WO1992016508A1 - Composes reissert utilises comme agents anti-hiv - Google Patents

Composes reissert utilises comme agents anti-hiv Download PDF

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Publication number
WO1992016508A1
WO1992016508A1 PCT/US1992/001746 US9201746W WO9216508A1 WO 1992016508 A1 WO1992016508 A1 WO 1992016508A1 US 9201746 W US9201746 W US 9201746W WO 9216508 A1 WO9216508 A1 WO 9216508A1
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WIPO (PCT)
Prior art keywords
hydrogen
dihydroquinoline
cyano
och
oxo
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PCT/US1992/001746
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English (en)
Inventor
Paul Adrian Aristoff
Brian Bannister
Carolyn Biles
David Glenn Martin
Donna Lee Romero
Harvey Irving Skulnick
Herman Walden Smith
Irene Wilson Althaus
Fritz Reusser
Original Assignee
The Upjohn Company
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Priority to JP4508267A priority Critical patent/JPH06505992A/ja
Publication of WO1992016508A1 publication Critical patent/WO1992016508A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring

Definitions

  • This invention provides novel 1,2-dihydroquinolines, 1,4-dihydroquinolines, 1,2,3,4- tetrahydroquinolines, 1,2-dihydroquinazolines, and 1,2-dihydroquinoxalines, as well as known compounds of these classes, which are useful as anti-AIDS drugs.
  • HIV-1 human immunodeficiency virus type I
  • AZT zidovudine
  • Japanese Patent Application JO 2049-782-A discloses quinolidine compounds which are stated as useful in treating AIDS. These quinolidines are not structurally related to the compounds of the present invention.
  • R 10 is hydrogen, C 1 -C 4 alkyl, -Ac, -C(O)OCH 3 , -C(O)OC 2 H 5 , -phenyl, -PO 2 -O-cation + , -CO-CH(AA)NH 2 , -CO-C 6 H 6 -NR 11 R 12 , and -CO-C 6 H 6 -CH 2 -NR 11 R 12 ;
  • AA is -CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 ,-CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -(CH 2 ) 4 NH 2 , and -(CH 2 ) 3 -NH 2 ;
  • R 11 and R 12 may be the same or different and are hydrogen and C 1 -C 4 alkyl
  • R 11 and R 12 taken together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and
  • R 3 present when the connection between positions 2 and 3 is a single bond, is hydrogen, C 1 -C 4 alkyl, -(CH 2 ) a CN, and -(CH 2 ) b R 13 ;
  • R 13 is -N(CH 3 ) 2 , -OH, -OPO 3 H, -OCH 2 CH(-OH)CH 2 OH, -OCH 2 CO 2 H,
  • R 14 is a N-terminal amino acid
  • a is zero to six
  • b is one to five
  • A is CH, CH 2 , N, and CHN(CH 3 ) 2 ;
  • X is CH, CH 2 , NH, O, and C-R 4 ;
  • R 4 is -CH 3 , -OCH 3 , and -OAc;
  • R 5 , R 6 , R 7 , and R 8 may be the same or different and are hydrogen and fluorine;
  • W is oxygen and sulfur
  • Z is a direct bond or a linker selected from the group consisting of -(CO)-,
  • R 15 and R 16 may be the same or different and are hydrogen and fluorine
  • Y 1 is hydrogen, -Cl, -F, -Br, -CH 3 , -CF 3 , -(CH 2 ) C R 17 , -CHO, -CO 2 CH 3 , -OH, -OCH 3 , -OAc, -CN, -NO 2 , -SH, and -SCH 3 ;
  • c is zero to five
  • R 17 is -CH 2 N(CH 3 ) 2 , -OH, -OPO 3 H, -CH 2 N(C 2 H 5 ) 2 , -O-sugar,
  • R 18 is an N-terminal amino acid
  • Y 2 is hydrogen, -F, -Cl, -OCH 3 , and -CF 3 ;
  • Y 1 and Y 2 taken together can form -OCH 2 O-, -OC(CH 3 ) 2 O-, -OCH 2 NH-,
  • R 19 is hydrogen, -Cl, -Br, -NO 2 , -CF 3 , -CO 2 CH 3 , -OH, -CN, and -OAc;
  • Z is a direct bond and A and X are each CH, and R 5 , R 6 , R 7 , and R 8 are each hydrogen, and R 2 is -CN, Y 1 is not -Cl, -F, or -CH 3 and R 19 is not hydrogen,
  • R 3 is hydrogen
  • R 4 is -CH 3
  • Y 1 is -Cl, -F, -Br, -CF 3 , -CN, or -NO 2 ,
  • the preferred compound is 1-E-(3-(4-chlorophenyI)-1-oxo-2-propenyl)-2-cyano-1,2- dihydroquinoline.
  • the invention further provides compounds of formula II wherein
  • R 10 is hydrogen, C 1 -C 4 alkyl, -Ac, -C(O)OCH 3 , -C(O)OC 2 H 5 , -phenyl, -PO 2 -O- cation + , -CO-CH(AA)NH 2 , -CO-C 6 H 6 -NR 11 R 12 , and -CO-C 6 H 6 -CH 2 -NR 11 R 12 ;
  • AA is -CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 ,-CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -(CH 2 ) 4 NH 2 , and -(CH 2 ) 3 -NH 2 ;
  • R 11 and R 12 may be the same or different and are hydrogen and C 1 -C 4 alkyl
  • R 11 and R 12 taken together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and
  • R 3 present when the connection between positions 2 and 3 is a single bond, is hydrogen, C 1 -C 4 alkyl, -(CH 2 ) a CN, and -(CH 2 ) b R 13 ;
  • R 13 is -N(CH 3 ) 2 , -OH, -OPO 3 H, -OCH 2 CH(OH)CH 2 OH, -OCH 2 CO 2 H,
  • R 14 is a N-terminal amino acid
  • a is zero to six
  • b is one to five
  • A is CH, CH 2 , and CHN(CH 3 ) 2 ;
  • X is CH, CH 2 , and C-R 4 ;
  • R 4 is -CH 3 , -OCH 3 , and -OAc;
  • R 5 , R 6 , R 7 , R 8 may be the same or different and are hydrogen and fluorine;
  • W is oxygen and sulfur
  • Y 1 is -Cl, -F, -Br, -CH 3 , -CF 3 , -(CH 2 ) c R 17 , -CHO, -CO 2 CH 3 , -OH, -OCH 3 -OAc, -CN, -NO 2 , -SH, and -SCH 3 ;
  • c is zero to four
  • R I7 is -CH 2 N(CH 3 ) 2 , -OH, -OPO 3 H, -CH 2 N(C 2 H 5 ) 2 , -O-sugar,
  • R 18 is a N-terminal amino acid
  • R 19 is hydrogen, -Cl, -Br, -NO 2 , -CF 3 , -CO 2 CH 3 , -OH, -CN, and -OAc;
  • a and X are each CH, and R 5 , R 6 , R 7 , and R 8 are each hydrogen, and R 2 is -CN, Y 1 is not -Cl, -F, or -CH 3 and R 19 is not hydrogen,
  • R 19 is not hydrogen
  • R 5 , R 6 , R 7 or R 8 is fluorine
  • R 4 is -CH 3
  • Y 1 is -Cl, -F, -Br, -CF 3 , -CN, or -NO 2
  • Y 1 is -Cl, -F, -Br, -CF 3 , -CN, or -NO 2
  • R 5 is fluorine
  • R 6 , R 7 and R 8 are each hydrogen
  • R 10 is hydrogen, C 1 -C 4 alkyl, -Ac, -C(O)OCH 3 , -C(O)OC 2H5 , -phenyl, -PO 2 -O- cation + , -CO-CH(AA)NH 2 , -CO-C 6 H 6 -NR 11 R 12 , and -CO-C 6 H 6 -CH 2 -NR 11 R 12 ;
  • AA is -CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 ,-CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -(CH 2 ) 4 NH 2 , and -(CH 2 ) 3 -NH 2 ;
  • R 11 and R 12 may be the same or different and are hydrogen and C 1 -C 4 alkyl
  • R 11 and R 12 taken together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and
  • A is CH, CH 2 , and N;
  • X is C-R 4 , and NH
  • R 4 is -CH 3 -OCH 3 , and -OAc;
  • R 3 present when the connection between positions 2 and 3 is a single bond, is hydrogen
  • R 5 , R 6 , R 7 , R 8 may be the same or different and are hydrogen and fluorine;
  • W is oxygen
  • Y 1 is -Cl, -F, -Br, -CH 3 , -CF 3 , -CHO, -CO 2 CH 3 , -OH, -OCH 3 , -OAc, -CN, -NO 2 , -SH, and -SCH 3 ;
  • Y 2 is hydrogen
  • R 19 is hydrogen, -Cl, -Br, -NO 2 , -CF 3 , -CO 2 CH 3 , -OH, -CN, and -OAc;
  • Y 1 is -OCH 3
  • at least one of R 5 , R 6 , R 7 or R 8 is fluorine
  • Y 1 is -CF 3
  • the connection between positions 3 and 4 is a double bond
  • A is N
  • X is C-R 4 and R 4 is -OCH 3 or -OAc and the connection between position 3 and 4 is a double bond
  • R 3 is hydrogen
  • R 4 is -CH 3
  • Y 1 is -Cl, -F, -Br, -CF 3 , -CN, or -NO 2
  • Y 1 is -Cl, -F, -Br, -CF 3 , -CN, or -NO 2
  • R5 is fluorine
  • R 6 , R 7 and R 8 are each hydrogen
  • the invention further provides compounds of formula I wherein
  • R 10 is hydrogen, C 1 -C 4 alkyl, -Ac, -C(O)OCH 3 , -C(O)OC 2 H 5 , -phenyl, -PO 2 -O- cation + , -CO-CH(AA)NH 2 , -CO-C 6 H 6 -NR 11 R 12 , and -CO-C 6 H 6 -CH 2 -NR 11 R 12;
  • AA is -CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 ,-CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -(CH 2 ) 4 NH 2 , and -(CH 2 ) 3 -NH 2 ;
  • R 11 and R 12 may be the same or different and are hydrogen and C 1 -C 4 alkyl
  • R 11 and R 12 taken together are morpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, and N-(C 1 -C 4 alkyl)piperazinyl;
  • R 3 present when the connection between positions 2 and 3 is a single bond, is hydrogen, C 1 -C 4 alkyl, -(CH 2 ) a CN, and -(CH 2 ) b R 13 ;
  • R 13 is -N(CH 3 ) 2 , -OH, -OPO 3 H, -OCH 2 CH(OH)CH 2 OH, -OCH 2 CO 2 H,
  • R 14 is a N-terminal amino acid
  • a is zero to six
  • b is one to five
  • A is CH, CH 2 , and CHN(CH 3 ) 2 ;
  • X is CH, CH 2 , and C-R 4 ;
  • R 4 is -CH 3 , -OCH 3 , and -OAc;
  • R 5 , R 6 , R 7 , and R 8 may be the same or different and are hydrogen and fluorine;
  • W is oxygen and sulfur
  • R 15 and R 16 may be the same or different and are hydrogen and fluorine
  • Y 1 is hydrogen, -Cl, -F, -Br, -CH 3 , -CF 3 , -(CH 2 ) c R 17 , -CHO, -CO 2 CH 3 , -OH, -OCH 3 , -OAc, -CN, -NO 2 , -SH, and -SCH 3 ;
  • c is zero to five
  • R 17 is -CH 2 N(CH 3 ) 2 , -OH, -OPO 3 H, -CH 2N (C 2 H 5 ) 2 , -O-sugar,
  • R 18 is a N-terminal amino acid
  • Y 2 is hydrogen, -Cl, -F, -OCH 3 , and -CF 3 ;
  • Y- and Y 2 taken together are -OCH 2 O-, -OC(CH 3 ) 2 O-, -OCH 2 NH-, -NHCH 2 O-, -OCH 2 S, or -SCH 2 O-;
  • R 3 is hydrogen
  • R 4 is -CH 3
  • Y- is -Cl, -F, -Br, -CF 3 , -CN, or -NO 2
  • Y- is -Cl, -F, -Br, -CF 3 , -CN, or -NO 2
  • R 5 is fluorine
  • R 6 , R 7 and R 8 are each hydrogen
  • the invention also provides a method for treating a human infected with one or more than one strain of a human immunodeficiency virus (HIV) which comprises administering an effective amount of a compound of formula I wherein
  • R 10 is hydrogen, C 1 -C 4 alkyl, -Ac, -CO 2 CH 3 , -CO 2 C 2 H 5 , -phenyl, -PO 2 -O- cation + , -CO-CH(AA)NH 2 , -CO-CgHg-NR 11 R 12 , and -CO-C 6 H 6 -CH 2 -NR 11 R 12 ;
  • AA is -CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 ,-CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -(CH 2 ) 4 NH 2 , and -(CH 2 ) 3 -NH 2 ;
  • R 11 and R 12 may be the same or different and are hydrogen and C 1 -C 4 alkyl
  • R 11 and R 12 taken together are mo ⁇ holinyl, piperazinyl, pyrrolidinyl, piperadinyl, and N-(C 1 -C 4 alkyl)piperazinyl;
  • R 3 present when the connection between positions 2 and 3 is a single bond, is hydrogen, C j -C 4 alkyl, -(CH 2 ) a CN, and -(CH 2 ) b R 13 ;
  • R 13 is -N(CH 3 ) 2 , -OH, -OPO 3 H, -OCH 2 CH(-OH)CH 2 OH, -OCH 2 CO 2 H,
  • R 14 is a N-terminal amino acid
  • a is zero to six
  • b is one to five
  • A is CH, CH 2 , N, and CHN(CH 3 ) 2 ;
  • X is CH, CH 2 , NH, O, and C-R 4 ;
  • R 4 is -CH 3 , -OCH 3 , and -OAc;
  • R 5 , R 6 , R 7 , and R 8 may be the same or different and are hydrogen and fluorine;
  • W is oxygen and sulfur
  • Z is a direct bond or a linker selected from the group consisting of -(CO)-,
  • R 15 and R 16 may be the same or different and are hydrogen and fluorine;
  • Y 1 is hydrogen, -Cl, -F, -Br, -CH 3 , -CF 3 , -(CH 2 ) C R 17 , -CHO, -CO 2 CH 3 , -OH, -OCH 3 -OAc, -CN, -NO 2 , -SH, and -SCH 3 ;
  • c is zero to five
  • R 17 is -CH 2 N(CH 3 ) 2 , -OH, -OPO 3 H, -CH 2 N(C 2 H 5 ) 2 , -O-sugar,
  • R 18 is an N-terminal amino acid
  • Y 2 is hydrogen, -Cl, -F, -OCH 3 , and -CF 3 ;
  • Y 1 and Y 2 taken together can form -OCH 2 O-, -OC(CH 3 ) 2 O-, -OCH 2 NH-,
  • R 19 is hydrogen, -Cl, -Br, -NO 2 , -CF 3 , -CO 2 CH 3 , -OH, -CN, and -OAc;
  • R 3 is hydrogen
  • R 4 is -CH 3
  • Y 1 is -Cl, -F, -Br, -CF 3 , -CN, or -NO 2 ,
  • R 5 is fluorine
  • R 6 , R 7 and R 8 are each hydrogen
  • Z is a direct bond, and when Y 1 and Y 2 taken together can form -OCH 2 O-, -OC(CH 3 ) 2 O-, -OCH 2 NH-, -NHCH 2 O-, -OCH 2 S-, and -SCH 2 O-, Z is a linker; to a human patient.
  • the preferred compound for this method is 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline.
  • the invention further provides the use of the compounds of the invention and/or their pharmaceutically acceptable salts, hydrates, and solvates for the preparation of pharmaceutical formulations. These formulations are useful to practice the method claimed in this invention.
  • Particularly preferred are the compounds of the invention wherein there is a double bond between A and X, and A is CH. It is preferred that X is CH. It is preferred that Z is -CR 15 CR 16 - (E), and that R 15 and R 16 are hydrogen. It is preferred that W is O. It is preferred that R 3 and R 5 are hydrogen and R 6 R 7 and R 8 are either hydrogen or F. It is preferred that R 2 is CN. It is preferred that Y 2 is hydrogen. It is preferred that Y 1 is Cl or CN, most preferred is where Y 1 is Cl.
  • the compounds of the invention are useful as inhibitors of viral reverse transcriptase, an enzyme necessary for human immunodeficiency virus replication, and therefore would be useful in the treatment of disease, such as acquired immune deficiency syndrome (AIDS).
  • AIDS acquired immune deficiency syndrome
  • human retrovirus includes human immunodeficiency virus type I (HIV-I), or variant strains thereof, apparent to one skilled in the art, which belong to the same viral families and which create similar physiological effects in humans as HRV.
  • HBV-I human immunodeficiency virus type I
  • Patients to be treated would be those individuals: 1) infected with one or more than one strain of a human retrovirus as determined by the presence of either measurable viral antibody or antigen in the serum and 2) having either a symptomatic AIDS defining infection such as (a) disseminated histoplasmosis, (b) isopsoriasis, (c) bronchial and pulmonary candidiasis including pneumocystic pneumonia, (d) non-Hodgkin's lymphoma, or (e) Kaposi's sarcoma and being less than sixty years old; or having an absolute CD4 lymphocyte count of less than 500/mm 3 in the peripheral blood.
  • a symptomatic AIDS defining infection such as (a) disseminated histoplasmosis, (b) isopsoriasis, (c) bronchial and pulmonary candidiasis including pneumocystic pneumonia, (d) non-Hodgkin's lymphoma, or (e) Kaposi'
  • AIDS-related complex may be treated with the compounds of this invention.
  • signs and symptoms include, but are not limited to, generalized lymph adenopathy, weight loss, anemia, candidiasis, and immunologic abnormalities characteristic of AIDS.
  • Treatment of ARC and AIDS patients would consist of maintaining an inhibitory level of the compound of the invention used according to this invention in the patient at all times and would continue until the occurrence of a second symptomatic AIDS defining infection indicates alternate therapy is needed. Treatment of asymptomatic patients would typically require lower daily maintenance dosages.
  • the compounds of the invention may be used in conjunction with other antiviral agents such as AZT.
  • the compounds of the invention can be used and administered in practicing the method claimed in this invention.
  • the compounds of the invention may form acid addition salts when reacted with acids of sufficient strength to produce the corresponding salt.
  • some of the variable substituents are acids and thus form base addition salts when reacted with bases of sufficient strength.
  • Pharmaceutically acceptable salts refers to those salts of the compounds of the invention which would be readily apparent to a manufacturing pharmaceutical chemist to be equivalent to, or better than, the parent compound in properties such as formulation, stability, patient acceptance, and bioavailability.
  • the pharmaceutically acceptable salts are preferable over the free acid or base since the salt is more water soluble and more crystalline.
  • the pharmaceutically acceptable salts include both inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable salts include salts of the following acids: methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, tartaric, fumaric, maleic, p-toluenesulfonic, benzenesulfonic, and the like.
  • Examples of pharmaceutically acceptable salts include salts of the following bases: hydroxide, ammonia, tromethamine (THAM), and the like. Suitable cations include, for example, sodium, potassium, calcium, and magnesium.
  • dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions.
  • an effective amount is from about 0.2 to about 100 mg per kg per day for asymptomatic patients, and about 1 to about 500 mg per kg per day for ARC and AIDS patients.
  • a typical unit dose for a 70 kg human AIDS patients would be from about 50 mg to 1000 mg, preferably 200 mg to 1000 mg taken one to four times per day.
  • Either solid or fluid dosage forms can be prepared for oral administration.
  • Solid compositions are prepared by mixing the compounds used to practice the method claimed in this invention with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methyl cellulose, or functionally similar pharmaceutical diluents and carriers.
  • Capsules are prepared by mixing the compounds used to practice the method claimed in this invention with an inert pharmaceutical diluent and placing the mixture into an appropriately sized hard gelatin capsule.
  • Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compounds used to practice the method claimed in mis invention with an acceptable inert oil such as vegetable oil or light liquid petrolatum.
  • Syrups are prepared by dissolving the compounds used to practice the method claimed in this invention in an aqueous vehicle and adding sugar, aromatic flavoring agents and preservatives.
  • Elixirs are prepared using a hydroalcoholic vehicle such as ethanol, suitable sweeteners such as sugar or saccharin and an aromatic flavoring agent.
  • Suspensions are prepared with an aqueous or organic vehicle and a suspending agent such as acacia, tragacanth, or methyl cellulose.
  • parenteral solutions are prepared by dissolving the compounds used to practice the method claimed in this invention in an appropriate solvent and filter sterilizing the solution before placing in a suitable scalable vial or ampule.
  • Parenteral suspensions are prepared in substantially the same way except a sterile suspension vehicle is used and the compounds used to practice the method claimed in this invention are sterilized with ethylene oxide, suitable gas or other methods known in the art, before it is suspended in the vehicle.
  • AIDS means acquired immune deficiency syndrome.
  • ARC means AIDS-related complex.
  • E or Z designates stereochemistry around a double bond.
  • the two groups attached to each atom of the double bond are assigned priorities according to the Prelog-Cahn-Ingold system.
  • E refers to an arrangement in which the two higher priority or two lower priority groups are on the opposite sides of the double bond.
  • Z refers to an arrangement in which the two higher priority groups are on the same side of the double bond.
  • N-terminal amino acid means a naturally occurring amino acid, and synthetic derivatives thereof, in which the amino group is free, i.e., the amino acid is linked via the carboxyl group to form either an ester or an amide.
  • O-sugar means a hexose or pentose monosaccharide linked at the 2-hydroxyl group.
  • C m -C n indicates a moiety of integer "m” to the integer "n” carbon atoms, inclusive and includes the isomeric forms.
  • C 1 -C 6 alkyl refers to an alkyl of one to six carbons, inclusive, including the isomeric forms.
  • Chemical formulas, or portions thereof, drawn in a linear fashion may use the symbol "-" to represent a single chemical bond between atoms in the linear chain.
  • the symbol “ " represents a double bond, and " ⁇ " a triple bond, between atoms in the chain.
  • the symbol “ ⁇ ” represents a bond between two atoms which may be a single or a double bond; the symbol “ ⁇ ” represents a bond which may or may not be present, and if present, is a single bond.
  • MS mass spectrometry. MS data are expressed as m/e or mass/change unit.
  • Reissert compounds from quinoline.
  • preparation in aqueous potassium cyanide potassium cyanide in a dimethylformamide-water mixture, liquid sulphur dioxide as a solvent, anhydrous benzeneliquid hydrogen cyanide, and trimethylsilyl cyanide-aluminum chloride in methylene chloride.
  • liquid sulphur dioxide as a solvent
  • anhydrous benzeneliquid hydrogen cyanide trimethylsilyl cyanide-aluminum chloride in methylene chloride.
  • trimethylsilyl cyanide-aluminum chloride trimethylsilyl cyanide-aluminum chloride in methylene chloride.
  • the Reissert reaction is carried out under ambient temperature conditions, e.g. 23-27 degrees, or refluxing acetonitrile for 8-substituted compounds, for a time sufficient to effect as complete a reaction as possible, e.g. from 0.5 to 48 hours.
  • the products of the reaction (Chart A, fig. 2) are followed by TLC using solvent systems known in the art.
  • the reaction is concentrated in vacuo and then placed on a silica gel column and eluted under flash chromatography conditions.
  • the product is recrystallized from a low boiling point aliphatic alcohol, preferably 95% ethanol, or ethylacetate/hexane.
  • the dihydroquinoline (Chart A, fig. 2) is dissolved in alcohol, preferably 95% ethanol, and reduced by hydrogenation in the presence of platinum. The reaction is followed and the product (Chart A, fig. 3) recrystallized as outlined above.
  • 6,8-difluoroquinoline is synthesized by substituting 2,4-difluoroaniline for 3,4-difluoroaniline in Preparation 1. The remaining procedure and purification are substantially unchanged.
  • 7,8-difluoroquinoline is synthesized by substituting 2,3-difluoroaniline for the 3,4-difluoroaniline in Preparation 1. The remainder of the procedure and purification are substantially unchanged.
  • the reaction is filtered through a pad of silica gel and the pad is washed with 20 mL of methylene chloride.
  • the combined filtrates are washed first with 10 mL of water, men with 10 mL of saturated aqueous sodium bicarbonate and finally 5 mL of water.
  • the organic layers are concentrated in vacuo to afford an oil which is dissolved in 4 ml of 95 percent ethanol. This is evaporated to 2.5 mL and cooled at 0°C for 30 min.
  • the crystals are collected and dried in a vacuum oven to afford 85 mg of 1-(4-bromobenzoyl)-2-cyano-1,2-dihydroquinoline (m.p. 149-151°C).
  • the mother liquor is evaporated and triturated with 1 mL of 95 percent ethanol.
  • the crystals formed are collected and dried to afford 31 mg of a second crop.
  • Example 10 1-E-(3-(3,4-dichlorophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline
  • E-3,4-dichlorocinnamoyl chloride is used as the acid chloride.
  • the product, 1-E-(3,4-dichlorophenyl-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline has a m.p. 152-153°C.
  • E-4-cyanocinnamoyI chloride (Preparation 5) is used as the acid chloride.
  • the product, 1-E-(3-(4-cyanophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline has a m.p. 176°C.
  • E-3,4-methylenedioxycinnamoyl chloride is used as the acid chloride.
  • the product, 1-E-(3-(3,4-methylenedioxyphenyl)-1-oxo-2-propenyl)-2- cyano-1,2-dihydroquinoline has a m.p. 176-177°C.
  • E-4-methoxycinnamoyl chloride is used as the acid chloride.
  • the product is 1-E-(3-(4-methoxyphenyl)-1-oxo-2-propenyI)-2-cyano-1,2-dihydroquinoline.
  • E-4-acetoxycinnamoyl chloride is used as the acid chloride.
  • the product is 1-E-(3-(4-acetoxyphenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline.
  • E-4-carbomethoxycinnamoyl chloride is used as the acid chloride.
  • Example 15 1-E-(3-(4-methylphenyI)-1-oxo-2-trans-propenyl)-2-cyano-1,2-dihydroquinoline Following the procedure of Example 1a, E-(4-methylcinnamoyl chloride) is used as the acid chloride. The product is 1-E-(3-(4-methylphenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline.
  • 4-chlorobenzoyl chloride is used as the acid chloride.
  • 4-chlorobenzoyl chloride is used as the acid chloride.
  • Example 19a The product of Example 19a is subjected to reverse-phase HPLC separation (isocratic 40% THF/60% water mobile phase). Pure 1-(4-chlorobenzoyl)-6-fluoro-2-cyano-1,4- dihydroquinoline is isolated (m.p. 144-150°C).
  • 4-chlorobenzoyl chloride is used as the acid chloride.
  • 6,7-difluoroquinoline (Preparation 1) is the quionoline and 4-chlorobenzoyl chloride is the acid halide.
  • the product, 1-(4-chlorobenzoyl)-2-cyano-6,7-difluoro-1,2-dihydroquinoline has a m.p. 184-185°C.
  • Example 27 1-E-(3-(4-bromophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline Following the procedure of Example la, E-4-bromocinnamoyl chloride is substituted for the acid halide.
  • the product, 1-E-(3-(4-bromophenyl)-1-oxo-2-propenyl)-2-cyano-1,2-dihydroquinoline has a m.p. 175-177°C.
  • Example 31 1-(4-trifluorobenzoyl)-2-cyano-3-dimethylamino-1,2,3,4-tetrahydroquinoline
  • To 500 mg (1.52 mmol) of 1-(4-trifluoromethylbenzoyl)-2-cyano-1,2-dihydroquinoline is added 20 ml of methylene dichloride and 3 ml of anhydrous dimethylamine (the dimethylamine is cooled to below -20°C before carefully opening the sealed botde).
  • the reaction is allowed to stir at ambient temperature for 48 h., filtered and the resulting methylene chloride solution evaporated to dryness. The residue is distributed between methylene chloride and water, and the organic phase washed twice with water.
  • Phenylpropiolic acid (K&K Chemicals, 1.05 g, 7.2 mmol) is dissolved in 14 ml of methylene chloride and cooled to 0°C. Oxalyl chloride (0.63 ml) and dimethylformamide (140 ⁇ l) are added. The reaction is stirred at 0°C for 30 min., then warmed to ambient temperature and stirred an additional 3 hours. The reaction is concentrated in vacuo and further dried in vacuo for 3 h. at ambient temperature. Quinoline (0.57 ml, 4.8 mmol) is dissolved in 14 ml of methylene chloride and 0.42 ml of trimethylsilylcyanide is added.
  • the reactants are added to saturated sodium bicarbonate and extracted with methylene chloride.
  • the organic layers are combined, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo.
  • the amide product (Chart B, fig. 2) is purified using flash chromatography in ethyl acetate/hexanes.
  • the amide (Chart B. fig. 2) (1 eq.) is dissolved in methylene chloride (0.4-0.5M) and the reaction cooled to -20oC.
  • An acid, preferably boron trifluoride etherate, (1-1.2 eq.) is added and the reaction mixture is stirred and slowly warmed to ambient temperatures. Stirring continues for from 12 to 20 hours.
  • the mixture is diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated in vacuo.
  • the product, a substituted 3,4-dihydro-3-ethoxy-2H-1,4-benzoxazine (Chart B, fig. 3), is purified by flash chromatography using a chloroform/methanol solvent.
  • step (b) 4-(p-ChlorocinnamoyI)-3,4-dihydro-3-ethoxy-2H-1,4-benzoxazine (1 mmol) synthesized in step (b) is dissolved in 7 ml of methylene chloride. Azidotrimethylsilane (1 mmol) and boron trifluoride etherate (1 mmol) are added. After stirring about 3 hours at room temperature, the reaction is diluted with methylene chloride, washed with saturated sodium bicarbonate, saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo.
  • hydroxylamine is prepared by adding sodium methoxide (10 eq.) to hydroxylamine hydrochloride (1 eq.) in methanol and then filtering.
  • the Reissert-hydroxylamine reaction is allowed to warm to room temperature while stirring. It is then heated from 30°C to reflux for 1 to 24 hours.
  • the reaction mixture is cooled to room temperature, diluted with chloroform, washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo.
  • the product (Chart C, fig. 2) is recrystallized from aqueous (95%) methanol.
  • Hydroxylamine hydrochloride (1 eq.) is added to a stirred mixture of 1 eq. sodium carbonate in 50 percent aqueous ethanol (0.6-0.8M). The reaction is diluted to 0.06-0.08M with absolute ethanol. Then 0.8 eq. of the desired Reissert compound is added and the reaction is heated at from 50°C to reflux temperature under nitrogen for 2.5 to 24 hours. The reaction poured is mixed into ice water and extracted with ethyl acetate or butanol. The organics are concentrated in vacuo, dissolved in ethanol, and chilled. The solid product is collected and dried.
  • the pharmacological salt of the amidoxime may be synthesized by use of an appropriate acid.
  • examples of such salts include hydrochloride, hydrobromide, fumarate, maleate, succinate, citrate, tosylate, and mesylate.
  • 1-(4-chlorobenzoyl)-2-cyano-1,2-dihydroquinoline (0.2g, 0.68 mmol, see Popp, cited above) is dissolved in warm methanol and added to a solution of hydroxylamine in methanol.
  • the hydroxylamine is prepared by the addition of sodium methoxide (0.232 ml of 25% w/w solution in methanol, 1 mmol) to 70 mg of hydroxylamine hydrochloride (1 mmol) in methanol followed by filtration to remove precipitate.
  • the Reissert-hydroxylamine reaction is stirred at ambient temperature for 3 h and subsequendy heated to 40°C for 1 hour.
  • Example 36b 1-E-[3-(4-bromophenyl)-1-oxo-2-propenyI]-N-(acetyloxy)-2- quinolinecarboximidamide
  • the purified product of Example 36(a) is dissolved in 0.75 ml methylene chloride.
  • Example 37a The product of Example 37a, 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2- carboximidamide-1,2-dihydroquinoline, is dissolved in methanol and chlorotrimethyl silane is added. The addition of diethyl ether causes the desired salt to crystallize. The crystals are collected to afford 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinoline, hydrochloride (m.p. 158-160°C).
  • Example 37a 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinoline, is dissolved in methanol and methane sulfonic acid is added. The volatiles are removed in vacuo and the residue recrystallized from diethyl ether/chloroform. The crystals are collected and dried to yield 1-E-(3-(4-chlorophenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinoline, methane sulfonate (m.p. 139-140°C).
  • Example 37d 1-E-[3-(4-chlorophenyl)-1-oxo-2-propenyl]-N-(acetyloxy)-2-quinolinecarboximidamide
  • Example 11 the tide compound is obtained (1-E-(3-(4-cyanophenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinoline, 0.11g, m.p. 205-206°C).
  • Example 42b 1-E-(3-(4-cyanophenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2- dihydroquinoline hydrochloride
  • the product of Example 42a (1.0 g) is suspended in 10 ml of methanol and concentrated hydrochloric acid (0.29 ml) is added. The solution is diluted with ether until crystals formed and then it is cooled to 5°C. The crystals are collected and dried to afford 0.68 g of the hydrochloride salt (1-E-(3-(4-cyanophenyl)-1-oxo-2-propenyl)-2-carboximidamide-1,2-dihydroquinoline hydrochloride, m.p. 157-158°C).
  • Extracts prepared according to the procedure of Kleid, D. G., et al., Science, 1125-1129 (1981) are incubated in a mixture of inhibitor, 20 mM dithiothreitol, 60 mM sodium chloride, 0.05% NP-40, 10 mM magnesium chloride, 50 mM Tris pH 8.3, 10 ⁇ M [ 35 S]-Iabeled deoxynucleoside-5'-triphosphate, 10 ⁇ g/ml RNA template (poly rC or poly rG) and 5 ⁇ g/ml DNA primer (oligo dG or oligo dT) for 15 minutes at 37 °C.
  • Incorporation of radio labeled precursor is determined by spotting aliquots of the reaction mixture on DE 81 paper, washing the papers to remove unicorporated precursor, drying, and determining counts. The results of various assays are combined and reported as % inhibition of reverse transcriptase activity at a 100 ⁇ M dose in Table I.
  • the assays are performed with primary human lymphocytes. Thereby, undesired testing of transformed cell lines is avoided in which host cell and virus may have undergone processes of mutual adaptation. Performance of cell culture in serum containing media closely mimics the in vivo situation, (b) The primary PBL assay distinguishes between true antiviral effect which is due to the drug and cytostatic/cytotoxic reactions, (c) Viral replication is precisely followed by kinetic measurement of viral nucleic acids and proteins, (d) Nucleic acids (total HIV -RNA intra- and extracellular) and protein (secreted p24) are measured in parallel which permits one to differentiate between the compound's effect on virus replication and on the expression of viral proteins.
  • the primary PBL assay uses the following procedure:
  • Effects of the compounds of the invention on cell proliferation are determined by lymphocyte proliferation assays. Starting with a 100 micromolar solution, the compound is serially diluted 10 fold. One tenth of the concentration of a compound causing half maximal inhibition of cellular proliferation is employed for all subsequent testing.
  • Peripheral human lymphocytes are isolated by density gradient centrifugation. After stimulation by mitogen the cells are infected with a standardized preparation of HIV.
  • the infected cells are cultured in the presence of the drug for four days. Individual cultures are established to measure viral replication three and four days following infection. Untreated cells and AZT-treated cells are included as controls in parallel with the drugs under investigation.
  • the amount of viral core protein p24 synthesized and released by the infected cells is determined in the supernatant by the capture-ELISA technique on days three and four. By comparing with a standard preparation, the amount of protein produced by the virus
  • infected cells is quantified.
  • the total amount of viral RNA synthesized by the infected lymphocytes is determined by a special nucleic acid hybridization technique on days three and four of culture. By including a standard preparation of HIV-RNA the amount of synthesized RNA is quantified.
  • a drug shows antiviral effects in the primary assay, all steps of the primary assay are repeated.
  • viability of HIV-infected cells is determined in parallel with assays for viral p24 and RNA.
  • a concentration dependency of the drug action is measured.
  • the compounds of the invention are assayed according to this procedure.
  • the anti-HIV activity as measured by the inhibition of the release of core p24 protein in HIV infected human lymphocytes, is used to calculate antiviral ED 50 (the concentration required to give a 50% reduction in p24 synthesis). Results are shown in Table I.

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Abstract

L'invention se rapporte à des composés hétérocycliques représentés par la formule (I), qui servent au traitement du sida et du syndrome associé au sida. Ces composés sont généralement synthétisés en suivant les réactions et les conditions utilisées pour produire les composés Reissert. Les composés de la formule (I) sont les 1,2-dihydroquinolines, les 1,4-dihydroquinolines, les 1,2,3,4-tétrahydroquinolines, les 1,2-dihydroquinazolines et les 1,2-dihydroquinoxalines. Les composés types sont 1-(4-bromobenzoyl)-2-cyano-1,2-dihydroquinoline, 1-(4-chlorobenzoyl)-2-cyano-5-fluoro-1,2-dihydroquinoline, 1-(4-chlorobenzoyl)-2-cyano-6-fluoro-1,4-dihydroquinoline, 1-(4-chlorobenzoyl)-2-cyano-1,2,3,4-tétrahydroquinoline, 1-(4-chlorobenzoyl)-2-carboximidamide-8-fluoro-1,2-dihydroxyquinoline, 1-(4-chlorobenzoyl)-2-cyano-1,4-dihydroquinoxaline, 1-E-(3-(4-chlorophényl)-1-oxo-2-propényl)-2-cyano-1,2-dihydroquinoline et 1-E-(3-(4-chlorophényl)-1-oxo-2-propényl)-2-carboximidamide-1,2-dihydroquinoline. L'invention décrit également un procédé de traitement du sida ou du syndrome associé au sida grâce à une quantité efficace d'un de ces composés.
PCT/US1992/001746 1991-03-14 1992-03-12 Composes reissert utilises comme agents anti-hiv WO1992016508A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0697405A1 (fr) * 1994-08-16 1996-02-21 Hoechst Aktiengesellschaft Dérivés de quinoléines substituées, procédé pour leur préparation et leur utilisation
US5519021A (en) * 1992-08-07 1996-05-21 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
US5939435A (en) * 1997-02-03 1999-08-17 American Home Products Corporation 2-substituted-1-acyl-1,2-dihydroquinoline derivatives
WO2005090309A1 (fr) * 2004-03-12 2005-09-29 Wyeth Derives de la 1,2-dihydroquinoline et leur methode d'utilisation pour traiter les infections par le vih

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990005523A2 (fr) * 1988-11-15 1990-05-31 The Upjohn Company Esters de phenanthrolinedicarboxylate, derives de 4-aminoquinoline et isoquinoline en tant qu'inhibiteurs de la transcriptase d'inversion de hiv

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990005523A2 (fr) * 1988-11-15 1990-05-31 The Upjohn Company Esters de phenanthrolinedicarboxylate, derives de 4-aminoquinoline et isoquinoline en tant qu'inhibiteurs de la transcriptase d'inversion de hiv

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5519021A (en) * 1992-08-07 1996-05-21 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
US5663169A (en) * 1992-08-07 1997-09-02 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
US5665720A (en) * 1992-08-07 1997-09-09 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
EP0697405A1 (fr) * 1994-08-16 1996-02-21 Hoechst Aktiengesellschaft Dérivés de quinoléines substituées, procédé pour leur préparation et leur utilisation
US5798365A (en) * 1994-08-16 1998-08-25 Hoechst Aktiengesellschaft Substituted quinoline derivatives, a process for their preparation, and their use
US5939435A (en) * 1997-02-03 1999-08-17 American Home Products Corporation 2-substituted-1-acyl-1,2-dihydroquinoline derivatives
WO2005090309A1 (fr) * 2004-03-12 2005-09-29 Wyeth Derives de la 1,2-dihydroquinoline et leur methode d'utilisation pour traiter les infections par le vih
US7553967B2 (en) 2004-03-12 2009-06-30 Wyeth 1,2-Dihydroquinoline derivatives and method for using the same to treat HIV infections

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