JPH04257584A - 5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepine and a composition for preventing or treating HIV infection containing the compound - Google Patents

Abstract

PURPOSE: To provide a compd. which suppresses the enzymatic function of an HIV-1 reverse transcriptase and is useful for the prevention and treatment of a human HIV-1 infection.

CONSTITUTION: The compd. of formula I (R¹ is H, 1 to 6C alkyl, etc., when Z is O, S, NCN, etc.; R² is H, and when R¹ is not H, 1 to 6C alkyl, etc.; R³ to R⁵ are H, or one thereof is 1 to 6C alkyl, 2 to 6C alkenyl, etc., and the other two substituents are H, methyl, etc., or two are 1 to 2C alkyl, halogen, etc., and the remaining one is H, methyl; R⁶ to R⁸ are H or one is 1 to 4C alkyl, 2 to 4C alkenyl and the two substituents are H, etc.), and the pharmaceutically permissible acid additive salts. For example, 11-cyclopropyl-5,-11-dihydro-4- methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepine-6-on or -4 on. The compd. of the formula I is obtd. by bringing the compd. of formula II (R²' is the same as R² exclusive of H; Hal is F, Cl, Br, I) into reaction at 110 to 220°C by adding a catalyst thereto in an inert solvent and bipolar nonprotonic soln. in the presence of a metal chlorinating agent.

COPYRIGHT: (C)1992,JPO

Description

Detailed description of the invention [0001] [Industrial field of application and problem to be solved by the invention]
The present invention provides a novel 5,11-dihydro-6H-dipyrid [
3,2-b:2',3'-e][1,4]Diazepine and
and pharmaceutically acceptable acid addition salts thereof, and compounds thereof.
methods for the preparation of these compounds, and the use of these compounds for the prevention or treatment of HIV infection.
Medical uses and pharmaceutical compositions containing these compounds
relating to things. [0002] The human disease acquired immunodeficiency syndrome (AI)
DS) is human immunodeficiency virus (HIV), especially HIV
-1. It's another virus.
In sea urchins, HIV-1 is responsible for the biosynthesis of infected host cells.
Cannot be duplicated without forcibly removing the device
. HIV-1 has a structure that creates virus descendants in this device.
Produces white matter. These proteins carry their infectious
Genetic material contained within the virus particle or pillion
is coded. However, since it is a retrovirus,
, the genetic material of HIV is stored in the genome of the host cell.
It's not DNA, it's RNA. Therefore, virus R
NA helps host cells produce the necessary viral proteins.
In order to obtain
must be incorporated into the system. Transfer of RNA to DNA
The conversion is carried out by the use of an enzyme, namely reverse transcriptase (RT).
This enzyme is contained along the RNA within infectious virions.
is possessed. Reverse transcriptase has three enzymatic functions;
As an NA-dependent DNA polymerase, ribonuclease
as a DNA-dependent DNA polymerase and as a DNA-dependent DNA polymerase.
act. First, as an RNA-dependent DNA polymerase
In action, RT generates a single-stranded DNA copy of the viral RNA.
make. Next, acting as a ribonuclease, RT
releases the DNA just produced from the original viral RNA
The original RNA is then destroyed. Finally, once again the DNA
Acting as a natural DNA polymerase, RT is the first
Using the DNA strand as a template, a second complementary DNA
Make strands. The two strands make up double-stranded DNA.
This DNA is processed by another enzyme called integrase.
integrated into the host cell genome. [0003] Inhibiting the enzymatic function of HIV-1 reverse transcriptase
Compounds inhibit HIV-1 replication in infected cells
Will. Such compounds may inhibit human HIV-1 infection.
Useful for prevention or treatment. Means for Solving the Problems In an embodiment of the composition,
The present invention is based on the formula: ##STR6## where Z is oxygen, sulfur, =NCN, or
is the formula=NOR9 (wherein, R9 is 1 to 3 carbon atoms
is alkyl); R1 is hydrogen, 1-6
alkyl of 1 to 6 carbon atoms, and 1 to 6 carbon atoms;
Fluoroalkyl of 3 fluorine atoms, 3 to 6 carbons
Atomic cycloalkyl, alkenyl of 2 to 6 carbon atoms
or alkynyl, 2-halo-2-propene-1-
yl, mono- or di-halovinyl, aryl or
is arylmethyl (the aryl part is unsubstituted)
Substituted with squid or methyl, methoxy or halogen
phenyl, thienyl or furanyl), 2-
Alkanoyl, aminoethyl, mono- of 4 carbon atoms
or di-alkylaminoethyl (each alkyl moiety
minute contains 1 to 2 carbon atoms), 2 to 4 carbon atoms
alkyloxyalkyl or alkylthioalkyl
, alkyloxycarbonyl (the alkyl part is 1
~4 carbon atoms), alkenyloxy- or
is alkynyloxycarbonyl (each alkenyl
or the alkynyl moiety contains 2 to 4 carbon atoms),
droxy, alkyloxy of 1 to 4 carbon atoms, amino
-, mono- or di-alkylamino (each alkylamino)
(the carbonyl moiety contains 1 to 4 carbon atoms), aminocarbonyl
methyl, or cyanoalkyl (the alkyl portion of which is
1 to 4 carbon atoms); R2 is hydrogen (R1 is not hydrogen);
), alkyl of 1 to 6 carbon atoms, 1 to
Fluoroalk of 6 carbon atoms and 1 to 3 fluorine atoms
kyl, cycloalkyl of 3 to 6 carbon atoms, oxeta
Nil, thietanil, tetrahydrofuranyl or tet
lahydrothienyl, also alkenyl of 2 to 6 carbon atoms
or alkynyl, alkyloxy of 2 to 5 carbon atoms
sialkyl or alkylthioalkyl, 2 to 5
Alkanoyl of carbon atoms, cyano, 2 to 6 carbon atoms
hydroxyalkyl, aryl or arylmethy
(the aryl portion is unsubstituted or 1-
Alkyl or alkyloxy, hydrogen of 3 carbon atoms
Droxyl or halogen-substituted phenyl, thie
or furanyl), or alkyloxycarboxylic acid
Rubonylmethyl (the alkyl portion of which has 1 to 5 carbon atoms)
and one of R3, R4 and R5 is 1 to 6
alkyl of 3 to 6 carbon atoms, cyclo of 3 to 6 carbon atoms
Alkyl, alkenyl or aryl of 2 to 6 carbon atoms
ruquinyl, trihalomethyl, hydrogen of 1 to 6 carbon atoms
loxyalkyl, alkyloxy of 2 to 5 carbon atoms
Alkyl or alkylthioalkyl, alkyloxy
cyclocarbonylalkyl (the alkyl moiety is 1 to 2, respectively)
1 to 5 carbon atoms), hydroxyl, 1 to 5 carbon atoms
alkyloxy or alkylthio atoms, 2 to 4
hydroxyalkyloxy of 2 to 4 carbon atoms
elementary alkanoyloxy, alkanoyloxy of 1 to 4 carbon atoms;
Rukylsulfinyl or alkylsulfonyl, 2-
Alkanoyl, alkyloxycarbo of 6 carbon atoms
Nyl (the alkyl portion of which contains 1 to 3 carbon atoms)
, mono- or di-alkylaminocarbonyl (respectively
the alkyl portion of contains 1 to 3 carbon atoms), 1 to 4
aminoalkyl, mono- or di-atom of carbon atoms
rukylaminoalkyl (each alkyl moiety is 1 to 3)
carbon atoms), aryl or arylmethyl
(The aryl moiety is unsubstituted or 1-3
Alkyl or alkyloxy, hydroxyl or
or halogen-substituted phenyl, thienyl or phenyl
ranyl), a group of formula -NR10R11, halogen
, cyano, nitro, azide or carbonyl;
The other two substituents are hydrogen, methyl or chloro
; or two of R3, R4 and R5
are independently alkyl or hydro of 1 to 2 carbon atoms
xyalkyl, trihalomethyl, with 1 to 2 carbon atoms
Alkyloxy or alkylthio, halogen or
It is a group of the formula -NR10R11, and the remaining substituents are hydrogen.
or methyl; or R3, R4 and R5
are each hydrogen; one of R6, R7 and R8 is
Alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms
or alkynyl, trihalomethyl, 1-4 carbons
atomic hydroxyalkyl, alkyl of 2 to 4 carbon atoms
Kyloxyalkyl or alkylthioalkyl,
Rukyloxycarbonylalkyl (the alkyl part is
each containing 1 to 2 carbon atoms), hydroxyl, 1 to
alkyloxy or alkylthio of 4 carbon atoms
, hydroxyalkyloxy of 2 to 4 carbon atoms, 2
Alkanoyloxy of ~4 carbon atoms, 1 to 4 carbon atoms
Subatomic alkylsulfinyl or alkylsulfonyl
Nyl, alkanoyl, alkoxy of 2 to 6 carbon atoms
carbonyl (the alkyl portion of which has 1 to 3 carbon atoms)
), aminoalkyl of 1 to 4 carbon atoms, mono-
or di-alkylaminoalkyl (each alkyl
moiety contains 1-2 carbon atoms), formula -NR12R1
3 groups, halogen, cyano, nitro, azide or carbon
ruboxyl, and the other two substituents are hydrogen.
; or, two of R6, R7 and R8 are independently
Alkyl of 1-2 carbon atoms, trihalomethyl, 1-2
Alkyloxy or alkylthio of 2 carbon atoms
, halogen or a group of the formula -NR12R13, and the remainder
The substituents of R are hydrogen; or R6, R7 and R
8 are each hydrogen; and R10, R11, R12
and R13 are each independently hydrogen, atom of 1 to 4 carbon atoms;
alkyl, alkenylmethyl of 2 to 4 carbon atoms or
is alkynylmethyl, aryl or arylmethyl
(The aryl part is unsubstituted or methyl
, phenyl substituted with methoxy or halogen,
enyl or furanyl), of 2 to 4 carbon atoms
mono- or dihydroxyalkylmethyl, 1 to 3
Alkyloxy, hydroxy, 3 to 4 carbon atoms
Alkyloxyethyl or alkylthio of a carbon atom
ethyl, aminoalkylmethyl of 1 to 4 carbon atoms,
mono- or dialkylaminoalkylmethyl (respectively
the alkyl portion of contains 1 or 2 carbon atoms), or
or alkanoyl of 1 to 4 carbon atoms; or
, R10 and R11, and R12 and R13 are
azetidine each independently, together with the nitrogen atoms between them
-1-yl or saturated or unsaturated, optionally
and one halogen atom (chosen from O, S or N)
) or, if necessary, in place of a carbon atom
Formula = NR14 (in the formula, R14 is hydrogen or 1 to 2 carbons)
is an alkyl of an elementary atom), and the ring is necessary.
more independently hydroxymethyl, aminomethyl, 1 to 4
substituted with a methyl group and 1 to 2 hydroxy groups
a) Z is oxygen or sulfur; b) R2 is hydrogen, alkyl of 1 to 5 carbon atoms;
, 2-5 alkenyl or alkynyl, 2-4
alkoxyalkyl or alkylthio of carbon atoms
alkyl, alkanoyl of 2 to 4 carbon atoms, 2 to 5
hydroxyalkyl, phenyl (as required) of 4 carbon atoms
Alkyl or alkoxy of 1 to 3 carbon atoms
, hydroxyl or halogen substituted), or
or alkoxycarbonylmethyl (the alkyl part is
c) i) R3 , R4 , R5 , R6 , R7
and R8 are each hydrogen, or ii) R3 , R4 , R5 , R6 , R7 and
One of R8 is alkyl of 1 to 4 carbon atoms, 1 to 4
hydroxyalkyl, alkyloxyca of carbon atoms
Rubonylalkyl (the alkyl moiety is 1 or 2, respectively)
1 to 4 carbon atoms), hydroxyl, 1 to 4 carbon atoms
alkoxy or alkylthio atoms, up to 4 carbons
Subatomic alkanoyloxy, alkanoyloxy of up to 4 carbon atoms
Lucanoyl, amino, aminoalk of up to 4 carbon atoms
Kyl, mono- or di-alkylaminoalkyl (husband)
each alkyl moiety contains 1-2 carbon atoms), halo
Gen, cyano, nitro, azide, or carboxyl
Yes, and R3, R4, R5, R6, R7 and
and the remaining five of R8 are hydrogen, or iii) R3, R4 and R5 are
each independently hydrogen or alkyl of 1 to 1 carbon atoms;
(provided that at least one is hydrogen), or R3
, one of R4 and R5 is butyl and the remaining two
is hydrogen, and R6, R7 and R8 are each independently
hydrogen or alkyl of 1 to 3 carbon atoms (
provided that at least one is hydrogen), or R6,
One of R7 and R8 is butyl and the other two are water.
when R1 is hydrogen, 1 to 5 carbon atoms
alkyl, alkenyl of 3 to 5 carbon atoms or
Alkynyl, 2-halo-2-propen-1-yl, aryl
methyl (the aryl part of which is unsubstituted or
or substituted with methyl, methoxy or halogen.
phenyl, thienyl or furanyl), 2 or 3
alkanoyl containing 2 to 4 carbon atoms
alkoxyalkyl or alkylthioalkyl
5,11-dihydro-6H-dipyrido [impossible]
3,2-b:2',3'-e] [1,4] diazepine;
or a compound of formula I which satisfies the following conditions:
[wherein Z is oxygen and i) R1 is methyl and R2 is ethyl]
, and R7 is azide, amino or nitro, and
R3 to R6 and R8 are hydrogen, or R3
is ethylamino or diethylamino, and R4
~R8 is hydrogen, or R6 and R8 are methyl
and R3 to R5 and R7 are hydrogen,
or R3 and R4 are methyl and R5 to R
8 is hydrogen, or R5 is methyl and R
3, R4, R6, R7 and R8 are hydrogen;
, or ii) R1 is methyl and R2 is ethyl, t-
butyl, s-butyl or isopropyl, and R3
~R8 is hydrogen, or iii) R1 and R2 are methoxymethyl
, R5 is methyl and R3 , R4 and R6
, R7 and R8 are hydrogen, or iv) R1 is hydrogen and R2 is
and R3 to R8 are hydrogen] or the formula
I, wherein Z is sulfur, and (a
) R2 is ethyl, R3 and R5 are methyl, R1,
R4, R6 to R8 are hydrogen, or (b) R
1 is methyl, R2 is ethyl, R3 is methoxy, R
4 to R8 are hydrogen. A subconceptual feature of the present invention is that Z is oxygen, sulfur,
yellow or a group of formula=NOR9 (in the formula, R9 is 1 to 2
is alkyl of carbon atoms); R1 is hydrogen,
alkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms
Fluoroalkyl, cyclopropyl, 3-4 carbon atoms
Child alkenylmethyl or alkynylmethyl, 2-
halo-2-propen-1-yl, of 2 to 3 carbon atoms
alkanoyl, alkyloxya of 2 to 3 carbon atoms
alkyl or alkylthioalkyl, or cyanoa
alkyl (the alkyl portion of which contains 1 to 3 carbon atoms)
); R2 is hydrogen (remember that R1 is not hydrogen);
), alkyl of 1 to 5 carbon atoms, 1 to 5
fluoroalkyl of 3 to 5 carbon atoms
cycloalkyl, oxetanyl, thietanyl, 3-5
alkenylmethyl or alkynylmethyl of carbon atoms
til, also alkyloxyalkyl of 2 to 4 carbon atoms
or alkylthioalkyl, alkylthioalkyl, alkyl of 2 to 4 carbon atoms;
Lucanoyl, hydroxyalkyl of 2 to 5 carbon atoms
, aryl or arylmethyl (the aryl part
is unsubstituted or alkyl of 1 to 3 carbon atoms
Kyl or alkyloxy, hydroxyl or halo
phenyl, thienyl or furanyl substituted with gen
), or alkyloxycarbonylmethyl (that
the alkyl moiety contains 1 to 4 carbon atoms);
[0016] 1 to 4 of one of R3, R4 and R5
Alkyl of 2 to 4 carbon atoms, alkeni of 2 to 4 carbon atoms
or alkynyl, trihalomethyl, 1 to 4 carbons
elementary hydroxyalkyl, atom of 2 to 4 carbon atoms
rukyloxyalkyl or alkylthioalkyl,
Alkyloxycarbonylalkyl (the alkyl portion thereof
each containing 1 to 2 carbon atoms), hydroxyl, 1
alkyloxy or alkylthi of ~3 carbon atoms
E, hydroxyalkyloxy of 2 to 3 carbon atoms,
alkanoyloxy of 2 to 3 carbon atoms, 1 to 3 carbon atoms
Alkylsulfinyl or alkylsulfonyl of a carbon atom
Honyl, alkanoyl, alkyl of 2 to 4 carbon atoms
oxycarbonyl (the alkyl portion of which has 1 to 2 carbons)
atom), aminoalkyl of 1 to 3 carbon atoms,
Mono- or di-alkylaminoalkyl (each alkyl)
1-2 carbon atoms), amino, mole
no- or di-alkylamino (each alkyl moiety
contains 1 to 4 carbon atoms), acetidin-1-yl
, pyrrol-1-yl, pyrrolin-1-yl, pyrrolidi
-1-yl, pyrazol-1-yl, pyrazoline-1
-yl, pyrazolidin-1-yl, imidazole-1-yl
yl, imidazolin-1-yl, imidazolidine-1-yl
yl, tetrahydropyridin-1-yl, piperidin-
1-yl, morpholin-1-yl, (4-methyl)pipe
Radin-1-yl, piperazin-1-yl, N,N-bi
(2-hydroxyethyl)amino, N,N-bis(2
-methoxyethyl)amino, or halogen;
the other two substituents are hydrogen, methyl or chloro
; or, two of R3, R4 and R5 are independently
alkyl of 1 to 2 carbon atoms, alkyl of 1 to 2 carbon atoms
Alkyloxy or alkylthio, amino, mono-
or di-alkylamino (each alkyl moiety is 1
~3 carbon atoms), azetidin-1-yl, pi
Roll-1-yl, pyrrolin-1-yl, pyrrolidine-
1-yl, pyrazol-1-yl, pyrazolin-1-y
pyrazolidin-1-yl, imidazol-1-yl
, imidazolin-1-yl, imidazolidin-1-yl
, tetrahydropyridin-1-yl, piperidine-1-
yl, morpholin-1-yl, (4-methyl)piperazi
N-1-yl, piperazin-1-yl, N,N-bis(
2-hydroxyethyl)amino, N,N-bis(2-methane)
(toxyethyl) amino, or halogen, and the remaining
the substituent is hydrogen, methyl or chloro; or [
[0018] R3, R4 and R5 are each hydrogen;
;One of R6, R7 and R8 has 1 to 2 carbons
alkyl, vinyl, trifluoromethyl, 1-2 atoms
hydroxyalkyl, hydroxyl, 1 carbon atoms
alkyloxy or alkylthi of ~2 carbon atoms
E, hydroxyalkyloxy of 2 to 3 carbon atoms,
Alkanoyloxy, amino, mono of 2 to 3 carbon atoms
no- or di-alkylamino (each alkyl moiety
contains 1-2 carbon atoms), azetidin-1-yl
, pyrrol-1-yl, pyrrolin-1-yl, pyrrolidi
-1-yl, pyrazol-1-yl, pyrazoline-1
-yl, pyrazolidin-1-yl, imidazole-1-yl
yl, imidazolin-1-yl, imidazolidine-1-yl
yl, tetrahydropyridin-1-yl, piperidin-
1-yl, morpholin-1-yl, (4-methyl)pipe
Radin-1-yne, piperazin-1-yl, N,N-bi
(2-hydroxyethyl)amino, N,N-bis(2
-methoxyethyl)amino, or halogen;
the other two substituents of are hydrogen; or R6, R7
and R8 are each hydrogen; A special subcharacteristic of the invention is that Z is an acid
or sulfur; R1 is hydrogen, 1 to 3 carbon atoms
child alkyl or allyl; R2 is 2 to 3
Alkyl of carbon atoms, or cyclo of 3 to 4 carbon atoms
is loalkyl; R3 is hydrogen, methyl, 1 to 3
Alkyloxy or alkylthio of a carbon atom, chloro
b, amino, mono- or di-alkylamino (respectively)
the alkyl portion of contains 1 to 3 carbon atoms), allyl
amino, azetidin-1-yl, pyrrol-1-yl,
Pyrrolin-1-yl, pyrrolidin-1-yl, pyrazole
l-1-yl, pyrazolin-1-yl, pyrazolidine-
1-yl, imidazol-1-yl, imidazoline-1
-yl, imidazolidin-1-yl, tetrahydropylyl
Zin-1-yl, piperidin-1-yl, morpholine-
1-yl, (4-methyl)piperazin-1-yl, pipepe
Radin-1-yl, or N,N-bis(2-hydroxy
ethyl)amino; R4 is hydrogen, methyl or carbon;
Rolo; R5 is hydrogen, methyl, ethyl, chloro,
or trifluoromethyl; R6 and R8 are
is hydrogen; and R7 is hydrogen or amino;
Compounds of formula I are included. A further sub-conceptual feature of the invention is that Z
is oxygen or sulfur; R1 is hydrogen, 1 to 3 carbon atoms
is an elementary alkyl or allyl; R2 is 2-3
alkyl of 3 to 4 carbon atoms, or alkyl of 3 to 4 carbon atoms
is cycloalkyl; R3 is hydrogen, methyl, chloro, methoxy
, ethoxy, amino, mono- or di-alkylami
(each alkyl moiety contains 1-2 carbon atoms)
, allylamino, allylmethylamino, pyrroline-1-
yl, pyrrolidin-1-yl, tetrahydropyridine-
1-yl, piperidin-1-yl or morpholine-1
-yl; R4 is hydrogen; R5 is hydrogen,
methyl, ethyl, chloro, or trifluoromethyl.
R6 and R8 are hydrogen; and R7 is hydrogen
or amino; including compounds of Formula I. Preferred compounds of formula I are 5,11-dihydrogen
Dro-11-ethyl-4-methyl-6H-dipyrid [3
,2-b:2',3'-e][1,4]diazepine-6
-one; 11-cyclopropyl-5,11-dihydro-4-methy
Ru-6H-dipyrid [3,2-b:2',3'-e] [
1,4] diazepin-6-one or -thione; 5,1
1-dihydro-11-ethyl-2,4-dimethyl-6H
-dipyrid [3,2-b:2',3'-e] [1,4]
Diazepine-6-thione; 11-cyclopropyl-5,11-dihydro-2,4-
Dimethyl-6H-dipyrid [3,2-b:2',3'-
e] [1,4] diazepin-6-one or -thione;
2-chloro-5,11-dihydro-11-ethyl-4-
Methyl-6H-dipyrido [3,2-b:2',3'-e
] [1,4] diazepin-6-one or -thione; 2
-chloro-11-cyclopropyl-5,11-dihydro
-4-Methyl-6H-dipyrid [3,2-b:2',3
'-e] [1,4] diazepin-6-one or -thio
5,11-dihydro-11-ethyl-2-methoxy-4
-Methyl-6H-dipyrid [3,2-b:2',3'-
e] [1,4] diazepin-6-one or -thione;
11-cyclopropyl-5,11-dihyde
rho-2-methoxy-4-methyl-6H-dipyrid [3,
2-b:2',3'-e][1,4]diazepine-6-
one or -thione; 8-amino-5,11-dihydro-11-ethyl-2-
Methoxy-4-methyl-6H-dipyrido [3,2-b:
2',3'-e] [1,4] diazepin-6-one or
-thione; 8-amino-11-cyclopropyl-5,11-dihyde
rho-2-methoxy-4-methyl-6H-dipyrid [3,
2-b:2',3'-e][1,4]diazepine-6-
one or -thione; 5,11-dihydro-11-ethyl-2-methoxy-5
-Methyl-6H-dipyrid [3,2-b:2',3'-
e] [1,4] diazepine-6-thione; 11-cyclo
Propyl-5,11-dihydro-2-methoxy-5-methane
Chil-6H-dipyrid [3,2-b:2',3'-e]
[1,4]Diazepin-6-one or -thione; 5,11-dihydro-11-ethyl-4-
Methyl-2-(N-pyrrolidino)-6H-dipyrido[3
,2-b:2',3'-e][1,4]diazepine-6
-one or -thione; 11-cyclopropyl-5,11-dihydro-4-methyone
-2-(N-pyrrolidino)-6H-dipyrido[3,2
-b:2',3'-e][1,4]diazepine-6-o
5,11-dihydro-11-ethyl-5-methyl-2-
(N-pyrrolidino)-6H-dipyrido[3,2-b:2
',3'-e] [1,4] diazepin-6-one or
-thione; 11-cyclopropyl-5,11-dihydro-5-methy
-2-(N-pyrrolidino)-6H-dipyrido[3,2
-b:2',3'-e][1,4]diazepine-6-o
5,11-dihydro-11-ethyl-4-methyl-2-
(N,N-dimethylamino)-6H-dipyrido[3,2
-b:2',3'-e][1,4]diazepine-6-o
11-cyclopropyl-5,11-dihydro-4-methyone;
-2-(N,N-dimethylamino)-6H-dipyrido
[3,2-b:2',3'-e][1,4]Diazepine
-6-one or -thione; 8-amino-5,11-dihydro-11-ethyl-4-
Methyl-2-(N,N-dimethylamino)-6H-dipy
Lido[3,2-b:2',3'-e][1,4]diaze
pin-6-one or -thione; and 8-amino-11-cyclopropyl-5,11-dihyde
rho-4-methyl-2-(N,N-dimethylamino)-6
H-dipyrid [3,2-b:2',3'-e][1,4
] diazepine-6-one or -thione; Synthesis of compounds of formula I and their salts
Compounds and their salts can be prepared by known methods or their obvious
It can be prepared by modified methods. Methods A to H below are based on these conversions.
1 is an illustration of a method for preparing a compound. Method A [0026] [0027] (wherein R1 and R3 to R8 are
As described above, R2' is the same as R2 except for hydrogen.
Compounds of the general formula II: [0028] [0029] (wherein R1, R3 to R8 and R
2' has the same meaning as stated in formula Ia, Ha
l represents fluorine, chlorine, bromine or iodine)
It can be obtained by cyclizing an acid amide. Alternatives to this method (which include R6, R7, or R8
, especially of formula Ia where R7 is a charge-withdrawing group such as nitro.
(preferably used to prepare the compound) is
Formula IIa [0030] [0031] (wherein R3 to R8 are as described above)
, R2' has the same meaning as R2 except for hydrogen,
and Hal represents fluorine, chlorine, bromine or iodine)
involves cyclizing a carboxylic acid amide. Cyclization is 0
of formula II or I at a temperature between °C and the boiling point of the reaction temperature.
Conversion of compounds of Ia to their alkali metal salts and
Conveniently this is carried out by subsequent condensation. In starting compounds of general formula II or IIa,
and when R1 is different from hydrogen, metal chloride (meta
llation) with at least 1 mol of metal chloride.
I need. On the other hand, when R1 is hydrogen,
At least 2 moles of metal chlorinating agent should be used. metal salt
lithium, sodium and potassium hydrogen
or lithium aluminum such as n-butyllithium.
The use of kills is preferred. The cyclization reaction is carried out in an inert solvent, such as tetrahydrogen.
Dorofuran, 1,4-dioxane, glycol dimethyl
Ether, diethylene glycol dimethyl ether,
Liethylene glycol dimethyl ether, dimethylform
Usually carried out in muamide, benzene or anisole. ring
may also be used for carboxylic acid amides of general formula II or IIa.
in a dipolar aprotic solvent, preferably sulfolane or
It can also be done by heating in dimethylsulfone.
. Catalytic amounts of strong acids such as sulfuric acid, hydrochloric acid, hydrobromic acid,
acid, polyphosphoric acid, methanesulfonic acid or p-toluene
It has been proven that sulfonic acid can be used. need
The reaction temperature is usually 110 to 220°C. Method B General formula Ib: ##STR10## where R1 and R3 to R8 are
As described above, Ar is, for example, phenyl or
may be a 4-methoxyphenyl group)
can be prepared by hydrolytic cleavage of the methyl group. Addition of water
Decomposition is performed using strong acids or Lewis acids at temperatures between -20 and +150°C.
done by. Such acids are sulfuric acid, methanesulfonic acid
, trifluoroacetic acid, trifluoromethanesulfonic acid,
It can be phosphoric acid or polyphosphoric acid. phosphoric acid or poly
When using phosphoric acid, benzene, toluene, and
of solvents like nol, anisole or veratrol.
Additions have been found to be advantageous. Rui such as aluminum chloride or bromide
When removing the arylmethyl group using sulfuric acid, the aromatic
Hydrocarbons, such as benzene, toluene, anisole,
or a solvent such as a mixture of these with dichloromethane
is suitable. Method B includes R1 and R3 to R8
If either of them is a substituent that can be easily hydrolyzed
, for example, if R1 is alkanoyl or R3
~R8 is alkanoylamino or alkanoyl
If it is carbonyl, it is not preferred.
It will be obvious to those skilled in the art that this is not the case. R1 is Al
Kanoyl or any one of R3 to R8 is alkoxy
In the case of cyclocarbonyl, for example, using method A described above,
preferably; when R1 is hydrogen, 2 equivalents of the salt
group should be used. Any one of R3 to R8 is a
In the case of lucanoylamino, for example, hydrolysis (and
and subsequent acylation) on the corresponding nitro derivatives.
, then reduce the nitro moiety to the amine and then reduce the acyl
It is preferred to obtain the desired product. Method C: ##STR11## where R1' is the same as R1 except for hydrogen.
have the same meaning, and R2 to R8 are as described above.
) is a compound of formula IV: ##STR12## where R2 to R8 are as defined above.
5,11-dihydro-6H-dipyrido [3,2
-b:2',3'-e][1,4]diazepine-6-o
corresponding 5-alkali or alkaline earth metal compounds
and then convert the resulting alkali metal compound into the formula
V: R1'X
(V) (wherein R1' is of formula Ic)
has the same meaning as in case, X is a reactive ester group, halogen
atom, group OSO2OR1', methanesulfonyloxy
or ethanesulfonyloxy group, or aromatic sulfonyl group
obtained by reacting with a compound of
can be done. Compounds of general formula IV are prepared in a first step by
Instead of converting to the corresponding alkali metal salt, the formula IV
Triethylamine, diazabicic alkylation of compounds
of lowundecene or 4-(dimethylamino)pyridine
In the presence of amino acids such as sodium carbonate, potassium carbonate
alkaline carbonates such as sodium bicarbonate or sodium bicarbonate.
or by reaction with a compound of formula V in the presence of bicarbonate.
It can be done by Corresponding alkali gold compounds of the general formula IV
Conversion to a group or alkaline earth metal compound of formula IV
Lithium hydroxide, barium hydroxide, sodium hydroxide
Alkali metals such as um or potassium hydroxide or
Alkaline earth metal hydroxide; sodium methoxide or
is potassium tert. -Alkali gold such as butoxide
genus alcoholates; sodium amide or potassium amide
Alkali metal amides such as hydrogen; or sodium hydride
alkali metal hydrides such as aluminum or potassium hydride
This can be done by reacting with The reaction is preferably
This is carried out at elevated temperature in the presence of a suitable organic solvent. dimethylform
Muamide, dimethyl sulfoxide, tetrahydrofuran
or an inert organic such as glycol dimethyl ether
If the solvent uses an alkali metal hydride as the metal chlorination agent,
preferred when alkali or alkaline earth metals
When using hydroxide, methanol or tetra
Aqueous mixtures with organic solvents such as hydrofuran can also be used.
Wear. The alkali or alkaline earth metal substitution thus obtained
5,11-dihydro-6H-dipyrido[3,2-b:2
',3'-e][1,4]Diazepin-6-one to one
For conversion to compounds of general formula Ic, alkali or
A solution or suspension of an alkaline earth compound directly, i.e.
Without isolation, the compound of formula V can be heated at -20°C or
at elevated temperature to the boiling point of the solvent or the reaction medium, whichever is lower.
React with. The substitution involves 1 equivalent of base and 1 equivalent of formula V.
Assuming that the compound R in the starting material of formula IV is
Dihydrodipyridodiazepine even if 2 is a hydrogen atom
occurs almost exclusively at the nitrogen atom at the 5-position. Presence of nucleophilic substituents in compounds of formula Ic
gives a given group without nucleophilic properties other than the nitrogen at the 11-position.
Use of intermediates of formula Ic with substituents derivable as
It is clear to those skilled in the art that this may require
cormorant. For example, amino or
The monoalkylamino substituents are preferably R3 to R8
An intermediate of formula Ic having a nitro group in either
kylation or acylation and then reducing the nitro group,
If appropriate, alkylation may be performed to obtain the final product.
Therefore, it is obtained. Method D ##STR13## where Z is oxygen and R1 to R8 are
5,11- of the general formula Ib
Dihydro-6H-dipyrid [3,2-b:2',3'-
e] Diazepin-6-one with the corresponding gold of general formula VIa
or a compound of formula VIb (R1 of a compound of formula Ib)
is hydrogen), that is, [Chemical formula 14] (where M is lithium, sodium, potassium
Alkali metals such as aluminum, rubidium or cesium
or M represents the group Mg Hal+ and Ha
l is a chlorine, bromine or iodine atom) and then
and formula VII R2
VII (wherein R2 and X are as described above)
can be prepared by alkylation with a compound of
Ru. Formulas VIa and VI of compounds of general formula Ib
Conversion of b to the corresponding alkali metal compound of formula Ib
of tetramethylethylenediamine as needed.
alkyl lithium (e.g. n-butyl lithium) in the presence of
or t-butyllithium), lithium dialkyl lithium
(e.g., lithium diisopropylamide, lithium diisopropylamide,
mudicyclohexylamide and lithium isopropyl
cyclohexylamide), aryllithium (e.g.
phenyllithium), alkali metal hydroxides (e.g.
lithium hydroxide, sodium or potassium), alkali
metal hydroxides (e.g. sodium or potassium hydride)
) or alkali metal amides (e.g. sodium
or potassium amide), or Grignard reagents (e.g.
For example, methylmagnesium iodide, methylmagnesium bromide
or phenylmagnesium bromide).
This can be done by One equivalent of base is added to the preparation of a compound of formula VIa.
2 equivalents of base are required for the preparation of the compound of formula VIb.
required for the preparation of Metal chlorides are conveniently dissolved in inert organic solvents.
medium at a temperature between -78°C and the boiling point of the reaction mixture.
conduct. Alkyl lithium, aryl lithium, lithium dial
Using kylamide or Grignard reagents for metal chlorination
the preferred solvent is hexane or
Mixing with aliphatic or aromatic hydrocarbons like benzene
Tetrahydrofuran, diethyl ether or
It is an ether like dioxane and can be operated from -20 to +
Carry out at a temperature of 80°C. Metal chloride alkali metal hydride
and alkali metal amides, other than the above-mentioned solvents.
xylene, toluene, acetonitrile, dimethyl fluoride.
using lumamide and dimethyl sulfoxide
Also, when using an alkali metal hydroxide,
, alcohols such as ethanol, methanol, and
Aliphatic ketones such as acetone and these solvents and water
Mixtures of can also be used. From the alkali metal salt thus obtained, formula I
For conversion to compounds, alkali metal compounds must be dissolved.
liquid or suspension directly, i.e., isolating the reaction product.
of the compound of formula VII and the reaction mixture at -20°C.
The reaction is carried out at a temperature between the boiling point, preferably room temperature. Formula I
The presence of a nucleophilic substituent in the compound indicates that the nucleophilic substituent other than the 11-position nitrogen
have a substituent that can be induced to provide the required group without the
requires the use of an intermediate of formula Ic. For example, R3
Amino or monoalkyl amine at any of ~R8
The substituent is preferably any one of R3 to R8.
Alkylated or acyl intermediates of formula Ic having a
and then reduce the nitro group and, if appropriate, reduce the alkyl group.
The final product is obtained by Starting Materials for Methods A to D Carboxylic acid amides of general formula II used as starting materials
is, for example, the general formula VIII: ##STR15## where R1 to R8 and Hal are
2-chloro-nicotinic acid (as defined above)
General formula IX of amide: H2N-R2'
(IX) (wherein R2' is the above
Amination of (as defined) with a primary amine
It is obtained by The reaction also works with triethylamine, N,N
- dimethylaniline, sodium and potassium carbonate
This may be carried out in the presence of an inorganic or organic auxiliary base such as. anti
Although the reaction can be carried out without the use of a solvent, an inert organic solvent may be used.
It can be used at a temperature of 0°C to 175°C, preferably at reflux temperature.
has several advantages. Any suitable inert solution that can be used
The medium contains an excess of a primary amine of general formula IX;
Dorofuran, 1,4-dioxane, glycol dimethyl
Ethers, such as diethylene glycol dimethyl ether
open chain or cyclic ethers such as benzene, toluene,
Fragrances like xylene, chlorobenzene or pyridine
Group hydrocarbons; methanol, ethanol, isopropanol
Alcohols such as alcohol; such as dimethylformamide
Dipolar aprotic solution; 1,3-dimethyl-2-imida
Lysinone, 1,3-dimethyl-tetrahydro-2 (1H
)-pyrimidinones and sulfolanes. The carboxylic acid amide of formula IIa can be
Appropriately substituted 2-chloronicotinic acid chloride under suitable conditions
lido and appropriately substituted 3-amino-2-(alkyla
can be prepared by condensation with mino)pyridine. R1 is water
Starting materials of general formula VIII that are different from the general formula X: [
[0056] From 2-chloronicotinamide of [Chemical formula 16]
An alkylating agent of formula V and, for example, triethylamine, di
Azabicycloundecene, 4-(dimethylamino)pyri
Amines such as gin; sodium hydroxide, calcium hydroxide
alkaline or alkali such as sium, calcium hydroxide
Potassium earth metal hydroxide; or sodium carbonate, carbonate
Alkali metal charcoal such as potassium bicarbonate or potassium bicarbonate
of acid salts or alkaline earth metal carbonates or bicarbonates.
prepared by reacting in the presence of a proton acceptor
obtain. 2-chloronicotinic acid amide of general formula
Suitably substituted 2-chloronicotinic acid chloride and
with 3-amino-2-halogen-pyridine substituted with
It can be prepared by condensation under known reaction conditions. other departures
All substances are known in the literature, can be purchased, or
It can be obtained by known procedures. Method E In Method E, compounds of formula I where Z is sulfur are
is oxygen.
Cyphenyl)-1,3-dithia-2,4-diphospheta
-2,4-disulfide, bis(trichlorohexyl)
tin) sulfide, bis(tri-n-butyltin) sulfide
Do, bis(triphenyltin), bis(trimethylsilyl)
) reacts with sulfurizing agents such as sulfides or phosphorous pentasulfide.
It can be obtained by The reaction is carbon disulfide, benzene
above room temperature in an inert organic solvent such as chlorine or toluene.
, preferably at elevated temperature to the boiling point of the reaction mixture.
is carried out under anhydrous conditions. tin or silyl sulfide as mentioned above
When using a sulfuric acid, such as boron trichloride, the sulfurization reaction is
Preferably, the reaction is carried out in the presence of sulfuric acid. Compounds of formula I, for example, where Z is oxygen and R
In compounds in which any one of 3 to R8 is alkanoyl
The presence of an additional carbonyl moiety in the ketone carbonyl
is protected by a known method with an appropriate protecting group before the sulfurization reaction.
to obtain the desired compound by deprotection after sulfurization reaction
It will be obvious to those skilled in the art that this is necessary. same
Similarly, when R2 is, for example, alkanoyl,
, the sulfurization reaction is carried out before the acylation of the 11-position nitrogen.
Obviously, this is the best option. R3 to R8
The substituents at either can be derived from nitro, e.g.
For example, in the case of alkanoylamino, the sulfurization reaction is
on a nitro derivative, followed by a suitable (known) reduction.
and finally acylation to obtain the desired product.
Wear. Method F R1 is hydrogen and R2 to R8 are as above.
and Z is a group of formula =NCN, compounds of formula
I: [Chemical formula 17] [0063] (wherein R2 to R8 are as above)
obtained by reacting a compound) with cyanamide.
can be done. The reaction is potassium carbonate, sodium carbonate
um, triethylamine, or diisopropylethyl
Methylene chloride, 1,4-di
Oxane, tetrahydrofuran, diethyl ether,
Inert such as loloform or dimethylformamide
carried out in a solvent at a temperature between 0 °C and the boiling point of the reaction mixture.
It will be done. Method G R1 is hydrogen and R2 to R8 are as described above.
and Z is a group of formula =NOR9,
In a similar manner to Method F, R2 to R8 are as above.
A compound of formula XI, which is
-alkylhydroxylamines) or their salts (e.g.
for example, by reacting with methoxylamine hydrochloride).
can be obtained. The reaction is of formula X with cyanamide
Conditions similar to those described for treatment of compounds of I.
It takes place below. Compounds of formula XI in which the starting materials R2 to R8 of methods F and G are as described above are
, R1 is hydrogen and R2 to R8 are as above.
and Z is oxygen, the compound of formula I is trifluoromethane
Obtained by reacting with tansulfonic anhydride
Can be done. The reaction begins with 1 to 2 equivalents of trifluoromethane.
1 to 2 equivalents of sulfonic anhydride in an inert solvent.
Preferably, the reaction is carried out in the presence of a base. Bases are examples
For example, triethylamine or diisopropylethylamine
Tertiary amines such as amines may also be used;
Examples of sterile solvents include methylene chloride, chloroform, and diethyl chloride.
thyl ether, tetrahydrofuran, or toluene
May include. Addition of reagents is generally done below ambient temperature.
The mixture is then allowed to react at around room temperature. Alkoxylamine starting materials are available commercially;
or is known in the literature, or by an operation known in the literature.
Obtainable. Preparation of salts and other derivatives Compounds of formula I may optionally be prepared in their non-toxic pharmaceutically acceptable form.
For example, acid addition salts of formula I can be prepared by conventional methods.
Dissolve the compound in a suitable solvent and add 1 molar equivalent or more of the solution.
Conversion can be achieved by acidification with the desired acid above. Main departure
Ming also includes such salts. Compounds of Formula I and Non-toxic Pharmaceutically Acceptable Acids
Examples of inorganic and organic acids that form addition salts are:
: Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methane
sulfonic acid etc. The compound of general formula I is acidified with 1 molar equivalent of acid.
May form salts. A person skilled in the art can use one of the methods described above.
By directly preparing certain compounds of formula I,
However, by derivatization of other compounds of formula I, they can be
I admit that it is often convenient to create. This way
Such derivatization uses known reaction techniques. non-limiting example
If R1 is hydrogen, it oxidizes to hydrogen.
Can produce droxy; nitro group can be reduced to produce amine
possible; the methoxy group can be converted to hydrochloride by the usual demethylation procedure.
can be converted to hydroxy, which in turn can be converted to
Via trifluoromethanesulfonyloxy derivatives
Can be substituted with amine; amine can be acylated to form alkanoyl
Can produce amines or alkylate to mono- or
can produce dialkylamines; halogens can be set appropriately
Can be substituted with amines under conditions; protecting groups can be removed. BIOLOGICAL PROPERTIES The compounds of formula I as described above have a
Has inhibitory activity. When administered in a suitable dosage form, this
Their compounds are associated with AIDS, ARC and HIV infection.
Useful in the prevention or treatment of related diseases. therefore
, another aspect of the invention is that patients exposed to or susceptible to HIV-1
A prophylactically or therapeutically effective amount as described above for infected humans.
HIV-
1. It is a method for preventing or treating infection. Compounds of formula I can be administered orally, parenterally or topically.
It can be administered in single or divided doses depending on the route. Formula I
A suitable oral dosage of the compound is in the range of about 0.5 mg/g/day.
Will. For parenteral formulations, the appropriate dosage unit is
It may contain from 0.1 to 250 mg of the above compound and may be used for topical administration.
In preparation, products containing 0.01-1% of active ingredients are used.
Agents are preferred. However, it is important to understand that the dosage
will vary between patients, and the dosage for a particular patient will depend on his or her clinical
The criteria for determining the appropriate dosage are as follows:
Patient weight and condition and patient response to medications
This means that they will probably use . The compounds of the invention should be administered by the oral route.
Sometimes these compounds are carried in a compatible pharmaceutical carrier, i.e.
a medicament in the form of a pharmaceutical preparation containing together with a carrier substance;
can be administered. Such carrier substances may be administered orally.
can be inert organic and inorganic carrier materials suitable for
Ru. Examples of such carrier materials are water, gelatin, tar
Luku, Starch, Magnesium Stearate, Arabic
Rubber, vegetable oil, polyalkylene glycol, petroleum jelly
-etc. Pharmaceutical formulations can be prepared in a conventional manner and the final
Dosage forms include solid dosage forms, e.g. tablets, dragees, capsules.
or liquid dosage forms, such as solutions, suspensions, emulsions, etc.
It can be. Pharmaceutical preparations are subject to normal pharmaceutical procedures such as sterilization.
It can be subjected to manipulation. In addition, pharmaceutical preparations contain preservatives, stabilizers
, emulsifiers, flavor improvers, wetting agents, buffers, osmotic pressure modifiers
It may contain conventional adjuvants such as salts for oxidation. use
Possible solid carrier materials include, for example, starch, resin, etc.
Cutose, mannitol, methylcellulose, microcrystalline
Cellulose, talc, silica, dibasic calcium phosphate
and high molecular weight polymers (polyethylene glycol).
). For parenteral use, compounds of formula I can be used as pharmaceuticals.
Aqueous or non-aqueous in a scientifically acceptable oil or liquid mixture
can be administered as a liquid solution, suspension or emulsion;
These fluids contain sterilants, antioxidants, preservatives, and
Isotonic buffers or other lysates, thickeners, suspensions
It may contain clouding agents or other pharmaceutically acceptable additives. Additives of this type include, for example, tartrate, citric acid
Salt and acetate buffers, ethanol, propylene
glycol, polyethylene glycol, complexing agent
(like EDTA), antioxidants (sodium bisulfite),
, like sodium metabisulfite and ascorbic acid
), high molecular weight polymer for viscosity adjustment (liquid polyethylene)
sorbitol anhydride) and sorbitol anhydride.
There are lyethylene derivatives. Benzoic acid, methyl or pro
Pirparaben, benzalkonium chloride and other
Preservatives such as quaternary ammonium compounds may also be used as needed.
can be added. The compounds of the invention may also be formulated into solutions for nasal administration.
In addition to the compound of the invention, a suitable buffer can be administered.
, tonic preparations, microbial preservatives, antioxidants and aqueous
A thickening agent may be included in the vehicle. Agent used for thickening
Examples are polyvinyl alcohol, cellulose derivatives, and polyvinyl alcohol.
vinylpyrrolidone, polysorbate or gelatin.
Ru. The microbial preservative added is benzalkonium salt.
loride, thimerosal, chlorobutanol, or
phenyl ethyl alcohol. Furthermore, the compounds of the present invention can also be administered as suppositories.
I can give. As mentioned above, the compounds of the present invention are effective against HIV-
Inhibits the enzyme activity of 1RT. These changes as described below
Based on fairly extensive testing of compounds, the
Suppression of RNA-dependent DNA polymerase activity
I found out. The compounds of the present invention are derived from the DNA of HIV-1 RT.
found that it also suppresses dependent DNA polymerase activity.
(data not shown). Using the following reverse transcriptase (RT) assay:
each compound to its RNA-dependent DNA of HIV-1 RT.
Can be tested for the ability to inhibit A polymerase activity
. Some specific compounds shown in the following examples
That's how it was tested. The test results are shown in Table 1 below.
show. Reverse transcriptase (RT) assay Assay theory: Human immunodeficiency virus (HIV-1)
Some enzymes encode RNA templates (templates).
) so named because it transcribes DNA copies from
There is a reverse transcriptase (1). This activity was previously
quantitatively in the cell-free enzyme assay (2) disclosed in
can be measured using a synthetic template (oligo d(G)).
sensitized polyr(c)] based on 3H-dGTP.
Radiolabeled acid-precipitated DNA strands used as templates
Based on the observation that it is possible to transcribe . Materials: a) Preparation of enzymes from the LAV strain of human immunodeficiency virus (HIV-1).
Reverse transcriptase (1) in expression vector pIBI21 (4)
DNA clone under the control of the lac promoter of
Strain JM109 expressing pBPTprt1+(2) (
3). 100 μg/ml aliquot for positive selection.
Overnight cultures grown in 2XYT medium with ampicillin (
37°C, 225 rpm) (5) with 10 μg/ml chia
amine, 0.5% casamino acids and 50 μg/ml
Inoculate at a 1:40 dilution into M9 medium (5) supplemented with ampicillin.
Ru. Culture until reaching OD540 of 0.3-0.4
Keep warm (37°C, 225 rpm). At this point, the reply
Lesser inhibitor IPTG (isopropyl β-D-
thiogalactopyranoside) to 0.5mM and further
Keep the mixture warm for an hour. Pelletize bacteria and 50m
M Tris, 0.6mM EDTA, 0.375M N
Resuspend in aCl buffer and add lysozyme.
Digest on ice for 30 minutes. cells with 0.2% NP-4
0 to 1M NaCl. After removing insoluble debris by centrifugation
, the protein was added with 3 volumes of saturated ammonium sulfate aqueous solution.
Precipitate by adding. The resulting enzyme was pelleted and R
T buffer (50mM Tris pH 7.5, 1mM
EDTA, 5mM DTT, 0.1% NP-40, 0
．． 1M NaCl, and 50% glycerin).
Suspend and store at 70°C for later use. b) Composition of the 2x concentrated stock reaction mixture
Preservative drugs
2x mixed concentrated 1M Tris p
H7.4
100mM 1M dithiothrietol
40
1M NaCl
120mM
1% Nonidet P-40
0.1% 1M MgCl
　　　　　　　　　　　　　　　　　　　　　　　　　
4mM [polyr(C)
/oligo d(G)] (5:1)
2 μg/ml 3H-dGTP (81 μM)
0.6
μM Assay procedure: Aliquot 2x concentrated stock reaction mixture
Store at -20°C. The mixture is stable for each assay.
Dissolve for use. This enzyme assay
Compatible with Elle microtiter plate apparatus and conventionally disclosed
(6) Tris buffer (50mM, pH
7.4) Vehicle (diluted to suit compound dilution)
diluted solvent) or the compound in vehicle to 96 wells.
Dispense into microtiter plates (10 μl/u
3 wells/compound). Lyses HIV-1 RT enzyme
dilute the enzyme by diluting it in 50mM Tris pH 7.4.
15 μl is 0.001 unit (1 unit is 25℃
of the enzyme that transforms 1 micromole of substrate per minute at
volume) and add 15 μl to each well.
distribute. 20μl of 0.12-0.5M EDTA
In addition to the first three wells of the microtiter plate
Ru. EDTA chelates the Mg++ present and reverse transcription
prevent. This group has a background weight subtracted from all other groups.
It works as a combination. Add all 25 μl of the above 2x reaction mixture.
wells and incubate the assay for 60 minutes at room temperature.
Ru. The assay consists of diluting the DNA in each well with sodium pyrophosphate.
Trichloroacetic acid (TCA) (10
% w/v) by precipitation with 50 μl of
Ru. Incubate the microtiter plate at 4°C for 15 minutes.
, the sediment was collected using a Skatron semi-automatic harvester.
#30 glass fiber paper (Sehleich
er & Schuell). Then,
Add this filter to a solution containing 1% sodium pyrophosphate.
Wash with additional 5% TCA and 70% aqueous alcohol.
Rinse, dry, and transfer to a scintillation vial (
6). Each vial contains 2ml of scintillation cocktail
is accepted and counted in the Beckman beta counter. The calculation of % suppression is as follows:
Dedication: 1. Benn, S. etc., SCIENCE 230
: 949, 19852. Farmerie,
W. G. et al., SCIENCE 236:305, 19
873. Yanisch-Perron, C. ，
Viera, J. , and Messing, J.
．． GENE 33: 103, 19854. I
international biotechnology
ies, Inc. New Haven (Connecticut) 0
6535 5. Maniatis, T. , Fvitsch
, E, F. , and J. Edited by Sambrook, M.
OLECULAR CLONING: A LABOR
ATORY MANUAL, Cold Spring Harbor
- Laboratory Co., Ltd., 19826. Spira, T.
．． et al., J. Clinical Microbiol
ogy, 25: 97, 1987. Compounds that are active in the RT assay are
confirming that it has the ability to suppress HIV replication even if
For human T-cells described below, each compound of the present invention
It was also tested in a culture assay. Display the results of this test
Shown in 1. Human T cell culture assay Assay theory: Generation of fused cells
+ Has characteristics of in vitro cultures of T cells. This assay
In B., T cells were treated with a putative replication-inhibitory compound.
and then infected with HIV-1. After incubation, thaw the culture.
Check for generation of synaptic cells. Absence of fused cells
or decrease in the number of test compounds inhibiting HIV replication.
used as a measure of the ability to Assay method: target cells, labeled C8
166 is a subclone of human lymphoid cells originating from T cells.
Yes, RPMI1640 (
+10% fetal bovine serum) 5 x 104/10 in medium
Establish an initial density of 0 μl. dissolved in DMSO
Contain a selected amount of test compound. 24 hours later, HIV
-1 HTLV-III B strain 50-100TCID
50 (had an induced effect in 50% of the test cultures)
(2) inoculate each culture. control culture
accepts only compounds or viruses. Virus attack
Five days after challenge, cultures were transformed into virus-induced giant cell fusion cells.
Visually test for frequency and distribution. to test compound
The % inhibition is determined by comparison with control values. virus
Confirmation of the presence or absence of replication is based on samples from all study groups.
This is done by harvesting the cell-free culture, and the second harvest after 3 days.
Next, via induction of fusion cell generation in human T cell cultures
Determine the presence or absence of infected progeny. Literature: (1) M. Somasundaran and H.
．． L. Robinson, Science 24
2, 1554 (1988) (2) G. M. Shaw, R. H. Hahn
, S. K. Arya, J. E. Groupma
n, R. C. Gallo and F. Wong-S
tal, Science 226, 1165 (19
84) To evaluate the specificity of the enzyme inhibitory activity of the compounds of the present invention
a few compounds using assay methods known per se.
Reverse transcriptase derived from feline leukemia virus and bovine thymus
Its ability to inhibit derived DNA alpha polymerase
was tested. The compounds thus tested showed that these
It has been observed that it has some inhibitory activity against enzymes.
There was nothing. These results demonstrate that the compounds of the present invention are
The primary inhibitory activity is rather specific to HIV-1 RT.
It is shown that. Approximate evaluation of cytotoxicity of compounds of the invention
Some such compounds are mentioned below in order to
Tested in MTT cytotoxicity assay. The results of this test are
It is shown in Table 1 below. Compounds with relatively high EC50
is preferred. MTT assay for cytotoxicity Assay theory: MTT [3-(4,5-dimethylthiazo
-2yl]-2,5 diphenyltetrazolium bro
[mide] assay is performed using metabolically active cells.
Generates highly quantitative blue color based on the splitting of lium bromide.
Jiru. This assay has been previously disclosed (1);
Ideal for the purpose of this study. Assay method: H9 cell line
(2), i.e. RPMI1640 with 10% fetal bovine serum
This assay uses an established human lymphocyte suspension cell line grown in
Used as a target cell line. Cells (100μ
l) at 105 cells/m in the presence of various concentrations of inhibitors.
into the microtest plate wells at a concentration of
. Cells were kept in a warm CO2 incubator at 37°C.
Warm up. After 5 days, 20 μl of MTT (sonicated, 0.
RPMI filtered 2 microns and stored at 4°C.
1640 (5 mg/ml) into each well. 37
After an additional 4 hours of incubation at °C, 60 μl of Triton-X was added to each
mix well to promote dissolution of the crystals. Nothing
Hydroalcohol (5 μl) was added to each well and the resulting mixture
The compound was incubated at 60°C for 30 minutes and immediately
Plate reader (Dynatech) at a wavelength of 0 nm.
) I Read. Using the data from this assay, the EC5
0, perform a non-linear regression analysis to give the highest non-toxic concentration. Literature: 1. Mosmann, Tim, J. Immu
nol. Methods, 65:55, 1983 2. Jacobs. J. P. , J. Nat
l. CancerInst. , 34:231, 19
65
Table 1 Compound RT assay
% inhibition T cell assay % inhibition Cytotoxicity assay
B (Example No.) (a) 10 μg/ml
(a) 3 μg/ml (
EC50, μM) 10
100
NT NT 1
1 100
100
200 12
100 100
250 13
36 *
N.T.
NT 15 91
+100
45 16
96 +
100 350
17 40
*NT
NT 18
75*N
TNT 19
85 *
NT NT
20 76 *
N.T.
NT 21
91*NT
NT22
90*
NT NT
23 99
100
NT 24
87N
TNT 25
63 *
NT NT
26 99
N.T.
NT 27
99 N.T.
NT 28
50*
NT NT
29 93
N.T.
NT 30
85 N.T.
NT 31
100
NT NT
32 88
N.T.
NT 33
35*NT
NT 34
94 *
NT NT
35 86 *
N.T.
NT36
2*NT
NT37
34 *
NT NT
38 0
N.T.
NT 39 1
00NT
NT 40
99
NT NT 4
1 100
N.T.
NT 42 8
3*NT
NT43
85 *
NT NT 44
91
N.T.
NT 45 64
*NT
NT46
70*
NT NT 47
34 *
NT N
T 48 0
*NT
NT49
0*N
TNT 50
43 *
NT NT
51 90 *
N.T.
NT52
44 N.T.
NT53
90 *
NT NT
54 35 *
N.T.
NT55
44 N.T.
NT56
100
100NT
57 77
N.T.
NT58
52 *NT
N.T.59
44 *
NT NT
60 20 *
N.T.
NT61
72 *NT
NT62
17 *
NT NT
63 30 #
N.T.
NT64
61 *NT
NT65
68 *
NT NT
66 66 *
N.T.
N.T.67
37 + N.T.
NT68
8 *
NT NT
69 90 *
N.T.
N.T.70
75*NT
NT71
0*
NT NT 7
2 98 *
N.T.
NT 73 9
4*NT
N.T.74
82 *
NT NT 75
100
N.T.
NT 76 88
*NT
NT* = (a) 1 μM + = (a) 1.25 μM # = (a) 0.5 μM NT = Not tested [0086] Examples The following examples further illustrate the present invention.
The present invention will be more fully understood by those skilled in the art.
make it possible. However, the present invention has the following specific features.
It should be understood that the examples are not limited.
Ru. [Example 1] 5,11-dihydro-6H-dipyrid [3
,2-b:2',3'-e][1,4]diazepine-6
-one a) 2-chloro-N-(2-chloro-3-pyridiny
)-3-pyridinecarboxamide efficient reflux condenser, mechanical stirrer and
In a three-necked round-bottomed flask fitted with a dropping funnel, add 40
0ml dioxane, 500ml cyclohexane and
21 and 130 ml of pyridine.
5 g (1.672 mol) of 3-amino-2-chloropyri
I added gin. 299.2 g (1.7 mol) of freshly prepared
of the prepared 2-chloro-3-pyridinecarboxylic acid chloride.
Keep the vigorous reaction under control by keeping the solution in 200 ml dioxane.
I added it at a rate that would hold it. The reaction mixture was then heated to room temperature.
The resulting crystal precipitate was filtered and cyclohexane
and ether. Pour the dark brown product into 5 liters of sodium hydroxide.
It was dissolved in a 3% aqueous solution of aluminum. Pour the resulting solution into activated carbon.
The filtrate was acidified by adding 50% dilute acetic acid.
It became sexualized. Collect the resulting precipitate by filtration and wash thoroughly with water.
did. After drying overnight in a stream of nitrogen at room temperature, almost no
The colored product is produced at m.p. of 156-159°C. p. has
It was pure enough for further reactions. Yield is 37
6.0 (84% of the theoretical value). b) N-(2-chloro-3-pyridinyl)-2-{
[(4-methoxyphenyl)methyl]amino}-3-py
The product obtained in step a) of 13.4 g (0.05 mol) of lysine carboxamide was
Dissolve the resulting solution in 20 ml of xylene in 13.
Mixed with 8 g (0.1 mol) of p-methoxybenzylamide.
It matched. The mixture was then refluxed for 2 hours. reaction mixture
The material was evaporated in vacuo and the residue was dissolved in silica gel (0.2-0.
dichloromethane by column chromatography on
Using ethyl acetate/ethyl acetate 10/1 (v/v) as eluent
and purified. It is concentrated and melts at 122-124℃.
Colored crystals were obtained (after recrystallization from acetonitrile). Collection
The amount was 17.2 g (93% of theory). c) 5,11-dihydro-11-[(
4-methoxyphenyl)methyl]-6H-dipyrido[3
,2-b:2',3'-e][1,4]diazepine-6
The product obtained in step b) of 16.7 g (0.0453 mol) of -one
Dissolve the substance in 150 ml of anhydrous dioxane and dissolve the resulting solution.
The solution was diluted with 6.7 g (0.14 mol) of 50% sodium hydride in mineral oil.
Mixed with thorium dispersion. Then, mix the mixture with low nitrogen
The flow ensures that the starting materials are protected from the external atmosphere.
The mixture was refluxed until it could no longer be detected by TLC. Hydrogenation
Dissolve the excess sodium with 10 ml of methanol and tetrahedron.
Carefully add a mixture of dolofuran (50/50 v/v).
It was decomposed by adding Addition of acetic acid to the reaction mixture
and then evaporated in vacuo. Silicage the residue
Column chromatography on a column (0.2-0.5 mm)
dichloromethane/ethyl acetate (10/1, v/v
) and dichloromethane/ethyl acetate 1/1 (v/v)
was purified using continuously as eluent. suitable flak
The crystalline product obtained by evaporation of the solution was dissolved in acetonitrile and
and 2-propanol. The product is 21
m. of 3-215°C. p. and 5,11-dihydro-
11-[(4-methoxyphenyl)methyl]-6H-di
Pyrido[3,2-b:2',3'-e][1,4]dia
It was identified as zepin-6-one. Yield is 10.3g
(68% of the theoretical value). d) 5,11-dihydro-6H-dipyrido[3,2
-b:2',3'-e][1,4]diazepine-6-o
10.0 g (0.3 mol) of the product obtained in step c)
Dissolve in 50 ml of trifluoroacetic acid and mix.
The mixture became somewhat warm. Then, the reaction mixture was heated to 60°C.
The mixture was stirred for 1 hour. The starting material was then analyzed by TLC.
could not be detected. The mixture was then evaporated in vacuo
Ta. The residue thus obtained was mixed with 0.5% ammonia water.
The mixture was stirred for several minutes and then filtered with suction. 150ml of crude product
recrystallized from dimethyl sulfoxide at >340°C.
m. p. Colorless crystals were obtained. The yield was 4.8g.
(75% of theoretical value). This product is 5,11-dihydrogen
Dro-6H-dipyrid [3,2-b:2',3'-e]
It was identified as [1,4]diazepin-6-one. [Example 2] 5,11-dihydro-11-
Propyl-6H-dipyrid [3,2-b:2',3'-
e][1,4]diazepin-6-one a) N-(2-chloro-3-pyridinyl)-2-(
propylamino)-3-pyridinecarboxamide 2-
Chloro-N-(2-chloro-3-pyridinyl)-3-py
26.8 g (0.1 mol) of lysine carboxamide was
Dissolve in 200 ml of oxane and add the resulting solution to propyl
Mixed with 21.4 g (0.362 mol) of amine. the
Afterwards, the mixture was heated in a stainless steel pressure vessel at 150°C for 6 hours.
Shake for a while. The reaction mixture was then evaporated under reduced pressure,
Dichloromethane/ethyl acetate 10/1 (v
/v) and dichloromethane/cyclohexane/ethyl acetate
1/2/1 (v/v/v) in succession to remove the residue.
Purified by chromatography on silica gel. evaporation
The product obtained is of sufficient quality for the following reaction.
It was a highly viscous resin. b) 5,11-dihydro-11-propyl-6H-
Dipyrid [3,2-b:2',3'-e][1,4]di
Azepin-6-one Using a procedure similar to that described in Example 1c),
The product obtained in step a) above and sodium hydride
to 5,11-dihydro-11-propyl-6H-dipy
Lido[3,2-b:2',3'-e][1,4]diaze
Pin-6-one, melting point 184-186°C (acetonitrile
) was prepared by recrystallizing with The yield is 74% of the theoretical value.
there were. [Example 3] 5,11-dihydro-5-methane
Tyl-11-propyl-6H-dipyrido [3,2-b:
2',3'-e][1,4]-diazepine-6-one a
) 2-chloro-N-(2-chloro-3-pyridinyl
)-N-methyl-3-pyridinecarboxamide mechanical stirring
Equipped with stirrer, dropping funnel, thermometer and active reflux condenser
In a four-necked round bottom flask, add 2-chloro-N-(2-chloro-N-
rho-3-pyridinyl)-3-pyridinecarboxamide
268.1 g (1.0 mol), 50% aqueous sodium hydroxide
260ml of aluminum, 1500ml of toluene and benzyl
Triethylammonium chloride 8.0g (0.035
2 mol) was added. Start stirring and add 1 liter of toluene.
134 ml of dimethyl sulfate (178.5 g, 1.4
15 mol) solution dropwise over a period of approximately 3 hours.
was added, which caused the temperature to rise to 50-60°C. Ji
After the addition of methyl sulfate is complete, continue stirring at 60°C.
It lasted two hours. Cool the reaction mixture to room temperature and add 1 liter of water.
was added. Separate the layers and add 300ml of toluene to the aqueous layer.
Extracted three times with Combine the organic layers and add 300 ml of water, 1
% aqueous acetic acid solution and 300 ml of water successively. The combined organic extracts were dried over sodium sulfate and the solvent was removed.
It was removed by distillation under reduced pressure. Toluene and eluent
Ethyl acetate/cyclohexane/tetrahydrofuran 1
/9/10 (v/v/v) continuously to remove the residue.
Column chromatography using silica gel (0.2-0.5 mm)
Purified by roughy. obtained by evaporation of appropriate fractions.
The obtained product was dissolved in acetonitrile/tert-butylmethyl
Recrystallized with ether 1/1 (v/v). That's Giklo
It is highly soluble in lomethane, with a melting point of 98-101°C.
and 2-chloro-N-(2-chloro-3-pyridinyl
)-N-methyl-3-pyridinecarboxamide
was identified. Yield: 232.5g (theoretical value: 82.5g)
%)Met. b) N-(2-chloro-3-pyridiny)
)-N-methyl-2-(propylamino)-3-pyri
Dine Carboxamide Using a procedure similar to that described in Example 2a,
N-2 from the product obtained in step and propylamine
-Chloro-3-pyridinyl)-N-methyl-2-(pro-
Preparation of (pyramino)-3-piperidinecarboxamide
did. The yield was 91% of theory. c) 5,11-dihydro-5-methyl-11-pro
Pyr-6H-dipyrid [3,2-b:2',3'-e]
[1,4]Diazepin-6-one dioxane as solvent
Tetrahydrofuran is used instead of the equimolar amount of hydrogen.
As described in Example 1c, except that only sodium chloride is applied.
Using a procedure similar to that described above, a very viscous oil
5,11-dihydro-5-methyl-11-propyl-
6H-dipyrid [3,2-b:2',3'-e] [1,
4] Add diazepin-6-one to the raw material obtained in the above step.
Prepared from a compound. The yield was 75% of theory. [Example 4] 5,11-diethyl-5,1
1-dihydro-6H-dipyrido [3,2-b:2',3
'-e] [1,4]-diazepin-6-one 5,11-
Dihydro-6H-dipyrid [3,2-b:2',3'-
e] [1,4] diazepin-6-one 6.4 g (0.0
3 mol) in 100 ml of anhydrous dimethylformamide
and the resulting solution was diluted with 50% sodium hydride in mineral oil.
It was mixed with 3.4 g (0.071 mol) of the dispersion. nitrogen flow
The mixture is protected against the external atmosphere by
was stirred at 50-70°C for 1 hour. Hydrogen generation stops
After that, the mixture was cooled to 30°C and 10.9 g of ethyl iodide was added.
(0.07 mol) was added dropwise within 15 minutes. Departure
The mixture was heated at 80-90°C for an additional hour to complete the thermal reaction.
It was heated for a while. The solvent was removed by distillation under reduced pressure. residue
was mixed with water and the suspension thus obtained was dissolved in dichloromethane.
Thoroughly extracted with Product obtained after normal processing
was recrystallized from 150 ml of isooctane. The product has a melting point
102-103°C, 5,11-diethyl-5,1
1-dihydro-6H-dipyrido [3,2-b:2',3
'-e][1,4]Identified as diazepin-6-one
It was. Yield was 5.7 g (71% of theory). [Example 5] 5,11-dihydro-5-e
Chil-6H-dipyrid [3,2-b:2',3'-e]
[1,4]Diazepin-6-one a) N-(2-chloro-3-pyridinyl)-2-[
(phenylmethyl)amino]-3-pyridinecarboxy
Diethylene glycol replaces xylene as amide solvent
As described in Example 1b, except that dimethyl ether is used.
Using a procedure similar to that described, 2-chloro-N-
(2-chloro-3-pyridinyl)-3-pyridinecarbo
N-(2-chloro-
3-pyridinyl)-2-[(phenylmethyl)amino]
-3-pyridinecarboxamide, melting point 95-97°C (
(recrystallized from diethylene glycol dimethyl ether)
was prepared. The yield was 72% of theory. b) 5,11-dihydro-11-(phenylmethyl
)-6H-dipyrid [3,2-b:2',3'-e] [
1,4] Diazepin-6-one in dioxane as a solvent
Use diethylene glycol dimethyl ether instead.
Similar operations to those described in Example 1c were performed, except that
using the product obtained in step a) and sodium hydride
5,11-dihydro-11-(phenylmethyl) from
-6H-dipyrid [3,2-b:2',3'-e][1
, 4] diazepin-6-one, melting point 212-213°C (
(recrystallized from 1-propanol) was prepared. Yield is reasonable
It was 61% of the theoretical value. c) 5,11-dihydro-5-ethyl
-11-(phenylmethyl)-6H-dipyrido[3,2
-b:2',3'-e][1,4]diazepine-6-o
Using a procedure similar to that described in Example 3a,
5,1 from the product obtained in step b) and diethyl sulfate
1-dihydro-5-ethyl-11-(phenylmethyl)
-6H-dipyrid [3,2-b:2',3'-e] [1
, 4] diazepin-6-one, melting point 209-211°C (
(Recrystallized with toluene/acetonitrile 1/1 v/v)
was prepared. The yield was 82% of theory. d) 5,11-dihydro-5-ethyl-6H-dipy
Lido[3,2-b:2',3'-e][1,4]diaze
Using a pressurized container instead of a pin-6-on open container, the mixture was heated to 120°C.
Procedure as described in Example 1d, except heating for 10 hours.
From the product obtained in step c) using a similar procedure as
5,11-dihydro-5-ethyl-6H-dipyrido [3
,2-b:2',3'-e][1,4]diazepine-6
-one, melting point 161-163°C (isooctane/acetic acid ethyl alcohol)
(recrystallized in chill 1/1 v/v) was prepared. Yield is reasonable
It was 57% of the theoretical value. [Example 6] 5,11-dihydro-5-methane
Chil-6H-dipyrid [3,2-b:2',3'-e]
[1,4]Diazepin-6-one a) N-(2-chloro-3-pyridinyl)-N-methane
Thyl-2-[(phenylmethyl)amino]-3-pyridi
using a procedure similar to that described in Example 1b.
-chloro-N-(2-chloro-3-pyridinyl)-N-
Methyl-3-pyridinecarboxamide and benzylua
min to N-(2-chloro-3-pyridinyl)-N-methane
Thyl-2-[(phenylmethyl)amino]-3-pyridi
carboxamide, melting point 114-116°C (tert
-Butyl methyl ether/dichloromethane/ethyl acetate
3/1 v/v recrystallized) was prepared. Yield is theoretical value
It was 87% of the total. b) 5,11-dihydro-5-methyl-11-(F)
phenylmethyl)-6H-dipyrido[3,2-b:2',
3′-e][1,4]Diazepin-6-one Example 3b
obtained in step (a) using a procedure similar to that described in
5,11-dihydro-5-methyl-1
1-(phenylmethyl)-6H-dipyrido[3,2-b
:2',3'-e] [1,4] diazepin-6-one,
Melting point: 198-199°C (recrystallized from acetonitrile)
was prepared. The yield was 80% of theory. c) 5,11-dihydro-5-methyl
-6H-dipyrid [3,2-b:2',3'-e][1
, 4] diazepin-6-one 75.5 g (0.239 mol) of the product obtained in step b)
), polyphosphoric acid 2.5 kg, and anisole 425 ml
The mixture was stirred at 140-160°C for 2 hours. While still hot, the reaction mixture was stirred in crushed ice. The mixture is then slightly alkalized by the addition of aqueous ammonia.
and then thoroughly extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure.
I set it. Dichloromethane/ethyl acetate 1/1 as eluent
Chromatograph the residue on silica gel using (v/v)
I put it on the phone. Products obtained by evaporation of suitable fractions
was recrystallized from acetonitrile to give a melting point of 236-237°C.
Obtained 21.6 g (40% of theory) of colorless crystals with
. [Example 7] 5,11-dihydro-6H-
Dipyrid [3,2-b:2',3'-e][1,4]di
Azepin-6-one 3.8 g (0.0126 mole) of the product obtained in Example 5b.
) was dissolved in 20 ml of trifluoroacetic acid and mixed.
The mixture became slightly warm. Then, the reaction mixture was
Refluxed for an hour. At that point the starting material was detected by TLC.
I couldn't get it out. The mixture was then evaporated under reduced pressure and
Fill the resulting residue with 0.5% ammonia water.
The mixture was stirred for several minutes and then filtered with suction. Acetate the crude material
Suspended in 20 ml of nitrile, refluxed for 15 minutes, hot
I suction filtered it. Heat the filter cake in dimethyls
Recrystallized with sulfoxide to produce 1.2 g of colorless crystals (theoretical value).
45%), which has a melting point of >340°C, with a melting point of
Mixed melting points and UV spectra, IR spectra and M
Identical to the compound obtained in Example 1d by S spectrum
It was identified that [Example 8] 5,11-dihydro-11-
Ethyl-5-methyl-6H-dipyrido [3,2-b:2
',3'-e] [1,4] diazepin-6-one a)
2-chloro-N-(2-chloro-3-pyridinyl)-
3-Pyridinecarboxamide Using a procedure similar to that described in Example 1a, 2
-chloro-N-(2-chloro-3-pyridinyl)-3-
Pyridine carboxamide was prepared. Bring the reaction mixture to the chamber
By cooling to room temperature and allowing the supernatant to settle, decant it.
A purified product was obtained. Then dissolve the solid in methylene chloride
Wash the solution with water, dry (anhydrous sodium sulfate), and remove the solution.
The medium was removed under reduced pressure. Then wash the solid with ethyl acetate
7.24 Products suitable for drying and use in subsequent reactions
g (84% of theory). b) N-(2-chloro-3-pyridinyl)-2-[
[(4-methoxyphenyl)methyl]amino]-3-py
Lysine Carboxamide Using a procedure similar to that described in Example 1b, N
-(2-chloro-3-pyridinyl)-2-[[(4-methyl
Toxyphenyl)methyl]amino]-3-pyridinecal
Boxamide was prepared. Remove the solvent under reduced pressure, leaving water behind.
The product was extracted by adding it to the residue and extracting the product with methylene chloride.
A purified product was obtained. Dry this solution (anhydrous sodium sulfate)
After removal of the solvent, a brown oil was obtained which was dissolved in ether.
It was treated with 10 ml. The crystallized product is filtered and
It is washed successively with diluent and hexane to give an off-white powder (melting point
78.0 g of the title compound (121-122°C)
91% of the theoretical value) was obtained. c) 5,11-dihydro-11-[(
4-methoxyphenyl)methyl]-6H-dipyrido[3
,2-b:2',3'-e][1,4]diazepine-6
- 50% dispersion of sodium hydride in mineral oil 1.
44 g of N-(2
-chloro-3-pyridinyl)-2-[[(4-methoxy
phenyl)methyl]amino]-3-pyridine-carboxy
Added to a solution of 3.69 g (0.010 mol) of cyamide
Ta. After hydrogen evolution stopped, the mixture was heated for 16 hours (
110° C.) and then refluxed for 8 hours. the mixture is cold
After cooling, excess sodium hydride is added gradually to ice.
More decomposed. The mixture was further diluted with water and the product
It was extracted with tel and concentrated. Filter the crystallized residue and remove the ash
5,11- as a white powder (melting point 209-210°C)
Dihydro-11-[(4-methoxyphenyl)methyl]
-6H-dipyrid [3,2-b:2',3'-e] [1
, 4] diazepin-6-one 1.60 g (theoretical value 50
%) was obtained. d) 5,11-dihydro-11-[(4-methoxy
phenyl)methyl]-5-methyl-6H-dipyrido[3
,2-b:2',3'-e][1,4]diazepine-6
-one 5,11-dihydro-11-[(4-meth
xyphenyl)methyl]-6H-dipyrido[3,2-b
:2',3'-e] [1,4] diazepin-6-one 1
0.0 g (0.030 mol) of sodium hydride in mineral oil
2.16 g of a 50% dispersion of
The mixture was added to a flask containing 100 ml of the solution. The resulting mixture
The mixture was stirred at room temperature for 30 minutes, then at 50°C for 30 minutes.
Heated. After cooling, in 10 ml of dimethylformamide
8.51 g (0.060 mol) of methyl iodide was added dropwise.
and the mixture was stirred at room temperature overnight. excess sodium hydride
Lium was decomposed by careful addition of ice. Then water
The product was extracted with ether and dried (anhydrous sulfuric acid).
sodium), concentrated and suitable for use in the next reaction.
5,11-dihydro-11-[(meth)
toxyphenyl)methyl]-5-methyl-6H-dipyry
Do-[3,2-b:2',3'-e][1,4]diaze
10.3 g (99% of theory) of pin-6-one were obtained. e] 5,11-dihydro-5-methyl
-6H-dipyrid [3,2-b:2',3'-e][1
, 4] diazepine-6-one trifluoroacetic acid (50 ml) to 5,11-dihydro-11
-[(4-methoxyphenyl)methyl]-5-methyl-
6H-dipyrid [3,2-b:2',3'-e] [1,
4]-Diazepin-6-one 10.3 g (0.030 mole)
and the mixture was stirred at room temperature for 1 hour. the acid
was removed under reduced pressure and the residue was dissolved with 0.5% ammonia at 1
Stir for hours. Filter and dry the solid to obtain pure 5,11-di
Hydro-5-methyl-6H-dipyrido [3,2-b:2
',3'-e] [1,4] diazepin-6-one (melting point
230-232℃) 6.70g (98% of theory) was obtained.
Ta. f) 5,11-dihydro-11-ethyl-5-methy
Ru-6H-dipyrid [3,2-b:2',3'-e] [
1,4] Diazepin-6-one Sodium hydride in mineral oil
2.00 g of a 50% dispersion of
5,11-dihydro-5-methyl-6H- in 00ml
Dipyrid [3,2-b:2',3'-e][1,4]di
Dissolution of 5.75 g (0.025 mol) of azepin-6-one
added to the liquid. When hydrogen evolution stopped, the mixture was heated to 50
℃ for 30 minutes, then cooled to room temperature. after that,
7.80 g of ethyl iodide (neat) over 15 minutes
was added dropwise and the resulting mixture was stirred at room temperature overnight.
. Careful addition of excess sodium hydride to ice, then
Decomposed by addition of water. Extract the product with ether
, dried (anhydrous sodium sulfate) and evaporated to give 5,11-
Dihydro-11-ethyl-5-methyl-6H-dipyride
[3,2-b:2',3'-e][1,4]Diazepine
-6-one (melting point 130-132°) 4.5g (theoretical value
70%). [Example 9] 5,11-dihydro-11-
Ethyl-5-methyl-6H-dipyrido [3,2-b:2
',3'-e] [1,4] diazepine-6-thiontole
5,11-dihydro-11-ethyl- in 50 ml of
5-Methyl-6H-dipyrido [3,2-b:2',3'
-e] [1,4] diazepin-6-one and Lauesse
reagent (2,4-bis(4-methoxyphenyl)-1,
3-dithia-2,4-diphosphetane-2,4-disul
A mixture of 2.10 g (0.005 mol) of
The mixture was refluxed for /2 hours. The solvent was then removed under reduced pressure,
Water was added to the residue. The product was extracted with ethyl acetate and dried.
Dry (anhydrous sodium sulfate) and concentrate under reduced pressure. First melt
Methylene chloride was used as a release agent followed by ethyl acetate/
Purification was performed on silica gel using hexane (1:4).
It was. The solvent was removed under reduced pressure to give 5,11-dihydro-11
-ethyl-5-methyl-6H-dipyrido [3,2-b:
2',3'-e] [1,4] diazepine-6-thione 2
．． 20 g (74% of theory) were obtained as a yellow powder;
This was recrystallized from 10% hexane/ethyl acetate to give a yellow color.
Title compound 1 as needle-like crystals (melting point 157-158°C)
．． 1g was obtained. [Example 10] 5,11-dihydro-11
-ethyl-2-methyl-4-trifluoromethyl-6H
-dipyrid [3,2-b:2',3'-e] [1,4]
Diazepin-6-one a) 3-cyano-2-hydroxy-6-methyl-4
- (trifluoromethyl)pyridine 14.0 g of cyanoacetamide in 80 ml of ethanol
Warm the solution to 50°C, then add 14g of piperidine and
25 g of refluoroacetylacetone was added. obtained
The mixture was stirred at 70°C for 30 minutes and then at room temperature overnight.
Stirred. The mixture was concentrated under reduced pressure and then poured with 100 m
diluted with l. Be careful while stirring concentrated hydrochloric acid (15 ml).
After 15 minutes, the precipitate was filtered and dried under reduced pressure overnight.
27.8 g of the desired cyanopyridine was obtained. b) 3-aminocarbonyl-2-chloro-6-methy
Ru-4-(trifluoromethyl)pyricineoxychloride
35 ml of cyanopyridine and 9.8 g of cyanopyridine obtained above.
The mixture was refluxed for 5 hours. Pour the cooled mixture into ice water for 40 minutes.
The reaction was stopped by carefully adding 0 ml of
. The product was extracted with methylene chloride and saturated sodium bicarbonate.
and dried (magnesium sulfate). filter,
After concentration under reduced pressure, the crude chloro compound was dissolved in 50 ml of concentrated sulfuric acid.
It was dissolved and heated to 140°C for 20 minutes. cooled mixture
Carefully pour over 600ml of ice, filter the precipitate, and add to ice water.
After washing with water and drying, 7.6 g of the desired amide was obtained. filtrate
was extracted with 200 ml of ethyl acetate and dried (magnesium sulfate).
um), filtered and concentrated to give an additional 1.7 g of product.
. c) 3-amino-2-chloro-6-methane
Chyl-4-(trifluoromethyl)pyricine 5°C water 6
A solution of 6.6 g of sodium hydroxide in 0 ml contains 9.9 g of bromine.
3g was added. When a clear solution is obtained, 3-aminocal
Bonyl-2-chloro-6-methyl-4-(trifluoro
9.2 g of pyridine (methyl)pyridine was quickly added and the temperature was lowered to 5°C.
I kept it lower. 3-(aminocarbonyl)pyridine
The resulting mixture was stirred until dissolved (approximately 30 minutes).
. Remove the cooling bath and then heat the mixture to 75°C for 30 min.
Warmed. After cooling to room temperature, the 2-aminopyridine product
was extracted with ethyl acetate, dried (magnesium sulfate),
Filtration and evaporation gave 4.9 g of the desired product. d) 2-chloro-N-(2-chloro-6-methyl-
4-trifluoromethyl-3-pyridinyl)-3-pyri
Dinecarboxamide 3-amino-2-chloro-6-methylene in 10 ml THF
2.1 g of cold Ru-4-(trifluoromethyl)pyridine
Add lithium diisopropyl amine to the cooled (-78°C) solution.
(LDA, 1.5M in cyclohexane) for 3 minutes.
It was added dropwise in between. The mixture was stirred for 5 minutes and then diluted with THF.
0.9g of 2-chloronicotinoyl chloride in 3ml
Added in 1 minute. After 5 minutes, add another 3 ml of LDA solution.
Then add another 0.5 g of acid chloride in 1 ml of THF.
Added. The resulting mixture was stirred for 10 minutes, then water
The reaction was stopped at 100 ml. 30ml of ethyl acetate
After separation, the organic phase was extracted with water and the combined aqueous phase was washed with chloride solution.
Extracted with tyrene, dried (magnesium sulfate) and filtered.
Evaporation gave the crude product. Add this with a small amount of ethyl acetate
After washing and drying, 1.3 g of the title compound was obtained. e] N-(2-chloro-6-methyl-
4-trifluoromethyl-3-pyridinyl)-2-ethyl
Ruamino-3-pyridinecarboxamidoethylamine
(0.4 g) in 5 ml of xylene (2-chloro-N-(
2-chloro-6-methyl-4-trifluoromethyl-3
-pyridinyl)-3-pyridinecarboxamide 1.3
g of suspension and the resulting mixture was heated in a pressure tube to 16 g of suspension.
Heated at 0°C for 30 minutes. Cooled mixture in ethyl acetate
diluted with water, washed, dried, and concentrated. With silica gel
Lamb chromatography (ethyl acetate/hexane, 1:
1) to obtain 0.5 g of the title compound. f) 5,11-dihydro-11-ethyl-2-methy
-4-trifluoromethyl-6H-dipyrid [3,2
-b:2',3'-e][1,4]diazepine-6-o
N-(2-chloro-6-methyl-
4-trifluoromethyl-3-pyridinyl)-2-ethyl
Dissolve 0.5g of Ruamino-3-pyridinecarboxamide
0.2 g of a 50% dispersion of sodium hydride in oil
added to. The mixture was heated to 150°C and then cooled.
Concentrate under reduced pressure. Add water to the residue and convert the product into ethyl acetate.
Extract with, dry (magnesium sulfate), filter, and concentrate
did. The product was subjected to column chromatography on silica gel (chloride
Purified with methylene, then methylene chloride/methanol).
Manufactured. After concentration under reduced pressure, the residue was crystallized from hexane.
0.09 g of the title compound (melting point 150-151°C) was obtained.
Ta. [Example 11] 5,11-dihydro-11
-ethyl-4-methyl-6H-dipyrido [3,2-b:
2',3'-e] [1,4] diazepin-6-one a)
2-chloro-4-methyl-3-nitropyridine 2-
25 g of hydroxy-4-methyl-3-nitropyridine,
12.5 g of phosphorus pentachloride and 62 ml of phosphorus oxychloride
The mixture was refluxed for 2 hours. After cooling, mix the mixture with crushed ice
and stirred until a precipitate formed. Chloride the product
Extract with methylene, dry (sodium sulfate) and concentrate.
This resulted in a brown oil which was washed with hot hexane. Concentrate under reduced pressure
Condensation yielded 16.2 g of the title compound (melting point 45-47°C).
Ta. b) 3-amino-2-chloro-4-methylpyridine
2-chloro-4-methyl-3-nitropyridine 16.2
g to 470 ml of acetic acid and the resulting mixture was heated at room temperature.
Stir for 15 minutes. Then chloride in 200 ml of concentrated hydrochloric acid
A solution of 160 g of stannic dihydrate was added at once to obtain
The mixture was stirred at room temperature overnight. Then this mixture
When diluted with water to 1 liter, a white precipitate of tin hydrochloride was obtained.
Gradually add 10N sodium hydroxide until dissolved.
Ta. The product was extracted with methylene chloride and dried (sodium sulfate).
) and concentrated to obtain 12.8 g of yellow oil, which was
Almost pure 3-amino-2- suitable for use in the reaction
It is a chloro-4-methylpyridine oil that solidifies if left unattended.
did. c) 2-chloro-N-(2-chloro-4-methyl-
3-pyridinyl)-3-pyridinecarboxamide implementation
Using a procedure similar to that described in Example 1a, 3-A
12.8 g of mino-2-chloro-4-methylpyridine, 2
-15.8 g of chloronicotinoyl chloride, 7 g of pyridine
．． 1g, cyclohexane 30ml and dioxane 60ml
The carboxamide was prepared from l. After removal of solvent
, dissolve the product in methylene chloride, wash with water and dry (sulfuric acid solution)
thorium). After removing the solvent, the residue was washed with ethyl acetate.
1.2 g of the title compound (melting point 193-194°C)
Obtained. d) N-(2-chloro-4-methyl-
3-pyridinyl)-2-ethylamino-3-pyridinka
Ruboxiamidoethylamine (12.7 g) was added to xylene 1 in a steel container.
2-chloro-N-(2-chloro-4-methylene) in 50 ml
-3-pyridinyl)-3-pyridinecarboxamide
Added to 21.0 g of suspension. Then oil bath the mixture
heated to 165°C for 6 hours in a vacuum chamber, then stirred at room temperature overnight.
Ta. The solvent was removed under reduced pressure and water was added to the residue. product
was extracted with ether, dried (sodium sulfate) and concentrated.
and obtained oil. This was dissolved in ethyl acetate and then hexane.
was added, at which time a precipitate formed. Filter and dry solids
and 16.5 g of the title compound (melting point 122-124°C)
Obtained. e] 5,11-dihydro-11-ethyl-4-methy
Ru-6H-dipyrid [3,2-b:2',3'-e] [
1,4] A 50% suspension of diazepin-6-one sodium hydride (7.9 g) was
N-(2) obtained above in 200 ml of chillformamide
-chloro-4-methyl-3-pyridinyl)-2-ethyl
Dissolution of 16.0 g of amino-3-pyridinecarboxamide
It was added to the liquid and stirred for 30 minutes. Then leave the mixture for 2 hours
Reflux, cool and carefully treat with crushed ice. solvent
It was removed under reduced pressure and water was added to the residue. product in ether
Extracted, dried (sodium sulfate) and concentrated. Vinegar the residue
Boil with ethyl acid/cyclohexane (1:1) and filter.
4.1 g of almost pure product were obtained. This product 2.
0g was recrystallized from dichloroethane and further purified to obtain pure 5.
,11-dihydro-11-ethyl-4-methyl-6H-
Dipyrid [3,2-b:2',3'-e][1,4]di
Azepin-6-one (melting point 212-214℃) 1.0g
I got it. [Example 12] 11-cyclopropyl-5
, 11-dihydro-4-methyl-6H-dipyrid [3,
2-b:2',3'-e][1,4]diazepine-6-
Use cyclopropylamine instead of onethylamine
Otherwise, the same operations as those described in Example 11 were used.
to produce the title compound (melting point 247-249°C).
. [Example 13] 11-cyclopropyl-5
,11-dihydro-5-hydroxy-4-methyl-6H
-dipyrid [3,2-b:2',3'-e] [1,4]
Diazepine-6-one 11-cyclopropyl in 25 ml of tetrahydrofuran
-5,11-dihydro-4-methyl-6H-dipyrid [
3,2-b:2',3'-e][1,4]Diazepine-
6-one (Example 12) A mixture of 0.5 g of 5-one (Example 12) in mineral oil
0.12 g of 0% sodium hydride was added. reaction mixture
The mixture was stirred at room temperature for 1 h, then cooled to 0 °C and
Oxodiperoxymolybdenum (pyridine)
0.9g of hexamethylphosphoramide (MoOPH)
Added at the same time. The reaction mixture was then allowed to warm to room temperature overnight.
Stirred. The mixture was quenched with water and the solvent was removed under reduced pressure. Residue
The residue was extracted with warm ethyl acetate, concentrated under reduced pressure and transferred to silica gel.
Pure 11 was purified by column (eluent: ethyl acetate).
-cyclopropyl-5,11-dihydro-5-hydroxy
C-4-methyl-6H-dipyrid [3,2-b:2',
3'-e][1,4]diazepin-6-one (melting point 23
9-241°C) 0.05g was obtained. The yield is 9.9% of the theoretical value.
It was 5%. [Example 14] 5,11-dihydro-11
-ethyl-2-methoxy-5-methyl-6H-dipyrido
[3,2-b:2',3'-e][1,4]Diazepine
-6-one a) 3-amino-2-bromo-6-methoxypyridi
Sodium acetate (1.6g) in acetic acid (15ml)
Solution of 5-amino-2-methoxypyridine (2.5g)
added to. Bromine (3.0g) was added dropwise to the resulting solution.
was added and the mixture was stirred for 20 minutes, then water (10
Added to a solution of sodium hydroxide (10 g) in 0 ml)
did. The product was extracted with ethyl acetate (50 ml) and dried.
(anhydrous magnesium sulfate) and concentrated under reduced pressure. product
Silica gel column (ethyl acetate/hexane, 1:4)
The title compound is suitable for purification and use in the following reactions.
2.7g was obtained. b) N-(2-bromo-6-methoxy-3-pyridi
Nyl)-2-chloro-3-pyridinecarboxamide salt
3 in methylene chloride (20 ml) and pyridine (1 ml)
-amino-2-bromo-6-methoxypyridine (2.7
2-chloronicotinoyl chloride (2.2
g) was added and the resulting mixture was stirred for 20 minutes. So
After that, dilute the mixture with methylene chloride (100ml),
Wash with water (100 ml) and dry (anhydrous magnesium sulfate).
) and concentrated. Saturate the semi-solid residue with hexane,
Product suitable for filtering and drying to use in next reaction
4.1 g was obtained. c) N-(2-bromo-6-methoxy
-3-pyridinyl)-2-chloro-N-methyl-3-pyridinyl
Sodium lysine carboxamide hydride (0.3 g of 50% dispersion in mineral oil)
was added to dimethyl sulfoxide (10 ml) and heated to 50°C.
Warmed. After cooling the mixture to room temperature, N-(2-bromo
-6-methoxy-3-pyridinyl)-2-chloro-3-
Pyridinecarboxamide (2.0g) was added to obtain
The solution was stirred for 10 minutes. Then, methyl iodide (0
．． 4 ml) was added and the mixture was stirred for 30 minutes. reaction mixture
The reaction was stopped by adding water (10 ml) and the mixture was
Ethyl acetate (100ml) was then added. The organic phase was dissolved in water (
4 x 100 ml) and dried (anhydrous magnesium sulfate).
), concentrate, and apply a silica gel column (methylene chloride followed by
and purified with methylene/ethanol (98:2), followed by
1.9 g of the title compound suitable for use in the reaction was obtained. d) N-(2-bromo-6-methoxy-3-pyridi
Nyl)-2-ethylamino-N-methyl-3-pyridine
Carboxamidoethylamine (0.7g) in xylene (5ml) with N
-(2-bromo-6-methoxy-3-pyridinyl)-2
-Chloro-N-methyl-3-pyridinecarboxamide
(1.9 g) and pressurize the resulting mixture.
The mixture was sealed in a container and heated at 150°C for 4 hours. acetic acid solution
Diluted with ethyl, washed with water, dried (anhydrous magnesium sulfate)
), concentrate, and apply to a silica gel column (ethyl acetate/hexane).
suitable for use in the next reaction.
1.5 g of the title compound was obtained. e] 5,11-dihydro-11-ethyl
-2-methoxy-5-methyl-6H-dipyrid [3,
2-b:2',3'-e][1,4]diazepine-6-
Sodium hydride (0.9 g of 50% dispersion in mineral oil)
was dissolved in N-(2-bromo-6-methane) in xylene (20 ml).
Toxy-3-pyridinyl)-2-ethylamino-N-methane
Dissolution of thyl-3-pyridinecarboxamide (1.4g)
and the mixture was refluxed for 2 hours. After cooling, the mixture
quenched with methanol, diluted with ethyl acetate, and diluted with water.
Washed. The organic phase was dried (anhydrous magnesium sulfate) and concentrated.
and silica gel column (ethyl acetate/hexane, 1:
4) to obtain a fairly pure product, which is then purified by
Recrystallize twice from ethyl acetate/hexane to obtain pure 5,11
-dihydro-11-ethyl-2-methoxy-5-methyl
-6H-dipyrid [3,2-b:2',3'-e][1
, 4] diazepin-6-one (melting point 116-118°C)
0.52g was obtained. [Example 15] 5,11-dihydro-11
-ethyl-5-methyl-2-(N-pyrrolidino)-6H
-dipyrid [3,2-b:2',3'-e] [1,4]
Diazepin-6-one a) 5,11-dihydro-11-ethyl-2-hydro
Roxy-5-methyl-6H-dipyrido[3,2-b:2
',3'-e] [1,4] diazepine-6-one bromide water
acid (48%, 2 ml) in acetic acid (2 ml)
-dihydro-11-ethyl-2-methoxy-5-methyl
-6H-dipyrid [3,2-b:2',3'-e][1
, 4] added to a solution of diazepin-6-one (0.3 g)
and the resulting mixture was rapidly heated to reflux for 5 minutes.
. The reaction mixture was diluted with 10% sodium hydroxide (10ml).
The reaction was stopped and the product was extracted with ethyl acetate and dried (free).
(magnesium sulfate) and concentrated to obtain a solid, which was mixed with acetic acid.
Recrystallize from ethyl to obtain the product (melting point 215-218°C) 0
．． 08g was obtained. b) 5,11-dihydro-11-ethyl-5-methy
-2-trifluoromethanesulfonyloxy-6H-
Dipyrid [3,2-b:2',3'-e][1,4]di
Azepin-6-one 5,11-dihydre in methylene chloride (4 ml) under nitrogen
rho-11-ethyl-2-hydroxy-5-methyl-6H
-dipyrid [3,2-b:2',3'-e] [1,4]
diisopropylene in a solution of diazepin-6-one (0.2 g)
Pyrethylamine (0.2ml) followed by trifluoromethane
Tansulfonic anhydride (0.2ml) was added. Obtained
The mixture was stirred for 1 hour and then diluted with methylene chloride (20
ml) and washed with water. Dry the organic phase (anhydrous sulfuric acid)
gnesium), concentrated, and silica gel column (ethyl acetate).
1:3) to use in the next reaction.
A fairly pure product was obtained which was suitable for use in dialysis. c) 5,11-dihydro-11-ethyl
-5-methyl-2-(N-pyrrolidino)-6H-dipy
Lido[3,2-b:2',3'-e][1,4]diaze
Pin-6-one 5,11-dihydro-11-ethyl-5-methyl-2-
Trifluoromethanesulfonyloxy-6H-dipyrido
[3,2-b:2',3'-e][1,4]Diazepine
-6-one (0.25g) was dissolved in pyrrolidine (1ml).
The mixture was dissolved and refluxed for 30 minutes. The colored solution was diluted with ethyl acetate.
Dilute, wash with water, and dry the organic phase (anhydrous magnesium sulfate
) and concentrated. The resulting oily residue was dissolved in ethyl acetate/hexane.
5,11-dihydro-11-ethyl-5
-Methyl-2-N-(pyrrolidino)-6H-dipyrido
3,2-b:2',3'-e][1,4]Diazepine-
0.11 g of 6-one (melting point 185-188°C) was obtained. [Example 16] 5,11-dihydro-11
-ethyl-2-methoxy-4-methyl-6H-dipyrido
[3,2-b:2',3'-e][1,4]Diazepine
-6-one a) 2-methoxy-4-methyl-5-nitropyridi
Sodium methoxide (26.1g) was dissolved in methanol (
1-chloro-4-methyl-5-nitro in 100 ml)
Added to a solution of pyridine (19.0 g) and the resulting mixture
The material was refluxed for 12 hours. After cooling, pour the mixture into water (1 liter).
The product was extracted with ethyl acetate and washed with water. The organic phase was dried (anhydrous magnesium sulfate) and concentrated to leave a residue.
was dissolved in hot ether and filtered. crystallized in ether
10.2 g of the title compound suitable for use in the following reaction
Obtained. b) 5-amino-2-methoxy-4-methylpyridi
stannous chloride dihydrate (41 g) and concentrated hydrochloric acid (40 m
l) in acetic acid (40 ml).
-Methyl-5-nitropyridine (5.1 g)
The temperature was kept below 35°C. the resulting mixture
Stir the mixture at room temperature for 2 hours, then leave it in the refrigerator overnight.
Ta. Collect the solids and hydroxylate both the solids and supernatant to 20%
Made basic separately with sodium solution. Chlorine the product
Extracted with form, combined and dried (anhydrous magnesium sulfate)
) and concentrate as a solid suitable for use in the next reaction.
3.9 g of the title compound was obtained. c) 3-Amino-2-bromo-6-methane
Toxy-4-methylpyridine bromine (4.8 g) was dissolved in acetic acid (25 ml) and sodium acetate.
5-amino-2-methoxy-4-methane in 4.0 g
Chilpyridine (3.9g) was added in one portion to the mixture. The resulting mixture was stirred for 20 minutes, then water (200
ml) of sodium hydroxide (15 g) in
Ta. The product was extracted with chloroform and dried (anhydrous sulfuric acid macerate).
gnesium), concentrated, and silica gel column (methyl chloride).
ethyl acetate, 19:1 → 4:1) and then
Obtained 4.5 g of the title compound suitable for use in the reaction of
. d) N-(2-bromo-6-methoxy-4-methyl
-3-pyridinyl)-2-chloro-3-pyridinecarbo
Oxyamide 2-chloronicotinoyl chloride (3.5 g) was dissolved in methane chloride.
3-amino-2-bromo-6-methoxy-4 in tyrene
- added to a solution of methylpyridine (4.5 g) to obtain
The mixture was stirred at room temperature overnight and diisopropyl ether
It was powdered. Filter the precipitated solid and use it for the next reaction.
6.0 g of the title compound suitable for use were obtained. e] N-(2-bromo-6-methoxy-4-methyl
-3-pyridinyl)-2-ethylamino-3-pyridine
Carboxamide N-(2-bromo-6-methoxy-4-methyl-3-pi
Lysinyl)-2-chloro-3-pyridinecarboxyamide
(2.1 g), dioxane (10 ml), and ethyl
A mixture of amine (0.5 g) was added in a sealed tube to 140
℃ for 5 hours. Dilute the cooled mixture with ethyl acetate.
Diluted, washed with water, and dried the organic phase (anhydrous magnesium sulfate).
and concentrated. The product was transferred to a silica gel column (methylene chloride
/ethyl acetate, 99:1) and diisopropyl ether.
The title compound was crystallized by powdering with tel.0.95
I got g. f) 5,11-dihydro-11-ethyl
-2-methoxy-4-methyl-6H-dipyrid [3,
2-b:2',3'-e][1,4]diazepine-6-
Sodium hydride (0.14 g of 50% dispersion in mineral oil)
) in pyridine (4 ml) was dissolved in N-(2-bromo-6-methane) in pyridine (4 ml).
Toxy-4-methyl-3-pyridinyl)-2-ethyl
of mino-3-pyridinecarboxamide (0.54g)
solution and the resulting mixture was refluxed for 1.5 hours.
. The cooled mixture was diluted with ethyl acetate, washed with water, and the organic
The phase was dried (anhydrous magnesium sulfate) and concentrated. residue
Wash with diisopropyl ether then hot ethyl acetate,
After that, it was crystallized from ethanol and 5,11-dihydro-1
1-ethyl-2-methoxy-4-methyl-6H-dipyry
Do[3,2-b:2',3'-e][1,4]diazepi
Obtained 0.2 g of ion-6-one (melting point 249-251°C)
. [Examples 17 to 73] Similar operation as above
Examples 17-73 as listed below in Table II using the procedure
The compound was prepared. Table II The compounds in this table are of the following formula: [0120] [0121] (wherein, R1 to R8 are as shown below)
zymogen unless specified and Z is a sulfur atom.
Example R1 R2
others
Melting point (℃) 17 Methyl Ethyl
3-chloro, 2-nitro
215-216 18H
cyclobutyl 4-methyl
214-215
19H cyclopropyl
2,4-dimethyl >30
0 20 H cyclopropylene
4-ethyl
228-230 21H
Ethyl 2-chloro, 4
-Methyl 224-228 22
H cyclopropyl 2-k
Rolo, 4-methyl 310-320
23H ethyl
　　　　　　　　　　　　　　　　　　　　　　　　　
211-212 24 Methyl
t-butyl
192-194
25 methyl ethyl
8-Azide
265-266 26H
isopropyl
204-206 2
7H cyclopropyl
　　　　　　　　　　　　　　　　　　　　　　　　　
240-250 28 Methyl Siku
lopropyl 4-methyl
244-245 29 Methyl
cyclopropyl
138-139
-Methyl 0122
] 30H (R)-2-buty
le
172-174 31 Methi
ethyl 2,3-di
Methyl 143-145
32H (S)-2-butyl
　　　　　　　　　　　　　　　　　　　　　　　　　
173-175 33H
cyclopentyl
225-228
34 Methyl Ethyl
2-(pyrrolidin-1-i 244
-246
),4-methyl
35 methyl ethyl
2-(3-pyrroline-1-1
53-156
36
H ethyl
7,9-dimethyl 2
45-247 37 Methyl cyclo
Pentyl 38 Methoxy Methoxy-methy
4-methyl
135-137-methyl 39H ethyl
2-chloro,4-tri-
158-160
Fluoromethi
Le 40H cyclobutyl
　　　　　　　　　　　　　　　　　　　　　　　　　
241-243 41 Methyl
cyclobutyl
144-146
42H cyclopropyl
4-Chloro NA
43 Methyl Ethyl
2-(tetrahydro-13
8-140
Pyridine-1-
44H cyclopropyl
4-methoxy 1
85-187 45 Methyl Ethyl
2-(p-methoxy-ben
83-85
Jill
Methyl-amino) 46 Methyl E
chill 2-allylamino
167-170 47
H cyclopropyl 4-hydroxy
Cymethyl 243-246 48
methyl ethyl 3
,8-dinitro 167-1
69 49 Methyl Ethyl
2,8-dinitro,3-chloro
215-216 50H
Cyclopropyl 4-methyl, 7-hydroxy
225-227 51 H
Cyclopropyl 4-methyl, (Z=S
) 189-194 52
Methyl cyano
2
74-277 53 Methyl cyclo
hexyl
145-146 54
H cyclohexyl
199-20
1 55 H ethyl
7,9-dimethyl, 8-chloro
160-162 56 methyl
cyclopropyl
163-166 57
methyl methylsulfonyl
239-24
1 58 methyl ethyl
2-amino, 3-chloro
160-162 59 Allyl Si
clopropyl 4-methyl
146-149 60 Methi
ethyl 3,8-di
Amino 240-250
61 Vinyloxy cyclopropyl 4-
Methyl 140-1
43 c-carbonyl 62 methoxy cyclopropyl
4-methyl 169
-171 63 Acetyl cyclopropyl
4-methyl
176-179 64 Methyl
Ethyl 2-(p-methoxy-
Benji 133-135
　　　　　　　　　　　　　　　　　　　　　　　　　
65 methyl ethyl
2-(morpholin-1-yl
) 158-160 66 methyl
Ethyl 2-(piperidine-
1-il) 164-166 67
H cyclopropyl 4-cyano
243-245
68 dimethyl-cyclopropyl
8
8-89 Aminoethyl 69 Methyl Ethyl
2-dimethylamino 11
8-120 70 Methyl Ethyl
2-ethylamino
154-157 71 Methyl
ethyl 8-nitro
148-149
72H ethyl
2-dimethylamino, 20
9-211
4-methyl 7
3H ethyl
2-(pyrrolidin-1-yl), 215
-218
3-chloro, 4-
Methyl NA=unobtainable [Example 74] 8-Amino-5,11-di
Hydro-11-ethyl-5-methyl-6H-dipyrido
3,2-b:2',3'-e][1,4]Diazepine-
6-one hemihydrate a) 2-ethylamino-3-nitropyridine 2-k
Lolo-3-nitropyridine (8.60 g, 0.054 mole)
), ethylamine (5.37 g, 0.12 mol), and
and xylene (10 ml) in a sealed tube.
The mixture was heated at 100°C for 3 hours. After cooling, remove the solvent under reduced pressure.
and water was added to the residue. Extract the product with methylene chloride.
Remove, dry (sodium sulfate), concentrate under reduced pressure, and then
10.0 g of the title compound suitable for use in the reaction of
Obtained as a colored oil. b) 3-amino-2-ethylaminopyridine example
2-E using operations similar to those described in Section 11b.
The title compound was obtained from 9.1 g of thylamino-3-nitropyridine.
6.5 g of the product was prepared. c) 2-chloro-N-(2-ethylamino-3-pi
Lysinyl)-5-nitro-3-pyridinecarboxyamidine
2-chloro-5-di in 10 ml of dotetrahydrofuran
2.21 g of tronicotinoyl chloride (2-hydroxy
Nitration of nicotinic acid followed by 2-chloro-5-nito
ronicotinic acid, which is then treated with thionyl chloride.
A solution of 3-amino-2
-ethylaminopyridine 1.34g, diisopropylethate
1.29 g of thylamine and 40 m of tetrahydrofuran
1 of the cooled, stirred mixture over 15 minutes.
Added. The resulting mixture was stirred at room temperature overnight, then
, concentrated under reduced pressure. When the residue was treated with methylene chloride
The title compound precipitated (2.30 g, melting point 185-186
°C) was suitable for use in the next reaction. d) 5,11-dihydro-11-ethyl
-8-nitro-6H-dipyrid [3,2-b:2',
3'-e] [1,4] diazepine-6-one xylene 2
2-chloro-N-(2-ethylamino-3-
pyridinyl)-5-nitro-3-pyridinecarboxylate
A solution of 1.80 g of Midide was refluxed for 4 hours. Concentrate under reduced pressure
After that, the residue is liberated with 50% ethyl acetate/hexane.
Purify with a silica gel column to obtain 0.93 g of the title compound.
Obtained. e] 5,11-dihydro-11-ethyl-5-methy
-8-nitro-6H-dipyrid [3,2-b:2',
3'-e][1,4]Diazepin-6-one Example 8d
5,11-dihydro-
11-ethyl-8-nitro-6H-dipyrido[3,2-
b:2',3'-e][1,4]diazepin-6-one
From 0.93g, the title compound (0.72g, melting point 148~
149°C) was prepared. f) 8-amino-5,11-dihydro-11-ethyl
-5-methyl-6H-dipyrid [3,2-b:2',
3'-e] [1,4] diazepin-6-one hemihydrate fruit
Following a procedure similar to that described in Example 11b, 5
,11-dihydro-11-ethyl-5-methyl-8-di
Thoro-6H-dipyrid [3,2-b:2',3'-e]
[1,4] diazepin-6-one is reduced and 1,2-diazepin-6-one is reduced.
After recrystallization from chloroethane/hexane, the title compound 0
．． 060g as a yellowish brown powder (melting point 193-194℃)
I got it. [Example 75] 6-cyanoimino-5,1
1-dihydro-11-ethyl-2,4-dimethyl-6H
-dipyrid [3,2-b:2',3'-e] [1,4]
Diazepine 5,11-dihydro-11-ethyl-6-methanesulfo
Nyloxy-2,4-dimethyl-6H-dipyrido [3,
2-b: 2',3'-e] [1,4] diazepine (0.
25g, 0.63 mmol), cyanamide (0.034
g, 0.8 mmol), 5 ml of 1,4-dioxane, and
and potassium carbonate (0.11 g, 0.8 mmol)
The mixture was stirred at room temperature for 10 days. The mixture is then reduced under reduced pressure.
Concentrated and the residue was partitioned between ethyl acetate and water. organic phase
was dried, filtered and concentrated under reduced pressure. The residue was dissolved in 10% acetic acid.
Chromatographed on silica using ethyl/methylene chloride
The title compound (melting point 230-233°C) 0.0
25g was obtained. [Example 76] 5,11-dihydro-11
-ethyl-6-methoxyimino-2,4-dimethyl-6
H-dipyrid [3,2-b:2',3'-e][1,4
]Diazepine a) 5,11-dihydro-11-ethyl-6-meth
sulfonyloxy-2,4-dimethyl-6H-dipyry
Do[3,2-b:2',3'-e][1,4]diazepi
trifluoromethanesulfonic anhydride (0.24ml
, 14 mmol), diisopropylethylamine 0.
15 ml of methylene chloride containing 25 ml (14 mmol)
5,11-dihydro-11-ethyl-2,4-dime
Chil-6H-dipyrid [3,2-b:2',3'-e]
[1,4]Diazepin-6-one 0.314g (1.2
mmol) and the resulting mixture was purged with argon.
The mixture was refluxed for 3 hours at a lower temperature. Then, ethyl acetate (approximately 200
ml) was added and the solution was washed three times with water and four times with saline.
. After drying (magnesium sulfate), the solution was concentrated under reduced pressure and
The residue was dried under high vacuum for 2 hours. Dilute the residue with methylene chloride
Tetraethylammonium cyanide dissolved in 20 ml
0.23 g (14 mmol) was added. the resulting solution
After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure.
. Dissolve the residue in 100 ml of ethyl acetate and wash the solution with water.
Washed with saline. Dried (magnesium sulfate) solution
was concentrated under reduced pressure and the residue was diluted with 5% ethyl acetate/hexane.
Chromatographed on silica using obtained
The solid was crystallized from heptane to yield 0.033 g of the title compound.
Obtained as red crystals (melting point 154-155°C). b) 5,11-dihydro-11-ethyl-6-meth
xiimino-2,4-dimethyl-6H-dipyrid [3,
2-b:2',3'-e][1,4]Diazepine chloride
5,11-dihydro-11-ethyl-6-methane in tyrene
Tansulfonyloxy-2,4-dimethyl-6H-dipi
Lido[3,2-b:2',3'-e][1,4]diaze
Pin (0.3 g, 0.75 mmol), methoxylamine
hydrochloride (0.15 g, 1.8 mmol) and diisopropylene hydrochloride (0.15 g, 1.8 mmol)
A solution of lopylamine (0.3 g, 2 mmol) was prepared at room temperature.
Stirred for 4 days. The organic phase was washed with water, dried and filtered. The solution was concentrated under reduced pressure and the residue was dissolved in 20% ethyl acetate/hexane.
Chromatography on silica using Sun
0.07 g of a compound (melting point: 164-166°C) was obtained. [Example 77] 5,11-dihydro-6H
-11-cyclopropyl-4-methyl-dipyrid [3,
2-b:2',3'-e][1,4]diazepine-6-
Thione 5,11-dihydro-11-cyclopropyl-4-methy
Ludipyrid [3,2-b:2',3'-e][1,4
] Diazepin-6-one 5.0 g (18.77 mmol
) and p-methoxyphenylthienophosphine sulfi
dodimer (Lawesson's reagent: Lawesson's r
mixture of 3.8 g (9.40 mmol)
The material was refluxed in 100 ml of toluene for 2.5 hours. solution
was cooled to room temperature and left overnight. The toluene was removed by downward distillation and the residue was purified with fresh silica.
Chromatography through gel (methylene chloride/
ethyl acetate (6:1), it becomes a solid when left standing.
A yellow oil was obtained. Ethyl ether/petroleum ether?
Recrystallize from
1.7 g (32%) of a bright yellow solid at 89-194°C.
Obtained. [0130] [Example A] Capsule or tablet A-1
A-2
Quantity
Ingredients
Amount Compound of Example 12
50mg Compound of Example 12
50mg starch
160mg diphosphoric acid
Calcium 160mg Microcli
Starcello 90mg Microcris
Tarcellulo 90mg Rose
-
sodium starch gluc 10mg
Stearic acid 5m
g Magnesium tate stearate 2mg na
Thorium starch glyco 10mg
　　　　　　　　　　　　　　　　　　　　　　　　　
rate fumed colloidal silica
1mg fumed colloidal silica 1
mg of the compound of Example 12 in the above formulation except for the lubricant.
Mix with premixed excipient materials to form a powder mixture. then
, mixed with lubricant and compressed the resulting mixture into tablets.
or filled into hard gelatin capsules. [Example B] Parenteral solution ingredients
amount
Compound of Example 12
500mg tartaric acid
1.5g
benzyl alcohol
0.1% by weight water for injection
reaching 100mg
amount of excipient material is mixed with water and then the amount of excipient material of Example 12 is mixed with water.
Add compound. Continue mixing until the solution is clear.
. Adjust the pH of this solution to 3.0 and then place it in an appropriate vial.
Filter into bottles or ampoules and autoclave.
More sterile. [Example C] Nasal solution ingredients
amount
Compound of Example 12
100mg citric acid
　　　　　　　　　　　　　　　　　　　　　　　　　
1.92g Benzalkonium Chlora
id 0.025% by weight
EDTA
0.1% by weight
polyvinyl alcohol
10% by weight water
　　　　　　　　　　　　　　　　　　　　　　　　　
Mixing amounts of excipient substances with water amounting to 100 mg
Then the compound of Example 12 is added and the mixture becomes a solution.
Continue until it becomes transparent. Adjust the pH of this solution to 4.0
Prepare and then filter into a suitable vial or ampoule
and put it in.

Claims (13)

[Claims] Claim 1: A compound represented by formula I or a pharmaceutically acceptable acid addition salt thereof, [wherein Z is oxygen, sulfur, =NCN, or formula =NOR]
9 in which R9 is alkyl of 1 to 3 carbon atoms; R1 is hydrogen, alkyl of 1 to 6 carbon atoms, 1 to 6 carbon atoms and 1 to 3 carbon atoms; fluoroalkyl of fluorine atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, 2-halo-2-propen-1-yl, mono-
or di-halovinyl, aryl or arylmethyl (the aryl part of which is unsubstituted or phenyl, thienyl or furanyl substituted with methyl, methoxy or halogen), alkanoyl of 2 to 4 carbon atoms, aminoethyl , mono- or di-
alkylaminoethyl (each alkyl moiety contains 1 to 2 carbon atoms), alkyloxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms, alkyloxycarbonyl (each alkyl moiety contains 1 to 4 carbon atoms) ), alkenyloxy- or alkynyloxycarbonyl (each alkenyl or alkynyl moiety contains 2 to 4 carbon atoms), hydroxy, 1 to 4
alkyloxy, amino, mono- or di-alkylamino (each alkyl moiety contains 1 to 4 carbon atoms), aminocarbonylmethyl, or cyanoalkyl (wherein the alkyl moiety contains 1 to 4 carbon atoms) R2 is hydrogen (provided that R1 is not hydrogen), alkyl of 1 to 6 carbon atoms, 1 to 6 carbon atoms, and 1 to 3 fluorine atoms. fluoroalkyl, cycloalkyl of 3 to 6 carbon atoms,
oxetanyl, thietanyl, tetrahydrofuranyl or tetrahydrothienyl, alkenyl or alkynyl of 2 to 6 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 5 carbon atoms, 2
alkanoyl of ~5 carbon atoms, cyano, hydroxyalkyl, aryl or arylmethyl of 2 to 6 carbon atoms, the aryl portion of which is unsubstituted or alkyl or alkyloxy of 1 to 3 carbon atoms, phenyl, thienyl or furanyl substituted with hydroxyl or halogen), or alkyloxycarbonylmethyl (the alkyl portion of which contains 1 to 5 carbon atoms); and R3, R4 and R
One of 5 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, trihalomethyl, 1 to 6
hydroxyalkyl of 2 to 5 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 5 carbon atoms, alkyloxycarbonylalkyl (the alkyl portion of which each contains 1 to 2 carbon atoms), hydroxyl, 1 to 5 carbon atoms alkyloxy or alkylthio of 2 to 4 carbon atoms, hydroxyalkyloxy of 2 to 4 carbon atoms, alkanoyloxy of 2 to 4 carbon atoms, 1 to 4 carbon atoms;
Alkylsulfinyl or alkylsulfonyl of 4 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkyloxycarbonyl (the alkyl part of which contains 1 to 3 carbon atoms), mono- or di-alkylaminocarbonyl ( each alkyl moiety contains 1 to 3 carbon atoms), aminoalkyl of 1 to 4 carbon atoms, mono- or di-alkylaminoalkyl (each alkyl moiety contains 1 to 3 carbon atoms) ), aryl or arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, unsubstituted or substituted with 1 to 3 alkyl or alkyloxy, hydroxyl or halogen), formula -NR10R1
1 group is halogen, cyano, nitro, azide or carbonyl and the other two substituents are hydrogen, methyl or chloro; or R3, R4 and R5
are independently alkyl or hydroxyalkyl of 1 to 2 carbon atoms, trihalomethyl, alkyloxy or alkylthio of 1 to 2 carbon atoms, halogen or a group of the formula -NR10R11, and the remaining substituents are or R3, R4 and R5 are each hydrogen; one of R6, R7 and R8 is alkyl of 1 to 4 carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms, trihalomethyl, 1 hydroxyalkyl of ~4 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms, alkyloxycarbonylalkyl (the alkyl portion of which each contains 1 to 2 carbon atoms), hydroxyl, 1 to Alkyloxy or alkylthio of 4 carbon atoms, hydroxyalkyloxy of 2 to 4 carbon atoms, alkanoyloxy of 2 to 4 carbon atoms, 1 to 4
alkylsulfinyl or alkylsulfonyl of 2 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkoxycarbonyl (the alkyl part of which contains 1 to 3 carbon atoms), aminoalkyl of 1 to 4 carbon atoms,
mono- or di-alkylaminoalkyl (each alkyl moiety containing 1 to 2 carbon atoms), formula -NR1
The group 2R13 is halogen, cyano, nitro, azide or carboxyl and the other two substituents are hydrogen; or two of R6, R7 and R8 are independently alkyl of 1 to 2 carbon atoms, trihalomethyl,
alkyloxy or alkylthio of 1 to 2 carbon atoms, halogen or a group of formula -NR12R13 with the remaining substituents being hydrogen; or R6, R7
and R8 are each hydrogen; and R10, R11,
R12 and R13 are each independently hydrogen, alkyl of 1 to 4 carbon atoms, alkenylmethyl or alkynylmethyl of 2 to 4 carbon atoms, aryl or arylmethyl (the aryl portion of which is unsubstituted or methyl, phenyl, thienyl or furanyl substituted with methoxy or halogen), mono- or dihydroxyalkylmethyl of 2 to 4 carbon atoms, 1
~3 carbon atoms alkyloxy, hydroxy, 3~
alkyloxyethyl or alkylthioethyl of 4 carbon atoms, aminoalkylmethyl, mono- or dialkylaminoalkylmethyl of 2 to 4 carbon atoms (each alkyl moiety contains 1 or 2 carbon atoms), or is an alkanoyl of 1 to 4 carbon atoms;
Alternatively, R10 and R11, and R12 and R13, together with the nitrogen atom between them, each independently azetidine-1
-yl or saturated or unsaturated, optionally containing one further halogen atom (which may be chosen from O, S or N), or optionally replacing a carbon atom with the formula =
NR14 (wherein R14 is hydrogen or alkyl of 1 to 2 carbon atoms), and the ring optionally independently contains hydroxymethyl, aminomethyl, 1 to 4 methyl groups, and 1 to 2 methyl groups; 5 substituted with a hydroxy group of
, forming a 6- or 7-membered ring; provided that a) Z is oxygen or sulfur, b) R2 is hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl or alkynyl of 2 to 5 carbon atoms, alkoxyalkyl or alkylthioalkyl of 4 carbon atoms, alkanoyl of 2 to 4 carbon atoms, 2 to 5
hydroxyalkyl of 1 to 3 carbon atoms, phenyl (optionally substituted with alkyl or alkoxy of 1 to 3 carbon atoms, hydroxyl or halogen), or alkoxycarbonylmethyl (the alkyl portion of which is substituted with 1 to 5 carbon atoms) c) i) R3 , R4 , R5 , R6 , R7
and R8 are each hydrogen, or ii) one of R3, R4, R5, R6, R7 and R8 is alkyl of 1 to 4 carbon atoms, 1 to 4
hydroxyalkyl, alkyloxycarbonylalkyl of 1 or 2 carbon atoms, each of which has 1 or 2 carbon atoms.
(up to 4 carbon atoms), hydroxyl, alkoxy or alkylthio of 1 to 4 carbon atoms, alkanoyloxy of up to 4 carbon atoms, alkanoyl of up to 4 carbon atoms, amino, up to 4 carbon atoms aminoalkyl, mono- or di-alkylaminoalkyl (each alkyl moiety contains 1 to 2 carbon atoms), halogen, cyano, nitro, azide, or carboxyl, and R3, R4, R5, R6, the remaining five of R7 and R8 are each hydrogen, or iii) R3, R4 and R5 are each independently hydrogen or alkyl of 1 to 3 carbon atoms, with the proviso that
at least one is hydrogen), or R3, R4
and one of R5 is butyl and the remaining two are hydrogen, and R6, R7 and R8 are each independently hydrogen or alkyl of 1 to 3 carbon atoms (provided that at least one is hydrogen) , or when one of R6, R7 and R8 is butyl and the other two are hydrogen, R1 is hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl or alkynyl of 3 to 5 carbon atoms, 2-halo-2-propen-1-yl, arylmethyl (the aryl part of which is unsubstituted or phenyl, thienyl or furanyl substituted with methyl, methoxy or halogen), 2
or alkanoyl containing 3 carbon atoms, alkoxyalkyl or alkylthioalkyl containing 2 to 4 carbon atoms]; or a compound of formula I which satisfies the following conditions or its pharmaceutical composition: Acceptable acid addition salts, wherein Z is oxygen and i) R1 is methyl, R2 is ethyl, and R7 is azide, amino or nitro, and R3-R6 and R8 are hydrogen. or R3 is ethylamino or diethylamino and R4 to R8 are hydrogen, or R6 and R8 are methyl and R3 to R5 and R7 are hydrogen, or R3 and R4 are methyl and R5 to R8 is hydrogen, or R5 is methyl and R3, R4, R6, R
7 and R8 are hydrogen, or ii) R1 is methyl and R2 is ethyl, t-
butyl, s-butyl or isopropyl, and R3
~R8 is hydrogen, or iii) R1 and R2 are methoxymethyl, R5 is methyl and R3, R4 and R6
, R7 and R8 are hydrogen, or iv) R1 is hydrogen, R2 is ethyl and R3 to R8 are hydrogen] or a compound of formula I, where Z is sulfur; and (a) R2 is ethyl, R3 and R5 are methyl, R1, R4, R
6 to R8 are hydrogen, or (b) R1 is methyl, R2 is ethyl, R3 is methoxy, R4 to R8
is hydrogen or a pharmaceutically acceptable acid addition salt thereof. [Claim 2] Z is oxygen, sulfur or the formula = NOR9
in which R9 is alkyl of 1 to 2 carbon atoms; R1 is hydrogen, alkyl of 1 to 4 carbon atoms, fluoroalkyl of 1 to 4 carbon atoms, cyclopropyl , alkenylmethyl or alkynylmethyl of 3 to 4 carbon atoms, 2-halo-2-propene-1
-yl, alkanoyl of 2 to 3 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 3 carbon atoms, or cyanoalkyl, the alkyl portion of which contains 1 to 3 carbon atoms; R2 is hydrogen (provided that R1 is not hydrogen), alkyl of 1 to 5 carbon atoms, fluoroalkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, oxetanyl, thietanyl , alkenylmethyl or alkynylmethyl of 3 to 5 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms, alkanoyl of 2 to 4 carbon atoms, hydroxyalkyl of 2 to 5 carbon atoms , aryl or arylmethyl (the aryl portion of which is unsubstituted or phenyl, thienyl or furanyl substituted with alkyl or alkyloxy, hydroxyl or halogen of 1 to 3 carbon atoms), or alkyloxycarbonylmethyl (the alkyl portion thereof containing 1 to 4 carbon atoms); R3, R4 and R5
one of which is alkyl of 1 to 4 carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms, trihalomethyl, hydroxyalkyl of 1 to 4 carbon atoms, 2 to 4
alkyloxyalkyl or alkylthioalkyl, alkyloxycarbonylalkyl (
each of whose alkyl moieties contain 1 to 2 carbon atoms),
hydroxyl, alkyloxy or alkylthio of 1 to 3 carbon atoms, hydroxyalkyloxy of 2 to 3 carbon atoms, alkanoyloxy of 2 to 3 carbon atoms, alkylsulfinyl or alkyl of 1 to 3 carbon atoms Sulfonyl, alkanoyl of 2 to 4 carbon atoms, alkyloxycarbonyl (the alkyl part of which contains 1 to 2 carbon atoms), aminoalkyl of 1 to 3 carbon atoms, mono- or di-alkylaminoalkyl (each alkyl moiety contains 1 to 2 carbon atoms), amino, mono- or di-alkylamino (each alkyl moiety contains 1 to 4 carbon atoms), acetidin-1-yl, pyrrole -1-yl, pyrroline-1
-yl, pyrrolidin-1-yl, pyrazol-1-yl, pyrazolin-1-yl, pyrazolidin-1-yl, imidazol-1-yl, imidazolin-1-yl, imidazolidin-1-yl, tetrahydropyridin-1 -yl, piperidin-1-yl, morpholin-1-yl, (
4-methyl)piperazin-1-yl, piperazine-1-
yl, N,N-bis(2-hydroxyethyl)amino,
N,N-bis(2-methoxyethyl)amino, or halogen, and the other two substituents are hydrogen, methyl or chloro; or two of R3, R4 and R5 independently Alkyl of carbon atoms, alkyloxy or alkylthio of 1 to 2 carbon atoms, amino, mono- or di-alkylamino (each alkyl moiety contains 1 to 3 carbon atoms), azetidine-
1-yl, pyrrol-1-yl, pyrrolin-1-yl,
pyrrolidin-1-yl, pyrazol-1-yl, pyrazolin-1-yl, pyrazolidin-1-yl, imidazol-1-yl, imidazolin-1-yl, imidazolidin-1-yl, tetrahydropyridin-1-yl, piperidin-1-yl, morpholin-1-yl, (4-methyl)piperazin-1-yl, piperazin-1-yl, N
, N-bis(2-hydroxyethyl)amino, N,N-
bis(2-methoxyethyl)amino, or halogen, and the remaining substituents are hydrogen, methyl, or chloro; or R3, R4, and R5 are each hydrogen; one of R6, R7, and R8 is 1 to Alkyl of 2 carbon atoms, vinyl, trifluoromethyl, hydroxyalkyl of 1 to 2 carbon atoms, hydroxyl, 1 to 2 carbon atoms
Alkyloxy or alkylthio of 2 carbon atoms, hydroxyalkyloxy of 2 to 3 carbon atoms, 2
alkanoyloxy, amino, mono- or di-alkylamino of ~3 carbon atoms (each alkyl moiety contains 1 to 2 carbon atoms), azetidin-1-yl,
Pyrrol-1-yl, pyrrolin-1-yl, pyrrolidin-1-yl, pyrazol-1-yl, pyrazolin-1-yl
yl, pyrazolidin-1-yl, imidazol-1-yl, imidazolin-1-yl, imidazolidin-1-yl, tetrahydropyridin-1-yl, piperidin-1
-yl, morpholin-1-yl, (4-methyl)piperazin-1-yl, piperazin-1-yl, N,N-bis(2-hydroxyethyl)amino, N,N-bis(2-
methoxyethyl)amino, or halogen, and the other two substituents are hydrogen; or R6, R7, and R8 are each hydrogen; Claim 1
A compound as described or a pharmaceutically acceptable acid addition salt thereof. 3. Z is oxygen or sulfur; R1 is hydrogen, alkyl of 1 to 3 carbon atoms, or allyl; R2 is alkyl of 2 to 3 carbon atoms, or 3
cycloalkyl of ~4 carbon atoms; R3 is hydrogen, methyl, alkyloxy or alkylthio of 1 to 3 carbon atoms, chloro, amino, mono- or di-alkylamino (each alkyl moiety is 3 carbon atoms), allylamino, azetidin-1-yl, pyrrol-1-yl, pyrrolin-1-yl, pyrrolidin-1-yl, pyrazol-1-yl, pyrazolin-1
-yl, pyrazolidin-1-yl, imidazole-1-yl
yl, imidazolin-1-yl, imidazolidine-1-yl
yl, tetrahydropyridin-1-yl, piperidin-
1-yl, morpholin-1-yl, (4-methyl)piperazin-1-yl, piperazin-1-yl, N,N-bis(2-hydroxyethyl)amino; R4 is hydrogen, methyl or chloro; Yes; R5 is hydrogen, methyl, ethyl, chloro, or trifluoromethyl;
2. A compound of formula I according to claim 1, or a pharmaceutically acceptable acid addition salt thereof, wherein R6 and R8 are hydrogen; and R7 is hydrogen or amino. 4. Z is oxygen or sulfur; R1 is hydrogen, alkyl of 1 to 3 carbon atoms, or allyl; R2 is alkyl of 2 to 3 carbon atoms, or 3
cycloalkyl of ~4 carbon atoms; R3 is hydrogen, methyl, chloro, methoxy, ethoxy, amino, mono- or di-alkylamino (each alkyl moiety contains 1-2 carbon atoms), Allylamino, allylmethylamino, pyrrolin-1-yl, pyrrolidine-1-
yl, tetrahydropyridin-1-yl, piperidin-
1-yl or morpholin-1-yl; R4 is hydrogen; R5 is hydrogen, methyl, ethyl, chloro,
or trifluoromethyl; R6 and R8 are hydrogen; and R7 is hydrogen or amino;
A compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof. [Claim 5] 5,11-dihydro-11-ethyl-
4-Methyl-6H-dipyrido [3,2-b:2',3'
-e] [1,4] diazepin-6-one or -thione; 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b:2',3'-e]
[1,4] diazepin-6-one or -thione; 5,
11-dihydro-11-ethyl-2,4-dimethyl-6
H-dipyrid [3,2-b:2',3'-e][1,4
]Diazepin-6-one or -thione; 11-cyclopropyl-5,11-dihydro-2,4-dimethyl-6
H-dipyrid [3,2-b:2',3'-e][1,4
]Diazepin-6-one or -thione; 2-chloro-
5,11-dihydro-11-ethyl-4-methyl-6H
-dipyrid [3,2-b:2',3'-e] [1,4]
diazepin-6-one or -thione; 2-chloro-1
1-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrid [3,2-b:2',3'-e] [1
,4] diazepin-6-one or -thione; 5,11-dihydro-11-ethyl-2-methoxy-4
-Methyl-6H-dipyrid [3,2-b:2',3'-
e] [1,4] diazepin-6-one or -thione;
11-Cyclopropyl-5,11-dihydro-2-methoxy-4-methyl-6H-dipyrid [3,2-b:2'
,3'-e] [1,4] diazepin-6-one or -
Thione; 8-amino-5,11-dihydro-11-ethyl-2-
Methoxy-4-methyl-6H-dipyrido [3,2-b:
2',3'-e] [1,4] diazepin-6-one or -thione; 8-amino-11-cyclopropyl-5,11-dihydro-2-methoxy-4-methyl-6H-dipyrido [3 ，
2-b:2',3'-e][1,4]diazepine-6-
one or -thione; 5,11-dihydro-11-ethyl-2-methoxy-5
-Methyl-6H-dipyrid [3,2-b:2',3'-
e] [1,4] diazepin-6-one or -thione;
11-cyclopropyl-5,11-dihydro-2-methoxy-5-methyl-6H-dipyrid [3,2-b:2'
,3'-e] [1,4] diazepin-6-one or -
Thione; 5,11-dihydro-11-ethyl-4-methyl-2-
(N-pyrrolidino)-6H-dipyrido[3,2-b:2
',3'-e] [1,4] diazepin-6-one or -thione; 11-cyclopropyl-5,11-dihydro-4-methyl-2-(N-pyrrolidino)-6H-dipyrido [3, 2
-b:2',3'-e][1,4]diazepin-6-one or -thione; 5,11-dihydro-11-ethyl-5-methyl-2-
(N-pyrrolidino)-6H-dipyrido[3,2-b:2
',3'-e] [1,4] diazepin-6-one or -thione; 11-cyclopropyl-5,11-dihydro-5-methyl-2-(N-pyrrolidino)-6H-dipyrido [3, 2
-b:2',3'-e][1,4]diazepin-6-one or -thione; 5,11-dihydro-11-ethyl-4-methyl-2-
(N,N-dimethylamino)-6H-dipyrido[3,2
-b:2',3'-e] [1,4] diazepin-6-one or -thione; 11-cyclopropyl-5,11-dihydro-4-methyl-2-(N,N-dimethylamino) -6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one or -thione; 8-amino-5,11-dihydro-11-ethyl-4-
Methyl-2-(N,N-dimethylamino)-6H-dipyrido[3,2-b:2',3'-e][1,4]-diazepin-6-one or -thione; 8-amino- 11-cyclopropyl-5,11-dihydro-4-methyl-2-(N,N-dimethylamino)-6
H-dipyrid [3,2-b:2',3'-e][1,4
] -Diazepin-6-one or -thione; and a pharmaceutically acceptable salt thereof. 6. 11-Cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrid [3,2-b:2
',3'-e][1,4]Diazepin-6-one or -thione, or a pharmaceutically acceptable acid addition salt thereof. [Claim 7] 5,11-dihydro-11-ethyl-
4-Methyl-2-(N,N-dimethylamino)-6H-
Dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one or -thione, or a pharmaceutically acceptable acid addition salt thereof. [Claim 8] 11-cyclopropyl-5,11-dihydro-4-methyl-2-(N,N-dimethylamino)
-6H-dipyrid [3,2-b:2',3'-e][1
, 4] diazepin-6-one or -thione, or a pharmaceutically acceptable acid addition salt thereof. [Claim 9] 5,11-dihydro-11-ethyl-
2-Methoxy-4-methyl-6H-dipyrido [3,2-
b:2',3'-e][1,4]diazepin-6-one or -thione, or a pharmaceutically acceptable acid addition salt thereof. [Claim 10] 11-cyclopropyl-5,11-
Dihydro-2-methoxy-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one or -thione, or a pharmaceutically acceptable acid thereof Added salt. 11. Claims 1, 2, 3 of a prophylactically or therapeutically effective amount for humans exposed to or infected with HIV-1.
, 4, 5, 6, 7, 8, 9 or 10, or a pharmaceutically acceptable acid addition salt thereof. 12. A prophylactically or therapeutically effective amount of a compound of formula I according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 or a pharmaceutically acceptable acid addition thereof. salt,
and a pharmaceutically acceptable carrier.
A pharmaceutical composition suitable for the prevention or treatment of V-1 infection. 13. A method for producing the compound according to any one of claims 1 to 10, comprising at least one of the following steps.
The manufacturing method is characterized by employing two steps. (A) In formula I, R2 is other than hydrogen, and Z
To prepare a compound in which is oxygen, a carboxylic acid amide of formula II is cyclized, wherein R1, R3 to R8 are as described above,
R2' is the same as R2 except for hydrogen, and Hal represents fluorine, chlorine, bromine or iodine. ) or (B) hydrolytic cleavage of the arylmethyl group from a compound of formula III to produce a compound of formula I in which R2 is hydrogen and Z is oxygen, R1, R3 to R8 are as described above,
Ar represents an aryl group. ) or (C) to prepare a compound of formula I in which R1 is other than hydrogen and Z is oxygen, in which R1 is hydrogen and Z is oxygen. 5- corresponding to
converting it into an alkali or alkaline earth metal compound, then reacting said compound with a compound of formula V, R1'x
(V) (where R1' is R1 excluding hydrogen)
and X is a reactive ester group, halogen,
The group represented by OSO2OR1' is a methanesulfonyloxy, ethanesulfonyloxy, or aromatic sulfonyloxy group. ) or (C') In formula I, R1
is other than hydrogen and Z is oxygen.
Z is oxygen. ) with a compound of formula V, or (D) reacting a compound of formula I (R2 is hydrogen) with a compound of formula VIa to prepare a compound of formula I, in which Z is oxygen.
or the compound of formula I (R1
is hydrogen) to the corresponding metal salt of formula VIb, where M is an alkali metal such as lithium, sodium, potassium, rubidium, cesium, or
It is a group represented by gHal+ (where Hal is chlorine, bromine or iodine). ) then alkylated with a compound of formula VII, R2x
(VII) (wherein X is as defined above and R2 is as defined above for R2); or (E) to prepare a compound of formula I in which Z is sulfur, (Z is oxygen) with a sulfurizing agent, or (F) a compound of formula I, in which R1 is hydrogen, R2 to R8 are as described above, and Z is a group represented by =NCN. To prepare, a compound of formula XI is reacted with cyanamide to produce a compound of formula For the preparation, a compound of formula .