-CH(AA)NH2, -CO-C6H6-NRI IR12, and -CO-C6H6-CH2-NRI ~R12;
AA is-CH3, ~H(CH3)2, -CH2CH(CH3)2,-CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H, -(CH2)4NH2. and -(CH2)3-NH2;
R1~ and R12 may be the sarne or diffe-enl and are hydrogen and Cl-C4 aJkyl;
Rll and R12 taken together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and N-(CI-C4 alkyl)piperazinyl;
A is CH, CH2, and N;
X is C-R4, and NH;
R4 is -CH3 ~CH3, and -OAc;
R3, preseDt when the connection between positions 2 and 3 is a single bond, is hydrogen;
R5, R6, R7, R8 may be the sa ne or different and are hydrogen and fluorine;
W is oxygen;
Yl is-CI, -F, -Br, -CH3, -CF3, -CHO, -C02CH3,-OH, -OCH3 ~Ac, -CN, -NO2, -SH, and-SCH3;
Y2 is hydrogen;
Yl and Y2 taken together are -CH=CRI9-CH=CH-;
Rl9 is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CH3, -OH, -CN, and -OAc;
provided, however, when Yl is -OCH3, at least one of Rs, R6, R7 or R8 is fluorine, when Yl is -CF3, the connection between positions 3 and ~ is a double bond, when A is N, X is C-R4 and R4 is -OCH3 or -OAc and the connection between position - SUBSTITUTE SHEET
.. . . .... .... . . . . .
.. . ..
- . ... - .. ` . . : ~ -. . : -.
: ~ :. . .. ..
-`: ~ : ~ . . ~ . . ..
WO 92/16508 21 D 1 ~ 3 ~ PCr/US92/01746 3 and 4 is a double bond, when R4 is -CH3, R3 is hydrogen, when R4 is -CH3, Yl is-CI, -F, -Br, -CF3, -CN, or -NO2, and when R5 is fluorine, R6, R7 and R8 are each hydrogen;
S or the pharrnaceutically acceptable salts thereof.
llle invention further provides compourds of formula I wherein ~2 is -CN, -N3, -SCN, and the E or Z isomers of -C(=NORlo)NH2, -C(=NRlo)H, -C~=NNRlo)NH2, -C(=NRIo)NH2, -C(=NORlo)H, and -C(=NOH)NtRlo)H;
Rlo is hydrogen, Cl-C4 alkyl, -Ac, -C(O)OCH3, -C(O)OC2H5, -phenyl, -PO2-O-cation+, -CO-CH(AA)NH2, -CO-C6H6-NR~ ~R~2, and -CO-C6H6-CH2-NRI ~R~2;
AA is-CH3, -CH(CH3)2, -CH2CH(CH3)2,-CH2OH, ~H(OH)CH3, -CH2CO2H, -CH2CH2C02H. -(CH2)4NH2. and-(CH2)3-NH2;
Rl I and R12 may be the sarne or different and are hydrogen and Cl-C4 alkyl;
Rll and R12 talceD together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and N-(CI-C4 allcyl)piperazinyl;
R3, present when the connection between positions 2 and 3 is a single bond, is hydrogen, Cl-C4 allcyl, -(CH2),CN, and -(CH2)bR~3;
R~3 is-N(CH3)2, -OH, -OPO3H, -OCH2CH(OH)CH2OH, -OCH2CO2H, -O2C(CH2)2CO2H, 4R14, and-NRl4;
R14 is a N-termina~ arnino acid;
a is zero to six;
b is one to five;
A is CH, CH2, and CHNtCH3)2;
X is CH, CH2, and C-R4;
R4 is -CH3, -OCH3, and -OAc;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen and sulfur;
Z is a linker selected from the group consisting of -(CO)-, -CH=CH-CH=CH- (all E), -CR15=CRl6- (E or Z), or -CH=C=CH-;
R15 and R16 may be the same or different and are hydrogen and fluorine;
Yl is hydrogen, -I~l, -F, -Br, -CH3, -CF3, -~CH2)CR17, -CHO, -C02CH3, -OH, -OCH3 -OAc, -CN, -NO2, -SH, and -SCH3;
c is zero to five;
R17 is-CH2N(CH3)2, -OH, -OPO3H, -CH2N(C2Hs)2, -O-sugar, -OCH2CH(OH)CH2OH, -OCH2CO2H, -O2CCH2CH2CO2H, -CH2N= CHN(CH3)2, -OR18, and -NR18;
- SUBSTITUl'E SHEET
. . .
. . , , . . ~ :
- . ., :: -WO 92/16508 2 ~ 013 3 S PCI/-rS92/01746 R18 is a N-terminal arnino acid;
Y2 is hydrogen, -Cl. -F, -OCH3, and -CF3;
Yl and Y2 taken together are -OCH20-, -OC(CH3);!0-, -OCH2NH-, -NHCH2~, -OCH2S, or-SCH20-;
S provided, however, when Z is -CR15=CR16- (E), and Y2, R15, and R16 are each hydrogen, Yl is not hydrogen, when R4 is -CH3, R3 is hydrogen, when R4 is -CH3, Yl is -Cl, -F, -Br, -CF3, -CN, or -N02, and wben R5 is fluorine, R6, R7 and R8 are each hydrogen;
or the pharrnaceutically acceptable salts thereof.
The invention aJso provides a method for treating a human infected wi~ one or more than one strain of a human immunodeficiency virus (HIV) which comprises administering an effective amount of a compound of formula I wherein R2 is -CN, -N3, -SCN, and the E or Z isomers of -C(=NORlo)NH2, -C(=NRlo)H, -C(=NNR1o)NH2, -C(=NRlo)NH2, -C(=NORIo)H, and -C(=NOH)N(Rlo)H;
Rlo is hydrogen, Cl-C4 alkyl, -Ac, -C02CH3, -C02C2H5, -phenyl, -P02-0- cation+, -CO-CH(AA)NH2, -CO-C6H6-NRI ~R12, and -CO-C6H6-CH2-NR1 IR12;
M is-CH3, -CH(CH3)2, -CH2CH(CH3)2,-CH20H, -CH(OH)CH3, -CH2C02H, -CH2CH2C02H, -(CH2)4NH2. and-(CH2)3-NH2;
R11 and R12 may be the sarne or different and are hydrogen and Cl-C4 alkyl;
Rll and R12 tal~en together are morpholinyl, piperazinyJ, pyrrolidinyl, piperadinyl, and N-(CI-C4 allcyl)pipera~inyl;
R3, present when the connection between positions 2 and 3 is a single bond, is hydrogen, Cl-C4 allcyl, -(CH2)"CN, and -(CH2)bR~3;
R13 is-N(CH3)2, -OH, -OP03H, -OCH2CH(-OH)CH20H, -OCH2C02H, -02C(cH2)2co2H~ -ORI4, and -NRI4;
R14 is a N-terminal arnino acid;
a is zero ~o s~x;
b is one to five;
A is CH, CH2, N, and CHN(CH3)2;
X is CH, CH2, NH, O, and C-R4;
R4 is -CH3 ~CH3, and -OAc;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen and sulfur;
Z is a direct ~ond or a linker selected from the group consisting of -(CO)-, -CH=CH-CH=CH- (all E), -CR15=CRl6- (E or Z), and -CH=C=CH-;
SUBSTITUTE SHEET
- . ' . . ' , . ' ' . . .
., . - . , . `, ` . .. .
. . . -. . . . :.
. . .
-. . , - - , , .
. . . .. . . . .. . ..
~vo 92/16508 2 1 ~ ~ 3 3 ~ -8- PCI/US92/01746 R15 and R16 may be Lhe same or different and are hydrogen and fluorine;
Yl is hydrogen, -Cl, -F, -Br, -CH3, -CF3, -(CH2)cRl7, ~HO, -C02CH3. -OH, -OCH3 -OAc, ~N, -N02, -SH, and -SCH3;
c is zero ~o five;
R17 is ~H2N(CH3)2, -OH, -OP03H, -CH2N(C2Hs)2, -O-sugar~
-OCH2CH(OH)CH20H, -OCH2CO2H, -02CCH2CH2C02H, -CH2N=CHN(CH3)2, -OR~8, or -NR18;
R18 is an N-terminal amino acid;
Y2 is hydrogen, -Cl, -F, -OCH3, and -CF3;
Yl and Y2 taken together can forrn -OCH20-, -OC(CH3)20-, -OCH2NH-, -NHCH20-, ~CH2S-, -SCH20-, and-CH=CRIg-CH=CH-;
R19 is hydrogen, -Cl, -Br, -N02, ~F3, -C02CH3, -OH, -CN, and -OAc;
provided, however, when Z is a direct bond and R2 is ~(=NOH)N(RIo)H and Rlo is hydrogen, Rl9 is not hydrogen, when Z is a direct bond, Yl is not hydrogen, when Yl is -OCH3 and Z is a direct bond, at least one of Rs, R6, R7 or R8 is fluorine, when Y1 is -CF3 and Z is direct bond, the coMection between positions 3 and 4 is a double bond, when Z is a direct bond, X is not 0, when Z is a direct bond, R2 is not -N3, when Z is a direct bond, Y2 is hydrogen or -F, when A is N, X is C-R4 and R4 is -OCH3 or -OAc and the connection between position 3 and 4 is a double bond, when A is CHN(cH3)2~ X is CH
when R4 is -CH3, R3 is hydrogen, when R4 is -CH3, Yl is -Cl, -F, -Br, -CF3, -CN, or -N02, when R5 is fluorine, R6, R7 and R8 are each hydrogen, when Yl and Y2 taken together are -CH=CRI9-CH=CH-, Z is a direct bond, and when Yl and Y2 taken together can forrn -OCH20-, -OC(CH3)2~, -OCH2NH-, 30 -NHCH20-, -OCH2S-, and -SCH20-, Z is a linker; to a human patient.
The preferred compound for this method is l-E-(3-(4-chlorophenyl)-1-o~o-2-propenyl)-2-cyano-1 ,2-dihydroquinoline.
The invention further provides the use of the compounds of the invention and/or their pharmaceutically acceptable salts, hydrates, and solvates for the preparation of pharmaceutical 35 formulations. These formulations are useful to practice the method claimed in this invention.
DETAILED DESCRIPllON OF THE INVENTION
SUBSTITVTE SHEET
- - - - . , ` . - - .
.~: . . :
-. ` ' - ~
wo 92/16508 21 a 13 3 ~ . PCl/US92/01746 r 9 Generally, the compounds of forrnula I are preferred.
Particularly preferred are the compounds of the invention wherein there is a double bond berween A and X, and A is CH. It is preferred that X is CH. It is preferred that Z is ~R15=CR16- (E), and that R15 and R16 are hydrogen. It is preferred that W is O. It is
5 preferred that R3 and R5 are hydrogen and R6 R7 and R8 are eithe- hydrogen or F. It is preferred tha~ R2 is CN. It is preferred that Y2 is hydrogen. It is preferred that Y I is Cl or C:N, most preferred is where Y I is Cl.
It is understood by those sl~illed in the art that the stereoisomers and enantiomers of the compounds of the invention are included within the scope of the inventioD.
The compounds of the invention are useful as inhibitors of viral reverse transcriptase, an enzyme necessary for human immunodeficiency virus replication, and tnerefore would be useful in the treatment of disease, such as acquired immune deficiency syndrome (AIDS).
The term human retrovirus ~HRV) includes human immunodeficiency virus type I
(HIV-I), or variant strains thereof, apparent to one skilled in the art, which belong to the same 15 viral families and which create similar physiological effects in humans as HRV.
Patients to be treated would be those individuals: I) infected with one or more than one strain of a buman retrovirus as determined by the presence of either measurable viral antibody or antigen in the serum and 2) having either a symptomatic AlDS defining infection such as (a) dissèminated histoplasmosis, (b) isopsoriasis, (c) bronchial and puln onary candidiasis including 20 pneumocystic pneumonia, (d) non-Hodgkin's Iymphoma, or (e) Kaposi's sarcoma and being less than si~ty years old; or having an absolute CD4 Iymphocyte count of less than 500/mm3 in the peripheral blood. Additionally, persons who show the signs and symptoms of AI~S-re1ated comple~ (ARC) may be treated with the compounds of this invention Sucb signs andsymptoms include, but are not limited to, generali~ed Iymph adenopathy, weight loss, anemia, 25 candidiasis, and imrnunologic abnormalities characteristic of AIDS. Treatment of ARC and AIDS patients would consist of maintaining an inhibitory level of the compound of the invention used according to this invention in the patient at all times and would continue until the occurrence of a second symptomatic AIDS defining infection indicates alterrlate therapy is needed. Treatment of asymptomatic patients would typically require lower daily maintenance 30 dosages. In addition, the compounds of the invention may be used in conjunction with other antiviral agents such as AZT.
The compounds of the invention, or pharmaceutically acceptable salts, hydrates, and solvates thereof, can be used and administered in practicing the method claimed in this invention. The compounds of the invention may form acid addition salts when reacted with 35 acids of sufficient strength to produce the corresponding salt. ln addition, some of the variable substituents are acids and thus form base addition salts when reacted with bases of sufficient SUBSTITUTE SHEET
. . . .. . . . . . . .
:.' : . . - . , .
- , . . - , . ~ -- ., -WO92/1650X 2~ PCT/I~'S92/01746 1~ ~
strength. Pharmaceutically acceptable salts refers to those salts of the compounds of the invention which would be readily apparent to a manufacturing pharmaceutical chemist to be equiva]ent to, or bener than, the parent compound in properties such as formulation, stability, patient acceptance, and bioavailability. Generally, the pharmaceutically acceptable salts, either 5 acid or base as the case may be, are preferable over the free acid or base since the salt is more water soluble and more crystalline. The pharmaceutically acceptable salts include botb inorganic and organic acids and bases. Examples of pharmaceutically acceptable salts include salts of the following acids: methanesulfonic, hydrochloric, hydrobromic, sulfuric, pbosphoric, niuic, benzoic, tartaric, fumaric, maleic, p-toluenesulfonic, benzenesulfonic, and the lilce.
10 E~amples of pharmaceutically acceptable salts include salts of the following bases: hydroxide, ammonia, tromethamine (l~AM), and the like. Suitable cations include, for e%ample. sodium, potassium, calcium, and magnesium.
Those slcilled in the art would know how to formulate the compounds used to practice the method claimed in this invention into appropriate pharmaceutical dosage forms. E~amples 15 of the dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions.
When the compounds used to practice the method claimed in this invention are administered orally, an effective amount is from about 0,2 to about 100 mg per Icg per day for asymptomatic patients, and about I to about 500 mg per kg per day for ARC and AIDS
20 patients. A typical unit dose for a 70 kg human AlDS patients would be from about 50 mg to 1000 mg, preferably 200 mg to 1000 mg taken one to four times per day. Either solid or fluid dosage forms can be prepared for oral administration. Solid compositions are prepared by r~u%ing the compounds used to practice the method claimed in this invention with conventional iDgredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum sili-2S cate, calcium sulfate, starch, lactose, acacia, methyl cellulose, or functionally similarpbarmaceutical diluents and carriers. Capsules are prepared by mi%ing the compounds used to practice the method claimed in this invention with an inert pharmaceutical diluent and placing the mixture into aD appropriately sized hard gelatin capsule. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compounds used to practice the method claimed in 30 this invention with an acceptable inert oil such as vegetable oil or light liquid petrolatum.
Syrups are prepared by dissolving the compounds used to practice the method claimed in this invention in an aqueous vehicle and adding sugar, aromatic flavoring agents and preservatives.
Eli%irs are prepared using a hydroalcoholic vehicle such as ethanol, suitable sweeteners such as sugar or saccharin and an aromatic flavoring agent. Suspensions are prepared with an aqueous 35 or organic vehicle and a suspending agent such as acacia, tragaca~th, or methyl cellulose.
When the compounds used to practice the method claimed in this invention are SUBSTITUTE SHEET
~ .
~:
WO 92/16508 2 ~ O ~ 3 ~ 5 PCT/US92/0174b administered parenterally, it can be given by injection or by intravenous infusion. An effective amount is from about I to 100 mg per kg per day. Parenteral solutions are prepared by dissolving the compounds used to practice the method claimed in this invention in an appropriate solvent and filter sterilizing the solulion before placing in a suitable sealable vial or 5 ampule. Parenteral suspensions are prepared in substantially the same way except a sterile suspension vehicle is used and the compounds used to practice the method claimed in this invention are sterilized with ethylene oxide, suitable gas or other methods Lnown in the art, before it is suspended in the vehicle.
The exact route of administration, dose, or frequency of administration would be10 readily determined by one skilled in the art and is dependent on the particular compound of the invention being used, and on the age, weight, general physical condition, other medication the individual is taking, or other clinical symptoms specific to the patient to be treated.
Tenns used in this specification and claims have the following definitions:
~AIDS~ means acquired immune deficiency syndrome.
~ARC" means All)S-related complex.
"E or Z" designates stereochemistry around a double bond. The two groups attached to each atom of the double bond are assigned priorities according to the Prelog-Cahn-lngold system. "E~ refers to an arrangement in whicb the two higber priority or two lower priority groups are on the opposite sides of the double bond. ~Z" refers to an arrangement in which the 20 two higher priority groups are on the same side of the double bond "Phenyl~ mèans -C6H5 "N-terminal arnino acid~ means a naturally occurring amino acid, and synthetic derivatives thereof, in which the arnino group is free, i.e., the amino acid is linked via the carboxyi group to form either an ester or an arnide.
"-Ac~ means-C(O)CH3; ~-OAc~ means-OC(O)CH3.
~O-sugar~ means a hexose or pentose monosaccharide linked at the 2-hydroxyl group.
~-C02-~ or "-C(O~O-~ designates an es~er linked via the carbon.
~-O2C-~ or ~-OC(O)-~ also designates an ester, with the linkage Yia the oxygen.
~-CO2H~ designates a carboxylic acid.
"-CH=CRIg-CH=CH-~ designates a carbon chain linking Yl and Y2 where (Yl end) -CH-CR19-CH=CH- (Y2 end).
Throughout the disclosure and clairns, common shorthand chemical terms are used. The carbon atom content of the various hydrocarbon-contain. 3g moieties is indicated by designating the minimum and maxirmurn number of carbon atoms in the moiety, i.e. Cm-Cn indicates a moiety of integer ~m~ to the integer ~n~ carbon atoms, inclusive and includes the isomeric forms. For exarnple, Cl-C6 alkyl refers to an alkyl of one to six carbons, inclusive, including SUBSTITUTE SHEET
.
`
wo 92/16508 ~ :1 0 1 3 3 ~ PCr/US92/01746 the isomeric forms. Chemical formulas, or portions thereof, drawn in a linear fashion may use Ihe symbol ~ o represent a single chemical bond between atoms in the linear chain. Likewise, the symbol ~ = ~ represents a double bond, and ~ . ~ a uiple bond, between atoms in the chain.
In ~he structural formulas the symbol ~ represents a bond between two atoms which may be a single or a double bond; the symbol ~ represents a bond which may or may not be present, and if present, is a single bond.
Temperatures are in degrees Celsius. The letter "h~ means hours. "TLC~ means thin layer chromatography. MS refers to mass specuometry. MS data are expressed as m/e or mass/change unit.
Svnthesis of Representative Compounds In preparative methods that follow, the compounds of the invention are synthesized following techniques which are known, or readily acquired, by one skilled in the art. E~amples of such techniques are:
F.D. Popp, ~Reissen Compounds and Related N-acyldihydroquinolines~ in Quinolines, Par~ Il, Ed. G. lones, (1982) p. 353-372, is a general review covering the synthesis and reactions of Reissen compounds. This review specifically describes the synthesis of 1-(4-chlorobenzoyl)-2-cyano- 1,2-dihydroquinoline, 1 -(4-fluorobenzoyl~2-cyano- 1,2-dihydroquinoline, 1-(4-me~hoxybenzoyl)-2-cyano-1,2~ih~droquinoline, 1-(4-toluoyl)-2-cyano-1,2-dihydroquinolhe, 1-(~nitroben~oyl)-2-cyano-1,2-dihydroquinoline, 1-(2-naphthoyl~2-cyano-1,2-dihydroquinoline, and 1-(1-o~o-3-phenyl-2-propenyl)-2-cyano-1,2-dihydroquinoline.
F.D, Popp, W. Blount and P. Melvin, 1. Q~. Chem., 26, 4930 (1961), describes themethylene chloride/water method for synthesizing Reissert Compounds.
S. Ruchirawat, N. Phadungkul, M. Chuankamnerdkarn, and C. Thebtaranonth, Heterocvcles, 6, No. 1, 43 (1977), describes the trimethylsilyl cyanide method of synthesizing Reissert compounds.
M. Rozwadowska, Roczniki Chemii. 51, 2321 (1977), describes hydrogenation of dihydroquinoline Reisser~ compounds to tetrahydroquinolines.
L. Walters, M. Siegel, and R. Cook, L. Heterocvclic Chem., 5, 577 (1968), describes synthesis of amido%imes, also called carboxamidamides, via addition of hydro%ylamine to a Reissert compound.
H. Bartsch, O. Schwarz, and G. Neubauer, Heterocycles, 24, 3483 (1986), describes the synthesis of a benzoxazine Reissert compound.
F. Elroy and R. Lenaers, "The Chemistry of Amido%imes and Related Compounds,~
Chem. a~ev. 155 (1962), describes synthesis and reactions of amido~imes.
Uff, B.C., Budhram, R.S., Consterdine7 M.F., Hicks, J.K., and Slingsby, 33.P., 1 ~h~. Soç., Perkins7 Trans a (18):2018-22 (1977), describes synthesis of 1-(4-SUBSTITUTE SHEET
:, . . . . ~ ~
- . . . .
. . : ~ . - .. ~
wo 92/16508 2 ~ O 1 3 3 ~ PCI /US92/01746 f methoxybenzoyi)-2-cyanoJ,-me~hyl- I ,2-dihydroquinoline.
F.D. Popp and A. Soto, I Chem. Soc., 1760 (1963), describes the synthesis of 1-(~
fluorobenzoyl)-2-cyano- 1 ,2-dihydroquinoline.
All starting materials are icnown and are corrunercially available, or are readily prepared from icnown or readily available materials.
The synthesis of compounds of the invention proceed, generally, as outlined below and, more specifically, in the representative examples that follow. The synthesis of the dihydro- and teuahydroquinolines, the dihydroquinazolines and the dihydroquinoxalines are outlined in Chart A, the teuahydrobenzoxazines in Chart B, and ti~e a nidoxime compounds of the invention in Chart C. In the Chans the l-(benzoyl) or l-(cinnamoyl) substituents are designated "R~, and the halide of the acid halide is designated ~X~.
The exarnples that follow are illustrative and not limitations of the preceding disclosure.
The conditions described here and in the examples for the synthesis and purification of the compounds of the invention may be altered depending on the choice of reactants and solvents, the batch size, the degree to which the reaction is to be carried to completion, and other factors of concern to the chemist.
Procedure for ~reoaration of Reissert compounds (Chart A~.
There are numerous techniques available for the synthesis of Reissert compounds from quinoline. Among these are preparation in aqueous potassium cyanide, potassium cyanide in a dimethylformamide-water mixture, liquid sulphur dioxide as a solvent, anhydrous benzene-liquid hydrogen cyanide, and trimethylsilyl cyanide-aluminum chloride in methylene chloride.
See, F.D. Popp, ~Reissert Compounds and Related N-acyldihydroquinolines~ in Quinolines, Part II, Ed. G. Jones, (1982) p. 353-372. We prefer the methylene chloride-trimethylsilyl cyanide system.
Referring now to Chart A, one equivalent (I eq.) of the quinoline (Chart A fig. 1), quinazoline (Chart A, fig. 4), quinoxaline (Chart A, fig. 5), or substituted forms thereof, is dissolved in dichloromethane or acetonitrile to a concentration of 0.4-0.5 M. An acid halide, preferably chloride, (1.5-2 eq.), Lewis acid, preferably aluminum trichloride (anhydrous, 0.05 eq.) and trimethylsilyl cyanide (1.5-2 eq.) are added while stirring. A thio-acid halide is substituted when the corresponding thio-Reissert compound is desired. Thio-acid halides are synthesized following known procedures, for example, R. Mayer and S. Scheithauer, J.
Heterocyclic Chem. 16, 1589 (1977). The Reissert reaction is carried out under ambient temperature conditions, e.g. 23-27 degrees, or refluxing acetonitrile for 8-substituted compounds, for a time sufficient to effect as complete a reaction as possible, e.g. from 0.5 to 48 hours. The products of the reaction (Chart A, fig. 2) are followed by ll C using solvent systems known in the art. Upon completion, the reaction is concentrated in vacJlo and then SUBSTITUTE SHEE~
:
' : ;
.
Wo 92/16~08 ;~ 3 3 ~ PCr/l,'S92/0174 placed on a silica gel column and eluted under flash chroma~ography conditions. The product is recrystallized from a low boiling point aliphatic alcohol, preferably 95% ethanol, or ethylacetate/hexane.
When a tetrahydroquinoline product is desired, the dihydroquinoline (Chart A, fig. 2) is 5 dissolved in alcohol, preferably 95~o ethanol, and reduced by hydrogenation in the presence of platinum. The reaction is followed and the product lChart A, fig. 3) recrystallized as outlined above.
Preparation 1 6,7-difluoroquinoline Sodium 3-nitrobenzensulphonate ~27.25 B, 1.25 eq.), followed by glycerol (25.50 g, 10 20.22 ml, 2.86 equiv.), and aqueous sulphuric acid (80% w/w, 81 ml) are placed in a 1 L.
three-necked flask. With stirring, 3,4-difluoroaniline (12.50 g, 9.60 rnl, 1 eq.) is slowly added and then heated under gentle reflux in an oil bath at 175C for 5 hours. The reaction mixture is cooled to room temperature and treated with aqueous sodium nitrite (25% w/w, 55 ml) from a dropping funnel. The mi~ture is subjected to steam-distillation. The yellowish aqueous 15 distillate is discarded. The reaction product is cooled in an ice bath, made strongly alkaline, i.e. pH 9-12, by the cautious addition of aqueous sodium hydroxide (50% w/w), and again subjected to steam distillation. A colorless solid formed in both the condenser and receiver.
Extraction with ethyl acetate, drying over sodium sulphate, and removal of the solvent in the rotary evaporator at 35~C, under house vacuum gave a solid (13.20 g) TLC in hexane-methanol 20 (1:6 v/v) showed the presence of a major and a minor product Direct crystallization gave 6,7-difluoroquinoline (9.25 g) m.p. 112-113C. The mother liquors contain the minor 5,6-difluoro-isomer.
PreparatiQn 2 6,8-difluoroquinoline
It is understood by those sl~illed in the art that the stereoisomers and enantiomers of the compounds of the invention are included within the scope of the inventioD.
The compounds of the invention are useful as inhibitors of viral reverse transcriptase, an enzyme necessary for human immunodeficiency virus replication, and tnerefore would be useful in the treatment of disease, such as acquired immune deficiency syndrome (AIDS).
The term human retrovirus ~HRV) includes human immunodeficiency virus type I
(HIV-I), or variant strains thereof, apparent to one skilled in the art, which belong to the same 15 viral families and which create similar physiological effects in humans as HRV.
Patients to be treated would be those individuals: I) infected with one or more than one strain of a buman retrovirus as determined by the presence of either measurable viral antibody or antigen in the serum and 2) having either a symptomatic AlDS defining infection such as (a) dissèminated histoplasmosis, (b) isopsoriasis, (c) bronchial and puln onary candidiasis including 20 pneumocystic pneumonia, (d) non-Hodgkin's Iymphoma, or (e) Kaposi's sarcoma and being less than si~ty years old; or having an absolute CD4 Iymphocyte count of less than 500/mm3 in the peripheral blood. Additionally, persons who show the signs and symptoms of AI~S-re1ated comple~ (ARC) may be treated with the compounds of this invention Sucb signs andsymptoms include, but are not limited to, generali~ed Iymph adenopathy, weight loss, anemia, 25 candidiasis, and imrnunologic abnormalities characteristic of AIDS. Treatment of ARC and AIDS patients would consist of maintaining an inhibitory level of the compound of the invention used according to this invention in the patient at all times and would continue until the occurrence of a second symptomatic AIDS defining infection indicates alterrlate therapy is needed. Treatment of asymptomatic patients would typically require lower daily maintenance 30 dosages. In addition, the compounds of the invention may be used in conjunction with other antiviral agents such as AZT.
The compounds of the invention, or pharmaceutically acceptable salts, hydrates, and solvates thereof, can be used and administered in practicing the method claimed in this invention. The compounds of the invention may form acid addition salts when reacted with 35 acids of sufficient strength to produce the corresponding salt. ln addition, some of the variable substituents are acids and thus form base addition salts when reacted with bases of sufficient SUBSTITUTE SHEET
. . . .. . . . . . . .
:.' : . . - . , .
- , . . - , . ~ -- ., -WO92/1650X 2~ PCT/I~'S92/01746 1~ ~
strength. Pharmaceutically acceptable salts refers to those salts of the compounds of the invention which would be readily apparent to a manufacturing pharmaceutical chemist to be equiva]ent to, or bener than, the parent compound in properties such as formulation, stability, patient acceptance, and bioavailability. Generally, the pharmaceutically acceptable salts, either 5 acid or base as the case may be, are preferable over the free acid or base since the salt is more water soluble and more crystalline. The pharmaceutically acceptable salts include botb inorganic and organic acids and bases. Examples of pharmaceutically acceptable salts include salts of the following acids: methanesulfonic, hydrochloric, hydrobromic, sulfuric, pbosphoric, niuic, benzoic, tartaric, fumaric, maleic, p-toluenesulfonic, benzenesulfonic, and the lilce.
10 E~amples of pharmaceutically acceptable salts include salts of the following bases: hydroxide, ammonia, tromethamine (l~AM), and the like. Suitable cations include, for e%ample. sodium, potassium, calcium, and magnesium.
Those slcilled in the art would know how to formulate the compounds used to practice the method claimed in this invention into appropriate pharmaceutical dosage forms. E~amples 15 of the dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions.
When the compounds used to practice the method claimed in this invention are administered orally, an effective amount is from about 0,2 to about 100 mg per Icg per day for asymptomatic patients, and about I to about 500 mg per kg per day for ARC and AIDS
20 patients. A typical unit dose for a 70 kg human AlDS patients would be from about 50 mg to 1000 mg, preferably 200 mg to 1000 mg taken one to four times per day. Either solid or fluid dosage forms can be prepared for oral administration. Solid compositions are prepared by r~u%ing the compounds used to practice the method claimed in this invention with conventional iDgredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum sili-2S cate, calcium sulfate, starch, lactose, acacia, methyl cellulose, or functionally similarpbarmaceutical diluents and carriers. Capsules are prepared by mi%ing the compounds used to practice the method claimed in this invention with an inert pharmaceutical diluent and placing the mixture into aD appropriately sized hard gelatin capsule. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compounds used to practice the method claimed in 30 this invention with an acceptable inert oil such as vegetable oil or light liquid petrolatum.
Syrups are prepared by dissolving the compounds used to practice the method claimed in this invention in an aqueous vehicle and adding sugar, aromatic flavoring agents and preservatives.
Eli%irs are prepared using a hydroalcoholic vehicle such as ethanol, suitable sweeteners such as sugar or saccharin and an aromatic flavoring agent. Suspensions are prepared with an aqueous 35 or organic vehicle and a suspending agent such as acacia, tragaca~th, or methyl cellulose.
When the compounds used to practice the method claimed in this invention are SUBSTITUTE SHEET
~ .
~:
WO 92/16508 2 ~ O ~ 3 ~ 5 PCT/US92/0174b administered parenterally, it can be given by injection or by intravenous infusion. An effective amount is from about I to 100 mg per kg per day. Parenteral solutions are prepared by dissolving the compounds used to practice the method claimed in this invention in an appropriate solvent and filter sterilizing the solulion before placing in a suitable sealable vial or 5 ampule. Parenteral suspensions are prepared in substantially the same way except a sterile suspension vehicle is used and the compounds used to practice the method claimed in this invention are sterilized with ethylene oxide, suitable gas or other methods Lnown in the art, before it is suspended in the vehicle.
The exact route of administration, dose, or frequency of administration would be10 readily determined by one skilled in the art and is dependent on the particular compound of the invention being used, and on the age, weight, general physical condition, other medication the individual is taking, or other clinical symptoms specific to the patient to be treated.
Tenns used in this specification and claims have the following definitions:
~AIDS~ means acquired immune deficiency syndrome.
~ARC" means All)S-related complex.
"E or Z" designates stereochemistry around a double bond. The two groups attached to each atom of the double bond are assigned priorities according to the Prelog-Cahn-lngold system. "E~ refers to an arrangement in whicb the two higber priority or two lower priority groups are on the opposite sides of the double bond. ~Z" refers to an arrangement in which the 20 two higher priority groups are on the same side of the double bond "Phenyl~ mèans -C6H5 "N-terminal arnino acid~ means a naturally occurring amino acid, and synthetic derivatives thereof, in which the arnino group is free, i.e., the amino acid is linked via the carboxyi group to form either an ester or an arnide.
"-Ac~ means-C(O)CH3; ~-OAc~ means-OC(O)CH3.
~O-sugar~ means a hexose or pentose monosaccharide linked at the 2-hydroxyl group.
~-C02-~ or "-C(O~O-~ designates an es~er linked via the carbon.
~-O2C-~ or ~-OC(O)-~ also designates an ester, with the linkage Yia the oxygen.
~-CO2H~ designates a carboxylic acid.
"-CH=CRIg-CH=CH-~ designates a carbon chain linking Yl and Y2 where (Yl end) -CH-CR19-CH=CH- (Y2 end).
Throughout the disclosure and clairns, common shorthand chemical terms are used. The carbon atom content of the various hydrocarbon-contain. 3g moieties is indicated by designating the minimum and maxirmurn number of carbon atoms in the moiety, i.e. Cm-Cn indicates a moiety of integer ~m~ to the integer ~n~ carbon atoms, inclusive and includes the isomeric forms. For exarnple, Cl-C6 alkyl refers to an alkyl of one to six carbons, inclusive, including SUBSTITUTE SHEET
.
`
wo 92/16508 ~ :1 0 1 3 3 ~ PCr/US92/01746 the isomeric forms. Chemical formulas, or portions thereof, drawn in a linear fashion may use Ihe symbol ~ o represent a single chemical bond between atoms in the linear chain. Likewise, the symbol ~ = ~ represents a double bond, and ~ . ~ a uiple bond, between atoms in the chain.
In ~he structural formulas the symbol ~ represents a bond between two atoms which may be a single or a double bond; the symbol ~ represents a bond which may or may not be present, and if present, is a single bond.
Temperatures are in degrees Celsius. The letter "h~ means hours. "TLC~ means thin layer chromatography. MS refers to mass specuometry. MS data are expressed as m/e or mass/change unit.
Svnthesis of Representative Compounds In preparative methods that follow, the compounds of the invention are synthesized following techniques which are known, or readily acquired, by one skilled in the art. E~amples of such techniques are:
F.D. Popp, ~Reissen Compounds and Related N-acyldihydroquinolines~ in Quinolines, Par~ Il, Ed. G. lones, (1982) p. 353-372, is a general review covering the synthesis and reactions of Reissen compounds. This review specifically describes the synthesis of 1-(4-chlorobenzoyl)-2-cyano- 1,2-dihydroquinoline, 1 -(4-fluorobenzoyl~2-cyano- 1,2-dihydroquinoline, 1-(4-me~hoxybenzoyl)-2-cyano-1,2~ih~droquinoline, 1-(4-toluoyl)-2-cyano-1,2-dihydroquinolhe, 1-(~nitroben~oyl)-2-cyano-1,2-dihydroquinoline, 1-(2-naphthoyl~2-cyano-1,2-dihydroquinoline, and 1-(1-o~o-3-phenyl-2-propenyl)-2-cyano-1,2-dihydroquinoline.
F.D, Popp, W. Blount and P. Melvin, 1. Q~. Chem., 26, 4930 (1961), describes themethylene chloride/water method for synthesizing Reissert Compounds.
S. Ruchirawat, N. Phadungkul, M. Chuankamnerdkarn, and C. Thebtaranonth, Heterocvcles, 6, No. 1, 43 (1977), describes the trimethylsilyl cyanide method of synthesizing Reissert compounds.
M. Rozwadowska, Roczniki Chemii. 51, 2321 (1977), describes hydrogenation of dihydroquinoline Reisser~ compounds to tetrahydroquinolines.
L. Walters, M. Siegel, and R. Cook, L. Heterocvclic Chem., 5, 577 (1968), describes synthesis of amido%imes, also called carboxamidamides, via addition of hydro%ylamine to a Reissert compound.
H. Bartsch, O. Schwarz, and G. Neubauer, Heterocycles, 24, 3483 (1986), describes the synthesis of a benzoxazine Reissert compound.
F. Elroy and R. Lenaers, "The Chemistry of Amido%imes and Related Compounds,~
Chem. a~ev. 155 (1962), describes synthesis and reactions of amido~imes.
Uff, B.C., Budhram, R.S., Consterdine7 M.F., Hicks, J.K., and Slingsby, 33.P., 1 ~h~. Soç., Perkins7 Trans a (18):2018-22 (1977), describes synthesis of 1-(4-SUBSTITUTE SHEET
:, . . . . ~ ~
- . . . .
. . : ~ . - .. ~
wo 92/16508 2 ~ O 1 3 3 ~ PCI /US92/01746 f methoxybenzoyi)-2-cyanoJ,-me~hyl- I ,2-dihydroquinoline.
F.D. Popp and A. Soto, I Chem. Soc., 1760 (1963), describes the synthesis of 1-(~
fluorobenzoyl)-2-cyano- 1 ,2-dihydroquinoline.
All starting materials are icnown and are corrunercially available, or are readily prepared from icnown or readily available materials.
The synthesis of compounds of the invention proceed, generally, as outlined below and, more specifically, in the representative examples that follow. The synthesis of the dihydro- and teuahydroquinolines, the dihydroquinazolines and the dihydroquinoxalines are outlined in Chart A, the teuahydrobenzoxazines in Chart B, and ti~e a nidoxime compounds of the invention in Chart C. In the Chans the l-(benzoyl) or l-(cinnamoyl) substituents are designated "R~, and the halide of the acid halide is designated ~X~.
The exarnples that follow are illustrative and not limitations of the preceding disclosure.
The conditions described here and in the examples for the synthesis and purification of the compounds of the invention may be altered depending on the choice of reactants and solvents, the batch size, the degree to which the reaction is to be carried to completion, and other factors of concern to the chemist.
Procedure for ~reoaration of Reissert compounds (Chart A~.
There are numerous techniques available for the synthesis of Reissert compounds from quinoline. Among these are preparation in aqueous potassium cyanide, potassium cyanide in a dimethylformamide-water mixture, liquid sulphur dioxide as a solvent, anhydrous benzene-liquid hydrogen cyanide, and trimethylsilyl cyanide-aluminum chloride in methylene chloride.
See, F.D. Popp, ~Reissert Compounds and Related N-acyldihydroquinolines~ in Quinolines, Part II, Ed. G. Jones, (1982) p. 353-372. We prefer the methylene chloride-trimethylsilyl cyanide system.
Referring now to Chart A, one equivalent (I eq.) of the quinoline (Chart A fig. 1), quinazoline (Chart A, fig. 4), quinoxaline (Chart A, fig. 5), or substituted forms thereof, is dissolved in dichloromethane or acetonitrile to a concentration of 0.4-0.5 M. An acid halide, preferably chloride, (1.5-2 eq.), Lewis acid, preferably aluminum trichloride (anhydrous, 0.05 eq.) and trimethylsilyl cyanide (1.5-2 eq.) are added while stirring. A thio-acid halide is substituted when the corresponding thio-Reissert compound is desired. Thio-acid halides are synthesized following known procedures, for example, R. Mayer and S. Scheithauer, J.
Heterocyclic Chem. 16, 1589 (1977). The Reissert reaction is carried out under ambient temperature conditions, e.g. 23-27 degrees, or refluxing acetonitrile for 8-substituted compounds, for a time sufficient to effect as complete a reaction as possible, e.g. from 0.5 to 48 hours. The products of the reaction (Chart A, fig. 2) are followed by ll C using solvent systems known in the art. Upon completion, the reaction is concentrated in vacJlo and then SUBSTITUTE SHEE~
:
' : ;
.
Wo 92/16~08 ;~ 3 3 ~ PCr/l,'S92/0174 placed on a silica gel column and eluted under flash chroma~ography conditions. The product is recrystallized from a low boiling point aliphatic alcohol, preferably 95% ethanol, or ethylacetate/hexane.
When a tetrahydroquinoline product is desired, the dihydroquinoline (Chart A, fig. 2) is 5 dissolved in alcohol, preferably 95~o ethanol, and reduced by hydrogenation in the presence of platinum. The reaction is followed and the product lChart A, fig. 3) recrystallized as outlined above.
Preparation 1 6,7-difluoroquinoline Sodium 3-nitrobenzensulphonate ~27.25 B, 1.25 eq.), followed by glycerol (25.50 g, 10 20.22 ml, 2.86 equiv.), and aqueous sulphuric acid (80% w/w, 81 ml) are placed in a 1 L.
three-necked flask. With stirring, 3,4-difluoroaniline (12.50 g, 9.60 rnl, 1 eq.) is slowly added and then heated under gentle reflux in an oil bath at 175C for 5 hours. The reaction mixture is cooled to room temperature and treated with aqueous sodium nitrite (25% w/w, 55 ml) from a dropping funnel. The mi~ture is subjected to steam-distillation. The yellowish aqueous 15 distillate is discarded. The reaction product is cooled in an ice bath, made strongly alkaline, i.e. pH 9-12, by the cautious addition of aqueous sodium hydroxide (50% w/w), and again subjected to steam distillation. A colorless solid formed in both the condenser and receiver.
Extraction with ethyl acetate, drying over sodium sulphate, and removal of the solvent in the rotary evaporator at 35~C, under house vacuum gave a solid (13.20 g) TLC in hexane-methanol 20 (1:6 v/v) showed the presence of a major and a minor product Direct crystallization gave 6,7-difluoroquinoline (9.25 g) m.p. 112-113C. The mother liquors contain the minor 5,6-difluoro-isomer.
PreparatiQn 2 6,8-difluoroquinoline
6,8-difluoroquinoline is synthesized by substituting 2,~difluoroaniline for 3,~
25 difluoroaniline in Preparation 1. The remaining procedure and purification are substantially unchanged.
Preparation 3 7,8 difluoroquinoline
25 difluoroaniline in Preparation 1. The remaining procedure and purification are substantially unchanged.
Preparation 3 7,8 difluoroquinoline
7,8-difluoroquinoline is synthesized by substituting 2,3-difluoroaniline for the 3,4-difluoroaniline in Preparation 1. The remainder of the procedure and purification are 30 substantially unchanged.
Preparation 4 4-cyanociMamic acid 4-cyanobenzaldehyde (I eq.), malonic acid (I eq.), pyridine (0.8 M), and piperidine (1 ml/10 m] pyridine) are heated at reflux for 24 h. or until carbon dioxide is no longer evolved.
The mixture is evaporated to dryness in vacuo. The residue is redissolved in water and the pH
35 adjusted to 10 using concentrated ammonium hydroxide. The mixture is filtered through celite and the filter rinse~ with water. The pH of the filtrate is adjus~ed to 2 using IN hydrochloric SUBSTITUTE SHEET
, .. .. . .. .. - . . .
:: -' - . ' ' ....
- .-: - .. : . -wo 92/16508 2 1 0 1 3 3 ~ PCr/US~2/01746 ~- 15-acid. Chilling precipita~es solids which are collected, dissolved in acetone and 95X ethanol, and evaporated in vacuo until solids form. Chilling produces crystalline compound (1 cyanocinnamic acid).
Preparation 5 4-cyanocinnamoyl chloride 4{~yanocinnamic acid (Preparation 4, 1 eq.) is dissolved in methylene chloride at a concentration of 0.5 M. Oxalyl chloride (I eq.) is added and the mixture chilled to 0C. DMF
(0.5 eq.) is added, the mixture stirred at 0C for 0.5 h. warmed to ambient temperature, and stirred an additional 2 hours. Evaporation in v~cuo yields 4-cyanocinnamoyl chloride.
Example la 1-(4-bromobenzoyl)-2-cyano-1,2-dihydroquinoline Quinoline (0.104 g, 0.8 mmol) is dissolved in 0.5 ml of methylene chloride. 88 ~L of trimethylsilylcyanide is added at ambient temperature. 4-Bromobenzoyl chloride (0.25 g.) is dissolved in 0.5 mL of methylene chloride is added following 5 mg of aluminum trichloride.
After 40 min. the reaction is filtered through a pad of silica gel and the pad is washed with 20 mL of methylene chloride. The combined filtrates are washed first with 10 mL of water, then 15 with 10 mL of saturated aqueous sodium bicarbonate and finally S mL of water. The organic layers are concentrated in ~Jac~lo to afford an oil which is dissolved in 4 ml of 9S percent ethanol. This is evaporated to 2.5 mL and cooled at 0C for 30 min. The crystals are collected and dried in a vacuum oven to afford 85 mg of 1-(4-bromobenzoyl)-2-cyano-1,2-diSydroquinoline (m.p, 149-151C). The mother liqùor is evaporated and triturated with I rnL
20 of 9S percent ethanol. The crystaJs formed are collec~ed and dried to afford 31 mg of a second crop.
In an analogous manner, the following compounds are synthesized using the designated acid chloride.
E%asnple Ib 1-(4-fluorobenzoyl)-2-cyano-1,2-dihydroquinoline Following the procedure of Exarnple la, 4-fluorobenzoyl chloride is used as the acid chloride and the product, 1-(4-fluorobenzoyl)-2-cyano-1,2-dihydroquinoline, has a m.p. 114-116C.
Exarnple 2 1-(4-trifluoromethylbenzoyl)-2~yano-1,2-dihydroquinoline Following the procedure of Exarnple la, 4-trifluoromethylbenzoyl chloride is used as the acid chloride. The product, 1-(4-trifluoromethylbenzoyl)-2-cyano-1,2-dihydroquinoline, has a m.p. 135-136C.
Example 3 1-E-(I-oxo-3-phenyl-2-propeDyl)-2-cyano-1,2-dihydroquinoline - Following the procedure of E~arnple la, I-E-ci ~namoyl chloride is used as the acid chloride. The product. l-E-(I-oxo-3-phenyl-2-propenyl)-2-cyano-I,2~ihydroquinoline, has m.p.
149-150~.
Exarn~le 4 1 -E-(3-(~trifluoromethylphenyl)- 1 -oxo-2-propenyl)-2-cyano- 1,2-SUBSTITUTE SI~IEET
.
~VO 92f16508 2 ~ 3 3 ~ PC~/US92/0174b dihydroquinoline Following the procedure of Exarnple la, E-4-trifluoromethylcinnarnoyl chloride is used as the acid chloride. The product, I-E-(3-(4-trifluoromethylphenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, has a m.p. 172-173C.
Exarn~le 5 1-(4-carbomethoxybenzoyl)-2-cyano-1,2-dihydroquinoline Following the procedure of Exarnple 1, 4-carbomethoxybenzoyl chloride is used as the acid chloride. The product, 1-(4-carbomethoxybenzoyl)-2-cyano-1,2-dihydroquinoline, has a m.p. 165-166C.
Exarngle 6 1 -(4-cyanobenzoyl)-2-cyano- 1,2-dihydroquinoline Following the procedure of Example la, 4-cyanobenzoyl chloride is used as the acid chloride. The product, 1-(4-cyanobenzoyl)-2-cyano-1,2-dihydroquinoline. has a m.p. 154-155C.
Exarngle 7 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline Following the procedure of Example la, E4-chlorocinnarnoyl chloride is used as the acid chloride. The product, I-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline has a m.p. 166-167C.
Exarn~le 8 1 -E-(3-(4-fluorophenyl)- 1 -oxo-2-propenyl)-2-cyano- 1,2-dihydroquinoline Following the procedure of Exa nple la, E4-fluorocinnamoyl chloride is used as the acid chloride. The product, l-E-(3-(~fluorophenyl)-1-oxo-2-prophenyl)-2-cyano-1,2-dihydroquinoline has a m.p. 142- 143C.
Example 9 1-E-(2-fluoro-1-oxo-3-phenyl-2-propenyl)-2-cyano-1,2-dihydroquinoline Fol~owing the procedure of Example la, E-~x-fluorocinnamoyl chloride is used as the acid chloride. The product, I-E-(2-fluoro-1-oxo-3-phenyl-2-propenyl)-2-cyano-1,2-dihydroquinoline, has a m.p. 1~2-153C.
Example 10 1-E-(3-(3,4-dichlorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline Following the procedure of Example la, E-3,4-dichlorocinnamoyl chloride is used as the acid chloride. The product, I-E-(3,4-dichlorophenyl-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, has a m.p. 152-153C.
Example 11 1 -E-(3-(4-cyanophenyl)- 1 -oxo-2-propenyl)-2-cyano- 1,2-dihydroguinoline Following the procedure of Example la, E4-cyanocinnamoyl chloride (Preparation 5) is used as the acid chloride. The product, I-E-(3-(4-cyanophenyl)-1-oxo-2-propenyl)-2~yano-1,2-dihydroquinoline has a rn.p. 176C.
Ex n~le 12 1-E-(3-(3,4-methylenedioxyphenyl)-l~xo-2-propenyl)-2-cyano-1,2-dihydroquinol ine Following the procedure of Example la, E-3,4-methylenedioxyciMarnoyl chloride isused as the acid chloride. The producl, I-E-(3-(3,4-methylenedioxyphenyl)-l~xo-2-propenyl)-2-SUBSTiTUTE SHEE~
.. . . :
. ' ` ' -.~ . .
wo 92/1~508 2 1 0 1 ~ PCI/l~S92~01~46 r . . . 1 7 , .
cyano-1,2~ihydroquinoline, has a m.p. 176-177C.
Exam~le 13 1 -E-(3-(4-methoxyphenyl)- 1 -oxo-2-propenyl)-2-cyano-1,2~ihydroquinoline Following the procedure of Exarnple la, E-4-methoxycinnamoyl chloride is used as the acid chloride. The product is l-E-(3-(4-methoxyphenyl)-1-oxo-2-propenyl)-2-cyano-1,2-5 dihydroquinoline.
Calcd.: C,75.93; H, 5.10; N, 8.85 Found: C, 75.74; H, 5.31; N, 8.86E~,arnple 14a 1-E-(3-(4-acetoxyphenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline Following the procedure of Exarnple la, E4-acetoxycinnamoyl chloride is used as the 10 acid chloride. The product is l-E-(3-(4-acetoxyphenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinol ine.
Calcd.: C, 73.24; H, 4.68; N, 8.13 Found: C, 72.94; H, 4.51; N, 7.99 Exarnple 14b 1 -E-(3-(4-carbomethoxybenzoyl)- I -oxo-2-propenyl)-2-cyano- 1,2-lS dihydroquirJoline Following ~he procedure of Exarnple la, E4-carbomethoxycinnarnoyl chloride is used as the acid chloride. The product, I-E-(3~4~arbomethoxybenzoyl)-1-oxo-2-propenyl)-2-cyano-1,2~ihydroquinoline, has a m.p. 168-170~C.
~am~ l-E-(3-(4-methylphenyl)-1-oxo-2-trans-propenyl)-2~yano-1,2-dihydroquinolineFollowing the procedure of E%ample la, E-(4-methylcinnamoyl chloride) is used as the acid chloride. The product is l-E-(3-(4-methylphenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline.
Calcd.: C, 79.98; H, 5.37; N, 9.33 Found: C, 79.54; H, 5.40; N, 9.17 25 Example 16 1-(2-napthoyl)-2-cyano-1,2~ihydroquinoline Following the procedure of Example la, 2-napthoylchloride is used as the acid chloride.
The product, 1-(2-napthoyl)-2-cyano-1,2-dihydroquinoline, has a m.p. 185-186C.
Exasnple 17 1 -(4-chlorobenzoyl)-2-cyano~methyl- 1,2-dihydroquinoline Following the procedure of Example la, 4-methylquinoline is substituted for guinoline 30 and 4-chlorobenzoyl chloride is used as the acid chloride. The product, 1-(4-chlorobenzoyl~2-cyano 1 methyl-1,2-dihydroquinoline, has a m.p. 173-174C.
Calcd. for C18Hl3CIN2O: C, 70.02; H, 4.24; N, 9.08; Cl, 11.48.
Found: C, 69.95; ;H, 4.28; N, 8.90; Cl, 11.45.
Example 18 1-(4-chlorobenzoyl)-2-cyaDo S-fluoro-1,2-dihydroquinoline Following the procedure of Example la, 5-fluoroquinoline is substituted for quinoline and 4-chlorobenzoyl chloride is used as the acid chloride. The product. 1-~4-chlorobenzoyl)-2-SUBSTITUTE SHEET
.
wo 92/16~0X PCr/US92/01746 2 1 0 1 ~ ~ 5 --18 cyano-5-fluoro-1,2~ihydroquinoline, has a m.p. 144-145C.
Calcd. for C17HloClFN2O: C, 65.29; H, 3.22; N, 8.96; Cl, 11.34; F, 6.08.
Found: C, 65.37; H, 3.24; N, 9.03; Cl; 11.32; F, 6.47.
E~.arnple 19a 1 -(4-chlorobenzoyl)-2-cyano~fluoro- 1,2-dihydroquinoline Following the procedure of Exarnple la, 6-fluoroquinoline is substituted for quinoline and 4~hlorobenzoyl chloride is used as the acid chloride. The product, 1-(4-chlorobenzoyl)-2-cyano~fluoro-1,2-dihydroquinoline, has a m.p. 147-148C.
Calcd. for C17HloClFN20: C, 65.29; H, 3.22; N, 8.96; Cl, 11.34; F, 6.08.
Found: C, 65.18; H, 3.27; N, 8.87; Cl, 11.09; F, 6.36 Exarnple 19b 1-(4-chlorobenzoyl)~fluoro-2-cyano-1,4-dihydroquinoline The product of Exarnple 19a is subjected to reverse-phase HPLC separation (isocratic 40 THF/60% wa~er mobile phase). Pure 1-(4-chlorobenzoyl)~fluoro-2-cyano-1,4-dihydroquinoline is isolated (m.p. 14~150C).
Exarnple 20 1-(4-chlorobenzoyl)-2-cyano-7-fluoro-1,2-dihydroquinoline Following the procedure of Example la, 7-fluoroquinoline is substituted for quinoline and 4-chlorobenzoyl chloride is used as the acid chloride. The product, 1-(4-chlorobenzoyl)-2-cyano-7-fluoro-1,2~ihydroquinoline, has a m.p. 174-175C.
Calcd, for C17HloClFN2O: C, 65.29; H, 3.22; N, 8.96; Cl, 11.34; F, 6.08.
Found: C, 65.23; H, 3.27, N, 8.98; Cl, 10.99; F, 6.19.
Example 21 1-(4-chlorobenzoyl)-2-cyano-8-fluoro-1,2-dihydroquinoline Following the procedure of Example la, 8-fluoroquinoline is substituted for quinoline and 4-chlorobenzoyl chloride is used as the acid chloride in acetonitrile solvent and the solution refluxed as described above. The product, 1-(4-chlorobenzoyl)-2-cyano-8-flùoro-1,2-dihydroquinoline, has a m.p. 156-157C.
Calcd. for C17HIoClFN2O: C, 65.29; H, 3.22; N, 8.96; Cl, 11.34; F, 6.08.
Found: C, 65.36; H, 3.23; N, 8.92; Cl, 11.16: F, 6.02.
Example 22 1-(4-methoxybenzoyl)-2-cyano-6,7-difluoro-1,2-dihydroquinoline Following the procedure of Example la, 6,7-difluoroquinoline (Preparation 1) is substituted for quinoline and 4-methoxybenzoyl chloride is used as the acid chloride. m.p. 139-140C.
Calcd. for C~8H~2F2N2O2: C, 66.25; H, 3.71; N, 8.59; F, 11.65.
Found: C, 66.65; H, 3.73; N, 8.47; F, 12.09.
Exa nple 23 1-(4-chlorobenzoyl)-2-cyano-1,4-dihydroquinoxaline Following the procedure of Exarnple la, quinoxaline is used in place of quinoline and 4 chlorobenzoyl chloride is the acid halide. The product, 1~4-chlorobenzoyl)-2-cyano-1,4-dihydroquinoxaline, has a m.p. 231-232C.
SUBSTITUTE SHEE~
..
.
- . - :: .
WO 92/16~08 2 1 Q 1 3 3 ~ PCT/VS92/01746 _ 1 9_ CaJcd. for C16HloClN3O: C, 64 98; H, 3.40; N, 14.21.
Found: C, 65.05; H, 3.55; N, 14.30.
xarnple 24 1-(4-chlorobenzoyl)-2-cyano~,7~ifluoro-1,2-dihydroquinoline Following the procedure of Exarnple la, 6,7-difluoroquinoline (Preparaflon 1) is the 5 quionoline and 4-chlorobenzoyl chloride is the acid halide. llle product, 1-(4-chlorobenzoyl)-2-cyano-6,7-difluoro-1,2-dihydroquinoline, has a m.p. 184-185C.
Calcd for C17HgClF2N20: C, 61.74; H, 2.74; N, 8.47; Cl, 10.72; F, 11.49.
Found: C, 61.59; H, 2.82; N, 8.48; Cl, 10.6; F, 11.37.
ExamDle 25 1-(4-chlorobenzoyl)-6,8-difluoro-2-cyano-1,2-dihydroquinoline Following the procedure of Exarnple la, 6,8-difluoroquinoline (Preparation 2) issubstituted for quinoline and 4-chlorobenzoyl chloride is used as the acid chloride. The product, 1-(4-chlorobenzoyl)~,8-difluoro-2-cyano-1,2-dihydroquinoline, has a m.p. 164-165C.
Example 26 1 -(4-chlorobenzoyl)-7,8-difluoro-2-cyano-1,2-dihydroquinoline Following the procedure of ExarDple la, 7,8-difluoroquinoline (Preparation 3) issubstituted for quinoline and 4-chlorobenzoyl chloride is used as the acid chloride m.p. 154-lSgC.
Calcd: C, 72.72; H, 4.27; N, 8.48.
Found: C, 72,54; H, 4.35; N, 8.44.
~mEI~ 1-E-(3-(4-bromophenyl)-1-oxo-2-propenyl)-2-cyano-1,2~ihydroquinoline Following the procedure of Example la, E4-bromocinnamoyl chloride is substituted for the acid halide. The product, 1-E-(3-(4-bromophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-diDydroquinoline, has a m.p. 175-177C.
Example 28 1 -E-(3-(4-chlorophenyl)- 1 -oxo-2-propenyl)-2-cyano~,7-difluoro- 1,2-dihydroquinoline Following the procedure of ExaJnple la, 6,7-difluoroquinoline (Preparation 1) issubstituted for quinoline and 4-chlorocinnamoyl chloride is substituted for the acid halide. The product, l-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2~yano~,7-difluoro-1,2-dihydroquinoline, has a m.p. 97-98C.
Exarnple 29 1 -E-(3-(4-fluorophenyl)- 1 -oxo-2-propenyl)-2-cyano~,7-difluoro- 1,2-dihydroquinoline Following the procedure of Example la, 6,7-difluoroquinoline (Preparation 1) is substituted for quinoline and 4-fluorocinnarnoyl chloride is used as the acid chloride. Ihe prodùct, l-E-(3-(~fluorophenyl)-1-oxo-2-propenyl)-2-cyano~,7-difluoro-1,2-dihydroquinoline, has a m.p. 131-132C.
Exam~le 30a 1-(4-chlorobenzoyl)-2-cyano~,7,8-trifluoro-1,2-dihydroquinoline Following the procedure of ExaJnple la, 6,7,8-trifluoroquinoline is substituted for SUBSTITUTE SHEE~
wo 92t1650~ ~ I 0 1 3 ~ ~ PCT/US92/0~746 -20- ~
quinoline and 4~hlorociMamoyl chloride is substituted from the acid chloride. ll~e product, 1-(4~hlorobenzoyl)-2-cyano-6,7,8-trifluoro-1,2-dihydroquinoline, has a m.p. 159-160C.
Exam~le 30b 1 -E,E-( I -o~o-2,4-pentadienyl-5-phenyl)-2~yano-1,2-dihydroquinoline Following the procedure of Exarnple la, styryl acrolyl chloride is substituted for the acid 5 halide. The title product is ob~ained.
IH NMR (300 MH2, CDC13): d 6.04 (dd, ~ = I l,15 Hz, IH), 6.35 (d, J= 15 Hz, IH),6.37 (dd, 1= 1,6 Hz, IH), 6.77 (d, J= 9Hz, IH), 6.82 (dd, J=11,15 Hz, IH), 7.22-7.37 (m, 7H), 7.43 (m, 2H), 7.62 (dd, 1= 11,15 Hz, IH).
E%am~le 31 1 -(4-trifluorobenzoyl)-2-cyano-3-dimethylamino- 1,2,3,4-tçtrahydroquinoline To 500 mg (1.52 mmol) of 1-(4-trifluoromethylbenzoyl)-2~yano-1,2-dihydroquinoline is added 20 ml of methylene dichloride and 3 ml of anhydrous dimethylarnine (the dimethylamine is cooled to below -20C before carefully opening the sealed bottle). lbe reaction is allowed to stir at ambient temperature for 48 h., filtered and the resulting methylene chloride solution evaporated to dryness. The residue is distributed between methylene chloride and water, and 15 the organic phase washed twice with water. The organic phase is dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give crude product. The crude product is chromatographed using 35 percent ethyl acetate in hexane to give 1-(4-trifluorobeyl)-2-cyano-34imethylamino-1,2,3,4-tetrahydroquinoline which slowly crystallizes upon standing (m.p. 104-106C).
20 Example 32 1-(4~hlorobenzoyl)-2-cyano-1,2,3,4-tetrahydroquinoline.
To one gram of 1-(4~hlorobenzoyl)-2-cyano-1,24ihydroquinoline (3 4 mmol) in 100 ml of ssæ ethanol is added 0.10 g of platinum oxide The reduction reaction proceeds under hydrogen at atmospheric pressure 4 hours. The reaction is followed by l~C (35% ethyl acetate/he~ane). The reaction is filtered and the resulting ethanol solution is concentrated in 25 vacuo; the crude solid is recrystallized from 5 ml of absolute ethanol to give the tetrahydroquinoline (1-(4-chlorobenzoyl)-2-cyano-1,2,3,4-tetrahydroquinoline, 0.21 mg, m.p.
134-135C).
Calcd.: C, 68.78, H, 4.41; N, 9.44, Cl, 11.94.
Found: C, 68.66; H, 4.81; N, 9.16; Cl, 11.71.
30 E~ ample 33 1-Z-(I-oxo-3-phenyl-2-propenyl)-2-cyano-1,2-dihydroquinoline a) Phenylpropiolic acid (K~cK Chemicals, 1.05 g, 7.2 mmol) is dissolved in 14 ml of methylene chloride and cooled to 0C. Oxalyl chloride (0.63 ml) and dimethylformamide (140 ~1) are added. The reaction is stirred at 0C for 30 min., then warmed to ambient temperature and stirred an additional 3 hours. The reaction is concentrated in WCUO and further dried in 35 uacuo for 3 h. at ambient tçmperature. Quinoline (0.57 ml, 4.8 mmol) is dissolved in 14 m] of methylene chloride and 0.42 ml of trimethylsilylcyanide is added. Ihis solution is added to the SUBSTITUTE SHEET
, `. .
- . ...... -.
, .,.~. .
. ~
wo 92/16508 2 1 ~ 1 3 3 5 PCr/US9t/01746 !-` -21- .
phenylpropiolic acid chloride prepared above. Aluminum trichloride (catalytic, 5 mol percent) is added and the reac~ion is stirred overnight at ambient temperature. The reaaion is filtered Lhrough a plug of silica gel and washed with 75 ml of methylene chloride. The organics are washed with saturated aqueous sodium bicarbonate and evaporated in vacuo. Purification by S flash column chromatography (25 percent ethyl acetate/hexane) provides 600 mg of the desired product.
b) The above produa (200 mg) is dissolved in 7 ml of methanol and 22.6 mg of palladium on calcium carbonate poisoned with lead (5% palladium, Aldrich) and 9 mg of quinoline is added. The mixture is hydrogenated at 18 psi for 7.5 hours. Filtration of the 10 reaction and concentration in vacuo affords an oil which is dissolved in 95 percent ethanol and chilled at 5C for 20 hours. The crystalline product is collected to provide l-(l-oxo-3-phenyl-2-propenyl)-2-cyano-1,2-dihydroquinoline.
Calcd.: C, 79,70; H, 4.93; N, 9.79.
Found: C, 79.31; H, 5.01; N, 9.56.
15 Procedure fQr ~reparation Qf benzoxazineS~hart B!
Referring now to Chart B, figure 1, 1-(o-aminophenoxy)-2,2-diethoxyethane (I eq.) is prepared following the procedure of F. Choiccara et al., Tetrahedron 32, 1407 (1976). The diethoxyethanè is dissolved in, preferably ether, (0.1-0.3 M) and ethyl diisopropylamine (1-1.2 eq.) is added. The reactants are cooled to 0 C and one equivalent of the appropriate 20 ciMamoyl acid halide, preferably substituted c~nnamoyl acid chloride, is added dropwise. The reaction is allowed to proceed for a time sufficient to allow as complete a reaction as possible, e.g. 10 min. to I hour. The reactants are added to saturated sodium bicarbonate and ex~racted with methylene chloride. The organic layers are combined, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The arnide product (Chart B, fig. 2) is 25 purified using flash chromatography in ethyl acetate/hexanes.
The arnide (Chart B. fig. 2) (I eq.) is dissolved in methylene chloride (0.4-0.5M) and the reaction cooled to -20C. An acid, preferably boron trifluoride etherate, (1-1.2 eq.) is added and the reaction mixture is stirred and slowly warrned to arnbient temperatures. Stirring continues for from 12 to 20 hours. The mixrure is diluted with me~hylene chloride, washed 30 with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The product, a substituted 3,4~ihydro-3~thoxy-2H-1,4-benzoxazine (Chart B, fig. 3), is purified by flash chromatography using a chloroform/methanol solvent.
The benzoxazine (Chart B, fig. 3, 1 eq.) is dissolved jD methyleDe chloride (0.1 -0.2M) and I eq. (each) of azidotrimethylsilane and boron trifluoride etherate is added. ll~e reaction is 35 stirred at arnbient temperature for 3-24 h., diluted with methylene chloride, washed with saturated sodium bicarbonate and again with saturated sodium chloride, dried over sodium - SUBSTITUTE SHEE~
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wo 92/1650X 2 ~ O 1 ~ ~ 5 -22- PCT/US92/01746 sulfate, and concentrated ~n wcuo Purification by nash chromatography in e~hylacetate/hexane provides a substituted 3~4-dihydro-2H-1,4~ihydrobenzoxazine-3-azide (Chart B, fig. 4).
Fur~7er purification is accomplished by recrystallization in ethylene/hexane.
E~ample 34 4-(p-chlorocinnamoyl)-3,4-dihydro-2H- 1,4-benzoxazine-3-azide a) 2-(4-chlorocinnamidinyl)phenoxy-1, I-diethoxyethane 1.24 g of 1-(o-aminophenoxy)-2,2-diethoxyethane (4.85 mmol), prepared following the procedure of F Chioccara, F. Prota, R.H. Thompson, TetrahedrQn 32, 1407 (1976), is dissolved in 40 ml of e~her and ethyl diisopropylarnine (5.82 mrnol, 0.75 g) is added. The reaction is cooled to OC. p-Chlorocinnamoyl chloride (4.85 mmol) dissolved in 10 ml of ether is added dropwise. After 10 min. of stirring, the reaction is poured in~o saturated aqueous sodium bicarbonate and extracted with methylene chloride. The organic layers are combined, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo.
Purification via flash column chromatography (200 g silica gel, 10% ethyl acetate/hexane) provides 2-(2-cblorocinnamidinyl)phenoxy)~ diethoxyethane.
b) 4-(p-chlorocinnamoyl)-3,4-dihydro-3-ethoxy-2H-1,4-benzoxazine 2-~2-~p~hlorocinnamidinyl)phenoxy-1,1-diethoxyethane (I mmol), syntbesized above, is dissolved in 2 rnl of methylene cbloride and the reaction is cooled to -20C. E~oron trifluoride etherate (1.2 mmol) is added, tbe reacsion allowed to slowly warm to room temperature over approximately 2 hours and is then stirred overnight. The mixture is diluted witb methylene chloride, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by flash column chromatogtaphy (100 g silica gel, 100% chloroforrn) provides 4-(p-chlorocinnamoyl)-3,4-dihydro-3~thoxy-2H-1,4-benzoxazine c) 4-(p-chlorocinnamoyl)-3,4-dihydro-2H- 1,4-benzoxazine 3-azide 4-(p-Chlorocinnamoyl)-3,4-dibydro-3-ethoxy-2H-1,4-benzoxazine (1 m nol) synthesized in step (b) is dissolved in 7 ml of methylene chloride Azidotrimethylsilane (1 mmol) and boron trifluoride etherate (I mmol) are added. After stirring about 3 hours at room temperature, the reaction is diluted with methylene chloride, washed with saturated sodium bicarbonate, saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo.
Purification by flash column chromatogtaphy (10% ethyl aceta~e/hexane) provides product which is recrystallized from ethyl acetate/hexane to afford the desired product (~(p-chlorociMamoyl)-3, dihydro-2H-1,4-benzoxazine-3-azide).
Procedure for ~re~aration of amidoximes (Chart C).
Referring now to Chart C, figure 1, the Reissert compound (0.68 eq.) is dissolved in methanol at 30 to 50~C and slowly added to hydroxylamine in methanol at 0C. Thehydroxylamine is prepared by adding sodium metho%ide (10 ~q.) to hydroxylamine SUBSTITUTE SHEET
..
.: :
wo 92/~6~08 2 1 0 1 3 3 ~ PCr/~'S92/0174b hydrochloride (I eq.) in methanol and then filtering. The Reissen-hydroxylarnine reaction is allowed to warm to room temperature while stirring. It is then heated from 30C to reflux for 1 to 24 hours. The reaction mixture is cooled to room temperature, diluted with chloroform, washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in S wcuo, The product (Chart C, fig. 2) is recrystallized from aqueous (95%) methanol.
As an alternative procedure we use the following:
Hydroxylamine hydrochloride (I eq.) is added to a stirred mixture of I eq. sodium carbonate in 50 percent aqueous ethanol (0.6-0.8M). The reaction is diluted to 0.06-0.08M
with absolute ethanol. Then 0.8 eq. of the desired Reissen compound is added and the reaction 10 is heated at from 50C to reflux tempetature under Gitrogen for 2.5 to 24 hours. lbe reaction poured is mixed into ice water and extracted with ethyl acetate or butanol. The organics are concentrated in vacuo, dissolved in ethanol, and chilled. The solid product is collected and dried.
The pharmacological salt of the amidoxime may be synthesized by use of an appropriate 15 acid. Examples of such salts include hydrochloride, hydrobromide, fumarate, maleate, succinate, citrate, tosylate, and mesylate.
ExamDle 35 1-(~chlorobenzoyl)-2-carboximidamide-1,24ihydroquinoline l-(~chlorobenzoyl)-2-cyano-1,24ihyd-oquinoline (0.2g, 0.68 mmol, see Popp, citedabove) is dissolved in warm methanol and added to a solution of hydroxylamine in methanol.
20 The hydroxylamine is prepared by the addition of sodium methoxide (0.232 mJ of 259G w/w solution in methanol, I mmol) to 70 mg of hydroxylamine hydrochloride ~I mmol) in methanol followed by filtration to remove precipitate. The Reissert-hydroxylamine reaction is stirred at ambient temperature for 3 h and subsequently heated to 40C for I hour. The mixture is evaporated to dryness, dissolved in 2 ml methanol, one drop of water added, and chilled to 25 5C. The solids are collected and washed with methanol to afford 1-(4-chlorobenzoyl)-2-carboximidamide-1,2-dihydroquinoline, m.p. 160-161C.
In an analogous manner the following are synthesized by substituting the appropriate Reissert compound.
Example 36a 1 -E-(3-(4-bromophenyl)- 1 -oxo-2-propenyl)-2~arboximidamide-1,2-dihydroquinoline Following the procedure of Example 35, 1-E-(3-(4-bromophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline is used as the Reissert compound. The product, I-E-(3-(4-bromophenyl)- I -oxo-2-propenyl~2-car~oximidamide- I ,?-dihydroquinoline, has a m.p. 18 181C.
3s ExamD!e ~6~ 1-E-13-(4-bromophenyl)-1-oxo-2-propenyl]-N-(acetyloxy)-2-quinolinecarboximidarnide SUBSTITUTE SHEET
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.~ " . .:.,; .
. - -~.- . :
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Wo 92J1650X PCI/US92/01746 2~ ~133~ -24- ~
The purified product of Example 36(a) is dissolved in 0.75 ml methylene chloride.
Pyridine (21 ,~11) is added and the reaction is cooled lo 0C. Acetic anhydride (25 ~LI) is added and the reaction stirred 15 min. a~ 0C, and then brought to arnbient temperature. After I h., the reaction is diluted with methylene chloride, poured into saturated aqueous sodium S bicarbonate, dried over sodium sulfate, and concentrated in vacuo. The residue is triturated wilh 9596 aqueous ethanol and the solids collected to yield I E-13-(4-bromophenyl)-1-oxo-2-propenyl]-N~acetyloxy)-2-quinolinecarbo%imidamide(m.p. 151-153C).
Example 37a 1 -E-(3-(4-chlorophenyl)- 1 -oxo-2-propenyl)-2-carboximidarnide- 1,2-dihydro-quinoline Following the procedure of Example 35, 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline is used as the Reissert compound. The product, I-E-(3-(4-chlorophenyl)-l-oxo-2-propenyl)-2-carbo%imidamide-1,2-dihydroquinoline, has a m.p. 174-175C.
Exam,~le 37b 1 -E-(3-(4-chlorophenyl)- 1 -oxo-2-propenyl)-2-carboximidamide- 1,2-dihydro-quinoliDe, hydrochloride The product of Example 37a, 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinoline, is dissolved in methanol and chlorotrimethyl silane is added. The addition of diethyl ether causes the desired salt to crystallize. 'Ihe crystals are collected to afford l-E-(3-(4-chlorophenyl)-1-o%o-2-propenyl)-2-carbo~imidamide-1,2-dihydro-quinoline, hydrochloride (m.p. IS8-160C).
Example 37c 1 -E-(3-(4-chlorophenyl)- 1 -oxo-2-propenyl)-2-carboximidamide- 1,2-dihydro-quinoline, methane sulfonate The product of E%ample 37a, 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl~2-carboximidamide-1,2-dihydroquinoline, is dissolved in methanol and methane sulfonic acid is added. The volatiles are removed in vacuo and the residue recrystallized from d;ethyl ether/chloroforrn. The crystals are collected and dried to yield l-E-(3-(4~hlorophenyl~1-oxo-2-propenyl)-2-carbo%imidamide-1,2-dihydroquinoline, methane sulfonate (m.p. 139-140C).
Example 37d 1 -E-13-(4-chlorophenyl)- 1 -oxo-2-propenyl]-N-(acetyloxy)-2-quinoline-carboximidarnide Following the procedure of Example 36(b) and making non-critical variations, but starting with the product of Example 37(a), 1-E-3-~4-chlorophenyl)-1-oxo-2-propenyl~2-carboximidarnide-1,2-dihydroquinoline, the title compound is obtained. 1-E-[3-(4-chlorophenyl)-I -oxo-2-propenyl]-N-(acetyloxy)-2-quinolinecarboximidarnide (m.p . 132- 133C).Example 37e 1-E-13-(~chlorophenyl)-1-oxo-2-propenyl~-N-methoxycarbonyloxy-2-quir olinecarboximidamide Following the general procedure as described for Examples 36(b) and rnal~ing non~ritical SUBSTITUTE SHEE~
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.
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WO 92/16~08 21~1~ 3 5 PCr/~,'S92tO1746 f varia~ions, but staning with the product of E%ample 37ta), 1-E-(3-(4-chloropbenyl)-1-o%o-2-propenyl)-2 carboximidamide-1,2-dihydroquinoline, and using methylchloroforrnate. the title compound is obtained, I -E-~3-(4-chlorophenyl)- 1 -oxo-2-propenyll-N-methoxycarbonyloxy-2-quinolinecarbo%imidamide (m.p. 173-174C).
E~amPIe 38 1-E-(3-(4-hydroxyphenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinoline Sodium carbonate (0.31 g) is dissolved in 2 rnl of ethanol and 2 ml of water.
Hydro%ylamine hydrochloride (0.202 g) is added and the reaction is diluted with 40 mJ of absolute ethanol. I-E-(3-(4-acetoxyphenyl)-1-o%o-2-propenyl)-2-cyano-1,2-dihydroquinoline (Example 14, 0.80 g) is added and the reaction heated to reflux for 1.5 hours. After cooling, it is poured into 400 ml of ice water, and extracted with chloroform (3 x 200 rnl.) After concentration in vacuo, the residue is triturated with 3 mJ of methanol. The solids formed are collected to afford 199 mg of the title compound (1-E-(3-(4-hydroxyphenyl~1-o%o-2-propenyl)-2-carboximidamide- 1,2-dihydroquinol ine, m .p . 164- 166C) .
Example 39 1-(4-chlorobenzoyl)-8-fluoro-2-carboximidamide-1,2-dihydroquinoline Following the general procedure according to Example 38 and making non-critical variations, but using 1-(4-chlorobenzoyl)-2-cyano-8-fluoro-1,2-dihydroquinolu~e (Example 21) the title compound is obtained (1-(4~hlorobenzoyl)-8-fluoro-2 carboxamidamide-1,2-dihydroquirlolinc,m.p, 186-187C).
Exatncle 40 1-(4-chlorobenzoyl)~,7-difluoro-2 carboximidamide-1,2~ihydro-quinoline Following Exa nple 38 and using 1-(4-chlorobenzoyl)~,7-difluoro-2-cyano-1,2-dihydroquinoline (Example 24) the title compound is obtained (1-(4-chlorobenzoyl)~,7-difluoro-2-carbo%irnidamide-1,2-dihydroquinoline,m.p. 128-129C).
Exarn~le 41 1-(~chlorobenzoyl)~fluoro-2-carboximidamide-1,2-dihydroquinoline Following the general pro~edure of Example 38 and making non-critical variations, but using 1-(4 chlorophenyl)-2-cyano~fluoro-1,2-dihydroquinoline (Exarnple 19), the title compounD is obtained (1-(4-chlorobenzoyl)~fluoro-2~arboximidamide-1,2-dihydroquinoline, m.p.162-163C).
Exarnple 42a 1 -E-(3-(4-cyanophenyl)- 1 -oxo-2-propenyl)-2-carboximidamide- 1,2- dihydroquinoline Following ~e general procedure of Exarnple 35 and malcing non-critical variations, but starting with l-E-(3-(4-cyanophenyl~-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline (Example I l, 0.20 g), the title compound is obtained (1-E-(3-(~cyanophenyl)-1-oxo-2~ropenyl)-2-carboximidamide-l ,2~ihydroquinoline, O. l lg, m.p. 205-206~C).
Example 42b 1-E-(3-(4-cyanopneDyl)-l-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinoline hydrochloride - SUBSTITUTE SHEET
,: :
. ,--.
, . . .
. , .
wo 92/16508 ~ 3 3 5 - PCr/US92tol746 The product of E~ample 42a (1.0 g) is suspended in 10 ml of methanol and concentrated hydrochloric acid (0.29 ml) is added. llle solution is diluted with ether until crystals formed and then it is cooled to 5~C. The crystals are collected and dried to afford 0.68 g of the hydrochloride salt (I-E-(3-(4-cyanophenyl)-1-oxo-2-propenyl)-2-carbo%imidamide-1,2-dihydro-5 quinoline hydrochloride, m.p. 157-158C).
_olo~ical Activit~
The utility of the compounds of the invention is demonstrated by the ability of the compounds used to practice the method claimed in this invention to inhibit viral reverse transcriptase, an enzyme essential for human immunodeficiency virus replication. This enzyme 10 has characteristics which differentiate it from other known cellular polymerases and it is a unique enzyme which is not found in uninfected cells. Viral reverse transcriptase is found in e%traas from baaerial clones prepared according to the procedure described by Larder, B., Purifoy D.. Powell. K. and Darby, G., ~AIDS Virus Reverse Transcriptase Defined by High Level E%pression in Escherichia coli.~, EMBO J. 6:3133-3137 (1987). Inhibition of this enzyme is determined in a cell free assay which measures the level of radioactive precursors incorporated into DNA. Extracts prepared according to the procedure of Kleid, D. G., et al., Science, 1125-1129 (1981) are incubated in a mixture of inbibitor, 20 mM dithiothreitol, 60 mM sodium chloride, 0.05% NP40, 10 mM magnesium chloride, 50 mM Tris pH 8,3, 10 ~LM
t35S]-labeled deo%ynucleoside-S'-triphosphate, 10 ~g/ml RNA template (poly rC or poly rG) and 5 ~g/ml l)NA primer ~oligo dG or oligo dT) for 15 minutes at 37C. Incorporation of radio labeled precursor is determined by sponing aliquots of the reaction mixture on DE 81 paper, washing the papers to remove unicorporated precursor, drying, and determining counts.
The results of various assays are combined and reported as % inhibition of reverse transcriptase activity at a 100 f~M dose in Table I.
The utility of tbis invention is further demonstrated by the ability of various compounds used to practice the method(s) claimed in this invention to inhibit HlV-induced syncytia formation in a tissue culture assay using MT-2 cells infected wi~h HIV-I. l'his test is described by Nara et al., ~Quantitative infectivity assay for HIV-I and -2", Nature 332: 469470, 1988, as well as by Mariano Busso, et al., ~Nucleotide Dimers Suppress HIV Expression in utro" in AIDS RESEARCH AND HUMAN RETROVIRUSES, vol. 4, No. 6, pages 449455 (1988), Mary Ann Liebent, Inc., Publishers. The results (IC50 means the concentration, in ~M of drug, required to inhibit syncytia formation to the extent of 509G) of various assays are combined and report~d in Table I. In comparison, the known commercial compound, AZT, e~hibited similar anti~HrV poteney in uhis assay with 100 percent and 50 percent reductions in syncytia formation at concentrations of appro~imately 1 ~LM and 0.2 ~LM, respectively ~data not shown).
SUBSTITUTE SHEET
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The utility of the compounds of the invenlion to practice the method claimed in this inven-tion is further demonstrated by the activity of this compound in the inhibition of HIV infection in primary peripheral blood Iymphocytes ~primary PBL assay). The primary PBL assay offers the following advantages:
S (a) The assays are performed with primary human Iymphocytes. Thereby, undesired testing of transformed cell lines is avoided in which host cell and virus may have undergone processes of mutual adaptation. Performance of cell culture in serum containing media closely mimics the in vivo situation. (b) The primary PBL assay distinguishes between uue antiviral effect which is due to the drug and cytostatic/cytotoxic reactions. (c) Viral replication Is precisely followed by kinetic measurement of viral nucleic acids and proteins. (d) Nucleic acids (totaJ HIV-RNA
inua- and extracellular) and protein (secreted p24) are measured in parallel which permits one to differentiate between the compound's effect on virus replication and on the expression of viral proteins. This leads to additional information regarding the efficacy of the test compound.
(e) Tolerance of the cell culture against low arnounts of organic solvents also permits the investigation of hydrophobic substances. (f) The dose of the drug causing balf maximal suppression of virus replication is deterrnined. (g) The screening system is standardized and automated to a high degree.
The primary PBL assay uses the following procedure:
Effects of the compounds of the invention on cell proliferation are determined by Iymphocyte proliferation assays. Starting witb a 100 micromolar solution, the compound is serially diluted 10 fold. One tenth of the concentration of a compound causing half maximal inbibition of cellular proliferation is employed for all subseque~t testing.
Peripheral human Iymphocytes are isolated by density gradient centrifugation. After stimulation by mitogen the cells are infected with a standardized preparation of HIV.
Subsequently, the infected cells are cultured in the presence of the drug for four days. Indivi-dual cultures are established to measure viral replication three and four days following infection. Untreated cells and AZT-treated cells are included as controls in parallel with the drugs under investigation.
The amount of viral core protein p24 synthesized and released by the infected cells is determined in the supernatant by the capture-ELlSA technique on days three and four. By comparing with a standard preparation, the arnount of protein produced by the virus infected cells is quantified.
The total arnount of viral RNA synthesized by the; Ifected Iymphocytes is determined by a special nucleic acid hybridization technique on days three and four of culture. By including a standard preparation of HIV-RNA the amount of synthesized RNA is quantified.
If a drug shows antiviral effects in the primary assay, all steps of the primary assay are SUBSTITlJ~E SHEET
.
.
wo 92/165Q8 ;~ PCr/US92/01746 repeated, In addi~ion~ viability of HlV-infected cells is determined in parallel with assays for viral p24 and RNA. In order to evaluate the half ma~imal antiviral effect of the drug, a concentration dependency of the drug action is measured.
The compounds of the invention are assayed according to this procedure, The anti-HlV
5 acti1,dty, as measured by the inhibition of the release of core p24 protein in HIV infected human Iymphocytes, is used to calculate antiviral EDso (the concentration required to give a 50%
reduction in p24 synthesis), Results are shown in Table 1, - SUBSTITUTE~ SHEET
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2 1 ~ 1 3 3`~ PClt~'S92/~17~6 ~,- .`...................... ~ t -2~-FORMULAS
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Preparation 4 4-cyanociMamic acid 4-cyanobenzaldehyde (I eq.), malonic acid (I eq.), pyridine (0.8 M), and piperidine (1 ml/10 m] pyridine) are heated at reflux for 24 h. or until carbon dioxide is no longer evolved.
The mixture is evaporated to dryness in vacuo. The residue is redissolved in water and the pH
35 adjusted to 10 using concentrated ammonium hydroxide. The mixture is filtered through celite and the filter rinse~ with water. The pH of the filtrate is adjus~ed to 2 using IN hydrochloric SUBSTITUTE SHEET
, .. .. . .. .. - . . .
:: -' - . ' ' ....
- .-: - .. : . -wo 92/16508 2 1 0 1 3 3 ~ PCr/US~2/01746 ~- 15-acid. Chilling precipita~es solids which are collected, dissolved in acetone and 95X ethanol, and evaporated in vacuo until solids form. Chilling produces crystalline compound (1 cyanocinnamic acid).
Preparation 5 4-cyanocinnamoyl chloride 4{~yanocinnamic acid (Preparation 4, 1 eq.) is dissolved in methylene chloride at a concentration of 0.5 M. Oxalyl chloride (I eq.) is added and the mixture chilled to 0C. DMF
(0.5 eq.) is added, the mixture stirred at 0C for 0.5 h. warmed to ambient temperature, and stirred an additional 2 hours. Evaporation in v~cuo yields 4-cyanocinnamoyl chloride.
Example la 1-(4-bromobenzoyl)-2-cyano-1,2-dihydroquinoline Quinoline (0.104 g, 0.8 mmol) is dissolved in 0.5 ml of methylene chloride. 88 ~L of trimethylsilylcyanide is added at ambient temperature. 4-Bromobenzoyl chloride (0.25 g.) is dissolved in 0.5 mL of methylene chloride is added following 5 mg of aluminum trichloride.
After 40 min. the reaction is filtered through a pad of silica gel and the pad is washed with 20 mL of methylene chloride. The combined filtrates are washed first with 10 mL of water, then 15 with 10 mL of saturated aqueous sodium bicarbonate and finally S mL of water. The organic layers are concentrated in ~Jac~lo to afford an oil which is dissolved in 4 ml of 9S percent ethanol. This is evaporated to 2.5 mL and cooled at 0C for 30 min. The crystals are collected and dried in a vacuum oven to afford 85 mg of 1-(4-bromobenzoyl)-2-cyano-1,2-diSydroquinoline (m.p, 149-151C). The mother liqùor is evaporated and triturated with I rnL
20 of 9S percent ethanol. The crystaJs formed are collec~ed and dried to afford 31 mg of a second crop.
In an analogous manner, the following compounds are synthesized using the designated acid chloride.
E%asnple Ib 1-(4-fluorobenzoyl)-2-cyano-1,2-dihydroquinoline Following the procedure of Exarnple la, 4-fluorobenzoyl chloride is used as the acid chloride and the product, 1-(4-fluorobenzoyl)-2-cyano-1,2-dihydroquinoline, has a m.p. 114-116C.
Exarnple 2 1-(4-trifluoromethylbenzoyl)-2~yano-1,2-dihydroquinoline Following the procedure of Exarnple la, 4-trifluoromethylbenzoyl chloride is used as the acid chloride. The product, 1-(4-trifluoromethylbenzoyl)-2-cyano-1,2-dihydroquinoline, has a m.p. 135-136C.
Example 3 1-E-(I-oxo-3-phenyl-2-propeDyl)-2-cyano-1,2-dihydroquinoline - Following the procedure of E~arnple la, I-E-ci ~namoyl chloride is used as the acid chloride. The product. l-E-(I-oxo-3-phenyl-2-propenyl)-2-cyano-I,2~ihydroquinoline, has m.p.
149-150~.
Exarn~le 4 1 -E-(3-(~trifluoromethylphenyl)- 1 -oxo-2-propenyl)-2-cyano- 1,2-SUBSTITUTE SI~IEET
.
~VO 92f16508 2 ~ 3 3 ~ PC~/US92/0174b dihydroquinoline Following the procedure of Exarnple la, E-4-trifluoromethylcinnarnoyl chloride is used as the acid chloride. The product, I-E-(3-(4-trifluoromethylphenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, has a m.p. 172-173C.
Exarn~le 5 1-(4-carbomethoxybenzoyl)-2-cyano-1,2-dihydroquinoline Following the procedure of Exarnple 1, 4-carbomethoxybenzoyl chloride is used as the acid chloride. The product, 1-(4-carbomethoxybenzoyl)-2-cyano-1,2-dihydroquinoline, has a m.p. 165-166C.
Exarngle 6 1 -(4-cyanobenzoyl)-2-cyano- 1,2-dihydroquinoline Following the procedure of Example la, 4-cyanobenzoyl chloride is used as the acid chloride. The product, 1-(4-cyanobenzoyl)-2-cyano-1,2-dihydroquinoline. has a m.p. 154-155C.
Exarngle 7 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline Following the procedure of Example la, E4-chlorocinnarnoyl chloride is used as the acid chloride. The product, I-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline has a m.p. 166-167C.
Exarn~le 8 1 -E-(3-(4-fluorophenyl)- 1 -oxo-2-propenyl)-2-cyano- 1,2-dihydroquinoline Following the procedure of Exa nple la, E4-fluorocinnamoyl chloride is used as the acid chloride. The product, l-E-(3-(~fluorophenyl)-1-oxo-2-prophenyl)-2-cyano-1,2-dihydroquinoline has a m.p. 142- 143C.
Example 9 1-E-(2-fluoro-1-oxo-3-phenyl-2-propenyl)-2-cyano-1,2-dihydroquinoline Fol~owing the procedure of Example la, E-~x-fluorocinnamoyl chloride is used as the acid chloride. The product, I-E-(2-fluoro-1-oxo-3-phenyl-2-propenyl)-2-cyano-1,2-dihydroquinoline, has a m.p. 1~2-153C.
Example 10 1-E-(3-(3,4-dichlorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline Following the procedure of Example la, E-3,4-dichlorocinnamoyl chloride is used as the acid chloride. The product, I-E-(3,4-dichlorophenyl-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, has a m.p. 152-153C.
Example 11 1 -E-(3-(4-cyanophenyl)- 1 -oxo-2-propenyl)-2-cyano- 1,2-dihydroguinoline Following the procedure of Example la, E4-cyanocinnamoyl chloride (Preparation 5) is used as the acid chloride. The product, I-E-(3-(4-cyanophenyl)-1-oxo-2-propenyl)-2~yano-1,2-dihydroquinoline has a rn.p. 176C.
Ex n~le 12 1-E-(3-(3,4-methylenedioxyphenyl)-l~xo-2-propenyl)-2-cyano-1,2-dihydroquinol ine Following the procedure of Example la, E-3,4-methylenedioxyciMarnoyl chloride isused as the acid chloride. The producl, I-E-(3-(3,4-methylenedioxyphenyl)-l~xo-2-propenyl)-2-SUBSTiTUTE SHEE~
.. . . :
. ' ` ' -.~ . .
wo 92/1~508 2 1 0 1 ~ PCI/l~S92~01~46 r . . . 1 7 , .
cyano-1,2~ihydroquinoline, has a m.p. 176-177C.
Exam~le 13 1 -E-(3-(4-methoxyphenyl)- 1 -oxo-2-propenyl)-2-cyano-1,2~ihydroquinoline Following the procedure of Exarnple la, E-4-methoxycinnamoyl chloride is used as the acid chloride. The product is l-E-(3-(4-methoxyphenyl)-1-oxo-2-propenyl)-2-cyano-1,2-5 dihydroquinoline.
Calcd.: C,75.93; H, 5.10; N, 8.85 Found: C, 75.74; H, 5.31; N, 8.86E~,arnple 14a 1-E-(3-(4-acetoxyphenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline Following the procedure of Exarnple la, E4-acetoxycinnamoyl chloride is used as the 10 acid chloride. The product is l-E-(3-(4-acetoxyphenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinol ine.
Calcd.: C, 73.24; H, 4.68; N, 8.13 Found: C, 72.94; H, 4.51; N, 7.99 Exarnple 14b 1 -E-(3-(4-carbomethoxybenzoyl)- I -oxo-2-propenyl)-2-cyano- 1,2-lS dihydroquirJoline Following ~he procedure of Exarnple la, E4-carbomethoxycinnarnoyl chloride is used as the acid chloride. The product, I-E-(3~4~arbomethoxybenzoyl)-1-oxo-2-propenyl)-2-cyano-1,2~ihydroquinoline, has a m.p. 168-170~C.
~am~ l-E-(3-(4-methylphenyl)-1-oxo-2-trans-propenyl)-2~yano-1,2-dihydroquinolineFollowing the procedure of E%ample la, E-(4-methylcinnamoyl chloride) is used as the acid chloride. The product is l-E-(3-(4-methylphenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline.
Calcd.: C, 79.98; H, 5.37; N, 9.33 Found: C, 79.54; H, 5.40; N, 9.17 25 Example 16 1-(2-napthoyl)-2-cyano-1,2~ihydroquinoline Following the procedure of Example la, 2-napthoylchloride is used as the acid chloride.
The product, 1-(2-napthoyl)-2-cyano-1,2-dihydroquinoline, has a m.p. 185-186C.
Exasnple 17 1 -(4-chlorobenzoyl)-2-cyano~methyl- 1,2-dihydroquinoline Following the procedure of Example la, 4-methylquinoline is substituted for guinoline 30 and 4-chlorobenzoyl chloride is used as the acid chloride. The product, 1-(4-chlorobenzoyl~2-cyano 1 methyl-1,2-dihydroquinoline, has a m.p. 173-174C.
Calcd. for C18Hl3CIN2O: C, 70.02; H, 4.24; N, 9.08; Cl, 11.48.
Found: C, 69.95; ;H, 4.28; N, 8.90; Cl, 11.45.
Example 18 1-(4-chlorobenzoyl)-2-cyaDo S-fluoro-1,2-dihydroquinoline Following the procedure of Example la, 5-fluoroquinoline is substituted for quinoline and 4-chlorobenzoyl chloride is used as the acid chloride. The product. 1-~4-chlorobenzoyl)-2-SUBSTITUTE SHEET
.
wo 92/16~0X PCr/US92/01746 2 1 0 1 ~ ~ 5 --18 cyano-5-fluoro-1,2~ihydroquinoline, has a m.p. 144-145C.
Calcd. for C17HloClFN2O: C, 65.29; H, 3.22; N, 8.96; Cl, 11.34; F, 6.08.
Found: C, 65.37; H, 3.24; N, 9.03; Cl; 11.32; F, 6.47.
E~.arnple 19a 1 -(4-chlorobenzoyl)-2-cyano~fluoro- 1,2-dihydroquinoline Following the procedure of Exarnple la, 6-fluoroquinoline is substituted for quinoline and 4~hlorobenzoyl chloride is used as the acid chloride. The product, 1-(4-chlorobenzoyl)-2-cyano~fluoro-1,2-dihydroquinoline, has a m.p. 147-148C.
Calcd. for C17HloClFN20: C, 65.29; H, 3.22; N, 8.96; Cl, 11.34; F, 6.08.
Found: C, 65.18; H, 3.27; N, 8.87; Cl, 11.09; F, 6.36 Exarnple 19b 1-(4-chlorobenzoyl)~fluoro-2-cyano-1,4-dihydroquinoline The product of Exarnple 19a is subjected to reverse-phase HPLC separation (isocratic 40 THF/60% wa~er mobile phase). Pure 1-(4-chlorobenzoyl)~fluoro-2-cyano-1,4-dihydroquinoline is isolated (m.p. 14~150C).
Exarnple 20 1-(4-chlorobenzoyl)-2-cyano-7-fluoro-1,2-dihydroquinoline Following the procedure of Example la, 7-fluoroquinoline is substituted for quinoline and 4-chlorobenzoyl chloride is used as the acid chloride. The product, 1-(4-chlorobenzoyl)-2-cyano-7-fluoro-1,2~ihydroquinoline, has a m.p. 174-175C.
Calcd, for C17HloClFN2O: C, 65.29; H, 3.22; N, 8.96; Cl, 11.34; F, 6.08.
Found: C, 65.23; H, 3.27, N, 8.98; Cl, 10.99; F, 6.19.
Example 21 1-(4-chlorobenzoyl)-2-cyano-8-fluoro-1,2-dihydroquinoline Following the procedure of Example la, 8-fluoroquinoline is substituted for quinoline and 4-chlorobenzoyl chloride is used as the acid chloride in acetonitrile solvent and the solution refluxed as described above. The product, 1-(4-chlorobenzoyl)-2-cyano-8-flùoro-1,2-dihydroquinoline, has a m.p. 156-157C.
Calcd. for C17HIoClFN2O: C, 65.29; H, 3.22; N, 8.96; Cl, 11.34; F, 6.08.
Found: C, 65.36; H, 3.23; N, 8.92; Cl, 11.16: F, 6.02.
Example 22 1-(4-methoxybenzoyl)-2-cyano-6,7-difluoro-1,2-dihydroquinoline Following the procedure of Example la, 6,7-difluoroquinoline (Preparation 1) is substituted for quinoline and 4-methoxybenzoyl chloride is used as the acid chloride. m.p. 139-140C.
Calcd. for C~8H~2F2N2O2: C, 66.25; H, 3.71; N, 8.59; F, 11.65.
Found: C, 66.65; H, 3.73; N, 8.47; F, 12.09.
Exa nple 23 1-(4-chlorobenzoyl)-2-cyano-1,4-dihydroquinoxaline Following the procedure of Exarnple la, quinoxaline is used in place of quinoline and 4 chlorobenzoyl chloride is the acid halide. The product, 1~4-chlorobenzoyl)-2-cyano-1,4-dihydroquinoxaline, has a m.p. 231-232C.
SUBSTITUTE SHEE~
..
.
- . - :: .
WO 92/16~08 2 1 Q 1 3 3 ~ PCT/VS92/01746 _ 1 9_ CaJcd. for C16HloClN3O: C, 64 98; H, 3.40; N, 14.21.
Found: C, 65.05; H, 3.55; N, 14.30.
xarnple 24 1-(4-chlorobenzoyl)-2-cyano~,7~ifluoro-1,2-dihydroquinoline Following the procedure of Exarnple la, 6,7-difluoroquinoline (Preparaflon 1) is the 5 quionoline and 4-chlorobenzoyl chloride is the acid halide. llle product, 1-(4-chlorobenzoyl)-2-cyano-6,7-difluoro-1,2-dihydroquinoline, has a m.p. 184-185C.
Calcd for C17HgClF2N20: C, 61.74; H, 2.74; N, 8.47; Cl, 10.72; F, 11.49.
Found: C, 61.59; H, 2.82; N, 8.48; Cl, 10.6; F, 11.37.
ExamDle 25 1-(4-chlorobenzoyl)-6,8-difluoro-2-cyano-1,2-dihydroquinoline Following the procedure of Exarnple la, 6,8-difluoroquinoline (Preparation 2) issubstituted for quinoline and 4-chlorobenzoyl chloride is used as the acid chloride. The product, 1-(4-chlorobenzoyl)~,8-difluoro-2-cyano-1,2-dihydroquinoline, has a m.p. 164-165C.
Example 26 1 -(4-chlorobenzoyl)-7,8-difluoro-2-cyano-1,2-dihydroquinoline Following the procedure of ExarDple la, 7,8-difluoroquinoline (Preparation 3) issubstituted for quinoline and 4-chlorobenzoyl chloride is used as the acid chloride m.p. 154-lSgC.
Calcd: C, 72.72; H, 4.27; N, 8.48.
Found: C, 72,54; H, 4.35; N, 8.44.
~mEI~ 1-E-(3-(4-bromophenyl)-1-oxo-2-propenyl)-2-cyano-1,2~ihydroquinoline Following the procedure of Example la, E4-bromocinnamoyl chloride is substituted for the acid halide. The product, 1-E-(3-(4-bromophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-diDydroquinoline, has a m.p. 175-177C.
Example 28 1 -E-(3-(4-chlorophenyl)- 1 -oxo-2-propenyl)-2-cyano~,7-difluoro- 1,2-dihydroquinoline Following the procedure of ExaJnple la, 6,7-difluoroquinoline (Preparation 1) issubstituted for quinoline and 4-chlorocinnamoyl chloride is substituted for the acid halide. The product, l-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2~yano~,7-difluoro-1,2-dihydroquinoline, has a m.p. 97-98C.
Exarnple 29 1 -E-(3-(4-fluorophenyl)- 1 -oxo-2-propenyl)-2-cyano~,7-difluoro- 1,2-dihydroquinoline Following the procedure of Example la, 6,7-difluoroquinoline (Preparation 1) is substituted for quinoline and 4-fluorocinnarnoyl chloride is used as the acid chloride. Ihe prodùct, l-E-(3-(~fluorophenyl)-1-oxo-2-propenyl)-2-cyano~,7-difluoro-1,2-dihydroquinoline, has a m.p. 131-132C.
Exam~le 30a 1-(4-chlorobenzoyl)-2-cyano~,7,8-trifluoro-1,2-dihydroquinoline Following the procedure of ExaJnple la, 6,7,8-trifluoroquinoline is substituted for SUBSTITUTE SHEE~
wo 92t1650~ ~ I 0 1 3 ~ ~ PCT/US92/0~746 -20- ~
quinoline and 4~hlorociMamoyl chloride is substituted from the acid chloride. ll~e product, 1-(4~hlorobenzoyl)-2-cyano-6,7,8-trifluoro-1,2-dihydroquinoline, has a m.p. 159-160C.
Exam~le 30b 1 -E,E-( I -o~o-2,4-pentadienyl-5-phenyl)-2~yano-1,2-dihydroquinoline Following the procedure of Exarnple la, styryl acrolyl chloride is substituted for the acid 5 halide. The title product is ob~ained.
IH NMR (300 MH2, CDC13): d 6.04 (dd, ~ = I l,15 Hz, IH), 6.35 (d, J= 15 Hz, IH),6.37 (dd, 1= 1,6 Hz, IH), 6.77 (d, J= 9Hz, IH), 6.82 (dd, J=11,15 Hz, IH), 7.22-7.37 (m, 7H), 7.43 (m, 2H), 7.62 (dd, 1= 11,15 Hz, IH).
E%am~le 31 1 -(4-trifluorobenzoyl)-2-cyano-3-dimethylamino- 1,2,3,4-tçtrahydroquinoline To 500 mg (1.52 mmol) of 1-(4-trifluoromethylbenzoyl)-2~yano-1,2-dihydroquinoline is added 20 ml of methylene dichloride and 3 ml of anhydrous dimethylarnine (the dimethylamine is cooled to below -20C before carefully opening the sealed bottle). lbe reaction is allowed to stir at ambient temperature for 48 h., filtered and the resulting methylene chloride solution evaporated to dryness. The residue is distributed between methylene chloride and water, and 15 the organic phase washed twice with water. The organic phase is dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give crude product. The crude product is chromatographed using 35 percent ethyl acetate in hexane to give 1-(4-trifluorobeyl)-2-cyano-34imethylamino-1,2,3,4-tetrahydroquinoline which slowly crystallizes upon standing (m.p. 104-106C).
20 Example 32 1-(4~hlorobenzoyl)-2-cyano-1,2,3,4-tetrahydroquinoline.
To one gram of 1-(4~hlorobenzoyl)-2-cyano-1,24ihydroquinoline (3 4 mmol) in 100 ml of ssæ ethanol is added 0.10 g of platinum oxide The reduction reaction proceeds under hydrogen at atmospheric pressure 4 hours. The reaction is followed by l~C (35% ethyl acetate/he~ane). The reaction is filtered and the resulting ethanol solution is concentrated in 25 vacuo; the crude solid is recrystallized from 5 ml of absolute ethanol to give the tetrahydroquinoline (1-(4-chlorobenzoyl)-2-cyano-1,2,3,4-tetrahydroquinoline, 0.21 mg, m.p.
134-135C).
Calcd.: C, 68.78, H, 4.41; N, 9.44, Cl, 11.94.
Found: C, 68.66; H, 4.81; N, 9.16; Cl, 11.71.
30 E~ ample 33 1-Z-(I-oxo-3-phenyl-2-propenyl)-2-cyano-1,2-dihydroquinoline a) Phenylpropiolic acid (K~cK Chemicals, 1.05 g, 7.2 mmol) is dissolved in 14 ml of methylene chloride and cooled to 0C. Oxalyl chloride (0.63 ml) and dimethylformamide (140 ~1) are added. The reaction is stirred at 0C for 30 min., then warmed to ambient temperature and stirred an additional 3 hours. The reaction is concentrated in WCUO and further dried in 35 uacuo for 3 h. at ambient tçmperature. Quinoline (0.57 ml, 4.8 mmol) is dissolved in 14 m] of methylene chloride and 0.42 ml of trimethylsilylcyanide is added. Ihis solution is added to the SUBSTITUTE SHEET
, `. .
- . ...... -.
, .,.~. .
. ~
wo 92/16508 2 1 ~ 1 3 3 5 PCr/US9t/01746 !-` -21- .
phenylpropiolic acid chloride prepared above. Aluminum trichloride (catalytic, 5 mol percent) is added and the reac~ion is stirred overnight at ambient temperature. The reaaion is filtered Lhrough a plug of silica gel and washed with 75 ml of methylene chloride. The organics are washed with saturated aqueous sodium bicarbonate and evaporated in vacuo. Purification by S flash column chromatography (25 percent ethyl acetate/hexane) provides 600 mg of the desired product.
b) The above produa (200 mg) is dissolved in 7 ml of methanol and 22.6 mg of palladium on calcium carbonate poisoned with lead (5% palladium, Aldrich) and 9 mg of quinoline is added. The mixture is hydrogenated at 18 psi for 7.5 hours. Filtration of the 10 reaction and concentration in vacuo affords an oil which is dissolved in 95 percent ethanol and chilled at 5C for 20 hours. The crystalline product is collected to provide l-(l-oxo-3-phenyl-2-propenyl)-2-cyano-1,2-dihydroquinoline.
Calcd.: C, 79,70; H, 4.93; N, 9.79.
Found: C, 79.31; H, 5.01; N, 9.56.
15 Procedure fQr ~reparation Qf benzoxazineS~hart B!
Referring now to Chart B, figure 1, 1-(o-aminophenoxy)-2,2-diethoxyethane (I eq.) is prepared following the procedure of F. Choiccara et al., Tetrahedron 32, 1407 (1976). The diethoxyethanè is dissolved in, preferably ether, (0.1-0.3 M) and ethyl diisopropylamine (1-1.2 eq.) is added. The reactants are cooled to 0 C and one equivalent of the appropriate 20 ciMamoyl acid halide, preferably substituted c~nnamoyl acid chloride, is added dropwise. The reaction is allowed to proceed for a time sufficient to allow as complete a reaction as possible, e.g. 10 min. to I hour. The reactants are added to saturated sodium bicarbonate and ex~racted with methylene chloride. The organic layers are combined, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The arnide product (Chart B, fig. 2) is 25 purified using flash chromatography in ethyl acetate/hexanes.
The arnide (Chart B. fig. 2) (I eq.) is dissolved in methylene chloride (0.4-0.5M) and the reaction cooled to -20C. An acid, preferably boron trifluoride etherate, (1-1.2 eq.) is added and the reaction mixture is stirred and slowly warrned to arnbient temperatures. Stirring continues for from 12 to 20 hours. The mixrure is diluted with me~hylene chloride, washed 30 with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The product, a substituted 3,4~ihydro-3~thoxy-2H-1,4-benzoxazine (Chart B, fig. 3), is purified by flash chromatography using a chloroform/methanol solvent.
The benzoxazine (Chart B, fig. 3, 1 eq.) is dissolved jD methyleDe chloride (0.1 -0.2M) and I eq. (each) of azidotrimethylsilane and boron trifluoride etherate is added. ll~e reaction is 35 stirred at arnbient temperature for 3-24 h., diluted with methylene chloride, washed with saturated sodium bicarbonate and again with saturated sodium chloride, dried over sodium - SUBSTITUTE SHEE~
. ~ , , , , , ~ .
wo 92/1650X 2 ~ O 1 ~ ~ 5 -22- PCT/US92/01746 sulfate, and concentrated ~n wcuo Purification by nash chromatography in e~hylacetate/hexane provides a substituted 3~4-dihydro-2H-1,4~ihydrobenzoxazine-3-azide (Chart B, fig. 4).
Fur~7er purification is accomplished by recrystallization in ethylene/hexane.
E~ample 34 4-(p-chlorocinnamoyl)-3,4-dihydro-2H- 1,4-benzoxazine-3-azide a) 2-(4-chlorocinnamidinyl)phenoxy-1, I-diethoxyethane 1.24 g of 1-(o-aminophenoxy)-2,2-diethoxyethane (4.85 mmol), prepared following the procedure of F Chioccara, F. Prota, R.H. Thompson, TetrahedrQn 32, 1407 (1976), is dissolved in 40 ml of e~her and ethyl diisopropylarnine (5.82 mrnol, 0.75 g) is added. The reaction is cooled to OC. p-Chlorocinnamoyl chloride (4.85 mmol) dissolved in 10 ml of ether is added dropwise. After 10 min. of stirring, the reaction is poured in~o saturated aqueous sodium bicarbonate and extracted with methylene chloride. The organic layers are combined, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo.
Purification via flash column chromatography (200 g silica gel, 10% ethyl acetate/hexane) provides 2-(2-cblorocinnamidinyl)phenoxy)~ diethoxyethane.
b) 4-(p-chlorocinnamoyl)-3,4-dihydro-3-ethoxy-2H-1,4-benzoxazine 2-~2-~p~hlorocinnamidinyl)phenoxy-1,1-diethoxyethane (I mmol), syntbesized above, is dissolved in 2 rnl of methylene cbloride and the reaction is cooled to -20C. E~oron trifluoride etherate (1.2 mmol) is added, tbe reacsion allowed to slowly warm to room temperature over approximately 2 hours and is then stirred overnight. The mixture is diluted witb methylene chloride, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by flash column chromatogtaphy (100 g silica gel, 100% chloroforrn) provides 4-(p-chlorocinnamoyl)-3,4-dihydro-3~thoxy-2H-1,4-benzoxazine c) 4-(p-chlorocinnamoyl)-3,4-dihydro-2H- 1,4-benzoxazine 3-azide 4-(p-Chlorocinnamoyl)-3,4-dibydro-3-ethoxy-2H-1,4-benzoxazine (1 m nol) synthesized in step (b) is dissolved in 7 ml of methylene chloride Azidotrimethylsilane (1 mmol) and boron trifluoride etherate (I mmol) are added. After stirring about 3 hours at room temperature, the reaction is diluted with methylene chloride, washed with saturated sodium bicarbonate, saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo.
Purification by flash column chromatogtaphy (10% ethyl aceta~e/hexane) provides product which is recrystallized from ethyl acetate/hexane to afford the desired product (~(p-chlorociMamoyl)-3, dihydro-2H-1,4-benzoxazine-3-azide).
Procedure for ~re~aration of amidoximes (Chart C).
Referring now to Chart C, figure 1, the Reissert compound (0.68 eq.) is dissolved in methanol at 30 to 50~C and slowly added to hydroxylamine in methanol at 0C. Thehydroxylamine is prepared by adding sodium metho%ide (10 ~q.) to hydroxylamine SUBSTITUTE SHEET
..
.: :
wo 92/~6~08 2 1 0 1 3 3 ~ PCr/~'S92/0174b hydrochloride (I eq.) in methanol and then filtering. The Reissen-hydroxylarnine reaction is allowed to warm to room temperature while stirring. It is then heated from 30C to reflux for 1 to 24 hours. The reaction mixture is cooled to room temperature, diluted with chloroform, washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in S wcuo, The product (Chart C, fig. 2) is recrystallized from aqueous (95%) methanol.
As an alternative procedure we use the following:
Hydroxylamine hydrochloride (I eq.) is added to a stirred mixture of I eq. sodium carbonate in 50 percent aqueous ethanol (0.6-0.8M). The reaction is diluted to 0.06-0.08M
with absolute ethanol. Then 0.8 eq. of the desired Reissen compound is added and the reaction 10 is heated at from 50C to reflux tempetature under Gitrogen for 2.5 to 24 hours. lbe reaction poured is mixed into ice water and extracted with ethyl acetate or butanol. The organics are concentrated in vacuo, dissolved in ethanol, and chilled. The solid product is collected and dried.
The pharmacological salt of the amidoxime may be synthesized by use of an appropriate 15 acid. Examples of such salts include hydrochloride, hydrobromide, fumarate, maleate, succinate, citrate, tosylate, and mesylate.
ExamDle 35 1-(~chlorobenzoyl)-2-carboximidamide-1,24ihydroquinoline l-(~chlorobenzoyl)-2-cyano-1,24ihyd-oquinoline (0.2g, 0.68 mmol, see Popp, citedabove) is dissolved in warm methanol and added to a solution of hydroxylamine in methanol.
20 The hydroxylamine is prepared by the addition of sodium methoxide (0.232 mJ of 259G w/w solution in methanol, I mmol) to 70 mg of hydroxylamine hydrochloride ~I mmol) in methanol followed by filtration to remove precipitate. The Reissert-hydroxylamine reaction is stirred at ambient temperature for 3 h and subsequently heated to 40C for I hour. The mixture is evaporated to dryness, dissolved in 2 ml methanol, one drop of water added, and chilled to 25 5C. The solids are collected and washed with methanol to afford 1-(4-chlorobenzoyl)-2-carboximidamide-1,2-dihydroquinoline, m.p. 160-161C.
In an analogous manner the following are synthesized by substituting the appropriate Reissert compound.
Example 36a 1 -E-(3-(4-bromophenyl)- 1 -oxo-2-propenyl)-2~arboximidamide-1,2-dihydroquinoline Following the procedure of Example 35, 1-E-(3-(4-bromophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline is used as the Reissert compound. The product, I-E-(3-(4-bromophenyl)- I -oxo-2-propenyl~2-car~oximidamide- I ,?-dihydroquinoline, has a m.p. 18 181C.
3s ExamD!e ~6~ 1-E-13-(4-bromophenyl)-1-oxo-2-propenyl]-N-(acetyloxy)-2-quinolinecarboximidarnide SUBSTITUTE SHEET
. . - . ~ ~ , - ` '.
.~ " . .:.,; .
. - -~.- . :
:: :
Wo 92J1650X PCI/US92/01746 2~ ~133~ -24- ~
The purified product of Example 36(a) is dissolved in 0.75 ml methylene chloride.
Pyridine (21 ,~11) is added and the reaction is cooled lo 0C. Acetic anhydride (25 ~LI) is added and the reaction stirred 15 min. a~ 0C, and then brought to arnbient temperature. After I h., the reaction is diluted with methylene chloride, poured into saturated aqueous sodium S bicarbonate, dried over sodium sulfate, and concentrated in vacuo. The residue is triturated wilh 9596 aqueous ethanol and the solids collected to yield I E-13-(4-bromophenyl)-1-oxo-2-propenyl]-N~acetyloxy)-2-quinolinecarbo%imidamide(m.p. 151-153C).
Example 37a 1 -E-(3-(4-chlorophenyl)- 1 -oxo-2-propenyl)-2-carboximidarnide- 1,2-dihydro-quinoline Following the procedure of Example 35, 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline is used as the Reissert compound. The product, I-E-(3-(4-chlorophenyl)-l-oxo-2-propenyl)-2-carbo%imidamide-1,2-dihydroquinoline, has a m.p. 174-175C.
Exam,~le 37b 1 -E-(3-(4-chlorophenyl)- 1 -oxo-2-propenyl)-2-carboximidamide- 1,2-dihydro-quinoliDe, hydrochloride The product of Example 37a, 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinoline, is dissolved in methanol and chlorotrimethyl silane is added. The addition of diethyl ether causes the desired salt to crystallize. 'Ihe crystals are collected to afford l-E-(3-(4-chlorophenyl)-1-o%o-2-propenyl)-2-carbo~imidamide-1,2-dihydro-quinoline, hydrochloride (m.p. IS8-160C).
Example 37c 1 -E-(3-(4-chlorophenyl)- 1 -oxo-2-propenyl)-2-carboximidamide- 1,2-dihydro-quinoline, methane sulfonate The product of E%ample 37a, 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl~2-carboximidamide-1,2-dihydroquinoline, is dissolved in methanol and methane sulfonic acid is added. The volatiles are removed in vacuo and the residue recrystallized from d;ethyl ether/chloroforrn. The crystals are collected and dried to yield l-E-(3-(4~hlorophenyl~1-oxo-2-propenyl)-2-carbo%imidamide-1,2-dihydroquinoline, methane sulfonate (m.p. 139-140C).
Example 37d 1 -E-13-(4-chlorophenyl)- 1 -oxo-2-propenyl]-N-(acetyloxy)-2-quinoline-carboximidarnide Following the procedure of Example 36(b) and making non-critical variations, but starting with the product of Example 37(a), 1-E-3-~4-chlorophenyl)-1-oxo-2-propenyl~2-carboximidarnide-1,2-dihydroquinoline, the title compound is obtained. 1-E-[3-(4-chlorophenyl)-I -oxo-2-propenyl]-N-(acetyloxy)-2-quinolinecarboximidarnide (m.p . 132- 133C).Example 37e 1-E-13-(~chlorophenyl)-1-oxo-2-propenyl~-N-methoxycarbonyloxy-2-quir olinecarboximidamide Following the general procedure as described for Examples 36(b) and rnal~ing non~ritical SUBSTITUTE SHEE~
- . . ; . :
.
, .
WO 92/16~08 21~1~ 3 5 PCr/~,'S92tO1746 f varia~ions, but staning with the product of E%ample 37ta), 1-E-(3-(4-chloropbenyl)-1-o%o-2-propenyl)-2 carboximidamide-1,2-dihydroquinoline, and using methylchloroforrnate. the title compound is obtained, I -E-~3-(4-chlorophenyl)- 1 -oxo-2-propenyll-N-methoxycarbonyloxy-2-quinolinecarbo%imidamide (m.p. 173-174C).
E~amPIe 38 1-E-(3-(4-hydroxyphenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinoline Sodium carbonate (0.31 g) is dissolved in 2 rnl of ethanol and 2 ml of water.
Hydro%ylamine hydrochloride (0.202 g) is added and the reaction is diluted with 40 mJ of absolute ethanol. I-E-(3-(4-acetoxyphenyl)-1-o%o-2-propenyl)-2-cyano-1,2-dihydroquinoline (Example 14, 0.80 g) is added and the reaction heated to reflux for 1.5 hours. After cooling, it is poured into 400 ml of ice water, and extracted with chloroform (3 x 200 rnl.) After concentration in vacuo, the residue is triturated with 3 mJ of methanol. The solids formed are collected to afford 199 mg of the title compound (1-E-(3-(4-hydroxyphenyl~1-o%o-2-propenyl)-2-carboximidamide- 1,2-dihydroquinol ine, m .p . 164- 166C) .
Example 39 1-(4-chlorobenzoyl)-8-fluoro-2-carboximidamide-1,2-dihydroquinoline Following the general procedure according to Example 38 and making non-critical variations, but using 1-(4-chlorobenzoyl)-2-cyano-8-fluoro-1,2-dihydroquinolu~e (Example 21) the title compound is obtained (1-(4~hlorobenzoyl)-8-fluoro-2 carboxamidamide-1,2-dihydroquirlolinc,m.p, 186-187C).
Exatncle 40 1-(4-chlorobenzoyl)~,7-difluoro-2 carboximidamide-1,2~ihydro-quinoline Following Exa nple 38 and using 1-(4-chlorobenzoyl)~,7-difluoro-2-cyano-1,2-dihydroquinoline (Example 24) the title compound is obtained (1-(4-chlorobenzoyl)~,7-difluoro-2-carbo%irnidamide-1,2-dihydroquinoline,m.p. 128-129C).
Exarn~le 41 1-(~chlorobenzoyl)~fluoro-2-carboximidamide-1,2-dihydroquinoline Following the general pro~edure of Example 38 and making non-critical variations, but using 1-(4 chlorophenyl)-2-cyano~fluoro-1,2-dihydroquinoline (Exarnple 19), the title compounD is obtained (1-(4-chlorobenzoyl)~fluoro-2~arboximidamide-1,2-dihydroquinoline, m.p.162-163C).
Exarnple 42a 1 -E-(3-(4-cyanophenyl)- 1 -oxo-2-propenyl)-2-carboximidamide- 1,2- dihydroquinoline Following ~e general procedure of Exarnple 35 and malcing non-critical variations, but starting with l-E-(3-(4-cyanophenyl~-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline (Example I l, 0.20 g), the title compound is obtained (1-E-(3-(~cyanophenyl)-1-oxo-2~ropenyl)-2-carboximidamide-l ,2~ihydroquinoline, O. l lg, m.p. 205-206~C).
Example 42b 1-E-(3-(4-cyanopneDyl)-l-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinoline hydrochloride - SUBSTITUTE SHEET
,: :
. ,--.
, . . .
. , .
wo 92/16508 ~ 3 3 5 - PCr/US92tol746 The product of E~ample 42a (1.0 g) is suspended in 10 ml of methanol and concentrated hydrochloric acid (0.29 ml) is added. llle solution is diluted with ether until crystals formed and then it is cooled to 5~C. The crystals are collected and dried to afford 0.68 g of the hydrochloride salt (I-E-(3-(4-cyanophenyl)-1-oxo-2-propenyl)-2-carbo%imidamide-1,2-dihydro-5 quinoline hydrochloride, m.p. 157-158C).
_olo~ical Activit~
The utility of the compounds of the invention is demonstrated by the ability of the compounds used to practice the method claimed in this invention to inhibit viral reverse transcriptase, an enzyme essential for human immunodeficiency virus replication. This enzyme 10 has characteristics which differentiate it from other known cellular polymerases and it is a unique enzyme which is not found in uninfected cells. Viral reverse transcriptase is found in e%traas from baaerial clones prepared according to the procedure described by Larder, B., Purifoy D.. Powell. K. and Darby, G., ~AIDS Virus Reverse Transcriptase Defined by High Level E%pression in Escherichia coli.~, EMBO J. 6:3133-3137 (1987). Inhibition of this enzyme is determined in a cell free assay which measures the level of radioactive precursors incorporated into DNA. Extracts prepared according to the procedure of Kleid, D. G., et al., Science, 1125-1129 (1981) are incubated in a mixture of inbibitor, 20 mM dithiothreitol, 60 mM sodium chloride, 0.05% NP40, 10 mM magnesium chloride, 50 mM Tris pH 8,3, 10 ~LM
t35S]-labeled deo%ynucleoside-S'-triphosphate, 10 ~g/ml RNA template (poly rC or poly rG) and 5 ~g/ml l)NA primer ~oligo dG or oligo dT) for 15 minutes at 37C. Incorporation of radio labeled precursor is determined by sponing aliquots of the reaction mixture on DE 81 paper, washing the papers to remove unicorporated precursor, drying, and determining counts.
The results of various assays are combined and reported as % inhibition of reverse transcriptase activity at a 100 f~M dose in Table I.
The utility of tbis invention is further demonstrated by the ability of various compounds used to practice the method(s) claimed in this invention to inhibit HlV-induced syncytia formation in a tissue culture assay using MT-2 cells infected wi~h HIV-I. l'his test is described by Nara et al., ~Quantitative infectivity assay for HIV-I and -2", Nature 332: 469470, 1988, as well as by Mariano Busso, et al., ~Nucleotide Dimers Suppress HIV Expression in utro" in AIDS RESEARCH AND HUMAN RETROVIRUSES, vol. 4, No. 6, pages 449455 (1988), Mary Ann Liebent, Inc., Publishers. The results (IC50 means the concentration, in ~M of drug, required to inhibit syncytia formation to the extent of 509G) of various assays are combined and report~d in Table I. In comparison, the known commercial compound, AZT, e~hibited similar anti~HrV poteney in uhis assay with 100 percent and 50 percent reductions in syncytia formation at concentrations of appro~imately 1 ~LM and 0.2 ~LM, respectively ~data not shown).
SUBSTITUTE SHEET
.
- , . . ,. :
, . ~ ~ , . . . . , ~
,. . . .. : ~ . .. ` -. , .
,:
. .
., . ~ , wo 92/16~08 21 013 3`i~' ` ` PCl/VS92/017~6 /, ,.
The utility of the compounds of the invenlion to practice the method claimed in this inven-tion is further demonstrated by the activity of this compound in the inhibition of HIV infection in primary peripheral blood Iymphocytes ~primary PBL assay). The primary PBL assay offers the following advantages:
S (a) The assays are performed with primary human Iymphocytes. Thereby, undesired testing of transformed cell lines is avoided in which host cell and virus may have undergone processes of mutual adaptation. Performance of cell culture in serum containing media closely mimics the in vivo situation. (b) The primary PBL assay distinguishes between uue antiviral effect which is due to the drug and cytostatic/cytotoxic reactions. (c) Viral replication Is precisely followed by kinetic measurement of viral nucleic acids and proteins. (d) Nucleic acids (totaJ HIV-RNA
inua- and extracellular) and protein (secreted p24) are measured in parallel which permits one to differentiate between the compound's effect on virus replication and on the expression of viral proteins. This leads to additional information regarding the efficacy of the test compound.
(e) Tolerance of the cell culture against low arnounts of organic solvents also permits the investigation of hydrophobic substances. (f) The dose of the drug causing balf maximal suppression of virus replication is deterrnined. (g) The screening system is standardized and automated to a high degree.
The primary PBL assay uses the following procedure:
Effects of the compounds of the invention on cell proliferation are determined by Iymphocyte proliferation assays. Starting witb a 100 micromolar solution, the compound is serially diluted 10 fold. One tenth of the concentration of a compound causing half maximal inbibition of cellular proliferation is employed for all subseque~t testing.
Peripheral human Iymphocytes are isolated by density gradient centrifugation. After stimulation by mitogen the cells are infected with a standardized preparation of HIV.
Subsequently, the infected cells are cultured in the presence of the drug for four days. Indivi-dual cultures are established to measure viral replication three and four days following infection. Untreated cells and AZT-treated cells are included as controls in parallel with the drugs under investigation.
The amount of viral core protein p24 synthesized and released by the infected cells is determined in the supernatant by the capture-ELlSA technique on days three and four. By comparing with a standard preparation, the arnount of protein produced by the virus infected cells is quantified.
The total arnount of viral RNA synthesized by the; Ifected Iymphocytes is determined by a special nucleic acid hybridization technique on days three and four of culture. By including a standard preparation of HIV-RNA the amount of synthesized RNA is quantified.
If a drug shows antiviral effects in the primary assay, all steps of the primary assay are SUBSTITlJ~E SHEET
.
.
wo 92/165Q8 ;~ PCr/US92/01746 repeated, In addi~ion~ viability of HlV-infected cells is determined in parallel with assays for viral p24 and RNA. In order to evaluate the half ma~imal antiviral effect of the drug, a concentration dependency of the drug action is measured.
The compounds of the invention are assayed according to this procedure, The anti-HlV
5 acti1,dty, as measured by the inhibition of the release of core p24 protein in HIV infected human Iymphocytes, is used to calculate antiviral EDso (the concentration required to give a 50%
reduction in p24 synthesis), Results are shown in Table 1, - SUBSTITUTE~ SHEET
. ,. . . . . . - , .,~ ' . . . .
. . ~ . - : .
. ... ~ . . : . :
2 1 ~ 1 3 3`~ PClt~'S92/~17~6 ~,- .`...................... ~ t -2~-FORMULAS
~N~
l/~z I
~Y2 $ I I
8 w~
~Y~
Y
SUBSTITUTE SHEET
~' ' ' ' ': ' ~ ' :, :
WO 92/16~08 2 1 ~ 1 3 3 5 PCT/US92/017 ~
CHART A
C-N [~C~N
~ ~R
~C-N
w~R
~J ~ ~:
SUBSTITUTE SHEET
~........... . ~ ........ .. , . . . . ... . . .. . . - . .
WO 92t16508 2 ~ O ~ 3 ~ ~ PCrtU592/o~746 , -31- :
CHART B
OEt OEt [~ OEt R~
w,C~R
~N~;O BF3 ~ ~C_N
S C~ (~
W" R W" \R
CHART C
N~2~ H2 N, -N H NOH
2s C (~
W" `R ~' `R
SUBSTITUTE SHEET
.: - . ~ . : : . . : . . . .
wo 92/16508 i ~ ~ 1 3 ~ ~ PCr/US92/017~6 TABLE I
BIOASSAY RESULTSI
Syncytla PBL % RT Inhib InhibitionED50 at Example ED50(,UM) (JlM) 100 ~L
37a 0 I I _ 5~86 _ 35 0.1-1 77-89 7 <0.3 0.003 7~
l l <0.03 0.001-0.01 91-97 32 < 0.3 0.1-1 67-74 3 <0.3 0.1-1 50-74 8 0.1 0.1 75-91 2 0.3 _ 1-10 52-73 la l 0.1-1 69-72 6 0.1 0.1 60-82 17 <0.3 0.1-1 49-58 Ib2 3 10 3041 18 > 3 1-10 44~55 16 > 3 1-10 33-50 _ 12 30 0.1 37-68 l9a 1-10 65-73 21 l 62-76 24 _ I 60-85
~Y~
Y
SUBSTITUTE SHEET
~' ' ' ' ': ' ~ ' :, :
WO 92/16~08 2 1 ~ 1 3 3 5 PCT/US92/017 ~
CHART A
C-N [~C~N
~ ~R
~C-N
w~R
~J ~ ~:
SUBSTITUTE SHEET
~........... . ~ ........ .. , . . . . ... . . .. . . - . .
WO 92t16508 2 ~ O ~ 3 ~ ~ PCrtU592/o~746 , -31- :
CHART B
OEt OEt [~ OEt R~
w,C~R
~N~;O BF3 ~ ~C_N
S C~ (~
W" R W" \R
CHART C
N~2~ H2 N, -N H NOH
2s C (~
W" `R ~' `R
SUBSTITUTE SHEET
.: - . ~ . : : . . : . . . .
wo 92/16508 i ~ ~ 1 3 ~ ~ PCr/US92/017~6 TABLE I
BIOASSAY RESULTSI
Syncytla PBL % RT Inhib InhibitionED50 at Example ED50(,UM) (JlM) 100 ~L
37a 0 I I _ 5~86 _ 35 0.1-1 77-89 7 <0.3 0.003 7~
l l <0.03 0.001-0.01 91-97 32 < 0.3 0.1-1 67-74 3 <0.3 0.1-1 50-74 8 0.1 0.1 75-91 2 0.3 _ 1-10 52-73 la l 0.1-1 69-72 6 0.1 0.1 60-82 17 <0.3 0.1-1 49-58 Ib2 3 10 3041 18 > 3 1-10 44~55 16 > 3 1-10 33-50 _ 12 30 0.1 37-68 l9a 1-10 65-73 21 l 62-76 24 _ I 60-85
9 1 - 10 58-62 > 3 - 10 18-61 SUBSrlTUTE SHEET
,.
~. . . .
~ ,:
\ 0 92/16508 2 1 ~ 1 3 3 5 PCTfUS92/01746 TABLE I
BIOASSAY RESULTS
(Continued) r~ - Syncytia PBL % RT lnb Inhibition EDSo at lE~arnple EDso (~M) M) _100 /uM
I 10 0.3-2.8 I 42{i0 28 < I 78-85 14a I 54 66 ¦ 14b < 0.29 0.1-1 64-87 1 13 <3 0.1 48-7~
< 10 53-67 26 < 10 37-68 ¦ 36a 0.1-1 65-76 l 27 <0.27 0.01 K71 ¦ 42a 52-56 ¦ 37e ~ 0.1-1 18-42 ¦ 37d 2.5 0.010.1 17-28 ~ 36b 0.1-1 35-53 25 r 3~ 1-10 69-70 1 31 _1 11-36 30 1 - Assays are e~plained in specification.
2 - Known compound.
3 - Known compound: 1-(4-toluoyl)-2~yano-1,2-dihydroquinoline.
SUBSTITUTE SHEET
.... ,.. , - , - - . .
. - , , , . , - . .. . .
, -, :
,.
~. . . .
~ ,:
\ 0 92/16508 2 1 ~ 1 3 3 5 PCTfUS92/01746 TABLE I
BIOASSAY RESULTS
(Continued) r~ - Syncytia PBL % RT lnb Inhibition EDSo at lE~arnple EDso (~M) M) _100 /uM
I 10 0.3-2.8 I 42{i0 28 < I 78-85 14a I 54 66 ¦ 14b < 0.29 0.1-1 64-87 1 13 <3 0.1 48-7~
< 10 53-67 26 < 10 37-68 ¦ 36a 0.1-1 65-76 l 27 <0.27 0.01 K71 ¦ 42a 52-56 ¦ 37e ~ 0.1-1 18-42 ¦ 37d 2.5 0.010.1 17-28 ~ 36b 0.1-1 35-53 25 r 3~ 1-10 69-70 1 31 _1 11-36 30 1 - Assays are e~plained in specification.
2 - Known compound.
3 - Known compound: 1-(4-toluoyl)-2~yano-1,2-dihydroquinoline.
SUBSTITUTE SHEET
.... ,.. , - , - - . .
. - , , , . , - . .. . .
, -, :
Claims (20)
1. A compound according to formula II
II
wherein R2 is -CN, -N3, -SCN, and the E or Z isomers of -C(=NOR10)NH2, -C(=NR10)H, -C(=NNR10)NH2, -C(=NR10)NH2, -C(=NOR10)H, and -C(=NOH)N(R10)H;
Rlo is hydrogen, Cl-C4 alkyl, -Ac, ~(O)OCH3, -C(O)OC2H5, -phenyl, -P02-0-cation+, -CO-CH(AA)NH2, -CO-C6H6-NR11R12, and-CO-C6H6-CH2-NR11R12;
AA is-CH3, -CH(CH3)2, -CH2CH(CH3)2,-CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H, -(CH2)4NH2, and -(CH2)3-NH2;
R11 and R12 may be the same or different and are hydrogen and C1-C4 alkyl;
R11 and R12 taken together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and N-(C1-C4 alkyl)piperazinyl;
R3, present when the connection between positions 2 and 3 is a single bond, is bydrogen, C1-C4 alkyl, -(CH2)aCN, and -(CH2)bR13;
R13 is-N(CH3)2, -OH, -OPO3H,-OCH2CH(OH)CH2OH, -OCH2CO2H, -O2C(CH2)2CO2H. -OR14, and-NR14;
R14 is a N-terminal amino acid;
a is zero to six;
b is one to five;
A is CH, CH2, and CHN(CH3)2;
X is CH, CH2, and C-R4;
R4 is-CH3, -OCH3, and -OAc;
R5, R6, R7, R8 may be the same or different and are hydrogen and fluorine;
W is oxygen and sulfur;
Y1 is -Cl, -F, -Br, -CH3, -CF3, -(CH2)cR17, -CHO, -CO2CH3, -OH, -OCH3, -OAc, -CN, -NO2, -SH, and-SCH3;
c is zero to four;
R17is-CH2N(CH3)2, -OH, -OPO3H, -CH2N(C2HS)2, -O-sugar, -OCH2CH(OH)CH2OH,-OCH2CO2H,-O2CCH2CH2CO2H,-CH2N=CHN(CH3)2, -OR18 and -NR18;
R18 is a N-terminal amino acid;
Y2 is hydrogen;
Y1 and Y2 taken together are -CH=CR19-CH=CH-;
R19 is hydrogen, -Cl, -B-, -NO2, -CF3, -CO2CH3, -OH, -CN, and -OAc;
provided, however, when A and X are each CH, and R5, R6, R7, and R8 are each hydrogen, and R2 is -CN, Y1 is not -Cl, -F, or -CH3 and R19 is not hydrogen, when R2 is -C(=NOH)N(R10)H and R10 is hydrogen, R19 is not hydrogen, when Y1 is -OCH3, at least one of R5,R6, R7 or R8 is fluorine, when Y1 is -CF3, the connection between positions 3 and 4 is a double bond, or when Y
is -CF3 and X is CH2 and A is CHN(CH3)2, the connection between 3 and 4 is a single bond, when R4 is -CH3, R3 is hydrogen, when R4 is -CH3, Y1 is -Cl, -F, -Br, -CF3, -CN, or -NO2, and when R5 is fluorine, R6, R7 and R8 are each hydrogen, or the pharmaceutically acceptable salts thereof.
II
wherein R2 is -CN, -N3, -SCN, and the E or Z isomers of -C(=NOR10)NH2, -C(=NR10)H, -C(=NNR10)NH2, -C(=NR10)NH2, -C(=NOR10)H, and -C(=NOH)N(R10)H;
Rlo is hydrogen, Cl-C4 alkyl, -Ac, ~(O)OCH3, -C(O)OC2H5, -phenyl, -P02-0-cation+, -CO-CH(AA)NH2, -CO-C6H6-NR11R12, and-CO-C6H6-CH2-NR11R12;
AA is-CH3, -CH(CH3)2, -CH2CH(CH3)2,-CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H, -(CH2)4NH2, and -(CH2)3-NH2;
R11 and R12 may be the same or different and are hydrogen and C1-C4 alkyl;
R11 and R12 taken together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and N-(C1-C4 alkyl)piperazinyl;
R3, present when the connection between positions 2 and 3 is a single bond, is bydrogen, C1-C4 alkyl, -(CH2)aCN, and -(CH2)bR13;
R13 is-N(CH3)2, -OH, -OPO3H,-OCH2CH(OH)CH2OH, -OCH2CO2H, -O2C(CH2)2CO2H. -OR14, and-NR14;
R14 is a N-terminal amino acid;
a is zero to six;
b is one to five;
A is CH, CH2, and CHN(CH3)2;
X is CH, CH2, and C-R4;
R4 is-CH3, -OCH3, and -OAc;
R5, R6, R7, R8 may be the same or different and are hydrogen and fluorine;
W is oxygen and sulfur;
Y1 is -Cl, -F, -Br, -CH3, -CF3, -(CH2)cR17, -CHO, -CO2CH3, -OH, -OCH3, -OAc, -CN, -NO2, -SH, and-SCH3;
c is zero to four;
R17is-CH2N(CH3)2, -OH, -OPO3H, -CH2N(C2HS)2, -O-sugar, -OCH2CH(OH)CH2OH,-OCH2CO2H,-O2CCH2CH2CO2H,-CH2N=CHN(CH3)2, -OR18 and -NR18;
R18 is a N-terminal amino acid;
Y2 is hydrogen;
Y1 and Y2 taken together are -CH=CR19-CH=CH-;
R19 is hydrogen, -Cl, -B-, -NO2, -CF3, -CO2CH3, -OH, -CN, and -OAc;
provided, however, when A and X are each CH, and R5, R6, R7, and R8 are each hydrogen, and R2 is -CN, Y1 is not -Cl, -F, or -CH3 and R19 is not hydrogen, when R2 is -C(=NOH)N(R10)H and R10 is hydrogen, R19 is not hydrogen, when Y1 is -OCH3, at least one of R5,R6, R7 or R8 is fluorine, when Y1 is -CF3, the connection between positions 3 and 4 is a double bond, or when Y
is -CF3 and X is CH2 and A is CHN(CH3)2, the connection between 3 and 4 is a single bond, when R4 is -CH3, R3 is hydrogen, when R4 is -CH3, Y1 is -Cl, -F, -Br, -CF3, -CN, or -NO2, and when R5 is fluorine, R6, R7 and R8 are each hydrogen, or the pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 wherein R2 is -CN;
R3 is hydrogen;
A is CH;
X is CH and C-R4;
R4 is-CH3;
R5, R6, R7, and R9 are each hydrogen;
W is oxygen;
Y1 is-Cl,-F,-Br,-CH3,-CF3,-CHO,-CO2CH3,-OH,-OAc,-CN, NO2, -SH, and-SCH3;
Y1 and Y2 taken together are -CH=CR19-CH=CH-;
R19 is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CH3, -OH, -CN, and OAc;
provided, however, when A and X are each CH, and R5, R6, R7, and R8 are each hydrogen, and R2 is -CN, Y1 is not -Cl, -F, or -CH3 and R19 is not hydrogen, and when R4is -CH3, Y is -Cl, -F, -Br, -NO2, -CN, or -CF3.
R3 is hydrogen;
A is CH;
X is CH and C-R4;
R4 is-CH3;
R5, R6, R7, and R9 are each hydrogen;
W is oxygen;
Y1 is-Cl,-F,-Br,-CH3,-CF3,-CHO,-CO2CH3,-OH,-OAc,-CN, NO2, -SH, and-SCH3;
Y1 and Y2 taken together are -CH=CR19-CH=CH-;
R19 is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CH3, -OH, -CN, and OAc;
provided, however, when A and X are each CH, and R5, R6, R7, and R8 are each hydrogen, and R2 is -CN, Y1 is not -Cl, -F, or -CH3 and R19 is not hydrogen, and when R4is -CH3, Y is -Cl, -F, -Br, -NO2, -CN, or -CF3.
3. A compound according to claim 2 selected from the group consisting of 1-(4bromobenzoyl)-2-cyano-1,2-dihydroquinoline, 1-(trifluoromethylbenzoyl)-2-cyano-1,2-dihydroquinoline, 1-(4-carbomethoxybenzoyl)-2-cyano-1,2-dihydroquinoline, 1-(4-chlorobenzoyl)-2-cyano-4-methyl-1,2-dihydroquinoline, and 1-(4-cyanobenzoyl)-2-cyano-1,2-dihydroquinoline.
4. A compound according to claim 1 wherein R2 is -CN;
R3 is hydrogen;
A is CH;
X is CH or C-R4;
R4 is -CH3;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen;
Y1 is -Cl, -F, -Br, -CH3, -CF3, -CHO, -CO2CH3, -OH, -OCH3, -OAc, CN, -NO2, -SH, and-SCH3;
Y2 is hydrogen;
Y1 and Y2 talcen together are -CH=CR19-CH=CH-;
R19 is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CH3, -OH, -CN, and -OAc;
provided, however, that one of R5, R6, R7, and R8 are fluorine, wheo R4 is -CH3, Y1 is -Cl, -F, -Br, -CF3, -CN, or -NO2, and when R5 is fluorine, R6, R7, and R8 are each hydrogen
R3 is hydrogen;
A is CH;
X is CH or C-R4;
R4 is -CH3;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen;
Y1 is -Cl, -F, -Br, -CH3, -CF3, -CHO, -CO2CH3, -OH, -OCH3, -OAc, CN, -NO2, -SH, and-SCH3;
Y2 is hydrogen;
Y1 and Y2 talcen together are -CH=CR19-CH=CH-;
R19 is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CH3, -OH, -CN, and -OAc;
provided, however, that one of R5, R6, R7, and R8 are fluorine, wheo R4 is -CH3, Y1 is -Cl, -F, -Br, -CF3, -CN, or -NO2, and when R5 is fluorine, R6, R7, and R8 are each hydrogen
5. A compound according to claim 4 selected from the group consisting of 1-(4-chlorobenzoyl)-2-cyano-5-fluoro-1,2-dihydroquinoline, 1-(4-chlorobenzoyl)-2-cyano-7-fluoro-1,2-dihydroquinoline, 1-(4-chlorobenzoyl)-2-cyano-6,7-difluoro-1,2-dihydroquinoline, 1-(4-chlorobenzoyl)-2-cyano-6-fluoro-1,2-dihydroquinoline, 1-(4-methoxybenzoyl)-2-cyano-6,7-difluoro-1,2-dihydroquinoline, 1-(4-chlorobenzoyl)-2-cyano-8-fluoro-1,2-dihydroquinoline, 1-(4-chlorobenzoyl)-6,8-difluoro-2-cyano-1,2-dihydroquinoline, 1-(4-chlorobenzoyl)-7,8-difluoro-2-cyano-1,2-diihydroquinoline, and 1-(4-chlorobenzoyl)-2-cyano-6,7,8-trifluoro-1,2-dihydroquinoline
6. A compound according to claim 1 wherein R2 is -CN;
R3 is hydrogen;
A is CH2 and CHN(CH3)2;
X is CH2;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen;
Y1 is -Cl,-F,-Br,-CH3,-CF3,-CHO,-CO2CH3,-OH,-OCH3 -OAc,-CN,-NO2, -SH, and -SCH3;
Y1 and Y2 taken together are -CH=CR19-CH=CH-;
R19 is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CH3, -OH, -CN, and -OAc;
provided, however, when Y1 is -OCH3, at least one of R5, R6, R7 or R8 is fluorine, when R5 is fluorine, R6, R7, and R8 are each hydrogen, and when Y1 is -CF3, A is CHN(CH3)2.
R3 is hydrogen;
A is CH2 and CHN(CH3)2;
X is CH2;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen;
Y1 is -Cl,-F,-Br,-CH3,-CF3,-CHO,-CO2CH3,-OH,-OCH3 -OAc,-CN,-NO2, -SH, and -SCH3;
Y1 and Y2 taken together are -CH=CR19-CH=CH-;
R19 is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CH3, -OH, -CN, and -OAc;
provided, however, when Y1 is -OCH3, at least one of R5, R6, R7 or R8 is fluorine, when R5 is fluorine, R6, R7, and R8 are each hydrogen, and when Y1 is -CF3, A is CHN(CH3)2.
7. A compound according to claim 6 selected from the group consisting of 1-(4 cblorobenzoyl)-2-cyano-1,2,3,4-tetrahydroquinoline, and 1-(4 trifluorobenzoyl)-2-cyano-3-dimethylamino-1,2,3,4-tetrahydroquinoline.
8. A compound according to claim 1 wherein R2 is the E or Z isomers of -C(=NOR10)NH2, -C(=NR10)H, -C(=NNR10)NH2, -C(=NR10)NH2, -C(=NOR10)H, and -C(=NOH)N(R10)H;
R10 is hydrogen;
R14 is a N-terminal amino acid;
R3 is hydrogen;
A is CH;
X is CH;
R5, R6, R7, R8 rnay be the sarne or different and are hydrogen and fluorine;
W is oxygen;
Y1 is -Cl,-F,-Br,-CH3,-CF3, -CHO, -CO2CH3, -OH, -OCH3 -OAc,-CN, -NO2, -SH, and-SCH3;
Y2 is hydrogen;
Y1 and Y2 taken together are -CH=CR19-CH=CH-;
R19 is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CH3, -OH, -CN, and -OAc;
provided, however, when R2 is -C(=NOH)N(R10)H and R10 is hydrogen, R19 is not hydrogen, when Y1 is -OCH3, at least one of R5, R6, R1 or R8 is fluorine, and when R5 is fluorine, R6, R7, and R8 are each hydrogen.
R10 is hydrogen;
R14 is a N-terminal amino acid;
R3 is hydrogen;
A is CH;
X is CH;
R5, R6, R7, R8 rnay be the sarne or different and are hydrogen and fluorine;
W is oxygen;
Y1 is -Cl,-F,-Br,-CH3,-CF3, -CHO, -CO2CH3, -OH, -OCH3 -OAc,-CN, -NO2, -SH, and-SCH3;
Y2 is hydrogen;
Y1 and Y2 taken together are -CH=CR19-CH=CH-;
R19 is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CH3, -OH, -CN, and -OAc;
provided, however, when R2 is -C(=NOH)N(R10)H and R10 is hydrogen, R19 is not hydrogen, when Y1 is -OCH3, at least one of R5, R6, R1 or R8 is fluorine, and when R5 is fluorine, R6, R7, and R8 are each hydrogen.
9. A compound according to claim 8 selected from the group consisting of 1-(4-chlorobenzoyl)-2-carboximidamide-1,2-dihydroquinoline, 1-(4-chlorobenzoyl)-2-carboximidamide-8-fluoro-1,2-diihydroquinoline, 1-(4-chlorobenzoyl)-2-carboximidamide-6,7-diifluoro-1,2-dihydroquinoline, and 1-(4-chlorobenzoyl)-6-fluoro-2-carboximidamide-1,2-dihydroquinoline.
10. A compound according to formula II
II
wherein R2 is -CN, -SCN, and the E or Z isomers of -C(=NOR10)NH2, -C(=NR10)H, -C(=NNR10)NH2, -C(=NR10)NH2, -C(=NOR10)H, and -C(=NOH)N(R10)H;
R10 is hydrogen, C1-C4 alkyl, -Ac, -C(O)OCH3, -C(O)OC2H5, and -phenyl;
A is CH and CH2;
X is NH;
R3, present when the connection between positions 2 and 3 is a single bond, is hydrogen;
R5, R6, R7, R8 may be the same or different and are hydrogen and fluorine;
W is oxygen;
Y1 is -Cl,-F,-Br,-CH3,-CF3,-CHO,-CO2CH3,-OH,-OCH3 -OAc,-CN, -NO2, -SH, and-SCH3;
Y1 and Y2 taken together are -CH=CR19-CH=CH-;
R19 is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CH3, -OH, -CN, and -OAc;
provided, however, when R2 is -C(=NOH)N(R10)H and R10 is hydrogen, R19 is not hydrogen;
when Y1 is -OCH3, at least one of R5, R6, R7 or R8 is fluorine, when R5 is fluorine, R6, R7 and R8 are each hydrogen;
or the pharmacuetically acceptable salts thereof.
II
wherein R2 is -CN, -SCN, and the E or Z isomers of -C(=NOR10)NH2, -C(=NR10)H, -C(=NNR10)NH2, -C(=NR10)NH2, -C(=NOR10)H, and -C(=NOH)N(R10)H;
R10 is hydrogen, C1-C4 alkyl, -Ac, -C(O)OCH3, -C(O)OC2H5, and -phenyl;
A is CH and CH2;
X is NH;
R3, present when the connection between positions 2 and 3 is a single bond, is hydrogen;
R5, R6, R7, R8 may be the same or different and are hydrogen and fluorine;
W is oxygen;
Y1 is -Cl,-F,-Br,-CH3,-CF3,-CHO,-CO2CH3,-OH,-OCH3 -OAc,-CN, -NO2, -SH, and-SCH3;
Y1 and Y2 taken together are -CH=CR19-CH=CH-;
R19 is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CH3, -OH, -CN, and -OAc;
provided, however, when R2 is -C(=NOH)N(R10)H and R10 is hydrogen, R19 is not hydrogen;
when Y1 is -OCH3, at least one of R5, R6, R7 or R8 is fluorine, when R5 is fluorine, R6, R7 and R8 are each hydrogen;
or the pharmacuetically acceptable salts thereof.
11. A compound according to claim 10 which is 1-(4-chlorobenzoyl)-2-cyano-1,4-dihydroquinoxaline.
12. A compound according to formula I
I
wherein R2 is -CN, -N3, -SCN, and the E or Z isomers of -C(=NOR10)NH2, -C(=NR10)H, -C(=NNR10)NH2m -C(=NR10)NH2, -C(=NOR1-)H, and -C(=NOH)N(R10)H;
R20 is hydrogen, C1-C4 alkyl, -Ac, -C(O)OCH3, -C(O)OC2H5, -phenyl, -PO2-O-cation+, -CO-CH(AA)NH2, -COC6H6-NR11R12, and -CO-C6H6-CH2-NR11R12;
AA is -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H, -(CH2)4NH2, and -(CH2)3-NH2;
R11 and R12 may be the same or different and are hydrogen and C1-C4 alkyl;
R11 and R12 taken together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and N-(C1-C4 alkyl)piperazinyl;
R3, present when the connection between positions 2 and 3 is a single bond, is hydrogen, C1-C4 alkyl, -(CH2)aCN, and -(CH2)bR13;
R13 is-N(CH3)2, -OH, -OPO3H, -OCH2CH(OH)CH2OH, -OCH2CO2H, -O2C(CH2)2CO2H, -OR14, and -NR14;
R14 is a N-terminal amino acid;
a is zero to six;
b is one to five;
A is CH, CH2, and CHN(CH3)2;
X is CH, CH2, and C-R4;
R4 is -CH3, -OCH3, and -OAc;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen and sulfur;
Z is a linker selected from the group consisting of -(CO)-, -CH=CH-CH=CH- (all E), -CR15=CR16- (E or Z), or -CH=C=CH-;
R15 and R16 may be the same or different and are hydrogen and fluorine;
Y1 is hydrogen, -Cl, -F, -Br, -CH3, -CF3, -(CH2)cR17, -CHO, -CO2CH3, -OH, -OCH3 -OAc, -CN, -NO2, -SH, and-SCH3;
c is zero to five;
R17 is-CH2N(CH3)2, -OH, -OPO3H, -CH2N(C2H5)2, -O-sugar, -OCH2CH(OH)CH2OH,-OCH2CO2H, -O2CCH2CH2CO2H,-CH2N=CHN(CH3)2, -OR18, and -NR18;
R18 is a N-terminal amino acid;
Y2 is hydrogen, -Cl, -F, -OCH3, and -CF3;
Y1 and Y2 taken together are -OCH2O-, -OC(CH3)2O-, -OCH2NH-, -NHCH2O-, -OCH2S, or-SCH2O-;
provided, however, when Z is -CR15=CR16- (E), and Y2, R15, and R16 are each hydrogen, Y1 is not hydrogen, when R4 is -CH3, R3 is hydrogen, when R4 is -CH3, Y1 is -Cl, -F, -Br, -CF3, -CN, or -NO2, and when R5 is fluorine, R6, R7 and R8 are each hydrogen.
or the pharmaceutically acceptable salts thereof
I
wherein R2 is -CN, -N3, -SCN, and the E or Z isomers of -C(=NOR10)NH2, -C(=NR10)H, -C(=NNR10)NH2m -C(=NR10)NH2, -C(=NOR1-)H, and -C(=NOH)N(R10)H;
R20 is hydrogen, C1-C4 alkyl, -Ac, -C(O)OCH3, -C(O)OC2H5, -phenyl, -PO2-O-cation+, -CO-CH(AA)NH2, -COC6H6-NR11R12, and -CO-C6H6-CH2-NR11R12;
AA is -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H, -(CH2)4NH2, and -(CH2)3-NH2;
R11 and R12 may be the same or different and are hydrogen and C1-C4 alkyl;
R11 and R12 taken together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and N-(C1-C4 alkyl)piperazinyl;
R3, present when the connection between positions 2 and 3 is a single bond, is hydrogen, C1-C4 alkyl, -(CH2)aCN, and -(CH2)bR13;
R13 is-N(CH3)2, -OH, -OPO3H, -OCH2CH(OH)CH2OH, -OCH2CO2H, -O2C(CH2)2CO2H, -OR14, and -NR14;
R14 is a N-terminal amino acid;
a is zero to six;
b is one to five;
A is CH, CH2, and CHN(CH3)2;
X is CH, CH2, and C-R4;
R4 is -CH3, -OCH3, and -OAc;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen and sulfur;
Z is a linker selected from the group consisting of -(CO)-, -CH=CH-CH=CH- (all E), -CR15=CR16- (E or Z), or -CH=C=CH-;
R15 and R16 may be the same or different and are hydrogen and fluorine;
Y1 is hydrogen, -Cl, -F, -Br, -CH3, -CF3, -(CH2)cR17, -CHO, -CO2CH3, -OH, -OCH3 -OAc, -CN, -NO2, -SH, and-SCH3;
c is zero to five;
R17 is-CH2N(CH3)2, -OH, -OPO3H, -CH2N(C2H5)2, -O-sugar, -OCH2CH(OH)CH2OH,-OCH2CO2H, -O2CCH2CH2CO2H,-CH2N=CHN(CH3)2, -OR18, and -NR18;
R18 is a N-terminal amino acid;
Y2 is hydrogen, -Cl, -F, -OCH3, and -CF3;
Y1 and Y2 taken together are -OCH2O-, -OC(CH3)2O-, -OCH2NH-, -NHCH2O-, -OCH2S, or-SCH2O-;
provided, however, when Z is -CR15=CR16- (E), and Y2, R15, and R16 are each hydrogen, Y1 is not hydrogen, when R4 is -CH3, R3 is hydrogen, when R4 is -CH3, Y1 is -Cl, -F, -Br, -CF3, -CN, or -NO2, and when R5 is fluorine, R6, R7 and R8 are each hydrogen.
or the pharmaceutically acceptable salts thereof
13. A compound according to claim 12 wherein R2 is -CN and -N3;
R3 is hydrogen;
A is CH;
X is-CH and CH2;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen;
Z is a linker selected from the group consisting of -CH=CH-CH=CH- (all E) and -CR15=CR16- (E or Z);
R15 and R16 may be the same or different and are hydrogen and fluorine;
Y1 is hydrogen, -Cl, -F, -Br, -CH3, -CF3, -CHO, -CO2CH3, -OH, -OCH3 -OAc, -CN, -NO2, -SH, and -SCH3;
Y2 is hydrogen, -Cl, -F. -OCH3, and -CF3;
Y1 and Y2 taken together are -OCH2O-, -OC(CH3)2O-, -OCH2NH-, -NHCH2O-, -OCH2S, or-SCH2O-;
provided, however, when Z is -CR15=CR16- (E), and Y2, R15, and R16 are each hydrogen, Y1 is not hydrogen, and when R5 is fluorine, R6, R7 and R8 are each hydrogen.
R3 is hydrogen;
A is CH;
X is-CH and CH2;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen;
Z is a linker selected from the group consisting of -CH=CH-CH=CH- (all E) and -CR15=CR16- (E or Z);
R15 and R16 may be the same or different and are hydrogen and fluorine;
Y1 is hydrogen, -Cl, -F, -Br, -CH3, -CF3, -CHO, -CO2CH3, -OH, -OCH3 -OAc, -CN, -NO2, -SH, and -SCH3;
Y2 is hydrogen, -Cl, -F. -OCH3, and -CF3;
Y1 and Y2 taken together are -OCH2O-, -OC(CH3)2O-, -OCH2NH-, -NHCH2O-, -OCH2S, or-SCH2O-;
provided, however, when Z is -CR15=CR16- (E), and Y2, R15, and R16 are each hydrogen, Y1 is not hydrogen, and when R5 is fluorine, R6, R7 and R8 are each hydrogen.
14. A compound according to claim 13 selected from the group consisting of 1-E-(3-(4-tritluoromethylphenyl)-1-oxo-2-propenyl)-2-cyano- 1,2-dihydroquinoline, 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, I-E-(3-(4-fluorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, 1-E-(3-(3,4-dichlorophenyl)-1 -oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, 1-E-(2-fluoro-1-oxo-3-phenyl-2-propenyl)-2-cyano-1,2-dihydroquinoline, 1-E-(3-(4-cyanophenyl)-1-oxo-2-propenyl)-2-cyano-1,2 dihydroquinoline, 1-E-(3-(4-chloropbenyl)-1-oxo-2-propenyl)-2-cyano-6,7-difluoro-1,2-dihydroquinoline, 1-E-(3-(4-acetoxyphenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, 1-E-(3-(4-methoxyphenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, 1-Z-(1-oxo-3-phenyl-2-propenyl)-2-cyano-1,2-dihydroquinoline, 1-E-(3-(4-bromophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, 1-E-(3-(4-carbomethoxybenzoyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, 1-E-(3-(4-methylphenyl)-1-oxo-2-trans-propenyl)-2-cyano-1,2-dihydroquinoline, 1-E-(3-(3,4-methylenedioxyphenyl-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline,1-E-(3-(4-fluorophenyl)-1-oxo-2-propenyl)-2-cyano-6,7-difluoro-1,2-dihydroquinoline, and 1-E,E-(1-oxo-2,4-pentadienyl-5-phenyl)-2-cyano-1,2-dihydroquinoline.
15. A compound according to claim 14 which is 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline.
16. A compound according to claim 12 wherein R2 is the E or Z isomers of -C(=NOR10)NH2, -C(=NR10)H, -C(=NNR10)NH2, -C(=NR10)NH2, -C(=NOR10)H, and -C(=NOH)N(R10)H;
R10 is hydrogen, -Ac, and -C(O)OCH3;
R3 is hydrogen;
A is CH and CH2;
X is CH and CH2;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen;
Z is -CR15=CR16- (E or Z);
R15 and R16 may be the same or different and are hydrogen and fluorine;
Y1 is hydrogen, -Cl, -F, -Br, -CH3, -CF3, -CHO, -CO2CH3, OH, -OAc, -CN, -NO2, -SH, and -SCH3;
Y2 is hydrogen, -Cl, -F, -OCH3, and CF3;
Y1 and Y2 taken together are -OCH2O-, -OC(CH3)2O-, -OCH2NH-, -NHCH2O-, -OCH2S, or -SCH2O-;
provided, however, when Y2, R15, and R16 are each hydrogen, Y1 is not hydrogen, and when R5 is fluorine, R6, R7 and R8 are each hydrogen.
R10 is hydrogen, -Ac, and -C(O)OCH3;
R3 is hydrogen;
A is CH and CH2;
X is CH and CH2;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen;
Z is -CR15=CR16- (E or Z);
R15 and R16 may be the same or different and are hydrogen and fluorine;
Y1 is hydrogen, -Cl, -F, -Br, -CH3, -CF3, -CHO, -CO2CH3, OH, -OAc, -CN, -NO2, -SH, and -SCH3;
Y2 is hydrogen, -Cl, -F, -OCH3, and CF3;
Y1 and Y2 taken together are -OCH2O-, -OC(CH3)2O-, -OCH2NH-, -NHCH2O-, -OCH2S, or -SCH2O-;
provided, however, when Y2, R15, and R16 are each hydrogen, Y1 is not hydrogen, and when R5 is fluorine, R6, R7 and R8 are each hydrogen.
17. A compound according to claim 16 selected from the group consisting of 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinoline, 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinolinemonohydrochloride, 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinoline, monomethane sulfonate, 1-E-(3-(4-bromophenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinoline,1-E-(3-(4-hydroxyphenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinoline, 1-E-[3-(4-bromophenyl)-1-oxo-2-propenyl]-N-(acetyloxy)-2-quinolinecarboximidamide, 1-E-[3-(4-chlorophenyl)-1-oxo-2-propenyl]-N-methoxycarbonyloxy-2-quinolinecarb-oximidamide, 1-E-[3-(4-chlorophenyl)-1-oxo-2-propenyl]-N-(acetyloxy)-2-quinolinecarboximidamide, 1-E-(3-(4-cyanophenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinoline, and 1-E-(3-(4-cyanophenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinoline monohydrochloride.
18. Use of a compound of formula I
I
wherein R2 is -CN, -N3, -SCN, and the E or Z isomers of -C(=NOR10)NH2, -C(=NR10)H, -C(-NNR10)NH2, -C(=NR10)NH2, -C(=NOR10)H, and -C(=NOH)N(R10)H;
R10 is hydrogen, C1-C4 alkyl, -Ac, -CO2CH3, -CO2C2H5, -phenyl, -PO2-O- cation+, -CO-CH(AA)NH2, -CO-C6H6-NR11R12, and -CO-C6H6-CH2-NR11R12;
AA is -CH3, -CH(CH3)2, -CH2CH(CH3)2,-CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H, -(CH2)4NH3, and -(CH2)3-NH2;
R11 and R12 may be the same or different and are hydrogen and C1-C4 alkyl;
R11 and R12 taken together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and N-(C1-C4 alkyl)piperazinyl;
R3, present when the connection between positions 2 and 3 is a single bond, is hydrogen, C1-C4 alkyl, -(CH2)aCN, and -(CH2)bR13;
R13 is -N(CH3)2, -OH, OPO3H, -OCH2CH(-OH)CH2OH, -OCH2CO2H, -O2C(CH2)2CO2H, -OR14, and -NR14;
R14 is a N-terminal amino acid;
a is zero to six;
b is one to five;
A is CH, CH2, N, and CHN(CH3)2;
X is CH, CH2, NH, O, and C-R4;
R4 is -CH3, -OCH3, and -OAc;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen and sulfur;
Z is a direct bond or a linker selected from the group consisting of -(CO)-, -CH=CH-CH=CH- (all E), -CR15=CR16- (E or Z), and -CH=C=CH-;
R15 and R16 may be the same or different and are hydrogen and fluorine;
Y1 is hydrogen, -Cl, -F, -Br, -CH3, -CF3, -(CH2)CR17, -CHO, -CO2CH3, -OH, -OCH3 -OAc, -CN, -NO2, -SH, and -SCH3;
c is zero to five;
R17 is -CH2N(CH3)2 -OH, -OPO3H, -CH2N(C2HS)2, -O-sugar, -OCH2CH(OH)CH2OH, -OCH2CO2H, -O2CCH2CH2CO2H, -CH2N=CHN(CH3)2, -OR18, or -NR18;
R18 is an N-terminal amino acid;
Y2 is hydrogen, -Cl, -F, -OCH3, and -CF3;
Y1 and Y2 taken together can form -OCH2O-, -OC(CH3)2O, OCH2NH-, -NHCH2O-, -OCH2S-, -SCH2O-, and -CH = CR19-CH = CH-;
R19 is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CH3, -OH, -CN, and -OAc;
provided, however, when Z is a direct bond and R2 is -C(=NOH)N(R10)H and R10 is hydrogen, R19 is not hydrogen, when Z is a direct bond, Y1 is not hydrogen, when Y1 is -OCH3 and Z is a direct bond, at least one of R5, R6, R7 or R8 is fluorine, when Y1 is -CF3 and Z is direct bond, the connection between positions 3 and 4 is a double bond, when Z is a direct bond, X is not O, when Z is a direct bond, R2 is not -N3, when Z is a direct bond, Y2 is hydrogen or -F, when A is N, X is C-R4 and R4 is -OCH3 or -OAc and the connection between position 3 and 4 is a double bond, when A is CHN(CH3)2, X is CH2 when R4 is -CH3, R3 is hydrogen, when R4 is -CH3, Y1 is -Cl, -F, -Br, -CF3, -CN, or -NO2, when R5 is fluorine, R6, R7 and R8 are each hydrogen when Y1 and Y2 taken together are -CH=CR19-CH=CH-, Z is a direct bond, and when Y1 and Y2 taken together can form -OCH2O-, -OC(CH3)2O, -OCH2NH-, -NHCH2O-, -OCH2S-, and -SCH2O-, Z is a linker, and/or the pharmaceutically acceptable salts, hydrates, and solvates thereof for the manufacture of a medicament for use in treating a human infected with one or more than one strain of a human immunodeficiency virus (HIV).
I
wherein R2 is -CN, -N3, -SCN, and the E or Z isomers of -C(=NOR10)NH2, -C(=NR10)H, -C(-NNR10)NH2, -C(=NR10)NH2, -C(=NOR10)H, and -C(=NOH)N(R10)H;
R10 is hydrogen, C1-C4 alkyl, -Ac, -CO2CH3, -CO2C2H5, -phenyl, -PO2-O- cation+, -CO-CH(AA)NH2, -CO-C6H6-NR11R12, and -CO-C6H6-CH2-NR11R12;
AA is -CH3, -CH(CH3)2, -CH2CH(CH3)2,-CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H, -(CH2)4NH3, and -(CH2)3-NH2;
R11 and R12 may be the same or different and are hydrogen and C1-C4 alkyl;
R11 and R12 taken together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and N-(C1-C4 alkyl)piperazinyl;
R3, present when the connection between positions 2 and 3 is a single bond, is hydrogen, C1-C4 alkyl, -(CH2)aCN, and -(CH2)bR13;
R13 is -N(CH3)2, -OH, OPO3H, -OCH2CH(-OH)CH2OH, -OCH2CO2H, -O2C(CH2)2CO2H, -OR14, and -NR14;
R14 is a N-terminal amino acid;
a is zero to six;
b is one to five;
A is CH, CH2, N, and CHN(CH3)2;
X is CH, CH2, NH, O, and C-R4;
R4 is -CH3, -OCH3, and -OAc;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen and sulfur;
Z is a direct bond or a linker selected from the group consisting of -(CO)-, -CH=CH-CH=CH- (all E), -CR15=CR16- (E or Z), and -CH=C=CH-;
R15 and R16 may be the same or different and are hydrogen and fluorine;
Y1 is hydrogen, -Cl, -F, -Br, -CH3, -CF3, -(CH2)CR17, -CHO, -CO2CH3, -OH, -OCH3 -OAc, -CN, -NO2, -SH, and -SCH3;
c is zero to five;
R17 is -CH2N(CH3)2 -OH, -OPO3H, -CH2N(C2HS)2, -O-sugar, -OCH2CH(OH)CH2OH, -OCH2CO2H, -O2CCH2CH2CO2H, -CH2N=CHN(CH3)2, -OR18, or -NR18;
R18 is an N-terminal amino acid;
Y2 is hydrogen, -Cl, -F, -OCH3, and -CF3;
Y1 and Y2 taken together can form -OCH2O-, -OC(CH3)2O, OCH2NH-, -NHCH2O-, -OCH2S-, -SCH2O-, and -CH = CR19-CH = CH-;
R19 is hydrogen, -Cl, -Br, -NO2, -CF3, -CO2CH3, -OH, -CN, and -OAc;
provided, however, when Z is a direct bond and R2 is -C(=NOH)N(R10)H and R10 is hydrogen, R19 is not hydrogen, when Z is a direct bond, Y1 is not hydrogen, when Y1 is -OCH3 and Z is a direct bond, at least one of R5, R6, R7 or R8 is fluorine, when Y1 is -CF3 and Z is direct bond, the connection between positions 3 and 4 is a double bond, when Z is a direct bond, X is not O, when Z is a direct bond, R2 is not -N3, when Z is a direct bond, Y2 is hydrogen or -F, when A is N, X is C-R4 and R4 is -OCH3 or -OAc and the connection between position 3 and 4 is a double bond, when A is CHN(CH3)2, X is CH2 when R4 is -CH3, R3 is hydrogen, when R4 is -CH3, Y1 is -Cl, -F, -Br, -CF3, -CN, or -NO2, when R5 is fluorine, R6, R7 and R8 are each hydrogen when Y1 and Y2 taken together are -CH=CR19-CH=CH-, Z is a direct bond, and when Y1 and Y2 taken together can form -OCH2O-, -OC(CH3)2O, -OCH2NH-, -NHCH2O-, -OCH2S-, and -SCH2O-, Z is a linker, and/or the pharmaceutically acceptable salts, hydrates, and solvates thereof for the manufacture of a medicament for use in treating a human infected with one or more than one strain of a human immunodeficiency virus (HIV).
19. The use according to claim 18 wherein R2 is -CN and -N3;
R3 is hydrogen;
A is CH;
X is -CH and CH2;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen;
Z is a linker selected from the group consisting of -CH=CH-CH=CH- (all E) and -CR15=CR16- (E or Z);
R15 and R16 may be the same or different and are hydrogen and fluorine;
Y1 is hydrogen, -Cl, -F, -Br, -CH3, -CF3, -CHO, -CO2CH3, -OH, -OCH3 -OAc, -CN, -NO2, -SH, and -SCH3;
Y2 is hydrogen, -Cl, -F, -OCH3, and -CF3;
Y1 and Y2 taken together are -OCH20-, -OC(CH3)20-, -OCH2NH-, -NHCH20, -OCH2S, or -SCH20-;
provided, however, when Z is -CR=15=CR16- (E), and Y2, R15, and R16 are each hydrogen, Y1 is not hydrogen, and when R5 is fluorine, R6, R7 and R8 are each hydrogen.
R3 is hydrogen;
A is CH;
X is -CH and CH2;
R5, R6, R7, and R8 may be the same or different and are hydrogen and fluorine;
W is oxygen;
Z is a linker selected from the group consisting of -CH=CH-CH=CH- (all E) and -CR15=CR16- (E or Z);
R15 and R16 may be the same or different and are hydrogen and fluorine;
Y1 is hydrogen, -Cl, -F, -Br, -CH3, -CF3, -CHO, -CO2CH3, -OH, -OCH3 -OAc, -CN, -NO2, -SH, and -SCH3;
Y2 is hydrogen, -Cl, -F, -OCH3, and -CF3;
Y1 and Y2 taken together are -OCH20-, -OC(CH3)20-, -OCH2NH-, -NHCH20, -OCH2S, or -SCH20-;
provided, however, when Z is -CR=15=CR16- (E), and Y2, R15, and R16 are each hydrogen, Y1 is not hydrogen, and when R5 is fluorine, R6, R7 and R8 are each hydrogen.
20. The use according to claim 19 wherein the compound is I-E-(3-(4-trifluoromethylphenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, I-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, I-E-(3-(4-fluorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, I-E-(3-(3,4-dichlorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, I-E-(2-fluoro-1-oxo-3-phenyl-2-propenyl)-2-cyano-1,2-dihydroquinoline, I-E-(3-(4-cyanophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, I-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-cyano-6,7-difluoro-1,2-dihydroquinoline, I-E-(3-(4-acetoxyphenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, I-E-(3-(4-methoxyphenyl)-1 -oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, I-Z-(1-oxo-3-phenyl-2-propenyl)-2-cyano-1,2-dihydroquinoline, I-E-(3-(4-bromophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, I-E-(3-(4-carbomethoxybenzoyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, I-E-(3-(4-methylphenyl)-1-oxo-2-trans-propenyl)-2-cyano-1,2-dihydroquinoline, I-E-(3-(3,4-methylenedioxyphenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline, I-E-(3-(4-fluorophenyl)-1-oxo-2-propenyl)-2-cyano-6,7-difluoro-1,2-dihydroquinoline, and l-E,E-(1-oxo-2,4-pentadienyl-5-phenyl)-2-cyano-1,2-dihydroquinoline.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US66908291A | 1991-03-14 | 1991-03-14 | |
| US669,082 | 1991-03-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2101335A1 true CA2101335A1 (en) | 1992-09-15 |
Family
ID=24684937
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002101335A Abandoned CA2101335A1 (en) | 1991-03-14 | 1992-03-12 | Reissert compounds as anti-hiv agents |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0579695A1 (en) |
| JP (1) | JPH06505992A (en) |
| AU (1) | AU1580492A (en) |
| CA (1) | CA2101335A1 (en) |
| WO (1) | WO1992016508A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5663169A (en) * | 1992-08-07 | 1997-09-02 | Merck & Co., Inc. | Benzoxazinones as inhibitors of HIV reverse transcriptase |
| DE4428932A1 (en) * | 1994-08-16 | 1996-02-22 | Hoechst Ag | Substituted quinoline derivatives, process for their preparation and their use |
| US5939435A (en) * | 1997-02-03 | 1999-08-17 | American Home Products Corporation | 2-substituted-1-acyl-1,2-dihydroquinoline derivatives |
| US7553967B2 (en) | 2004-03-12 | 2009-06-30 | Wyeth | 1,2-Dihydroquinoline derivatives and method for using the same to treat HIV infections |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU4488989A (en) * | 1988-11-15 | 1990-06-12 | Upjohn Company, The | Phenanthrolinedicarboxylate esters, 4-aminoquinoline and isoquinoline derivatives as inhibitors of hiv reverse transcriptase |
-
1992
- 1992-03-12 CA CA002101335A patent/CA2101335A1/en not_active Abandoned
- 1992-03-12 WO PCT/US1992/001746 patent/WO1992016508A1/en not_active Application Discontinuation
- 1992-03-12 EP EP92908626A patent/EP0579695A1/en not_active Withdrawn
- 1992-03-12 AU AU15804/92A patent/AU1580492A/en not_active Abandoned
- 1992-03-12 JP JP4508267A patent/JPH06505992A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JPH06505992A (en) | 1994-07-07 |
| EP0579695A1 (en) | 1994-01-26 |
| AU1580492A (en) | 1992-10-21 |
| WO1992016508A1 (en) | 1992-10-01 |
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