CA2002414A1 - Phenanthrolinedicarboxylate esters, 4-aminoquinoline and isoquinoline derivatives as inhibitors of hiv reverse transcriptase - Google Patents
Phenanthrolinedicarboxylate esters, 4-aminoquinoline and isoquinoline derivatives as inhibitors of hiv reverse transcriptaseInfo
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- CA2002414A1 CA2002414A1 CA 2002414 CA2002414A CA2002414A1 CA 2002414 A1 CA2002414 A1 CA 2002414A1 CA 2002414 CA2002414 CA 2002414 CA 2002414 A CA2002414 A CA 2002414A CA 2002414 A1 CA2002414 A1 CA 2002414A1
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- use according
- formula
- pharmaceutically acceptable
- acceptable salt
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
ABSTRACT
A method for treating a human patient afflicted with human immunodeficiency virus comprising administering to such patient an effective amount of a compound of formula IA
IA
wherein R, R1 and R2 are as defined in the specification, e.g., dimethyl 1,4,7,10-tetrahydro-4,10-dioxo-6-(n-pentyl)-1,7-phenanthro-line-2,8-dicarboxylate; a compound of formula IB
IB
,e.g., 1-benzoyl-4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl-piperazine, and salts thereof such as the maleate salt are described;
a compound of formula IC
IC
,e.g., 4-[(7-chloro-4-quinolyl)amino]-.alpha.-[[4-[(6-methoxy-8-quinolyl)-amino]pentyl]amino]-.alpha.'-1-pyrrolidinyl-2,6-xylenol trihydrochloride , and a compound of Formula ID
ID
,e.g., 2'-[(5,5-dimethoxy-1-isoquinolyl)methyl]-4',5'-dimethoxyacetophenone.
A method for treating a human patient afflicted with human immunodeficiency virus comprising administering to such patient an effective amount of a compound of formula IA
IA
wherein R, R1 and R2 are as defined in the specification, e.g., dimethyl 1,4,7,10-tetrahydro-4,10-dioxo-6-(n-pentyl)-1,7-phenanthro-line-2,8-dicarboxylate; a compound of formula IB
IB
,e.g., 1-benzoyl-4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl-piperazine, and salts thereof such as the maleate salt are described;
a compound of formula IC
IC
,e.g., 4-[(7-chloro-4-quinolyl)amino]-.alpha.-[[4-[(6-methoxy-8-quinolyl)-amino]pentyl]amino]-.alpha.'-1-pyrrolidinyl-2,6-xylenol trihydrochloride , and a compound of Formula ID
ID
,e.g., 2'-[(5,5-dimethoxy-1-isoquinolyl)methyl]-4',5'-dimethoxyacetophenone.
Description
.
-1- 4312.P CP
PHENANTHROLINEDICARBOXYLATE ESTERS, 4-AMINOQUINOLINE A~D
ISOQUINOLINE DERIVATIVES AS INHIBITORS OF
HIV REVERSE TRANSCRIPTASE
Introduction This invention relates to a new medica~ use of some phenanthro-linedicarboxylate esters, 4-aminoquinoline and isoquinoline derivatives as drugs to treat human patients afflicted with a human immunodeficiency virus.
Background of the Invention and Information Disclosure An estimated one to one and one-half million people in the United States are infected with a human retrovirus, the human immunodeficiency virus type I, HIV-l, which is the etiological agent of acquired immunodeficiency symdrome, AIDS, Norman, C., Science 234:661-662 (1986). Of those infected, an estimated two hundred and fifty thousand people will develop AIDS in the next five years.
Curran, J.W., et al., Science, 229:1352-1357 (1985). On March 20, 1987 the FDA approved the use of the compound, zidovudine (AZT), to treat AIDS patients with a recent initial episode of Pneumocystis carinii pneumonia, AIDS patients with conditions other than Pneumo-cystis carinii pneumonia or patents infected with the virus with an absolute CD4 lymphocyte count of less than 100/mm3 in the peripheral blood. AZT is a known inhibitor of viral reverse transcriptase, an enzyme necessary for human immunodeficiency virus replication.
The phenanthroline-dioxo-dicarboxylic acid precursors and some of the esters thereof used to practice the method of use of this invention are known in the art, e.g., in Waring U.S. patent 3,790,577, which discloses similar compounds for use in treating asthms. However, to our knowledge, none of these compounds are known to be useful to treat humans infected with human imMunodeficiency virus or strains thereof.
Procedures for making some of the 4-aminoquinoline derivative compounds used according to the method of this invention are either known from or obvious to a person skilled in the art from the patent literature such a~ the Archer U.S. Patent 3,362,956, the Graham, et al. U.S. Patent 3,632,761, the Coverdale U.S. Patent 4,025,629 and the NcCall U.S. Patent 4,167,567. Some of the 4-aminoquinoline derivative test chemical materials found useful according to this invention were purchased form the Aldrich Chemical Company, Inc., . 200Z4~4
-1- 4312.P CP
PHENANTHROLINEDICARBOXYLATE ESTERS, 4-AMINOQUINOLINE A~D
ISOQUINOLINE DERIVATIVES AS INHIBITORS OF
HIV REVERSE TRANSCRIPTASE
Introduction This invention relates to a new medica~ use of some phenanthro-linedicarboxylate esters, 4-aminoquinoline and isoquinoline derivatives as drugs to treat human patients afflicted with a human immunodeficiency virus.
Background of the Invention and Information Disclosure An estimated one to one and one-half million people in the United States are infected with a human retrovirus, the human immunodeficiency virus type I, HIV-l, which is the etiological agent of acquired immunodeficiency symdrome, AIDS, Norman, C., Science 234:661-662 (1986). Of those infected, an estimated two hundred and fifty thousand people will develop AIDS in the next five years.
Curran, J.W., et al., Science, 229:1352-1357 (1985). On March 20, 1987 the FDA approved the use of the compound, zidovudine (AZT), to treat AIDS patients with a recent initial episode of Pneumocystis carinii pneumonia, AIDS patients with conditions other than Pneumo-cystis carinii pneumonia or patents infected with the virus with an absolute CD4 lymphocyte count of less than 100/mm3 in the peripheral blood. AZT is a known inhibitor of viral reverse transcriptase, an enzyme necessary for human immunodeficiency virus replication.
The phenanthroline-dioxo-dicarboxylic acid precursors and some of the esters thereof used to practice the method of use of this invention are known in the art, e.g., in Waring U.S. patent 3,790,577, which discloses similar compounds for use in treating asthms. However, to our knowledge, none of these compounds are known to be useful to treat humans infected with human imMunodeficiency virus or strains thereof.
Procedures for making some of the 4-aminoquinoline derivative compounds used according to the method of this invention are either known from or obvious to a person skilled in the art from the patent literature such a~ the Archer U.S. Patent 3,362,956, the Graham, et al. U.S. Patent 3,632,761, the Coverdale U.S. Patent 4,025,629 and the NcCall U.S. Patent 4,167,567. Some of the 4-aminoquinoline derivative test chemical materials found useful according to this invention were purchased form the Aldrich Chemical Company, Inc., . 200Z4~4
-2-P.O. Box 2060, Milwaukee, WI 53201. However, some of these com-pounds are believed to be new and procedures for making them are described here below.
Compounds such as 4-[4-(7-chloro-4-quinolyl)amino]-~-[[4-[(6-methoxy-8-quinolyl)amino]pentyl]amino]-~'-1-pyrrolidinyl-2,6-xylenol trihydrochloride are disclosed in published Netherlands Patent Application No. 6506950, Derwent Abstract No. 19308, this one being compound IV therein.
4-Aminoquinoline derivatives of the formula I type which have the morpholino ring in the Rl position are generically disclosed in Japanese published patent application J50018479, referred to in Derwent Abstract No. 28234 U/17. ; -The compound losulazine hydrochloride, 1-[(4-fluorophenyl)sul-fonyl]-4-[-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoylpipera-15 zine, is listed in the USAN and the USP of drug names for 1989, ~ ;
released for names through June 15, 1988, copyright by US Pharma-copeial Convention, Inc. 12601 Twinbrook Parkway, Rockville, MD
20852 (1988).
Procedures for making the isoquinoline derivative compounds used according to the method of this invention are either known from or obvious to a person of ordinary skill in the art from the technical or patent literature or are described hereinbelow. The compound 6,7-dimethoxy-1-(3,4,5-triethoxyphenyl)isoquinoline and its hydrochloride are disclosed in The Merck Index, 10th. Ed. (1983), pp 970-971, item 25 6596, as Octaverine, and its hydrochloride. The compound 5,6-dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxolo[5,6-a]quinolizinium salts; such as the iodide, is also disclosed in The Merck Index, 10th. Ed. (1983), page 165, item 1162 under the name berberine. The ~-compound 2'-[(5,6-dimethoxy-1-isoquinolyl)methyl]-4',5'-dimethoxy~
30 acetophenone is disclosed a~ item No. S44,370-0, pseudocaralyne, and ,aceotopapaverine in a catalog of the Alfred Bader Library of Rare Chemicals, a division of Aldrich Chemical Company, P.O. Box 2060, Milwaukee, WI 53201. Alkyl (l-isoquinolyl)-oxamic acid esters can be made from commercially available l-aminoisoquinoline and the selected alkyl chlorooxalate esters by known methods, exemplified hereinbelow.
The alkyl ~5-isoquinolinyl)acetate esters can also be made by known methods, exemplified hereinbelow.
However, to our knowledge, none of these compounds are known to - ~:.
~- . ZOOZ4~4
Compounds such as 4-[4-(7-chloro-4-quinolyl)amino]-~-[[4-[(6-methoxy-8-quinolyl)amino]pentyl]amino]-~'-1-pyrrolidinyl-2,6-xylenol trihydrochloride are disclosed in published Netherlands Patent Application No. 6506950, Derwent Abstract No. 19308, this one being compound IV therein.
4-Aminoquinoline derivatives of the formula I type which have the morpholino ring in the Rl position are generically disclosed in Japanese published patent application J50018479, referred to in Derwent Abstract No. 28234 U/17. ; -The compound losulazine hydrochloride, 1-[(4-fluorophenyl)sul-fonyl]-4-[-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoylpipera-15 zine, is listed in the USAN and the USP of drug names for 1989, ~ ;
released for names through June 15, 1988, copyright by US Pharma-copeial Convention, Inc. 12601 Twinbrook Parkway, Rockville, MD
20852 (1988).
Procedures for making the isoquinoline derivative compounds used according to the method of this invention are either known from or obvious to a person of ordinary skill in the art from the technical or patent literature or are described hereinbelow. The compound 6,7-dimethoxy-1-(3,4,5-triethoxyphenyl)isoquinoline and its hydrochloride are disclosed in The Merck Index, 10th. Ed. (1983), pp 970-971, item 25 6596, as Octaverine, and its hydrochloride. The compound 5,6-dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxolo[5,6-a]quinolizinium salts; such as the iodide, is also disclosed in The Merck Index, 10th. Ed. (1983), page 165, item 1162 under the name berberine. The ~-compound 2'-[(5,6-dimethoxy-1-isoquinolyl)methyl]-4',5'-dimethoxy~
30 acetophenone is disclosed a~ item No. S44,370-0, pseudocaralyne, and ,aceotopapaverine in a catalog of the Alfred Bader Library of Rare Chemicals, a division of Aldrich Chemical Company, P.O. Box 2060, Milwaukee, WI 53201. Alkyl (l-isoquinolyl)-oxamic acid esters can be made from commercially available l-aminoisoquinoline and the selected alkyl chlorooxalate esters by known methods, exemplified hereinbelow.
The alkyl ~5-isoquinolinyl)acetate esters can also be made by known methods, exemplified hereinbelow.
However, to our knowledge, none of these compounds are known to - ~:.
~- . ZOOZ4~4
-3-be useful to treat humans infected with human immunodeficiency virus (HIV) or strains thereof.
Summarv of the Invention This invention provides a method for treating a human patient infected with one or more strains of a human immunodeficiency virus (HIV) which comprises administering to said patient an effective amount of: ~
A) a phenanthroline-dioxo-dicarbo~ylate ester compound of ~ .
formula IA (see Structure Sheet) where Rl and R2 are the same or . :
different and each of Rl and R2 is a carboxyl protecting ester group, and R is a C4 to C8-alkyl, C5 to C6-cycloalkyl or a phenyl group; or B) a 4-aminoquinoline derivative compound of formula IB (See Structure Sheet), or a pharmaceutically acceptable salt or solvate thereof, where R' is selected from the group consisting of a halogen having an atomic number of from 9 to 35 or trifluoromethyl;
Y is carbonyl [-C(0)-] or sulfonyl [-S(0)2-];
R'l is selected from the ring structure groups (a), (b), (c) or (d) shown on the Structure Sheet page, and X is selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromethyl and Cl to C3-alkyloxy, or a pharmaceutically acceptable salt or solvate thereof; or C) a 4-aminoquinoline derivative compound of formula IC (See Structure Sheet), or a pharmaceutically acceptable salt or solvate 25 thereof, where R' is selected from the group consisting of a halogen . `~.
having an atomic number of from 9 to 35 or trifluoromethyl; and .
X is selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromet.hyl and Cl to '-~
C3-alkyloxy, or a pharmaceutically acceptable sal~ or solvate thereof; or D) an isoquinoline derivative compound of formula ID (see Structure Sheet) or a pharmaceutically acceptable salt thereof, where - R" is selected from the group consisting of hydrogen, the group (a) (see Structure Sheet) where X', Y' and Z are the same or different 35 and are selected from the group consisting of hydrogen, Cl to C3 ~S~
alkyloxy and Cl to C3-alkylcarbonyl and r is zero (0) or 1; and the group (b) (see Structure Sheet) where W is Cl to C3-alkyl; `:
Rl and R~2 are each selected from the group consisting of 20024~
, -4-hydrogen, Cl to C3-alkyloxy and Cl to C3-alkyloxycarbonylmethoxy, R3, alone, is not present;
R4, alone, is hydrogen, and R3 and R4 taken together with the isoquinoline ring define a ring structure of the formula IV (see Structure Sheet) where R~l and R"2 are as defined hereinabove, or a pharmaceutically acceptable salt thereof;
in an amotmt effective to inhibit the further replication of the HIV
in said patient.
The ester compounds (Formula IA) used according to this methGd of use invention are generally known and are included within the phenanthroline-dioxo-dicarboxylate esters described in column 3 of Waring U.S. patent 3,790,577, formula (X). In the compounds used according to this invention Rl and R2 can be, for example, a Cl to C6-alkyl, a phenyl-Cl to C6-alkyl or a benzyl ester group, and R can be a Cl to C8-alkyl, preferably a straight-chained or n-alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, branched hexyl, heptyl and octyl group, or a C5 to C6-cycloalkyl, e.g., cyclopentyl, cyclohexyl or a phenyl group.
Our preferred compounds of formula IA are those wherein Rl and R2 are a Cl to C3-alkyl, e.g., methyl, ethyl, n-propyl or isopropyl -and R is a straight or branched chain pentyl group such as n-pentyl, l-methyl-l-butyl and l,l-dimethyl-l-propyl.
Examples of such compounds include: -A. dimethyl 1,4,7,10-tetrahydro-4,10-dioxo-6-(n-pentyl)-1,7-phenan-throline-2,8-dicarboxylate, B. dimethyl 6-~1,1-dimethyl-1-propyl)-1,4,7,10-te~rahydro-4,10-dioxo-1,7-phenanthroline-2,8-dicarboxylate, and ~C. dimethyl 1,4,7,10-tetrahydro-6-(1-methyl-1-butyl)-4,10-dioxo-1,7-phenanthroline-2,8-dicarboxylate, and other esters of these compounds such as the phenyl and cyclohexyl esters, and the like.
In compounds of Formula IB and IC, used according to the method of this invention, by the term halogen having an atomic number of from 9 to 35 we mean fluorine, chlorine and bromine. The term Cl to C3-alkyloxy includes methoxy, ethoxy, n-propyloxy and isopropyloxy.
"',;' ~'"''`
20024~4 These compounds can be used for the method of this invention as the free amine, but may, for efficacy or pharmaceutical reasons, be used as a pharmaceutically acceptable salt or as a solvate with small adhering amounts of an acceptable alcohol such as methanol or ethanol. Pharmaceutically acceptable salts refer to those anion salt forming groups which would be readily apparent to a manufacturing pharmaceutical chemist to be equivalent or better than the parent compound in potency, or in properties such as formulation, stability, patient acceptance and bioavailability. Examples of such anionic salt forming groups which can be used include the hydrohalide salts such as the hydrochloride, hydrobromide, hydroiodide, maleate succinate, benzoate, p-toluenesulfonate methanesulfonate, acetate and the like.
Examples of specific compounds within this defined group of compounds (FORMnLA IB) found to be useful according to this invention include~
D. l-Benzoyl-4-[4-[[7-trifluoromethyl)-4-quinolinyl]amino]ben-zoylpiperazine, E. l-Benzoyl-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]-benzoylpiperazine maleate, F. 1-[(4-methoxyphenyl)sulfonyl]-4-[4-[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]plperazine, G. 1-[(4-chlorophenyl)sulfonyl]-4-[-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, H. N-(4-chlorophenyl)-N-[4-[(7-chloro-4-quinolinyl]amino]-phenyl]urea, I. N-[4-[3-(trifluoromethyl)phenyl]-3-cyclohexen-1-yl]-4-[[7-(tri$1uoromethyl)-4-quinolyl]aminobenzamide, K. 4-[m-[(7-chloro-4-quinolyl)amino]benzoyl]morpholine hydrochloride, and the like.
Summarv of the Invention This invention provides a method for treating a human patient infected with one or more strains of a human immunodeficiency virus (HIV) which comprises administering to said patient an effective amount of: ~
A) a phenanthroline-dioxo-dicarbo~ylate ester compound of ~ .
formula IA (see Structure Sheet) where Rl and R2 are the same or . :
different and each of Rl and R2 is a carboxyl protecting ester group, and R is a C4 to C8-alkyl, C5 to C6-cycloalkyl or a phenyl group; or B) a 4-aminoquinoline derivative compound of formula IB (See Structure Sheet), or a pharmaceutically acceptable salt or solvate thereof, where R' is selected from the group consisting of a halogen having an atomic number of from 9 to 35 or trifluoromethyl;
Y is carbonyl [-C(0)-] or sulfonyl [-S(0)2-];
R'l is selected from the ring structure groups (a), (b), (c) or (d) shown on the Structure Sheet page, and X is selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromethyl and Cl to C3-alkyloxy, or a pharmaceutically acceptable salt or solvate thereof; or C) a 4-aminoquinoline derivative compound of formula IC (See Structure Sheet), or a pharmaceutically acceptable salt or solvate 25 thereof, where R' is selected from the group consisting of a halogen . `~.
having an atomic number of from 9 to 35 or trifluoromethyl; and .
X is selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromet.hyl and Cl to '-~
C3-alkyloxy, or a pharmaceutically acceptable sal~ or solvate thereof; or D) an isoquinoline derivative compound of formula ID (see Structure Sheet) or a pharmaceutically acceptable salt thereof, where - R" is selected from the group consisting of hydrogen, the group (a) (see Structure Sheet) where X', Y' and Z are the same or different 35 and are selected from the group consisting of hydrogen, Cl to C3 ~S~
alkyloxy and Cl to C3-alkylcarbonyl and r is zero (0) or 1; and the group (b) (see Structure Sheet) where W is Cl to C3-alkyl; `:
Rl and R~2 are each selected from the group consisting of 20024~
, -4-hydrogen, Cl to C3-alkyloxy and Cl to C3-alkyloxycarbonylmethoxy, R3, alone, is not present;
R4, alone, is hydrogen, and R3 and R4 taken together with the isoquinoline ring define a ring structure of the formula IV (see Structure Sheet) where R~l and R"2 are as defined hereinabove, or a pharmaceutically acceptable salt thereof;
in an amotmt effective to inhibit the further replication of the HIV
in said patient.
The ester compounds (Formula IA) used according to this methGd of use invention are generally known and are included within the phenanthroline-dioxo-dicarboxylate esters described in column 3 of Waring U.S. patent 3,790,577, formula (X). In the compounds used according to this invention Rl and R2 can be, for example, a Cl to C6-alkyl, a phenyl-Cl to C6-alkyl or a benzyl ester group, and R can be a Cl to C8-alkyl, preferably a straight-chained or n-alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, branched hexyl, heptyl and octyl group, or a C5 to C6-cycloalkyl, e.g., cyclopentyl, cyclohexyl or a phenyl group.
Our preferred compounds of formula IA are those wherein Rl and R2 are a Cl to C3-alkyl, e.g., methyl, ethyl, n-propyl or isopropyl -and R is a straight or branched chain pentyl group such as n-pentyl, l-methyl-l-butyl and l,l-dimethyl-l-propyl.
Examples of such compounds include: -A. dimethyl 1,4,7,10-tetrahydro-4,10-dioxo-6-(n-pentyl)-1,7-phenan-throline-2,8-dicarboxylate, B. dimethyl 6-~1,1-dimethyl-1-propyl)-1,4,7,10-te~rahydro-4,10-dioxo-1,7-phenanthroline-2,8-dicarboxylate, and ~C. dimethyl 1,4,7,10-tetrahydro-6-(1-methyl-1-butyl)-4,10-dioxo-1,7-phenanthroline-2,8-dicarboxylate, and other esters of these compounds such as the phenyl and cyclohexyl esters, and the like.
In compounds of Formula IB and IC, used according to the method of this invention, by the term halogen having an atomic number of from 9 to 35 we mean fluorine, chlorine and bromine. The term Cl to C3-alkyloxy includes methoxy, ethoxy, n-propyloxy and isopropyloxy.
"',;' ~'"''`
20024~4 These compounds can be used for the method of this invention as the free amine, but may, for efficacy or pharmaceutical reasons, be used as a pharmaceutically acceptable salt or as a solvate with small adhering amounts of an acceptable alcohol such as methanol or ethanol. Pharmaceutically acceptable salts refer to those anion salt forming groups which would be readily apparent to a manufacturing pharmaceutical chemist to be equivalent or better than the parent compound in potency, or in properties such as formulation, stability, patient acceptance and bioavailability. Examples of such anionic salt forming groups which can be used include the hydrohalide salts such as the hydrochloride, hydrobromide, hydroiodide, maleate succinate, benzoate, p-toluenesulfonate methanesulfonate, acetate and the like.
Examples of specific compounds within this defined group of compounds (FORMnLA IB) found to be useful according to this invention include~
D. l-Benzoyl-4-[4-[[7-trifluoromethyl)-4-quinolinyl]amino]ben-zoylpiperazine, E. l-Benzoyl-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]-benzoylpiperazine maleate, F. 1-[(4-methoxyphenyl)sulfonyl]-4-[4-[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]plperazine, G. 1-[(4-chlorophenyl)sulfonyl]-4-[-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, H. N-(4-chlorophenyl)-N-[4-[(7-chloro-4-quinolinyl]amino]-phenyl]urea, I. N-[4-[3-(trifluoromethyl)phenyl]-3-cyclohexen-1-yl]-4-[[7-(tri$1uoromethyl)-4-quinolyl]aminobenzamide, K. 4-[m-[(7-chloro-4-quinolyl)amino]benzoyl]morpholine hydrochloride, and the like.
4-[(7-chloro-4-quinolyl)amino]-~-[[4-[(6-methoxy-8-quinol-yl)amino]pentyl]amino]-~'-l-pyrrolidinyl-2,6-xylenol trihydrochloride (Compound J) is an Example of a compound of Formula IC.
Examples of specific compounds within the defined group of compounds (Formula ID) which are useful accordin~ to this invention include~
L. 6,7-dimethoxy-1-(3,4,5-triethoxyphenyl)-isoquinoline ~ . :- :::
hydrochloride (Octaverine hydrochloride), : . , .:
; "- :- :".`, ' ,'' .
M. 5,6-dihydro-9,10-dimethoxy-benzo[~]-1,3-benzodioxolo-]5,6-a]quinolizinium iodide (Berberinium iodicle), N. 2'-[6,7-dimethoxy-1-isoquinolyl)methyl]-4',5'-dimethoxy-acetophenone, O. (l-isoquinolyl)oxamic acid, ethyl ester, P. (5-isoquinolinyloxy)acetic acid, methyl ester.
,:'', Detailed Descri~tion of the Invention The term human immunodeficiency virus (HIV) means human immuno-deficiency virus typs I, human immunodeficiency virus type II, or strains, apparent to one skilled in the art, which belong to the same viral family and which create similar physiological effects in humans as human immunodeficiency virus types I and II.
Patients to be treated would be those individuals: 1) infected with one or more than one strain of a human immunodeficiency virus as determined by the presence of either measurable viral antibody or antigen in the serum and 2) havin~ either a symptomatic AIDS defining infection such as i) disseminated histoplasmosis, ii) psoriasis, iii) bronchial and pulmonary candidiasis including pneumocystis pneumonia iv) non-Hodgkin's lymphoma or v) Kaposi's sarcoma and being less than sixty years old; or having an absolute CD4 lymphocyte-count of less than 200/mm3 in the peripheral blood. Treatment would consist of maintaining an inhibitory level of the compounds 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 alternate therapy is needed.
The utility of this invention is demonstrated by ~he ability of the test compounds used to practice the method claimed in this inven-tion in a standard laboratory test involving the ability of the test ::
compound or substance to inhibit the viral reverse transcriptase (RT), an enzyme essential for human immunodeficiency virus replica-tion. This enzyme has characterlstics 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 extracts from bacterial clones prepared according to the procedure described by Tanese, N., et al., Journal of Virology, 59:743-745 (1986). Inhibition of this enzyme by the test compound is determined in a cell free assay which measures the level of radioactive precur-.~ ::' ' : ,~-.,, sors incorporated into DNA. RT extrac~s prepared similar to the procedure of Kleid, D. G., et al., Science, 214:1125-1129 (1981) are incubated in a mixture of test compound, 20 mM dithiothreitol, 60 M
sodium chloride, 0.05% NP-40, 10 ~ magnesium chloride, 50 mM Tris pH
8.3, 10 M [35S]-radiolabeled deoxynuleoside-5'-triphosphate, 10 ~g/
ml R~A template (poly rC or poly rA) and 5 ~g/ml DNA primer (oligo dG
or oligo dT) for 30 minutes at 37C. Incorporation of radiolabeled precursor is determined by harvesting the trichloroacetic acid precipitated reaction mixtures on glass fiber filters, drying and determining counts. The results of various assay(s) are combined and reported in Table I as % inhibition of the enzyme compared to tne control test where no test compound enzyme inhibitor is present. It is preferred that the test compound inhibit the RT enzyme by at least 20% of the untreated control value in the same test procedure, - 15 preferably greater than 50% inhibition to be considered for more advanced testing. The percent numbers illustrate the percentage rate of RT enzyme inhibition by these compounds in this standard :: :: :: :.: :: -laboratory test.
Ue believe these percentage RT enzyme inhibition rates are20 unexpected because tests of other closely related compounds in this same test, such as the nonesterified phenanthroline-dioxo-6-pentyl-dicarboxylic acid, the phenanthroline-dioxo-2,5,8-tricarboxylic acid, the 6-hydrogen-phenanthroline-dioxo-2,8, dicarboxylic acid and the dimethyl 5-cyano-phenanthroline-dioxo-2,8-dicarboxylate ester gave RT
enzyme percent inhibition rates in this test which were too low to warrant further consideration of such compounds for advanced testing as possible anti-HIV disease drugs in humans. Ue do not believe that :: . .
the encouraging high percentage RT enzyme i ~ ibition results for the use of these Structure IA esters could have been predicted from the ~ ;
prior art or from the testing of these other somewhat related com-pounds . ' ' Ue believe these percentage rate RT e~ yme inhibition rates are unexpected because tests of other closely related 4-aminoquinoline compounds in this same test, such as 7-chloro-4-[N-(l-methylpiperidin-3-yl)methyl)amino]-4-quinoline, diethylaminoethyl 4-[(7-chloroquinol-4-yl) ~ ino]benzoate, 2-[N-(7-chloroquinol-4-yl)amino]acetic acid, N-[(7-chloroquinol-4-yl)-N-[4-methoxy-3-(2-chloroethylamino-'`''''''~; ''''. '`:~
:' ' ~' ~ ,.
.
20024~4 methyl)phenyl]amine, and N-(7-chloroquinol-4-yl)-N-[3,5-bis(pyrrolidin-1-ylmethyl)-4-hydroxyphenylamine, 7-chloro-N-[(N-methylpiperidin-3-yl)methyl]quinoline, and 7-chloro-4-[N-[4-[(4-methylpiperazin-1-yl)carbonyl]phenyl]quino-lin-4-ylamine gave RT enzyme percent inhibition rates in this test which were too low to warrant further consideration of such compounds for advanced testing as possible anti-HIV disease drugs in humans. We do not believe that the encouraging high percentage RT enzyme inhibition results for the use of these Structure IB compounds could have been predicted from the prior art or from the testing of these other somewhat related compounds.
The utility of this invention is further demonstrated by the ability of various compounds (Nos. A, H, K, and L) 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 with HIV-l. This test is described by Nara et al., Quantitative infectivity assay for HIV-l and -2., Nature 332: 469-20 470, 1988 as well as in AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol. 4, No. 6, pages 449-455 (1988), Mary Ann Liebent, Inc., Publishers in an article by Mariano Busso, et al., entitled "Nucleotide Dimers Suppress HIV Expression In VITRO". The results (IC50 means the concentration, in ~M of drug, required to inhibit syncytia formation to the extent of 50~) of various assay(s) are combined and reported as ~ inhibition and/or IC50 (calculated) in Table II. ~n comparison, the known commercial compound, AZT, exhibited anti-HIV potency in this assay system of 100 percent and 50 percent reduction in syncytia formation at concentrations of approximately l~M and 0.5 ~M, respectively.
! The utility~of 6,7-dimethoxy-1-(3,4,5-triethoxyphenyl)- ! ' isoquinoline hydrochloride (Octaverine hydrochloride; Compou~d L) to practice the method claimed in this invention is further demonstrated by the activity of this compound in the inhibition of HIV infection in primary peripheral blood lymphocytes (primary PBL assay). This assay is done by the following screening procedure.
The following features characterize the primary screening~
The screening tests are performed with primary human lympho~
'~ ' ' ~, 20024~4 ~- -9-cytes. 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.
True antiviral effects of drugs are readily distinguished from cytostatic/cytotoxic reactions.
. .. :.
By kinetic measurement of viral nucleic acids and proteins the viral replication is followed precisely.
Testing in parallel on the level of nucleic acids (total HIV-RNA
intra- and extracellular) and on the level of proteins (secreted p24) allows to differentiate the drug effects on virus replication and on the expression of viral proteins. This leads to additional informa-tion regarding the efficacy of the drug. ~ s Tolerance of the cell culture against low amounts of organic solvents permits the investigation of hydrophobic substances also.
The dose of the drug causing half maximal suppression of virus ~- ; f';
replication is determined.
The screening system is standardized and automated to a high degree.
1. TEST FOR TOXICITY
.- ~ ~ ., Effects of the drugs on cell proliferation are determined by lymphocyte proliferation assays. Starting with a 100 micromolar solution, ~he drug is 10 fold serially diluted.
One tenth of the concentration of the drug causing half maximal inhlbition of cellular proliferation is employed for all subsequent testing.
2. IN VITRO INFECTION OF LYMPHOCYTES
Peripheral human lymphocytes 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.
Individual cultures are established to measure viral replication two, three and four days following infection.
Untreated cells and AZT-treated cells are included as controls in parallel with the drugs under investigation.
2.1 DETECTION OF SECRETED VIRAL P24 The amount of viral core protein p24 synthesized and released by the infected cells is determined in the supernatant by capture-ELISA
!`, ~: ; ' ' .~ ,.. ,, ,~., ' ',:
'.' ~,,, ' `.:
. .
2~ 2~4 technique on days two, three and four. By comparing with a standard preparation, the amount of protein produced by the virus infected cells will be calibrated.
2.2 ASSAY FOR HIV-RNA
The total amount of vlral RNA synthesized by the infected lymphocytes is determined by a special nucleic acid hybridization technique on days two, three and four of culture. By including a standard preparation of HIV-RNA the amount of synthesized RNA will be quantified.
In case a drug shows antiviral effects in the primary screening, all steps of the primary screening will be repeated. In addition, viability of HIV-infected cells will be determined in parallel with assays for viral p24 and RNA. In order to evaluate the half maximal antiviral effect of the drug, a concentration dependency of the drug 15 action will be measured. -~
The anti-HIV activity of Octaverine hydrochloride (Compound L), as measured by the inhibitior. of the release of core p24 protein in HIV infected human lymphocytes was found to be 53.5% ~1 ~M) three days after HIV infection of the primary peripheral blood lymphocytes `
and 6.8~ M) four days after HIV infection of the primary peripheral blood lymphocytes. As measured by inhibition of viral RNA
synthesis, Compound L exhibited 38.9~ N) at day 3 and 13.4% (1 ~M) at day 4. ~ "
Compounds K and N were inactive (1 ~M), while compound A was 25 only marginally active (1 ~M), in inhibition of p24 protein ` ` "
synthesis. Compounds A, K and N were inactive in the inhibition of ~`
viral RNA synthesis at the dosage level tested (1 ~M). ` ~;~
The compound l-benzoyl-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]-amino]benzoyl~piperazine, and its pharmaceutically acceptable salts 30 e.g., its maleate salt, are believed to be new and patentable, and ~ `
,are claimed herein as such.
This quinoline-amine compound can be prepared as follows~
Preparation of l-benzoyl-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]-amino]benzoyl]piperazine.
3S To 4.73 gm (0.01 mole) of 1-[4-[[7-(trifluoromethyl)-4-quino-linyl]amino]benzoyl]piperazine (Chemical Abstracts RN 57975-86-7), prepared according to procedures described in U.S. Patent 4,025,629, in 100 ml. of tetrahydrofuran (THF) there was added 3.03 gm (0.03 20024~L4 .::
mole) of triethylamine (TEA) and then 1.41 gm (0.01 mole) of benzoyl -chloride dissolved in 40 ml of THF with stirring.
The resulting reaction mixture was stirred at ambient tempera-ture for 24 hours and then concentrated to dryness in vacuo. The `~
S yellow residue was slurried with 200 ml of water. The product was collected and dried. The product, named as above, was purified by - ~``
dissolving it in methylene chloride and then adding Skellysolve B
brand of hexanes to the cloud point to form a creamy product. The product separated from this mixture to give 4.2 gm (83 percent yield), m.p. 251.1 C, which analyzed as follows:
% Anal. Calcd: C, 66.67; H, 4.56; N, 11.11.
g Found: C, 66.50; H, 4.59; N, 11.03.
This 4-(N'-benzoylpiperazinyl benzoylamino) quinoline derivative was also made by adding benzoic acid anhydride in THF to a room temperature solution of the starting 7-(trifluoromethyl)-4-[(1-piperazinyl)-4-benzoylamino)quinoline, allowing the mixture to react for 3 hours, evaporating the mixture, to a low volume, taking up the i residue in methylene chloride/aqueous sodium carboxide solution, and filtering off the yellow solid which resulted. The methylene chloride layer filtrate was washed with water, evaporated partially and diluted with ethyl ether to precipitate some additional solid product. A thin layer chromatography test showed the two solids to be the same. The solids were combined to obtain 5.1 gm, m.p. 257- ;``
258 C of the l-benzoyl-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]- ` ' amino]ben2oyl]piperazine.
The maleate salt of this piperazine derivative was made in methanol from 5 gm of the named piperazine derivative and 2.5 gm of maleic acid. After filtering the solid salt and washing it with ethyl ether, there was obtained 5.5 g of the named piperazine derivative as its maleate salt, 231-232 C. ;~
We believe these percentage rate RT enzyme inhibition rates are ;~
unexpected because tests of other closely related compounds in this same test such as 6,7-diethoxy-1-(3,4-diethoxyphenylmethyl)-isoquinoline hydro-35 chloride, -~
6,7-dimethoxy-1-[(2-amino-4,5-dimethoxyphenyl)methyl]iso- -~
quinol~ne, and the like, gave RT enzyme percent inhibition rates in this test which were too low to warrant further consideration of such ' ~ ~
' . ~ . `~'` `', ; ; k ~
20024~4 compounds for advanced testing as possible anti-HIV disease drugs in humans. Ue do not believe that the encouraging percentage RT enzyme inhibition results for the use of these structure IC compounds could -have been predicted from the prior art or from the testing of these other somewhat related compounds.
The compound ethyl (l-isoquinolyl)-oxamate was made as follows:
A solution of 10 g. (0.068 mole) of l-aminoquinoline in 15 ml.
of dry ethyl acetate was stirred with 8.40 g. (0.083 mole) of triethylamine. To this mixture there was added 11.33 g. (0.083 mole) of ethyl oxalyl chloride and the resulting mixture was stirred at room temperature for several hours and then allowed to stir over-night.
A precipitate which resulted was removed by filtration and ~`
washed with ethyl acetate. The combined filtrate and wash liquids were evaporated to dryness in vacuo. The residue was taken up in and crystallized from ethanol to obtain 5.59 g. of the ethyl tl-iso-quinolyl)oxamate, m.p. 113-114C.
Anal. Calcd. for C13H12N23 ~ Calcd.: C, 63.72; H, 4.95; N, 11.47.
~ Found: C, 63,79; H, 4.90; N, 11.39.
- The infrared spectrum analysis (IR) was in agreement with this named product.
The compound methyl (5-isoquinolinyloxy)acetate was prepared as follows:
A solution of 5 g. (34.48 mmole) of 5-hydroxyisoquinoline in 200 ml. of d~methylformamide was stirred under a nitrogen atmosphere and cooled to -20C. in an ice/methanol bath. To this solution was added 3.27 ml. (34.48 mmole) of methyl bromoacetate followed by 1.39 g.
(34.48 mmole) of sodium hydride (60~ oil dispersion). The reaction mixture warmed to room temperature and the resulting solution was ,stirred under a nitrogen atmosphere for 24 hours. The mixture was poured into a solution of ice/water/ethyl acetate and extracted with ethyl acetate. The aqueous layer was found to have a pH of 8.4. The combined ethyl acetate extracts were washed with water three times and then with sodium chloride solution and then dried over magnesium sulfate, filtered and concentrated in vacuo to yield 6.8 g. of crude residue. The residue was chromatographed on 600 g. of silica gel.
The column was wet-packed and eluted with 5% methanol/methylene ,; ,' 2002414 ~-chloride and fractions of 35 ml. were collected. Fractions 37-62 were combined and concentrated in VACUO to yield 5.22 g. of residue which was found to be a mixture of materials by thin layer chroma-tography with 10% acetone/methylene chloride as a solvent system.
This material was rechrom~tographed on 520 g. of silica gel. The column was repacked and eluted with 10~ acetone/methylene chloride and fractions of 35 ml. were collected. Fractions 73-133 were combined and concentrated in vacuo to yield 3.92 g. of the methyl (5-isoquinolinyloxy)acetate ester which after recrystallizing in ether-10 hexane afforded 3.64 g. (484 of theory) of pure product with melting point 84-86C.
Infrared: ~max (mull) 3007, 1743, 1585, 1494, 1455, 1435, 1393, 1322, 1288, 1268, 1225, 1173, 1122, 1079, ~027, 1018, 821, 804, 755 731 cm~~
NMR (CDC13; TMS): ~ 9.28 (s, lH), 8.64, 8.58, 8.17, 8.13 (AB
quartet, 2H), 7.73-7.25 (m, 2H), 7.03-6.83 (m, lH), 4.82 (s, 2H), 3.83 (s, 3H).
Mass Spectrum: Ions at 217 (N~), 218, 189, 158, 145, 144, 131, 128, 116, 101, 89, 75, 63.
TLC (silica gel GF): Rf 0.25 (10% acetone/methylene chloride).
Those skilled in the art would know how to formulate the com-pounds (Formula IA or ID) used to practice the method claimed in this invention into appropriate pharmaceutical dosage forms. Examples of the dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions, and those in U.S. patent 3,790,577 which is incorporated herein by reference. -Tho~e skilled in the art would know how to form~llate the com-pounds (Formula IB or IC) used to practice the method claimed in this invention into appropriate pharmaceutical dosage forms. Examples of ,the dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions, and those in U.S. patents 3,790,577 and 4,025,629 which are incorporated herein by reference.
When the co~pounds used to practice the method claimed in this invention are administered orally, an effective amount is from about 1 to 100 mg/kg/day. The diethyl esters are expected to be preferred for oral dosing. A typical unit dose for a 70 kg human would be from '.'' ' '''~,'' : ~"
:,'-,'; '', 20~2414 about 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 mixing the compounds used to prac-tice the method claimed in this invention with conventional ingredi-ents such as talc, magnesium stearate, dicalcium phosphate, magnesiumaluminum silicate, calcium sulfate, starch, lactose, acacia, methyl cellulose, or functionally similar pharmaceutical diluents and carriers. Capsules are prepared by mixing the compound used to practice the method claimed in this invention with an inert pharma-ceutical diluent and placing the mixture into an appropriately sizedhard ~elatin capsule. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compounds used to practice the method claimed in this invention with an acceptable inert oil such a 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 fla~oring agents and preservatives. Elixirs are prepared using a hydroalco-holic vehicle such as ethanol, suitable sweeteners such as sugar or - saccharin and an aromatic flavoring agent. ~uspensions are prepared with an aqueous vehicle and a suspending agent such as acacia, traga-canth, or methyl cellulose.
~ hen the compounds used to practice the method claimed in this invention are administered parenterally, it can be given by in~ection or by intravenous infusion. ;An effective amount is from about l to lO0 mg/kg/day. Parenteral solutions are prepared by dissolving the compounds used to practice the method claimed in this invention in water or other physiological solvent or mixture of solution or suspension ingredients for esters, e.g., normal saline, and filter sterilizing the solution before placing in a suitable sealable vial or ampule. Parenteral suspensions are prepared in substantially the same way except a sterile suspension vehicle is used and the com-pounds used to practice the method claimed in this invention are sterilized with ethylene oxide or suitable gas before it is suspended in the vehicle.
The exact route of administration, dose, or frequency of admin-istration would be readily determined by those skilled in the art and is dependant on the age, weight, general physical condition, or other clinical symptoms specific to the patient to be treated.
~. ;~."'' 2002414 ~
-~ -15-Without further elaboration, those skilled in the art can prac- ;
tice the prssent invention to its fullest extent. The following detailed examples further describe how to use the compounds claimed in this invention to treat humans infected with one or more than one ,.
strain of a human immunodeficiency virus. These examples are merely illustrative and are not limitations of the preceding disclosure.
Those skilled in the art will promptly recognize appropriate varia-tions from the examples. In each example, any compound claimed in this invention could replace the compound used in the particular ~
10 example. - -Exam~le 1 Hard Gelatin Capsules One thousand two-piece hard gelatin capsules for oral use, each capsule containing 50 mg of dimethyl 1,4,7,10-tetrahydro-4,10-dioxo- ~:
6-(n-pentyl)-1,7-phenanthroline-2,8-dicarboxylate (Compound A) are ;-lS prepared from the following~
Compound A 50 gm - ~ :
Lactose 100 gm Cornstarch 20 gm Talc 20 gm Magnesium Stearate 2 gm -Compound A is added to the other ingredients, mixed and encapsu-lated in the usual manner.
Ex myle 2 Tablets One thousand tablets, each containing 50 mg of dimethyl 1,4,7,-25 10-tetrahydro-4,10-dioxo-6-(n-pentyl)-1,7-phenanthroline-2,8-dicarb-oxylate (Compound B) are prepared from the following: `
Compound B 50 gm ~ `
Lactose 75 gm Cornstarch 50 gm 30 Magnesium Stearate 4 gm ~ ~, Light liquid petrolatum 5 gm - ~ ;
Compound B is added to the other ingredients, mixed and slugged.
The slugs are broken down by forcing through a number sixteen screen. - ~ `
The resulting granules are then compressed into tablets. ;-~
Example 3 Parenteral solution A sterile aqueous solution for parenteral intravenous in~ection containing 150 mg of dimethyl 1,4,7,10-tetrahydro-6-(1-methyl-1- -butyl)-4,10-dioxo-1,7-phenanthroline-2,8-dicarboxylate (Compound C) '' ~' ' ,.',.. ,' Z002~4 in one liter of solution is prepared from the following: -Compound C 150 mg Water for in~ection, qs 1000 mg Compound C is st~rilized, added to the sterile water, filled into sterile containers and sealed.
Example 4 Hard Gelatin Capsules One thousand two-piece hard gelatin capsules for oral use, each capsule containing 50 mg of 1-Benzoyl-4-[4-[[7-trifluoromethyl)-4-quinolinyl]amino]benzoylpiperazine (Compound D) are prepared from the following:
Compound D 50 gm Lactose 100 gm Cornstarch 20 gm Talc 20 gm Magnesium Stearate 2 gm Compound D is added to the other ingredients, mixed and encapsu-lated in the usual manner.
Example 5 Tablets One thousand tablets, each containing 50 mg of 1-Benzoyl-4-[4-[[7-trifluoromethyl)-4-quinolinyl]amino]benzoylpiperazine maleate (Compound E) are prepared from the following:
Compound E 50 gm Lactose 75 gm Cornstarch 50 gm -Magnesium Stearate 4 gm Light liquid petrolatum5 gm Compound E is added to the other ingredients, mixed and slugged.
The slugs are broken down by forcing through a number sixteen screen.
The resulting granules are then compressed into tablets.
Exam~le 6 Parenteral solution A sterile aqueous solution for parenteral intravenous in~ection ~ ~ ;
containing 150 mg of 1-[(4-methoxyphenyl)sulfonyl]-4-[4-[7-(tri-fluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (Compound F): ~;
Compound F 150 mg `
Water for injection, qs 1000 mg Compound F is sterilized, added to the sterile water, filled - ~ .
into sterile containers and sealed.
Example 7 Hard Gelatin Capsules Z00;~414 -- - -17- ; -~
One thousand two-piece hard gelatin capsules for oral use, each ~
capsule containing 50 mg of 2'-[(6,7-dimethoxy-l-isoquinolyl)methyl]- ~:
4',5'-dimethoxyscetophenone (Compound N) are prepared from the following~
Compound N 50 gm Lactose 100 gm Cornstarch 20 gm Talc 20 gm ~ -Magnesium Stearate 2 gm Co~pound N is added to the other ingredients, mixed and encap~u-lated in the usual manner.
Example 8 Tablets One thousand tablets, each containing 50 mg of 6,7-dimethoxy-l-(3,4,5-triethoxyphenyl)isoquinoline hydrochloride (Compound L) are ;
prepared from the following:
Compound L 50 gm Lactose 75 gm -Cornstarch 50 gm Magnesium Stearate 4 gm -~
20 Light liquid petrolatum 5 gm Compound L is added to the other ingredients, mixed and slugged. ;
The slugs are broken down by forcing through a number sixteen screen. -The resulting granules are then compressed into tablets. ~ -~
Exam~le 9 Parenteral solution A sterile aqueous solution for parenteral intravenous in~ection containing 150 mg of (Compound N) above as prepared.
Compound N 150 mg Water for inJection, qs 1000 mg ;
Compound N is sterilized, added to the sterile water, filled into sterile containers and sealed.
': ' .,:, .; .
-'. ''::
20024~4 Compound ~ Inbibitiona A. Dimethyl 1,4,7,10-tetrahydro-4,10-dioxo-6-(n-pentyl)-1,7-phenanthroline-2,8-dicarb-oxylate 74 B. Dimethyl 1,4,7,10-tetrahydro-4,10-dioxo-6-(l,l-dimethylpropyl)-1,7-phenanthroline-2,8-dicarboxylate 40 .
C. Dimethyl 1,4,7,10-tetrahydro-4,10-dioxo-6-(1-methyl-1-butyl)-1,7-phenanthroline-2,8-dicarboxylate 68 . .
D. l-Benzoyl-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoylpiperazine 22 :~
E. l-Benzoyl-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoylpiperazine maleate 36 F. 1-[(4-methoxyphenyl)sulfonyl]-4-[4-[7- : . :~
(trifluoromethyl)-4-quinolinyl]amino]benzoyl-piperazine 27 G. 1-[(4-chlorophenyl)sulfonyl]-4-[4-[[7-trifluoromethyl)-4-quinolinyl]amino]benzoyl]-piperazine 37 H. N-(4-chlorophenyl)-N-[4-[(7-chloro-4-quinolinyl)amino]phenyl]urea, methanol solvate 38 I. N-[4-[3-(trifluoromethylphenyl)-3-cyclohexen- ~ ~ .
l-yl]-4-[[7-(trifluoromethyl)-4-quinolinyl]- : ;:
amino]benzamide 29 ` :
J. 4-[(7-chloro-4-quinolyl)amino]-u-[[4-[(6-methoxy- `~
8-quinolyl)amino]pentyl]amino]-~'-1-pyrrolidinyl- ` `
`' ''".'"''-'.',-' ;;~002414 ~ ~
. .
2,6-xylenol trihydrochloride 45 K. 4-[m[[(7-chloro-4-quinolyl)amino]benzoyl]morpholine hydrochloride 22 -L. 6,7-dimethoxy-1-(3,4,5-triethoxyphenyl)-isoquinoline hydrochloride (Octaverine hydrochloride), 65 .. ' ' ': '.:
M. 5,6-dihydro-9,10-dimethoxy-benzo[g]-1,3-benzodioxolo-]5,6- .
10 a]quinolizinium ~odide (Berberinium iodide), 47 :
N. 2'-[6,7-dimethoxy-1-isoquinolyl)~ethyl]-4',5'-dimethoxy- ~ : ` , acetophenone, 97 ~ :.
15 0. (l-isoquinolyl)oxamic acid, ethyl ester, 28 ~ ~ .
P. (5-isoquinolinyloxy)acetic acid, methyl ester. 20 ~
- . ' ' ;, ,:- :' ~ ':
`, ' a (% Inhibition at 100 ~M) ; ;~
';;; ~:~.,'' '~
:
-20- :
TABLE II
Compounds ~ Inhibitiona IC50 A 50 (@ 2.51 ~M) -: .
G 10 (@ 0.17 ~M) H 40 (@ 2.36 ~M) J 0 (@ 1.36 ~M) : ~:
K 2.5 ~M ~`
L 70 (@ 2.30 ~M) 5.0 ~M
N 10 (@ 0.26 ~M) :;:;.
"''.'''''',''''".' ' ,,,,,",.", .",',., ,,' `,',-',.
,',' '., .' ~
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,. -. . .
-21- `
STRUCTURE SHEET : ~ ;
O
, c - OR2 R~O-C~
R
' ,', '` ~
:
:: :
R'~
\~ IB
-: - .
. . ~ ~., ;: ~
X ~:: ' R 1 ~ ~a) ( (b)-NH- C (O) -NH
. .
(c~ -C(O)-I
' ~''' ~' ~' '' .
-22~
STRUCTURE SHEET (CONTINUED) ;
(d) -C(O)-N ~ O
R' 2C-R~-(CH2)31H H~ ~ IC ;
~ R3 ID ~ ~
R"2 R4 . ~ "
`" ~
:`.''.'' ~' `'."','`
'~ ~ ' . '`'..'. .,.''`
2H5 ~ OC2H5 HCl C 33pound L
Z0024~.4 ~;
STRUCTURE SHEET (CONTINUED) .. : ;
OcH3 . ..
H3CO ~ ¦ . .
\~ o , .''''"- ~
~ C CH3 CH2 Compound N :
H3C~N
H3CO .~
: .' ~',,,~' R 2~J f~ IV
O
~' lt I I ' .'' '':;'.
11 11 '~ '` ~
; NH - C -C- OCH2CH3 N Compound O
H3CO -IC, - H2CO Compound P ..
~ ., .
O , ~
..~. ', ~ .. :~
,, . :.::;
, ~.", ., 20()2414 ~ ~;
: ` -24~
ST~CTURE SHEET (CONTINUED) X'~Z
(a) `~
(7H2)r O O ' ~
NH---C---C---O---W (b) , :
~,,, . e...~
Examples of specific compounds within the defined group of compounds (Formula ID) which are useful accordin~ to this invention include~
L. 6,7-dimethoxy-1-(3,4,5-triethoxyphenyl)-isoquinoline ~ . :- :::
hydrochloride (Octaverine hydrochloride), : . , .:
; "- :- :".`, ' ,'' .
M. 5,6-dihydro-9,10-dimethoxy-benzo[~]-1,3-benzodioxolo-]5,6-a]quinolizinium iodide (Berberinium iodicle), N. 2'-[6,7-dimethoxy-1-isoquinolyl)methyl]-4',5'-dimethoxy-acetophenone, O. (l-isoquinolyl)oxamic acid, ethyl ester, P. (5-isoquinolinyloxy)acetic acid, methyl ester.
,:'', Detailed Descri~tion of the Invention The term human immunodeficiency virus (HIV) means human immuno-deficiency virus typs I, human immunodeficiency virus type II, or strains, apparent to one skilled in the art, which belong to the same viral family and which create similar physiological effects in humans as human immunodeficiency virus types I and II.
Patients to be treated would be those individuals: 1) infected with one or more than one strain of a human immunodeficiency virus as determined by the presence of either measurable viral antibody or antigen in the serum and 2) havin~ either a symptomatic AIDS defining infection such as i) disseminated histoplasmosis, ii) psoriasis, iii) bronchial and pulmonary candidiasis including pneumocystis pneumonia iv) non-Hodgkin's lymphoma or v) Kaposi's sarcoma and being less than sixty years old; or having an absolute CD4 lymphocyte-count of less than 200/mm3 in the peripheral blood. Treatment would consist of maintaining an inhibitory level of the compounds 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 alternate therapy is needed.
The utility of this invention is demonstrated by ~he ability of the test compounds used to practice the method claimed in this inven-tion in a standard laboratory test involving the ability of the test ::
compound or substance to inhibit the viral reverse transcriptase (RT), an enzyme essential for human immunodeficiency virus replica-tion. This enzyme has characterlstics 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 extracts from bacterial clones prepared according to the procedure described by Tanese, N., et al., Journal of Virology, 59:743-745 (1986). Inhibition of this enzyme by the test compound is determined in a cell free assay which measures the level of radioactive precur-.~ ::' ' : ,~-.,, sors incorporated into DNA. RT extrac~s prepared similar to the procedure of Kleid, D. G., et al., Science, 214:1125-1129 (1981) are incubated in a mixture of test compound, 20 mM dithiothreitol, 60 M
sodium chloride, 0.05% NP-40, 10 ~ magnesium chloride, 50 mM Tris pH
8.3, 10 M [35S]-radiolabeled deoxynuleoside-5'-triphosphate, 10 ~g/
ml R~A template (poly rC or poly rA) and 5 ~g/ml DNA primer (oligo dG
or oligo dT) for 30 minutes at 37C. Incorporation of radiolabeled precursor is determined by harvesting the trichloroacetic acid precipitated reaction mixtures on glass fiber filters, drying and determining counts. The results of various assay(s) are combined and reported in Table I as % inhibition of the enzyme compared to tne control test where no test compound enzyme inhibitor is present. It is preferred that the test compound inhibit the RT enzyme by at least 20% of the untreated control value in the same test procedure, - 15 preferably greater than 50% inhibition to be considered for more advanced testing. The percent numbers illustrate the percentage rate of RT enzyme inhibition by these compounds in this standard :: :: :: :.: :: -laboratory test.
Ue believe these percentage RT enzyme inhibition rates are20 unexpected because tests of other closely related compounds in this same test, such as the nonesterified phenanthroline-dioxo-6-pentyl-dicarboxylic acid, the phenanthroline-dioxo-2,5,8-tricarboxylic acid, the 6-hydrogen-phenanthroline-dioxo-2,8, dicarboxylic acid and the dimethyl 5-cyano-phenanthroline-dioxo-2,8-dicarboxylate ester gave RT
enzyme percent inhibition rates in this test which were too low to warrant further consideration of such compounds for advanced testing as possible anti-HIV disease drugs in humans. Ue do not believe that :: . .
the encouraging high percentage RT enzyme i ~ ibition results for the use of these Structure IA esters could have been predicted from the ~ ;
prior art or from the testing of these other somewhat related com-pounds . ' ' Ue believe these percentage rate RT e~ yme inhibition rates are unexpected because tests of other closely related 4-aminoquinoline compounds in this same test, such as 7-chloro-4-[N-(l-methylpiperidin-3-yl)methyl)amino]-4-quinoline, diethylaminoethyl 4-[(7-chloroquinol-4-yl) ~ ino]benzoate, 2-[N-(7-chloroquinol-4-yl)amino]acetic acid, N-[(7-chloroquinol-4-yl)-N-[4-methoxy-3-(2-chloroethylamino-'`''''''~; ''''. '`:~
:' ' ~' ~ ,.
.
20024~4 methyl)phenyl]amine, and N-(7-chloroquinol-4-yl)-N-[3,5-bis(pyrrolidin-1-ylmethyl)-4-hydroxyphenylamine, 7-chloro-N-[(N-methylpiperidin-3-yl)methyl]quinoline, and 7-chloro-4-[N-[4-[(4-methylpiperazin-1-yl)carbonyl]phenyl]quino-lin-4-ylamine gave RT enzyme percent inhibition rates in this test which were too low to warrant further consideration of such compounds for advanced testing as possible anti-HIV disease drugs in humans. We do not believe that the encouraging high percentage RT enzyme inhibition results for the use of these Structure IB compounds could have been predicted from the prior art or from the testing of these other somewhat related compounds.
The utility of this invention is further demonstrated by the ability of various compounds (Nos. A, H, K, and L) 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 with HIV-l. This test is described by Nara et al., Quantitative infectivity assay for HIV-l and -2., Nature 332: 469-20 470, 1988 as well as in AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol. 4, No. 6, pages 449-455 (1988), Mary Ann Liebent, Inc., Publishers in an article by Mariano Busso, et al., entitled "Nucleotide Dimers Suppress HIV Expression In VITRO". The results (IC50 means the concentration, in ~M of drug, required to inhibit syncytia formation to the extent of 50~) of various assay(s) are combined and reported as ~ inhibition and/or IC50 (calculated) in Table II. ~n comparison, the known commercial compound, AZT, exhibited anti-HIV potency in this assay system of 100 percent and 50 percent reduction in syncytia formation at concentrations of approximately l~M and 0.5 ~M, respectively.
! The utility~of 6,7-dimethoxy-1-(3,4,5-triethoxyphenyl)- ! ' isoquinoline hydrochloride (Octaverine hydrochloride; Compou~d L) to practice the method claimed in this invention is further demonstrated by the activity of this compound in the inhibition of HIV infection in primary peripheral blood lymphocytes (primary PBL assay). This assay is done by the following screening procedure.
The following features characterize the primary screening~
The screening tests are performed with primary human lympho~
'~ ' ' ~, 20024~4 ~- -9-cytes. 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.
True antiviral effects of drugs are readily distinguished from cytostatic/cytotoxic reactions.
. .. :.
By kinetic measurement of viral nucleic acids and proteins the viral replication is followed precisely.
Testing in parallel on the level of nucleic acids (total HIV-RNA
intra- and extracellular) and on the level of proteins (secreted p24) allows to differentiate the drug effects on virus replication and on the expression of viral proteins. This leads to additional informa-tion regarding the efficacy of the drug. ~ s Tolerance of the cell culture against low amounts of organic solvents permits the investigation of hydrophobic substances also.
The dose of the drug causing half maximal suppression of virus ~- ; f';
replication is determined.
The screening system is standardized and automated to a high degree.
1. TEST FOR TOXICITY
.- ~ ~ ., Effects of the drugs on cell proliferation are determined by lymphocyte proliferation assays. Starting with a 100 micromolar solution, ~he drug is 10 fold serially diluted.
One tenth of the concentration of the drug causing half maximal inhlbition of cellular proliferation is employed for all subsequent testing.
2. IN VITRO INFECTION OF LYMPHOCYTES
Peripheral human lymphocytes 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.
Individual cultures are established to measure viral replication two, three and four days following infection.
Untreated cells and AZT-treated cells are included as controls in parallel with the drugs under investigation.
2.1 DETECTION OF SECRETED VIRAL P24 The amount of viral core protein p24 synthesized and released by the infected cells is determined in the supernatant by capture-ELISA
!`, ~: ; ' ' .~ ,.. ,, ,~., ' ',:
'.' ~,,, ' `.:
. .
2~ 2~4 technique on days two, three and four. By comparing with a standard preparation, the amount of protein produced by the virus infected cells will be calibrated.
2.2 ASSAY FOR HIV-RNA
The total amount of vlral RNA synthesized by the infected lymphocytes is determined by a special nucleic acid hybridization technique on days two, three and four of culture. By including a standard preparation of HIV-RNA the amount of synthesized RNA will be quantified.
In case a drug shows antiviral effects in the primary screening, all steps of the primary screening will be repeated. In addition, viability of HIV-infected cells will be determined in parallel with assays for viral p24 and RNA. In order to evaluate the half maximal antiviral effect of the drug, a concentration dependency of the drug 15 action will be measured. -~
The anti-HIV activity of Octaverine hydrochloride (Compound L), as measured by the inhibitior. of the release of core p24 protein in HIV infected human lymphocytes was found to be 53.5% ~1 ~M) three days after HIV infection of the primary peripheral blood lymphocytes `
and 6.8~ M) four days after HIV infection of the primary peripheral blood lymphocytes. As measured by inhibition of viral RNA
synthesis, Compound L exhibited 38.9~ N) at day 3 and 13.4% (1 ~M) at day 4. ~ "
Compounds K and N were inactive (1 ~M), while compound A was 25 only marginally active (1 ~M), in inhibition of p24 protein ` ` "
synthesis. Compounds A, K and N were inactive in the inhibition of ~`
viral RNA synthesis at the dosage level tested (1 ~M). ` ~;~
The compound l-benzoyl-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]-amino]benzoyl~piperazine, and its pharmaceutically acceptable salts 30 e.g., its maleate salt, are believed to be new and patentable, and ~ `
,are claimed herein as such.
This quinoline-amine compound can be prepared as follows~
Preparation of l-benzoyl-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]-amino]benzoyl]piperazine.
3S To 4.73 gm (0.01 mole) of 1-[4-[[7-(trifluoromethyl)-4-quino-linyl]amino]benzoyl]piperazine (Chemical Abstracts RN 57975-86-7), prepared according to procedures described in U.S. Patent 4,025,629, in 100 ml. of tetrahydrofuran (THF) there was added 3.03 gm (0.03 20024~L4 .::
mole) of triethylamine (TEA) and then 1.41 gm (0.01 mole) of benzoyl -chloride dissolved in 40 ml of THF with stirring.
The resulting reaction mixture was stirred at ambient tempera-ture for 24 hours and then concentrated to dryness in vacuo. The `~
S yellow residue was slurried with 200 ml of water. The product was collected and dried. The product, named as above, was purified by - ~``
dissolving it in methylene chloride and then adding Skellysolve B
brand of hexanes to the cloud point to form a creamy product. The product separated from this mixture to give 4.2 gm (83 percent yield), m.p. 251.1 C, which analyzed as follows:
% Anal. Calcd: C, 66.67; H, 4.56; N, 11.11.
g Found: C, 66.50; H, 4.59; N, 11.03.
This 4-(N'-benzoylpiperazinyl benzoylamino) quinoline derivative was also made by adding benzoic acid anhydride in THF to a room temperature solution of the starting 7-(trifluoromethyl)-4-[(1-piperazinyl)-4-benzoylamino)quinoline, allowing the mixture to react for 3 hours, evaporating the mixture, to a low volume, taking up the i residue in methylene chloride/aqueous sodium carboxide solution, and filtering off the yellow solid which resulted. The methylene chloride layer filtrate was washed with water, evaporated partially and diluted with ethyl ether to precipitate some additional solid product. A thin layer chromatography test showed the two solids to be the same. The solids were combined to obtain 5.1 gm, m.p. 257- ;``
258 C of the l-benzoyl-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]- ` ' amino]ben2oyl]piperazine.
The maleate salt of this piperazine derivative was made in methanol from 5 gm of the named piperazine derivative and 2.5 gm of maleic acid. After filtering the solid salt and washing it with ethyl ether, there was obtained 5.5 g of the named piperazine derivative as its maleate salt, 231-232 C. ;~
We believe these percentage rate RT enzyme inhibition rates are ;~
unexpected because tests of other closely related compounds in this same test such as 6,7-diethoxy-1-(3,4-diethoxyphenylmethyl)-isoquinoline hydro-35 chloride, -~
6,7-dimethoxy-1-[(2-amino-4,5-dimethoxyphenyl)methyl]iso- -~
quinol~ne, and the like, gave RT enzyme percent inhibition rates in this test which were too low to warrant further consideration of such ' ~ ~
' . ~ . `~'` `', ; ; k ~
20024~4 compounds for advanced testing as possible anti-HIV disease drugs in humans. Ue do not believe that the encouraging percentage RT enzyme inhibition results for the use of these structure IC compounds could -have been predicted from the prior art or from the testing of these other somewhat related compounds.
The compound ethyl (l-isoquinolyl)-oxamate was made as follows:
A solution of 10 g. (0.068 mole) of l-aminoquinoline in 15 ml.
of dry ethyl acetate was stirred with 8.40 g. (0.083 mole) of triethylamine. To this mixture there was added 11.33 g. (0.083 mole) of ethyl oxalyl chloride and the resulting mixture was stirred at room temperature for several hours and then allowed to stir over-night.
A precipitate which resulted was removed by filtration and ~`
washed with ethyl acetate. The combined filtrate and wash liquids were evaporated to dryness in vacuo. The residue was taken up in and crystallized from ethanol to obtain 5.59 g. of the ethyl tl-iso-quinolyl)oxamate, m.p. 113-114C.
Anal. Calcd. for C13H12N23 ~ Calcd.: C, 63.72; H, 4.95; N, 11.47.
~ Found: C, 63,79; H, 4.90; N, 11.39.
- The infrared spectrum analysis (IR) was in agreement with this named product.
The compound methyl (5-isoquinolinyloxy)acetate was prepared as follows:
A solution of 5 g. (34.48 mmole) of 5-hydroxyisoquinoline in 200 ml. of d~methylformamide was stirred under a nitrogen atmosphere and cooled to -20C. in an ice/methanol bath. To this solution was added 3.27 ml. (34.48 mmole) of methyl bromoacetate followed by 1.39 g.
(34.48 mmole) of sodium hydride (60~ oil dispersion). The reaction mixture warmed to room temperature and the resulting solution was ,stirred under a nitrogen atmosphere for 24 hours. The mixture was poured into a solution of ice/water/ethyl acetate and extracted with ethyl acetate. The aqueous layer was found to have a pH of 8.4. The combined ethyl acetate extracts were washed with water three times and then with sodium chloride solution and then dried over magnesium sulfate, filtered and concentrated in vacuo to yield 6.8 g. of crude residue. The residue was chromatographed on 600 g. of silica gel.
The column was wet-packed and eluted with 5% methanol/methylene ,; ,' 2002414 ~-chloride and fractions of 35 ml. were collected. Fractions 37-62 were combined and concentrated in VACUO to yield 5.22 g. of residue which was found to be a mixture of materials by thin layer chroma-tography with 10% acetone/methylene chloride as a solvent system.
This material was rechrom~tographed on 520 g. of silica gel. The column was repacked and eluted with 10~ acetone/methylene chloride and fractions of 35 ml. were collected. Fractions 73-133 were combined and concentrated in vacuo to yield 3.92 g. of the methyl (5-isoquinolinyloxy)acetate ester which after recrystallizing in ether-10 hexane afforded 3.64 g. (484 of theory) of pure product with melting point 84-86C.
Infrared: ~max (mull) 3007, 1743, 1585, 1494, 1455, 1435, 1393, 1322, 1288, 1268, 1225, 1173, 1122, 1079, ~027, 1018, 821, 804, 755 731 cm~~
NMR (CDC13; TMS): ~ 9.28 (s, lH), 8.64, 8.58, 8.17, 8.13 (AB
quartet, 2H), 7.73-7.25 (m, 2H), 7.03-6.83 (m, lH), 4.82 (s, 2H), 3.83 (s, 3H).
Mass Spectrum: Ions at 217 (N~), 218, 189, 158, 145, 144, 131, 128, 116, 101, 89, 75, 63.
TLC (silica gel GF): Rf 0.25 (10% acetone/methylene chloride).
Those skilled in the art would know how to formulate the com-pounds (Formula IA or ID) used to practice the method claimed in this invention into appropriate pharmaceutical dosage forms. Examples of the dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions, and those in U.S. patent 3,790,577 which is incorporated herein by reference. -Tho~e skilled in the art would know how to form~llate the com-pounds (Formula IB or IC) used to practice the method claimed in this invention into appropriate pharmaceutical dosage forms. Examples of ,the dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions, and those in U.S. patents 3,790,577 and 4,025,629 which are incorporated herein by reference.
When the co~pounds used to practice the method claimed in this invention are administered orally, an effective amount is from about 1 to 100 mg/kg/day. The diethyl esters are expected to be preferred for oral dosing. A typical unit dose for a 70 kg human would be from '.'' ' '''~,'' : ~"
:,'-,'; '', 20~2414 about 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 mixing the compounds used to prac-tice the method claimed in this invention with conventional ingredi-ents such as talc, magnesium stearate, dicalcium phosphate, magnesiumaluminum silicate, calcium sulfate, starch, lactose, acacia, methyl cellulose, or functionally similar pharmaceutical diluents and carriers. Capsules are prepared by mixing the compound used to practice the method claimed in this invention with an inert pharma-ceutical diluent and placing the mixture into an appropriately sizedhard ~elatin capsule. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compounds used to practice the method claimed in this invention with an acceptable inert oil such a 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 fla~oring agents and preservatives. Elixirs are prepared using a hydroalco-holic vehicle such as ethanol, suitable sweeteners such as sugar or - saccharin and an aromatic flavoring agent. ~uspensions are prepared with an aqueous vehicle and a suspending agent such as acacia, traga-canth, or methyl cellulose.
~ hen the compounds used to practice the method claimed in this invention are administered parenterally, it can be given by in~ection or by intravenous infusion. ;An effective amount is from about l to lO0 mg/kg/day. Parenteral solutions are prepared by dissolving the compounds used to practice the method claimed in this invention in water or other physiological solvent or mixture of solution or suspension ingredients for esters, e.g., normal saline, and filter sterilizing the solution before placing in a suitable sealable vial or ampule. Parenteral suspensions are prepared in substantially the same way except a sterile suspension vehicle is used and the com-pounds used to practice the method claimed in this invention are sterilized with ethylene oxide or suitable gas before it is suspended in the vehicle.
The exact route of administration, dose, or frequency of admin-istration would be readily determined by those skilled in the art and is dependant on the age, weight, general physical condition, or other clinical symptoms specific to the patient to be treated.
~. ;~."'' 2002414 ~
-~ -15-Without further elaboration, those skilled in the art can prac- ;
tice the prssent invention to its fullest extent. The following detailed examples further describe how to use the compounds claimed in this invention to treat humans infected with one or more than one ,.
strain of a human immunodeficiency virus. These examples are merely illustrative and are not limitations of the preceding disclosure.
Those skilled in the art will promptly recognize appropriate varia-tions from the examples. In each example, any compound claimed in this invention could replace the compound used in the particular ~
10 example. - -Exam~le 1 Hard Gelatin Capsules One thousand two-piece hard gelatin capsules for oral use, each capsule containing 50 mg of dimethyl 1,4,7,10-tetrahydro-4,10-dioxo- ~:
6-(n-pentyl)-1,7-phenanthroline-2,8-dicarboxylate (Compound A) are ;-lS prepared from the following~
Compound A 50 gm - ~ :
Lactose 100 gm Cornstarch 20 gm Talc 20 gm Magnesium Stearate 2 gm -Compound A is added to the other ingredients, mixed and encapsu-lated in the usual manner.
Ex myle 2 Tablets One thousand tablets, each containing 50 mg of dimethyl 1,4,7,-25 10-tetrahydro-4,10-dioxo-6-(n-pentyl)-1,7-phenanthroline-2,8-dicarb-oxylate (Compound B) are prepared from the following: `
Compound B 50 gm ~ `
Lactose 75 gm Cornstarch 50 gm 30 Magnesium Stearate 4 gm ~ ~, Light liquid petrolatum 5 gm - ~ ;
Compound B is added to the other ingredients, mixed and slugged.
The slugs are broken down by forcing through a number sixteen screen. - ~ `
The resulting granules are then compressed into tablets. ;-~
Example 3 Parenteral solution A sterile aqueous solution for parenteral intravenous in~ection containing 150 mg of dimethyl 1,4,7,10-tetrahydro-6-(1-methyl-1- -butyl)-4,10-dioxo-1,7-phenanthroline-2,8-dicarboxylate (Compound C) '' ~' ' ,.',.. ,' Z002~4 in one liter of solution is prepared from the following: -Compound C 150 mg Water for in~ection, qs 1000 mg Compound C is st~rilized, added to the sterile water, filled into sterile containers and sealed.
Example 4 Hard Gelatin Capsules One thousand two-piece hard gelatin capsules for oral use, each capsule containing 50 mg of 1-Benzoyl-4-[4-[[7-trifluoromethyl)-4-quinolinyl]amino]benzoylpiperazine (Compound D) are prepared from the following:
Compound D 50 gm Lactose 100 gm Cornstarch 20 gm Talc 20 gm Magnesium Stearate 2 gm Compound D is added to the other ingredients, mixed and encapsu-lated in the usual manner.
Example 5 Tablets One thousand tablets, each containing 50 mg of 1-Benzoyl-4-[4-[[7-trifluoromethyl)-4-quinolinyl]amino]benzoylpiperazine maleate (Compound E) are prepared from the following:
Compound E 50 gm Lactose 75 gm Cornstarch 50 gm -Magnesium Stearate 4 gm Light liquid petrolatum5 gm Compound E is added to the other ingredients, mixed and slugged.
The slugs are broken down by forcing through a number sixteen screen.
The resulting granules are then compressed into tablets.
Exam~le 6 Parenteral solution A sterile aqueous solution for parenteral intravenous in~ection ~ ~ ;
containing 150 mg of 1-[(4-methoxyphenyl)sulfonyl]-4-[4-[7-(tri-fluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (Compound F): ~;
Compound F 150 mg `
Water for injection, qs 1000 mg Compound F is sterilized, added to the sterile water, filled - ~ .
into sterile containers and sealed.
Example 7 Hard Gelatin Capsules Z00;~414 -- - -17- ; -~
One thousand two-piece hard gelatin capsules for oral use, each ~
capsule containing 50 mg of 2'-[(6,7-dimethoxy-l-isoquinolyl)methyl]- ~:
4',5'-dimethoxyscetophenone (Compound N) are prepared from the following~
Compound N 50 gm Lactose 100 gm Cornstarch 20 gm Talc 20 gm ~ -Magnesium Stearate 2 gm Co~pound N is added to the other ingredients, mixed and encap~u-lated in the usual manner.
Example 8 Tablets One thousand tablets, each containing 50 mg of 6,7-dimethoxy-l-(3,4,5-triethoxyphenyl)isoquinoline hydrochloride (Compound L) are ;
prepared from the following:
Compound L 50 gm Lactose 75 gm -Cornstarch 50 gm Magnesium Stearate 4 gm -~
20 Light liquid petrolatum 5 gm Compound L is added to the other ingredients, mixed and slugged. ;
The slugs are broken down by forcing through a number sixteen screen. -The resulting granules are then compressed into tablets. ~ -~
Exam~le 9 Parenteral solution A sterile aqueous solution for parenteral intravenous in~ection containing 150 mg of (Compound N) above as prepared.
Compound N 150 mg Water for inJection, qs 1000 mg ;
Compound N is sterilized, added to the sterile water, filled into sterile containers and sealed.
': ' .,:, .; .
-'. ''::
20024~4 Compound ~ Inbibitiona A. Dimethyl 1,4,7,10-tetrahydro-4,10-dioxo-6-(n-pentyl)-1,7-phenanthroline-2,8-dicarb-oxylate 74 B. Dimethyl 1,4,7,10-tetrahydro-4,10-dioxo-6-(l,l-dimethylpropyl)-1,7-phenanthroline-2,8-dicarboxylate 40 .
C. Dimethyl 1,4,7,10-tetrahydro-4,10-dioxo-6-(1-methyl-1-butyl)-1,7-phenanthroline-2,8-dicarboxylate 68 . .
D. l-Benzoyl-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoylpiperazine 22 :~
E. l-Benzoyl-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoylpiperazine maleate 36 F. 1-[(4-methoxyphenyl)sulfonyl]-4-[4-[7- : . :~
(trifluoromethyl)-4-quinolinyl]amino]benzoyl-piperazine 27 G. 1-[(4-chlorophenyl)sulfonyl]-4-[4-[[7-trifluoromethyl)-4-quinolinyl]amino]benzoyl]-piperazine 37 H. N-(4-chlorophenyl)-N-[4-[(7-chloro-4-quinolinyl)amino]phenyl]urea, methanol solvate 38 I. N-[4-[3-(trifluoromethylphenyl)-3-cyclohexen- ~ ~ .
l-yl]-4-[[7-(trifluoromethyl)-4-quinolinyl]- : ;:
amino]benzamide 29 ` :
J. 4-[(7-chloro-4-quinolyl)amino]-u-[[4-[(6-methoxy- `~
8-quinolyl)amino]pentyl]amino]-~'-1-pyrrolidinyl- ` `
`' ''".'"''-'.',-' ;;~002414 ~ ~
. .
2,6-xylenol trihydrochloride 45 K. 4-[m[[(7-chloro-4-quinolyl)amino]benzoyl]morpholine hydrochloride 22 -L. 6,7-dimethoxy-1-(3,4,5-triethoxyphenyl)-isoquinoline hydrochloride (Octaverine hydrochloride), 65 .. ' ' ': '.:
M. 5,6-dihydro-9,10-dimethoxy-benzo[g]-1,3-benzodioxolo-]5,6- .
10 a]quinolizinium ~odide (Berberinium iodide), 47 :
N. 2'-[6,7-dimethoxy-1-isoquinolyl)~ethyl]-4',5'-dimethoxy- ~ : ` , acetophenone, 97 ~ :.
15 0. (l-isoquinolyl)oxamic acid, ethyl ester, 28 ~ ~ .
P. (5-isoquinolinyloxy)acetic acid, methyl ester. 20 ~
- . ' ' ;, ,:- :' ~ ':
`, ' a (% Inhibition at 100 ~M) ; ;~
';;; ~:~.,'' '~
:
-20- :
TABLE II
Compounds ~ Inhibitiona IC50 A 50 (@ 2.51 ~M) -: .
G 10 (@ 0.17 ~M) H 40 (@ 2.36 ~M) J 0 (@ 1.36 ~M) : ~:
K 2.5 ~M ~`
L 70 (@ 2.30 ~M) 5.0 ~M
N 10 (@ 0.26 ~M) :;:;.
"''.'''''',''''".' ' ,,,,,",.", .",',., ,,' `,',-',.
,',' '., .' ~
- :,:
,. -. . .
-21- `
STRUCTURE SHEET : ~ ;
O
, c - OR2 R~O-C~
R
' ,', '` ~
:
:: :
R'~
\~ IB
-: - .
. . ~ ~., ;: ~
X ~:: ' R 1 ~ ~a) ( (b)-NH- C (O) -NH
. .
(c~ -C(O)-I
' ~''' ~' ~' '' .
-22~
STRUCTURE SHEET (CONTINUED) ;
(d) -C(O)-N ~ O
R' 2C-R~-(CH2)31H H~ ~ IC ;
~ R3 ID ~ ~
R"2 R4 . ~ "
`" ~
:`.''.'' ~' `'."','`
'~ ~ ' . '`'..'. .,.''`
2H5 ~ OC2H5 HCl C 33pound L
Z0024~.4 ~;
STRUCTURE SHEET (CONTINUED) .. : ;
OcH3 . ..
H3CO ~ ¦ . .
\~ o , .''''"- ~
~ C CH3 CH2 Compound N :
H3C~N
H3CO .~
: .' ~',,,~' R 2~J f~ IV
O
~' lt I I ' .'' '':;'.
11 11 '~ '` ~
; NH - C -C- OCH2CH3 N Compound O
H3CO -IC, - H2CO Compound P ..
~ ., .
O , ~
..~. ', ~ .. :~
,, . :.::;
, ~.", ., 20()2414 ~ ~;
: ` -24~
ST~CTURE SHEET (CONTINUED) X'~Z
(a) `~
(7H2)r O O ' ~
NH---C---C---O---W (b) , :
~,,, . e...~
Claims (31)
1. Use of a compound of Formula IA
IA
wherein R1 and R2 are the same or different and each is a carboxyl-protecting ester group, and R is a C1 to C8-alkyl, a C5 to C6-cycloalkyl or a phenyl group; or a compound of Formula IB
IB
where R'1 is selected from the group consisting of (a) (b) (c) (d) where R' is selected from the group consisting of a halogen having an atomic number of from 9 to 35 or trifluoromethyl, Y is carbonyl or sulfonyl, and X is selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromethyl and C1 to C3-alkyloxy, or a pharmaceutically acceptable salt or solvate thereof; or a compound of Formula IC
IC
where R' is selected from the group consisting of a halogen having an atomic number of from 9 to 35 or trifluoromethyl, X is selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromethyl and C1 to C3-alkyloxy, or a pharmaceutically acceptable salt or solvate thereof; or a compound of Formula ID
ID
where R" is selected from the group consisting of hydrogen, the group (a) where X', Y' and Z are the same or different and are selected from the group consisting of hydrogen, C1 to C3-alkyloxy and C1 to C3-alkyl-carbonyl, and r is zero (0) or 1;
and (b) the group (b) where W is C1 to C3-alkyl;
R"1 and R"2 are selected from the group consisting of hydrogen, C1 to C3-alkyloxy and C1 to C3-alkyloxycarbonylmethoxy;
R3 alone is not present;
R4 alone is hydrogen;
and R3 and R4 can be taken together with the isoquinoline ring to define the following ring structure IV
or a pharmaceutically acceptable salt thereof;
to prepare a medicament for treating a human patient infected with one or more than one strain of a human immunodeficiency virus (HIV).
IA
wherein R1 and R2 are the same or different and each is a carboxyl-protecting ester group, and R is a C1 to C8-alkyl, a C5 to C6-cycloalkyl or a phenyl group; or a compound of Formula IB
IB
where R'1 is selected from the group consisting of (a) (b) (c) (d) where R' is selected from the group consisting of a halogen having an atomic number of from 9 to 35 or trifluoromethyl, Y is carbonyl or sulfonyl, and X is selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromethyl and C1 to C3-alkyloxy, or a pharmaceutically acceptable salt or solvate thereof; or a compound of Formula IC
IC
where R' is selected from the group consisting of a halogen having an atomic number of from 9 to 35 or trifluoromethyl, X is selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromethyl and C1 to C3-alkyloxy, or a pharmaceutically acceptable salt or solvate thereof; or a compound of Formula ID
ID
where R" is selected from the group consisting of hydrogen, the group (a) where X', Y' and Z are the same or different and are selected from the group consisting of hydrogen, C1 to C3-alkyloxy and C1 to C3-alkyl-carbonyl, and r is zero (0) or 1;
and (b) the group (b) where W is C1 to C3-alkyl;
R"1 and R"2 are selected from the group consisting of hydrogen, C1 to C3-alkyloxy and C1 to C3-alkyloxycarbonylmethoxy;
R3 alone is not present;
R4 alone is hydrogen;
and R3 and R4 can be taken together with the isoquinoline ring to define the following ring structure IV
or a pharmaceutically acceptable salt thereof;
to prepare a medicament for treating a human patient infected with one or more than one strain of a human immunodeficiency virus (HIV).
2. A use according to claim 1 wherein the compound is of Formula IA.
3. A use according to claim 2 wherein R1 and R2 are each a C1 to C3-alkyl group, and R is a straight or branched pentyl group.
4. A use according to claim 3 wherein the compound IA is selected from the group consisting of dimethyl 1,4,7,10-tetrahydro-4,10-dioxo-6-(n-pentyl)-1,7-phenanthroline-2,8-dicarboxylate, dimethyl 1,4,7,10-tetrahydro-4,10-dioxo-6-(1,1-dimethylpropyl)-1,7-phenanthro-line-2,8-dicarboxylate or dimethyl 1,4,7,10-tetrahydro-4,10-dioxo-6-(1-methyl-1-butyl)-1,7-phenanthroline-2,8-dicarboxylate.
5. A use according to claim 1 wherein the compound is of Formula IB.
6. A use according to Claim 5 wherein the formula IB compound is one in which R' is trifluoromethyl and R'1 is where X is hydrogen or a pharmaceutically acceptable salt thereof.
7. A use according to Claim 6 wherein the formula IB compound is 1-benzoyl-4-[4-[7-(trifluoromethyl)-4-quinolinyl]amino]benzoylpiperaz-ine maleate,
8. A use according to Claim 5 wherein the formula IB compound is one in which R' is trifluoromethyl and R'1 is where X is a halogen or a C1 to C3-alkyloxy, or a pharmaceutically acceptable salt thereof.
9. A use according to Claim 8 wherein the formula IB compound is 1-[(4-methoxyphenyl)sulfonyl]-4-[4-[7-trifluoromethyl)-4-quinolinyl]-amino]benzoylpiperazine, or a pharmaceutically acceptable salt thereof.
10. A use according to Claim 8 wherein the formula IB compound is 1-[(4-chlorophenyl)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolin-yl]amino]benzoyl]piperazine, or a pharmaceutically acceptable salt thereof.
ll. A use according to Claim 5 wherein the formula IB compound is one in which R' is a halogen having an atomic number of from 9 to 35, R'1 is where X is a halogen having an atomic number of from 9 to 35, or a pharmaceutically acceptable salt thereof.
12. A use according to Claim 11 wherein the compound is N-(4-chlorophenyl)-N'-[4-[7-chloro-4-quinolinyl)amino]phenyl]-urea, or a pharmaceutically acceptable salt or solvate thereof.
13. A use according to Claim 5 wherein the formula IB compound is one in which R' is trifluoromethyl R'1 is and X is trifluoromethyl, or a pharmaceutically acceptable salt thereof.
14. A use according to Claim 13 wherein the compound is N-[4-[3-(trifluoromethylphenyl)-3-cyclohexen-1-yl]-4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzamide, or a pharmaceutically acceptable salt thereof.
15. A use according to Claim 5 wherein the compound is of formula IC
where X is a C1 to C3-alkyloxy, or a pharmaceutically acceptable salt thereof.
where X is a C1 to C3-alkyloxy, or a pharmaceutically acceptable salt thereof.
16. A use according to Claim 15 wherein the compound is 4-[(7-chloro-4-quinolyl)amino]-.alpha.-[[4-[(6-methoxy-8-quinolyl)amino]pentyl]-amino]-.alpha.'-l-pyrrolidinyl-2,6-xylenol trihydrochloride.
17. A use according to Claim 5 where the formula IB compound is one in which R' is an atomic number of from 9 to 35 and R'1 is , or a pharmaceutically acceptable salt thereof.
18. A use according to Claim 17 wherein the compound is 4-[m-[(7-chloro-4-quinolyl)amino]benzoyl]morpholine hydrochloride.
19. A compound selected from the group consisting of 1-benzoyl-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl-piperazine, or a pharmaceutically acceptable salt thereof.
20. A compound according to Claim 19 which is 1-benzoyl-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine maleate.
21. A use according to Claim 1 wherein the compound is of Formula ID.
22. A use according to claim 21 wherein the formula ID compound is one in which R" is the ring group (a) where X' and Y' are C1 to C3-alkyloxy and Z is hydrogen and r is zero;
R"1 and R"2 are C1 to C3-alkyloxy;
R3 is not present; and R4 is hydrogen or a pharmaceutically acceptable salt thereof.
R"1 and R"2 are C1 to C3-alkyloxy;
R3 is not present; and R4 is hydrogen or a pharmaceutically acceptable salt thereof.
23. A use according to claim 22 wherein the compound is 6,7-dimetho-xy-1-(3,4,5-triethoxyphenyl)isoquinoline hydrochloride.
24. A use according to claim 21 wherein the formula ID compound is one in which R" is the ring group (a) where X' and Y' are C1 to C3-alkyloxy, and Z is C1 to C3-alkylcarbonyl, and r is 1;
R"1 and R"2 are each a C1 to C3-alkyloxy, R3 is not present, and R4 is hydrogen, or a pharmaceutically acceptable salt thereof.
R"1 and R"2 are each a C1 to C3-alkyloxy, R3 is not present, and R4 is hydrogen, or a pharmaceutically acceptable salt thereof.
25. A use according to claim 24 wherein the compound is 2'-[(6,7-dimethoxy-1-isoquinolyl)methyl]-4',5'-dimethoxyacetophenone, or a pharmaceutically acceptable salt thereof.
26. A use according to claim 21 wherein the formula ID compound is one in which R" is hydrogen, R3 and R4 are taken together with the isoquinoline ring to form the structure IV
where R"1 and R"2 are each C1 to C3-alkyloxy, or a pharmaceutically acceptable salt thereof.
where R"1 and R"2 are each C1 to C3-alkyloxy, or a pharmaceutically acceptable salt thereof.
27. A use according to claim 26 where the compound is 5,6-dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxolo[5,6-a]quinolizinium iodide.
28. A use according to claim 21 wherein the formula ID compound is one in which R" is where W is C1 to C3-alkyl;
R3 is not present;
R4 is hydrogen, R"1 and R"2 are each hydrogen, or a pharmaceutically acceptable salt thereof.
R3 is not present;
R4 is hydrogen, R"1 and R"2 are each hydrogen, or a pharmaceutically acceptable salt thereof.
29. A use according to claim 28 wherein the compound is (1-iso-quinolyl)oxamic acid, ethyl ester.
30. A use according to claim 21 wherein the formula ID compound is one in which R" is hydrogen, R3 is not present;
R4 is hydrogen, R"1 is hydrogen, R"2 is C1 to C3-alkyloxycarbonylmethyl, or a pharmaceutically acceptable salt thereof.
R4 is hydrogen, R"1 is hydrogen, R"2 is C1 to C3-alkyloxycarbonylmethyl, or a pharmaceutically acceptable salt thereof.
31. A use according to claim 30 where the compound is (5-iso-quinolinyloxy)acetic acid, methyl ester.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US27156788A | 1988-11-15 | 1988-11-15 | |
| US07/271,567 | 1988-11-15 | ||
| US27936488A | 1988-12-02 | 1988-12-02 | |
| US07/279,364 | 1988-12-02 | ||
| US28744888A | 1988-12-20 | 1988-12-20 | |
| US07/287,448 | 1988-12-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2002414A1 true CA2002414A1 (en) | 1990-05-15 |
Family
ID=27402391
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2002414 Abandoned CA2002414A1 (en) | 1988-11-15 | 1989-11-07 | Phenanthrolinedicarboxylate esters, 4-aminoquinoline and isoquinoline derivatives as inhibitors of hiv reverse transcriptase |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU4488989A (en) |
| CA (1) | CA2002414A1 (en) |
| WO (1) | WO1990005523A2 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3002700B2 (en) * | 1990-08-29 | 2000-01-24 | 化研生薬株式会社 | Anti-AIDS virus agent |
| CA2101335A1 (en) * | 1991-03-14 | 1992-09-15 | Paul Adrian Aristoff | Reissert compounds as anti-hiv agents |
| EP0533902A1 (en) * | 1991-04-10 | 1993-03-31 | Octamer, Inc. | A method for inhibition of retroviral replication |
| DE4344452A1 (en) * | 1993-12-24 | 1995-06-29 | Hoechst Ag | Aza-4-iminoquinolines, process for their preparation and their use |
| US6359134B1 (en) | 1997-05-30 | 2002-03-19 | Takeda Chemical Industries, Ltd. | Sulfonamide derivatives, their production and use |
| WO1999040075A1 (en) | 1998-02-05 | 1999-08-12 | Takeda Chemical Industries, Ltd. | Sulfonamide derivatives, process for producing the same and utilization thereof |
| MX2018004109A (en) | 2015-10-05 | 2018-09-27 | Univ Columbia | Activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies. |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3790577A (en) * | 1970-10-05 | 1974-02-05 | Ici Ltd | Pyridoquinoline dicarboxylic acid derivatives |
-
1989
- 1989-10-30 AU AU44889/89A patent/AU4488989A/en not_active Abandoned
- 1989-10-30 WO PCT/US1989/004774 patent/WO1990005523A2/en not_active Application Discontinuation
- 1989-11-07 CA CA 2002414 patent/CA2002414A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| AU4488989A (en) | 1990-06-12 |
| WO1990005523A2 (en) | 1990-05-31 |
| WO1990005523A3 (en) | 1990-07-12 |
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