JP2539116B2 - 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

Description

Detailed Description of the Invention

[0001]

[Field of Industrial Use and Problems to be Solved by the Invention]
The present invention provides novel 5,11-dihydro-6H-dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepines and their pharmaceutically acceptable acid addition salts, their compounds. , A use of these compounds in the prevention or treatment of HIV infection, and a pharmaceutical composition containing these compounds.

Human disease, acquired immunodeficiency syndrome (AI)
DS) is human immunodeficiency virus (HIV), especially HIV
Due to the strain known as -1. Like other viruses, HIV-1 cannot replicate except by forcibly removing the biosynthetic machinery of the host cells it infects. HIV-1 causes this device to produce structural proteins that make the virus progeny. These proteins are encoded by the genetic material contained within the infectious viral particle or pillion. However, being a retrovirus, the genetic material of HIV is RNA rather than DNA as in the host cell genome. Therefore, viral RNA must first be converted to DNA and then integrated into the host cell genome in order for the host cell to produce the required viral protein. The conversion of RNA to DNA is accomplished by the use of an enzyme, reverse transcriptase (RT), which is contained alongside the RNA in infectious virions. Reverse transcriptase has three enzymatic functions;
Acts as an RNA-dependent DNA polymerase, as a ribonuclease and as a DNA-dependent DNA polymerase. First, acting as an RNA-dependent DNA polymerase, RT makes a single-stranded DNA copy of the viral RNA. Next, it acts as a ribonuclease,
T releases the DNA just produced from the original viral RNA and then destroys the original RNA. Finally, DNA again
Acting as a dependent DNA polymerase, RT is the first
Second complementary DN using the DNA strand of
Make A strands. Two strands are double-stranded DNA
This DNA is incorporated into the host cell genome by another enzyme called integrase.

Compounds which inhibit the enzymatic function of HIV-1 reverse transcriptase will inhibit the replication of HIV-1 in infected cells. Such compounds are useful in the prevention or treatment of HIV-1 infection in humans.

[0004]

In an embodiment of the composition,
The present invention has the formula:

[0005]

[Chemical 6]

[Wherein Z is oxygen, sulfur, = NCN, or a group of the formula = NOR ⁹ (wherein R ⁹ is alkyl of 1 to 3 carbon atoms); R ¹ is hydrogen; Alkyl of 1 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms and 1 to 3 fluorine atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or Alkynyl, 2-halo-2-propen-1-yl,
Mono- or di-halovinyl, aryl or arylmethyl, the aryl part of which is unsubstituted or substituted with methyl, methoxy or halogen phenyl, thienyl or furanyl, alkanoyl of 2 to 4 carbon atoms, Aminoethyl, mono- or di-alkylaminoethyl (each alkyl moiety is 1
~ 2 carbon atoms), 2-4 carbon atoms alkyloxyalkyl or alkylthioalkyl, alkyloxycarbonyl (wherein the alkyl part contains 1-4 carbon atoms), alkenyloxy- or alkynyloxy. Carbonyl (each alkenyl or alkynyl moiety contains 2 to 4 carbon atoms), hydroxy, alkyloxy of 1 to 4 carbon atoms, amino, mono- or di-alkylamino (each alkyl moiety is 1 to 4). Containing 4 carbon atoms), aminocarbonylmethyl, or cyanoalkyl (wherein the alkyl portion is 1-4)
Including carbon atoms);

R ² is hydrogen (provided R ¹ is not hydrogen), alkyl of 1 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms and 1 to 3 fluorine atoms, 3 To cycloalkyl of 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 to 5 Alkanoyl of 1 carbon atom, cyano, hydroxyalkyl of 2 to 6 carbon atoms, aryl or arylmethyl (wherein the aryl moiety is unsubstituted or 1 to 3)
Is alkyl or alkyloxy of 8 carbon atoms, phenyl, thienyl or furanyl substituted with hydroxyl or halogen), or alkyloxycarbonylmethyl (wherein the alkyl portion contains 1 to 5 carbon atoms); and

One of R ³ , R ⁴ and R 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. , Hydroxyalkyl of 1 to 6 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 5 carbon atoms, alkyloxycarbonylalkyl (wherein the alkyl portion each contains 1 to 2 carbon atoms), hydroxyl, Alkyloxy or alkylthio having 1 to 5 carbon atoms, hydroxyalkyloxy having 2 to 4 carbon atoms, alkanoyloxy having 2 to 4 carbon atoms, alkylsulfinyl or alkylsulfonyl having 1 to 4 carbon atoms, Alkanoyl of 2 to 6 carbon atoms, alkyloxycarbonyl (wherein the alkyl part is Containing 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 unsubstituted or 1 to 3 alkyl or alkyloxy, hydroxyl or halogen) in substituted phenyl, thienyl or furanyl), groups of the formula -NR ¹⁰ R ^11, halogen, cyano, nitro, azido or carbonyl, others two substituents hydrogen, methyl or chloro; or

Two of R ³ , R ⁴ and R ⁵ are independently 1-2.
Alkyl or hydroxyalkyl of carbon atoms,
Trihalomethyl, alkyloxy or alkylthio of 1 to 2 carbon atoms, halogen or a group of formula -NR ¹⁰ R ¹¹ with the remaining substituents being hydrogen or methyl; or R ³ , R ⁴ and R ⁵ are Hydrogen respectively; R ⁶ , R ⁷
And one of R ⁸ is alkyl of 1 to 4 carbon atoms, 2 to
4 alkenyls or alkynyls, trihalomethyls, hydroxyalkyls of 1 to 4 carbon atoms, 2 to 4
Alkyloxyalkyl or alkylthioalkyl of 4 carbon atoms, alkyloxycarbonylalkyl (wherein the alkyl portion contains 1 to 2 carbon atoms, respectively), hydroxyl, alkyloxy or alkylthio of 1 to 4 carbon atoms, 2 Hydroxyalkyloxy having 4 carbon atoms, alkanoyloxy having 2 to 4 carbon atoms, alkylsulfinyl or alkylsulfonyl having 1 to 4 carbon atoms, alkanoyl having 2 to 6 carbon atoms, alkoxycarbonyl (the alkyl thereof). Moieties include 1 to 3 carbon atoms), aminoalkyls of 1 to 4 carbon atoms, mono- or di-alkylaminoalkyls (each alkyl moiety includes 1 to 2 carbon atoms), formula -NR ¹² R ¹³ groups, halogen, cyano, nitro, azido or carboxy And the other two substituents are hydrogen; or

Two of R ⁶ , R ⁷ and R ⁸ are independently 1-2.
Alkyl of 3 carbon atoms, trihalomethyl, alkyloxy or alkylthio of 1 to 2 carbon atoms, halogen or a group of formula -NR ¹² R ¹³ and the remaining substituents are hydrogen; or R ⁶ , R ⁷ and R ⁸ are each hydrogen; and R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently hydrogen, alkyl of 1 to 4 carbon atoms, alkenylmethyl of 2 to 4 carbon atoms. Or alkynylmethyl, aryl or arylmethyl, the aryl portion of which is phenyl, thienyl or furanyl which is unsubstituted or substituted by methyl, methoxy or halogen, mono- or dihydroxyalkyl of 2 to 4 carbon atoms. Methyl, alkyloxy of 1 to 3 carbon atoms, hydroxy, alkyloxyethyl or alkyl of 3 to 4 carbon atoms Ruthioethyl, aminoalkylmethyl of 1 to 4 carbon atoms, mono- or dialkylaminoalkylmethyl (each alkyl moiety comprises 1 or 2 carbon atoms) or alkanoyl of 1 to 4 carbon atoms ; Or

R ¹⁰ and R ¹¹ , and R ¹² and R ¹³ together with the nitrogen atom between them are each independently azetidin-1-yl or saturated or unsaturated, and optionally one further halogen atom. (May be selected from O, S, or N), or optionally in place of a carbon atom, a formula = N
R ¹⁴ (wherein R ¹⁴ is hydrogen or alkyl of 1 to 2 carbon atoms), and the ring is optionally independently hydroxymethyl, aminomethyl, 1 to 4 methyl groups and 1 to 4 Forms a 5, 6 or 7 membered ring substituted with two hydroxy groups; provided that a) Z is oxygen or sulfur, b) R ² is hydrogen, alkyl of 1 to 5 carbon atoms. , 2
5 alkenyl or alkynyl, alkoxyalkyl or alkylthioalkyl of 2-4 carbon atoms, alkanoyl of 2-4 carbon atoms, hydroxyalkyl of 2-5 carbon atoms, phenyl (optionally 1
~ 3 carbon atoms alkyl or alkoxy, substituted by hydroxyl or halogen), or alkoxycarbonylmethyl (wherein the alkyl portion is 1-5).
A containing carbon ^{atoms), c) i) R 3} , R 4, R 5, R 6, R 7 and R ⁸ are each hydrogen, or ^{ii) R 3, R 4,} R 5, R ^{One of 6} , R ⁷ and R ⁸ is 1
~ Alkyl of 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, alkyloxycarbonylalkyl (wherein the alkyl portion contains 1 or 2 carbon atoms, respectively), hydroxyl, 1 to 4 carbon atoms Alkoxy or alkylthio of, alkanoyloxy of up to 4 carbon atoms, alkanoyl of up to 4 carbon atoms, amino, aminoalkyl of up to 4 carbon atoms, mono- or di-alkylaminoalkyl (each alkyl moiety being 1 to 2 carbon atoms), halogen, cyano, nitro, azido, or carboxyl, and R ³ ,
The remaining ^{five of} R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each hydrogen, or

Iii) R ³ , R ⁴ and R ⁵ are each independently hydrogen or alkyl of 1 to 1 carbon atom, provided that at least one is hydrogen, or R ³ , R ⁴ and R 5
One of ⁵ is butyl and the other two are hydrogen, and R ⁶ , R ⁷ and R ⁸ are each independently hydrogen or alkyl of 1 to 3 carbon atoms, provided that at least one is hydrogen. Or if one of R ⁶ , R ⁷ and R ⁸ is butyl and the remaining two are hydrogen, then R ¹ 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 (wherein the aryl moiety is unsubstituted or methyl, methoxy) Or phenyl, thienyl or furanyl substituted with halogen) alkanoyl containing 2 or 3 carbon atoms,
5,11-dihydro-6H-dipyrido [3,2-b: 2 ′, 3′-e], which cannot be alkoxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms]
[1,4] diazepine; or

A compound of formula I, which satisfies the following conditions:
[Wherein Z is oxygen and i) R¹Is methyl and R²Is ethyl and R
⁷Is azido, amino or nitro and R³~ R⁶
And R⁸Is hydrogen, or R³Is ethylamino
Is diethylamino and R^Four~ R⁸Is hydrogen,
Or R⁶And R⁸Is methyl and R³~ R^Fiveas well as
R⁷Is hydrogen, or R³And R^FourIs methyl
And R^Five~ R⁸Is hydrogen, or R^FiveIs methyl
R and R³, R^Four, R⁶, R⁷And R⁸Is hydrogen,
Or ii) R¹Is methyl and R²Is ethyl, t-butyl,
s-butyl or isopropyl and R³~ R⁸Is
Hydrogen, or iii) R¹And R²Is methoxymethyl, R^FiveHame
Chill and R³, R ^FourAnd R⁶, R⁷And R⁸Is water
Plain or

Iv) R ¹ is hydrogen, R ² is ethyl and R ^{3 to} R ⁸ are hydrogen] or a compound of formula I wherein Z is sulfur and (a ) R ² is ethyl, R ³ and R ⁵ are methyl, R ¹ , R ⁴ , R ^{6 to} R ⁸ are hydrogen, or (b) R ¹ is methyl and R ² is ethyl,
R ³ comprises a methoxy, compound R ⁴ to R ⁸ are hydrogen.

A sub-conceptual feature of the invention is that Z is oxygen, sulfur or a group of the formula = NOR ⁹ where R ⁹ is alkyl of 1 to 2 carbon atoms; R ¹ is hydrogen. , 1-4
Alkyl of 1 carbon atom, fluoroalkyl of 1 to 4 carbon atoms, cyclopropyl, alkenylmethyl or alkynylmethyl of 3 to 4 carbon atoms, 2-halo-
2-propen-1-yl, alkanoyl of 2-3 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2-3 carbon atoms, or cyanoalkyl, the alkyl portion of which contains 1-3 carbon atoms. R ² is hydrogen (provided R ¹ is not hydrogen), alkyl of 1 to 5 carbon atoms, fluoroalkyl of 1 to 5 carbon atoms, 3 to 5 carbon atoms. Cycloalkyl, oxetanyl, thietanyl, alkenylmethyl or alkynylmethyl of 3-5 carbon atoms, 2
~ 4 carbon atoms of alkyloxyalkyl or alkylthioalkyl, 2 to 4 carbon atoms of alkanoyl, 2 to 5 carbon atoms of hydroxyalkyl, aryl or arylmethyl (wherein the aryl moiety is unsubstituted or Alkyl or alkyloxy of 1 to 3 carbon atoms, phenyl substituted with hydroxyl or halogen, thienyl or furanyl),
Or alkyloxycarbonylmethyl, the alkyl portion of which contains 1 to 4 carbon atoms;

One of R ³ , R ⁴ and R ⁵ 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, Alkyloxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms, alkyloxycarbonylalkyl (wherein the alkyl part contains 1 to 2 carbon atoms respectively), hydroxyl, 1 to 3
Alkyloxy or alkylthio of carbon atoms,
Hydroxyalkyloxy of 2 to 3 carbon atoms, 2 to
Alkanoyloxy of 3 carbon atoms, alkylsulfinyl or alkylsulfonyl of 1 to 3 carbon atoms, alkanoyl of 2 to 4 carbon atoms, alkyloxycarbonyl (wherein the alkyl part contains 1 to 2 carbon atoms) ), Aminoalkyls of 1 to 3 carbon atoms, mono- or di-alkylaminoalkyls, each alkyl moiety containing 1 to 2 carbon atoms, amino, mono-
Or di-alkylamino (each alkyl moiety is 1
~ 4 carbon atoms), acetylidin-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, piperidine- 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, methyl or chloro;
Or

Two of R ³ , R ⁴ and R ⁵ are independently 1-2.
Alkyl of 1 carbon atom, 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) piperazine-1
-Yl, piperazin-1-yl, N, N-bis (2-hydroxyethyl) amino, N, N-bis (2-methoxyethyl) amino, or halogen, with the remaining substituents being hydrogen, methyl or chloro. Or

R ³ , R ⁴ and R ⁵ are each hydrogen; R
⁶ , one of R ⁷ and R ⁸ is alkyl having 1 to 2 carbon atoms, vinyl, trifluoromethyl, hydroxyalkyl having 1 to 2 carbon atoms, hydroxyl, alkyloxy having 1 to 2 carbon atoms, or Alkylthio, 2-3
Hydroxyalkyloxy of 1 carbon atom, alkanoyloxy of 2 to 3 carbon atoms, amino, mono- or di-alkylamino (each alkyl moiety contains 1 to 2 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) piperazine-1
-Yne, piperazin-1-yl, N, N-bis (2-hydroxyethyl) amino, N, N-bis (2-methoxyethyl) amino, or halogen, the other two substituents being hydrogen Or R ⁶ , R ⁷ and R ⁸ are each hydrogen; including compounds of formula I;

A particular sub-conceptual feature of the invention is that Z is oxygen or sulfur; R ¹ is hydrogen, alkyl of 1 to 3 carbon atoms or allyl; R ² is ² to 3 carbons. Alkyl of atoms, or cycloalkyl of 3 to 4 carbon atoms; R ³ is hydrogen, methyl, alkyloxy or alkylthio of 1 to 3 carbon atoms, chloro, amino, mono- or di-alkylamino ( Each alkyl moiety contains from 1 to 3 carbon atoms), allylamino, azetidin-1-yl, pyrrol-1-yl, pyrrolin-1-yl, pyrrolidin-1-yl, pyrazole-
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
Yl, (4-methyl) piperazin-1-yl, piperazin-1-yl, or N, N-bis (2-hydroxyethyl) amino; R ⁴ is hydrogen, methyl or chloro; R ⁵ is hydrogen , Methyl, ethyl, chloro, or trifluoromethyl; R ⁶ and R ⁸ are hydrogen; and R ⁷ is hydrogen or amino;

A further particular sub-conceptual feature of the invention is Z
Is oxygen or sulfur; R ¹ is hydrogen, alkyl or allyl of 1 to 3 carbon atoms; R ² is alkyl of ² to 3 carbon atoms, or cycloalkyl of 3 to 4 carbon atoms. And

R ³ is hydrogen, methyl, chloro, methoxy,
Ethoxy, amino, mono- or di-alkylamino, each alkyl moiety containing 1 to 2 carbon atoms,
Allylamino, allylmethylamino, pyrrolin-1-yl, pyrrolidin-1-yl, tetrahydropyridin-1
-Yl, piperidin-1-yl or morpholin-1-
R ⁴ is hydrogen; R ⁵ is hydrogen, methyl,
Is ethyl, chloro, or trifluoromethyl; R
⁶ and R ⁸ are hydrogen; and R ⁷ is hydrogen or amino; including compounds of formula I.

The preferred compound of formula I is 5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepine-6. -One; 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-6H-dipyrido [3,2-b: 2 ', 3'-e]
[1,4] diazepine-6-thione; 11-cyclopropyl-5,11-dihydro-2,4-
Dimethyl-6H-dipyrido [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-dipyrido [3,2-b: 2 ',
3'-e] [1,4] diazepin-6-one or -thione; 5,11-dihydro-11-ethyl-2-methoxy-4
-Methyl-6H-dipyrido [3,2-b: 2 ', 3'-
e] [1,4] diazepin-6-one or -thione;

11-Cyclopropyl-5,11-dihydro-2-methoxy-4-methyl-6H-dipyrido [3,3]
2-b: 2 ', 3'-e] [1,4] diazepine-6-
On 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-
On or -thione; 5,11-dihydro-11-ethyl-2-methoxy-5
-Methyl-6H-dipyrido [3,2-b: 2 ', 3'-
e] [1,4] diazepine-6-thione; 11-cyclopropyl-5,11-dihydro-2-methoxy-5-methyl-6H-dipyrido [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; and 8-amino- 11-cyclopropyl-5,11-dihydro-4-methyl-2- (N, N-dimethylamino) -6
H-dipyrido [3,2-b: 2 ', 3'-e] [1,
4] diazepin-6-one or -thione;

Synthesis of Compounds of Formula I and their Salts The compounds of formula I and their salts can be prepared by known methods or obvious variations thereof. The following methods A to H are examples of methods for preparing these compounds. Method A

[0026]

[Chemical 7]

(In the formula, R¹And R³~ R⁸Is as mentioned above
And R²′ Is R except hydrogen ²Has the same meaning as
Of the general formula II:

[0028]

Embedded image

[0029] (wherein, R ^1, R ³ ~R ⁸ and R ² 'have the same meaning as described in formula Ia, Hal is fluorine, chlorine, bromine or an iodine) a carboxylic acid amide It can be obtained by cyclization. An alternative to this method, which is preferably used to prepare compounds of formula Ia in which R ⁶ , R ⁷ , or R ⁸ , especially R ⁷ is a charge-withdrawing group such as nitro, is described by formula IIa

[0030]

[Chemical 9]

(Wherein R ^{3 to} R ⁸ are as described above, R ² ′ has the same meaning as R ² except hydrogen, and H 2
al represents fluorine, chlorine, bromine or iodine) and involves the cyclization of a carboxamide. The cyclization is conveniently carried out by conversion of the compounds of formula II or IIa to their alkali metal salts and subsequent condensation at temperatures between 0 ° C. and the boiling point of the reaction temperature.

In the starting compounds of general formula II or IIa, when R ¹ is different from hydrogen, metal chloride
Requires at least 1 mole of metal chlorinating agent. On the other hand, when R ¹ is hydrogen, at least 2 moles of metal chlorinating agent should be used. Metal chlorides include lithium, sodium and potassium hydrides, or n
The use of lithium alkyls such as -butyllithium is preferred.

The cyclization reaction is usually carried out in an inert solvent such as tetrahydrofuran, 1,4-dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, dimethylformamide, benzene or anisole. The cyclization can also be carried out by heating the carboxamide of the general formula II or IIa in a dipolar aprotic solvent, preferably sulfolane or dimethyl sulfone. It has been demonstrated that catalytic amounts of strong acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, methanesulphonic acid or p-toluenesulphonic acid can be used. The required reaction temperature is usually 110 to 220 ° C.

Method B General Formula Ib:

[0035]

[Chemical 10]

Prepared by hydrolytic cleavage of the arylmethyl group of a compound of the formula (I) wherein R ¹ and R ^{3 to} R ⁸ are as described above and Ar may be, for example, a phenyl or 4-methoxyphenyl group. it can. Hydrolysis is-
It is carried out with a strong acid or a Lewis acid at a temperature of 20 to + 150 ° C. Such acids may be sulfuric acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, phosphoric acid or polyphosphoric acid. When using phosphoric acid or polyphosphoric acid, benzene, toluene, phenol,
It has been found advantageous to add a solvent such as anisole or veratrol.

When the arylmethyl group is removed with a Lewis acid such as aluminum chloride or bromide, aromatic hydrocarbons such as benzene, toluene, anisole,
Alternatively, solvents such as mixtures of these with dichloromethane are suitable. When the method B is such that R ¹ and any of R ^{3 to} R ⁸ are easily hydrolyzable substituents, for example, R ¹ is alkanoyl or R ^{3 to} R ⁸ is alkanoyl. It will be apparent to those skilled in the art that it is not preferred when it is amino or alkoxycarbonyl. When R ¹ is alkanoyl or any of R ^{3 to} R ⁸ is alkoxycarbonyl, it is preferable to use, for example, Method A described above; R
^{If 1} is hydrogen, then 2 equivalents of base should be used. If any of R ^{3 to} R ⁸ is an alkanoylamino, for example, hydrolysis (and subsequent acylation) is carried out on the corresponding nitro derivative, then the nitro moiety is reduced to an amine and then acylated to give the desired product. It is preferred to obtain the product of

Method C

[0039]

[Chemical 11]

(Wherein R ¹ ′ has the same meaning as R ¹ with the exception of hydrogen, and R ^{2 to} R ⁸ are as previously described), the compound of formula IV:

[0041]

[Chemical 12]

(Wherein R ^{2 to} R ⁸ are as described above) 5,11-dihydro-6H-dipyrido [3,2-
b: 2 ', 3'-e] [1,4] diazepin-6-one is converted to the corresponding 5-alkali or alkaline earth metal compound and the resulting alkali metal compound is then converted to the formula V: R ¹ ′ X (V) (wherein R ¹ ′ has the same meaning as in formula Ic, X is a reactive ester group, a halogen atom, a group OSO ₂ OR ¹ ′, methanesulfonyloxy or ethanesulfonyloxy. Group, or an aromatic sulfonyloxy group). Instead of converting the compound of general formula IV into its corresponding alkali metal salt in the first step, the alkylation of the compound of formula IV is carried out by triethylamine, diazabicycloundecene or 4- (dimethylamino).
It may be carried out by reaction with a compound of formula V in the presence of an amino such as pyridine or in the presence of an alkali carbonate or bicarbonate such as sodium carbonate, potassium carbonate or sodium bicarbonate.

The conversion of the compound of general formula IV into the corresponding alkali metal or alkaline earth metal compound is carried out by converting the compound of formula IV into an alkali metal or alkali metal such as lithium hydroxide, barium hydroxide, sodium hydroxide or potassium hydroxide. Earth metal hydroxide; sodium methoxide or potassium tert. It can be carried out by reacting with an alkali metal alcoholate such as butoxide; an alkali metal amide such as sodium amide or potassium amide; or an alkali metal hydride such as sodium hydride or potassium hydride. The reaction is preferably carried out at elevated temperature in the presence of a suitable organic solvent. Inert organic solvents such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran or glycol dimethyl ether are preferred when using alkali metal hydrides as the metal chlorinating agent and when using alkali or alkaline earth metal hydroxides. Aqueous mixtures with organic solvents such as methanol or tetrahydrofuran can also be used.
The thus obtained alkali or alkaline earth metal-substituted 5,11-dihydro-6H-dipyrido [3,2-b:
For the conversion of 2 ', 3'-e] [1,4] diazepin-6-one to compounds of general formula Ic, a solution or suspension of an alkaline or alkaline earth compound is directly, i.e. The compound of formula V is reacted without separation at elevated temperature up to -20 ° C or the boiling point of the solvent or reaction medium, whichever is lower. The substitution is based on the assumption that 1 equivalent of base and 1 equivalent of the compound of formula V were used, even if R ^{2 in} the starting material of formula IV is a hydrogen atom, the nitrogen atom at the 5-position of the dihydrodipyridodiazepine is So almost all happens.

The presence of a nucleophilic substituent in a compound of formula Ic provides an intermediate of formula Ic having a substituent other than the nitrogen at the 11-position which can be derivatized to provide the desired group. It will be apparent to those skilled in the art that use may be required. For example, amino or monoalkylamino substituents are preferably either an alkyl or acylated then the nitro group of intermediate of formula Ic having a nitro group in R ³ to R ⁸ in either R ³ to R ⁸ Is obtained by reduction and, if appropriate, alkylation to give the final product.

Method D

[0046]

[Chemical 13]

The compound of the formula (wherein Z is oxygen and R ^{1 to} R ⁸ represent the above groups) is represented by the general formula Ib of 5,11-dihydro-6H-dipyrido [3,2-b: 2 ', 3'-e]
Diazepin-6-one is a corresponding metal salt of the general formula VIa or a compound of the formula VIb (when R ¹ of the compound of the formula Ib is hydrogen), ie

[0048]

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Where M is an alkali metal such as lithium, sodium, potassium, rubidium or cesium, or M is a group Mg Hal + and Hal is a chlorine, bromine or iodine atom. , Then the expression
VII R ² X VII, where R ² and X are as described above, can be prepared by alkylation.

The conversion of compounds of general formula Ib to the corresponding alkali metal compounds of formulas VIa and VIb is carried out by converting compounds of formula Ib to alkyl lithium (eg n-butyl lithium or optionally in the presence of tetramethylethylenediamine). t-butyllithium), lithium dialkylamides (eg lithium diisopropylamide, lithium dicyclohexylamide and lithium isopropylcyclohexylamide), aryllithium (eg phenyllithium), alkali metal hydroxides (eg lithium hydroxide, sodium or potassium hydroxide). ), An alkali metal hydroxide (eg sodium or potassium hydride) or an alkali metal amide (eg sodium or potassium amide), or a Grignard reagent (eg methyl iodomagnesium). Sium, methylmagnesium bromide or phenylmagnesium bromide). One equivalent of base is required to prepare the compound of formula VIa and two equivalents of base are required to prepare the compound of formula VIb. The metal salification is conveniently carried out in an inert organic solvent at a temperature between -78 ° C and the boiling point of the reaction mixture.
When an alkyllithium, aryllithium, lithium dialkylamide or Grignard reagent is used for metal chlorination, preferred solvents are tetrahydrofuran, diethyl in a mixture with an aliphatic or aromatic hydrocarbon, such as hexane or benzene, if desired. Ether or ether such as dioxane, the operation is -20 to +
Perform at a temperature of 80 ° C. When metal chlorination is carried out with an alkali metal hydride and an alkali metal amide, in addition to the above-mentioned solvents, xylene, toluene, acetonitrile, dimethylformamide and dimethylsulfoxide can also be used, and when an alkali metal hydroxide is used. Can also use ethanol, alcohols such as methanol, and aliphatic ketones such as acetone, and mixtures of these solvents with water.

From the alkali metal salt thus obtained, the formula I
For the conversion to the compound of formula (III), a solution or suspension of the alkali metal compound is directly added, that is to say without isolating the reaction product, between the compound of formula VII and between -20 ° C and the boiling point of the reaction mixture. The reaction is carried out at a temperature, preferably room temperature. The presence of nucleophilic substituents in the compounds of formula I necessitates the use of intermediates of formula Ic having substituents other than the 11-position nitrogen which are derivatizable to give the required groups. For example, R ^{3 to} R ⁸
An amino or monoalkylamino substituent on any of the groups preferably alkylates or acylates an intermediate of formula Ic bearing a nitro group on any of R ^{3 to} R ⁸ and then reduces the nitro group, if appropriate. , Alkylation to obtain the final product.

Carboxamides of the general formula II used as starting materials for the processes A to D are, for example, those of the general formula VIII:

[0053]

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The general formula IX of 2-chloro-nicotinic acid amide of the formula: wherein R ^{1 to} R ⁸ and Hal are as defined above: H ₂ N—R ² ′ (IX) R ² ′ is as defined above) and is obtained by amination with a primary amine. The reaction may also be carried out in the presence of an inorganic or organic auxiliary base such as triethylamine, N, N-dimethylaniline, sodium and potassium carbonate. Although the reaction can be carried out without the use of a solvent, the use of an inert organic solvent at temperatures between 0 ° C. and 175 ° C., preferably at reflux temperature has several advantages. Suitable inert solvents that can be used include excess primary amine of the general formula IX; tetrahydrofuran, 1,4-dioxane,
Open chain or cyclic ethers such as glycol dimethyl ether, diethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene or pyridine; alcohols such as methanol, ethanol, isopropanol; dipolar aprotons such as dimethylformamide. Solution; there is 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-tetrahydro-2 (1H) -pyrimidinone and sulfolane.

Carboxamides of the formula IIa are prepared by condensation of appropriately substituted 2-chloronicotinic acid chloride with appropriately substituted 3-amino-2- (alkylamino) pyridine under known reaction conditions. You can Starting materials of general formula VIII in which R ¹ is different from hydrogen have general formula X:

[0056]

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From the 2-chloronicotinic acid amide of formula (I), an alkylating agent of the general formula V and amines such as triethylamine, diazabicycloundecene, 4- (dimethylamino) pyridine; sodium hydroxide, hydroxylation Proton acceptance of alkali or alkaline earth metal hydroxides such as calcium, calcium hydroxide; or alkali metal carbonates or alkaline earth metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate or potassium hydrogen carbonate It can be prepared by reacting in the presence of the body.

The 2-chloronicotinic acid amides of the general formula X are condensed under known reaction conditions with appropriately substituted 2-chloronicotinic acid chlorides and appropriately substituted 3-amino-2-halogen-pyridines. Can be prepared by All other starting materials are known in the literature and can be purchased or obtained by procedures known in the literature.

Method E In Method E, a compound of Formula I where Z is sulfur is Z
A compound of formula I in which is oxygen 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetan-2,4-disulfide, bis (trichlorohexyltin) sulfide, bis (tri It is obtained by reacting with a sulfiding agent such as -n-butyltin) sulfide, bis (triphenyltin), bis (trimethylsilyl) sulfide or phosphorus pentasulfide. The reaction is carried out in an inert organic solvent such as carbon disulfide, benzene or toluene at room temperature or above, preferably at an elevated temperature up to the boiling point of the reaction mixture, preferably under anhydrous conditions. When using the tin or silyl sulfides mentioned above, the sulfurization reaction is preferably carried out in the presence of a Lewis acid such as boron trichloride.

A compound of formula I, for example Z is oxygen and R
The presence of an additional carbonyl moiety in the compound wherein any of ^3- R ⁸ is alkanoyl protects the ketone carbonyl in a known manner with a suitable protecting group prior to the sulfurization reaction;
It will be apparent to those skilled in the art that deprotection after the sulfurization reaction requires obtaining the desired compound. Similarly, if R ² is, for example, alkanoyl, then it will be clear that the sulfurization reaction is best performed prior to acylation of the 11-position nitrogen. If the substituents on any of R ^{3 to} R ⁸ can be derived from nitro, eg alkanoylamino, the sulfurization reaction is carried out on the corresponding nitro derivative and then the appropriate (known) reduction is carried out and finally the acyl Can be carried out to give the desired product.

Method F Compounds of formula I wherein R ¹ is hydrogen, R ^{2 to} R ⁸ are as described above and Z is a group of formula ═NCN have the formula XI:

[0062]

[Chemical 17]

It can be obtained by reacting a compound of the formula (wherein R ^{2 to} R ⁸ are as described above) with cyanamide. The reaction is carried out at 0 ° C. in an inert solvent such as methylene chloride, 1,4-dioxane, tetrahydrofuran, diethyl ether, chloroform, or dimethylformamide in the presence of a base such as potassium carbonate, sodium carbonate, triethylamine, or diisopropylethylamine. It is carried out at a temperature between the boiling point of the reaction mixture.

[0064] Compounds of the methods G R ¹ is hydrogen R ² to R ⁸ are as defined above and Z is the formula I is a group of the formula = NOR ⁹ is in the process F and the same method, R ² ~ It can be obtained by reacting a compound of formula XI where R ⁸ is as described above with a suitable alkoxylamine (o-alkylhydroxylamine) or a salt thereof (eg methoxylamine hydrochloride). The reaction is carried out under conditions similar to those described for the treatment of the compound of formula XI with cyanamide.

[0065]Starting materials for methods F and G R²~ R⁸A compound of formula XI where R is₁
Is hydrogen and R²~ R ⁸Is as described above and Z is
A compound of formula I that is oxygen is converted to trifluoromethanesulfone.
It can be obtained by reacting with an acid anhydride. So
The reaction was conducted without 1 to 2 equivalents of trifluoromethanesulfonic acid.
Aqueous solution in the presence of 1-2 equivalents of base in an inert solvent
Is preferably carried out. The base may be, for example, Trier
Triamines such as tilamine or diisopropylethylamine
It may be a primary amine and the inert solvent used is, for example,
For example, methylene chloride, chloroform, diethyl ether
May include toluene, tetrahydrofuran, or toluene
Yes. Addition of reagents is generally performed at ambient temperature or below,
The post mixture is allowed to react near room temperature.

Alkoxylamine starting materials are commercially available,
It is also known in the literature or can be obtained by an operation known in the literature. Preparation of Salts and Other Derivatives Compounds of formula I, if desired, may be dissolved in their non-toxic pharmaceutically acceptable acid addition salts by conventional methods, eg by dissolving the compound of formula I in a suitable solvent, It can be converted by acidifying the solution with 1 molar equivalent or more of the desired acid. The present invention also includes such salts.

Examples of inorganic and organic acids which form non-toxic pharmaceutically acceptable acid addition salts with compounds of formula I are: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methane sulfone. Acid, etc. The compounds of general formula I are capable of forming acid addition salts with 1 molar equivalent of acid. Those skilled in the art will often find it convenient to make certain compounds of formula I by derivatization of other compounds of formula I, rather than by directly making certain compounds of formula I using one of the methods described above. Admit. Such derivatization uses known reaction techniques. By way of non-limiting example, when R ¹ is hydrogen, it can be oxidized to give hydroxy; the nitro group can be reduced to give an amine; the methoxy group can be converted to hydroxy by conventional demethylation procedures. , Hydroxy can in turn be displaced with amines via trifluoromethanesulfonyloxy derivatives under suitable set conditions; amines can be acylated to give alkanoylamines or alkylated to give mono- or dialkylamines; halogens can be It can be displaced by an amine under suitable set conditions; the protecting group can be removed.

Biological Properties The compounds of formula I described above have inhibitory activity against HIV-1 reverse transcriptase. When administered in suitable dosage forms, these compounds are useful in the prevention or treatment of AIDS, ARC and related diseases associated with HIV infection. Accordingly, another aspect of the invention involves the administration of a prophylactically or therapeutically effective amount of a novel compound of formula I as described above to a human exposed or infected with HIV-1.
-1 is a method for preventing or treating infection.

The compounds of formula I can be administered in single or divided doses by the oral, parenteral or topical routes. A suitable oral dose of a compound of formula I will be in the range of about 0.5 mg / g / day. For parenteral preparations, the appropriate dosage unit is 0.1
Formulations which may contain ˜250 mg of the above compounds, with 0.01 to 1% of active ingredient being preferred for topical administration. However, it should be understood that the dose will vary from patient to patient, and the dose for any particular patient will depend on its clinical judgment, and the criteria for determining an appropriate dose include the patient's weight and condition as well as the patient's weight. The responsiveness to the drug will be used.

When the compounds of this invention are to be administered by the oral route, they can be administered as a medicament in the form of a pharmaceutical formulation containing the compound with a compatible pharmaceutical carrier or carrier substance. Such carrier materials can be inert organic and inorganic carrier materials suitable for oral administration. Examples of such carrier substances are water, gelatin, talc, starch, magnesium stearate, gum arabic, vegetable oils, polyalkylene glycols, petroleum jelly and the like.

The pharmaceutical preparations can be prepared in a customary manner, the final dosage form being a solid dosage form such as tablets, dragees, capsules or the like or liquid dosage forms such as solutions, suspensions, emulsions and the like. obtain. The pharmaceutical formulation may be subjected to conventional pharmaceutical operations such as sterilization. In addition, the pharmaceutical formulations may contain conventional adjuvants such as preservatives, stabilizers, emulsifiers, flavor improvers, wetting agents, buffers, salts for osmotic pressure changes. Solid carrier materials that can be used include, for example, starch,
There are lactose, mannitol, methyl cellulose, microcrystalline cellulose, talc, silica, dibasic calcium phosphate, and high molecular weight polymers (such as polyethylene glycol).

For parenteral use, the compounds of formula I may be administered as an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable oil or liquid mixture,
These solutions contain sterilizing agents, antioxidants, preservatives, buffers or other lysates that make the solution isotonic with blood, thickeners, suspending agents or other pharmaceutically acceptable additives. obtain.
Additives of this type include, for example, tartrate, citrate and acetate buffers, ethanol, propylene glycol, polyethylene glycol, complexing agents (such as EDTA), antioxidants (sodium bisulfite, There are polyethylene derivatives of sodium metabisulfite and ascorbic acid), high molecular weight polymers for viscosity adjustment (such as liquid polyethylene oxide) and sorbitol anhydride. Preservatives such as benzoic acid, methyl or propylparaben, benzalkonium chloride and other quaternary ammonium compounds may also be added if desired.

The compounds of the present invention can also be administered as solutions for nasal administration, in addition to the compounds of the present invention, thickening agents in suitable buffers, tonicity adjusting agents, microbial preservatives, antioxidants and aqueous vehicles. Agents may be included. Examples of agents used for thickening are polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone, polysorbates or gelatin. Microbial preservatives added include benzalkonium chloride, thimerosal, chlorobutanol, or phenylethyl alcohol.

In addition, the compounds of this invention can be administered as suppositories. As mentioned above, the compound of the present invention is
Suppresses the enzyme activity of 1RT. It was found that the RNA-dependent DNA polymerase activity of HIV-1RT is suppressed based on fairly extensive testing of these compounds as described below. The compounds of the invention are HIV-1 RT DNA
It was also found to suppress the dependent DNA polymerase activity (data not shown).

Each compound was treated with its HIV-1 RT RNA-dependent DN using the following reverse transcriptase (RT) assay.
It can be tested for its ability to suppress A polymerase activity. Some specific compounds shown in the Examples below were so tested. The test results are shown in Table 1 below. Reverse Transcriptase (RT) Assay Assay Theory: Some enzymes encoded by the human immunodeficiency virus (HIV-1) are so named because they transcribe a DNA copy from an RNA template (template). ) Exists. This activity can be measured quantitatively in the previously disclosed cell-free enzyme assay (2) and reverse transcriptase is synthesized by a synthetic template (oligo d (G)).
Based on the observation that the radiolabeled acid-precipitable DNA strand using ³ H-dGTP as a substrate can be transcribed using the poly-r (c)) sensitized in (1). Materials: a) Preparation of enzyme DNA clone pB in which reverse transcriptase (1) from LAV strain of human immunodeficiency virus (HIV-1) is under the control of lac promoter in expression vector pIBI21 (4).
Isolated from strain JM109 (3) expressing PTprt1 + (2). Overnight culture (37 ° C., 2 ° C.) grown in 2XYT medium supplemented with 100 μg / ml ampicillin for positive selection.
25 rpm) (5) is inoculated into M9 medium (5) supplemented with 10 μg / ml thiamine, 0.5% casamino acid and 50 μg / ml ampicillin at a 1:40 dilution. Culture to 0.3-0.
Insulate until reaching OD540 of 4 (37 ° C, 225
rpm). At this point, the repressor inhibitor IPTG
(Isopropyl β-D-thiogalactopyranoside) to 0.
Add 5 mM and incubate the mixture for an additional 2 hours. Bacteria were pelleted, 50 mM Tris, 0.6 mM EDTA, 0.3
Resuspend in 75M NaCl buffer, add lysozyme and digest for 30 minutes on ice. 0.2% NP of cells
Dissolve to 1M NaCl by addition of -40.

After removing the insoluble debris by centrifugation, the protein is precipitated by the addition of 3 volumes of saturated aqueous ammonium sulphate solution. Pellet the resulting enzyme,
RT buffer (50 mM Tris pH 7.5, 1 mM EDT
A, 5 mM DTT, 0.1% NP-40, 0.1 M NaC
l, and 50% glycerin), 70
Store at ℃ for later use.

B) Composition of 2-fold concentrated preservative reaction mixture Preservative 2-fold mixed concentrate 1M Tris pH 7.4 100 mM 1M dithiothrietol 40 mM 1M NaCl 120 mM 1% Nonidet P-40 0.1% 1M MgCl 4 mM [poly r (C) / oligo d (G)] (5: 1) 2 μg / ml ³ H-dGTP (81 μM) 0.6 μM Assay procedure: 2 × concentrated Storage reaction mixture aliquoted-2
Store at 0 ° C. The mixture is stable and dissolves for use in each assay. This enzyme assay is compatible with the 96-well microtiter plate device and has been previously disclosed (6). Dispense Tris buffer (50 mM, pH 7.4), vehicle (solvent diluted to suit compound dilution), or compound in vehicle into 96-well microtiter plates (10 μl / well; 3).
Well / compound). Dissolve the HIV-1RT enzyme,
Dilute in mM Tris pH 7.4 to obtain 0.1 μl of diluted enzyme.
001 units (1 unit is the amount of enzyme that transforms 1 micromol of substrate per minute at 25 ° C.) and 15 μl is distributed to each well. 0.12
Add 20 μl of 0.5 M EDTA to the first 3 wells of the microtiter plate. EDTA chelates the existing Mg ⁺⁺ and prevents reverse transcription. This group acts as a background polymerization subtracted from all other groups. Add 25 μl of the 2-fold reaction mixture to all wells and incubate the assay at room temperature for 60 minutes. The assay is terminated by precipitating the DNA in each well with 50 μl of trichloroacetic acid (TCA) (10% w / v) in sodium pyrophosphate (1% w / v). Incubate the microtiter plate at 4 ° C for 15 minutes and remove the sediment by scatron (Sk).
atron) on a # 30 glass fiber paper (Sehleicher & Schuell) using a semi-automatic harvester. The filter is then washed with additional 5% TCA containing 1% sodium pyrophosphate, rinsed with 70% aqueous alcohol, dried and transferred to scintillation vials (6). Each vial receives 2 ml of scintillation cocktail and is counted in a Beckman beta counter.

The calculation of% inhibition is as follows: Documents: 1. Benn, S., etc., SCIENCE 230: 949, 1985 2. Farmerie, WG, etc., SCIENCE 236: 305, 1987 3. Yanisch-Perron, C., Viera, J., and Messing,
J. GENE 33: 103, 1985 4. International Biotechnologies, Inc. New Haven, Connecticut 06535 5. Maniatis, T., Fvitsch, E, F., and J. Sambrook.
Ed., MOLECULAR CLONING: A LABORATORY MANUAL, Cold Spring Harbor Laboratory, 1982 6. Spira, T. et al., J. Clinical Microbiology, 25: 9
In order to confirm that compounds active in the 7, 1987 RT assay have the ability to suppress HIV replication even in biological systems, each compound of the invention was also tested in the human T-cell culture assay described below. Table 1 shows the results of this test.

Human T Cell Culture Assay Assay Theory: Fusion Cell Generation is HIV-1 Infected CD4
It has the characteristics of an in vitro culture of + T cells. In this assay, T cells are treated with a putative replication-inhibitory compound and then infected with HIV-1. After incubation, the culture is checked for the production of fused cells. The absence or reduction in the number of fused cells is used as a measure of the ability of a test compound to suppress HIV replication.

Assay method: target cells, label C8
166 is a subclone of human lymphocytes of T cell origin, RPMI1640 in 96 well flat bottom plates.
(+ 10% fetal calf serum) 5 × 10 ^4/10 in the medium
Establish with an initial density of 0 μl. It contains a selected amount of test compound dissolved in DMSO. HIV after 24 hours
-1 50-100 TCID of HTLV-III B strain
Each culture is inoculated with ₅₀ (dose that produces an evoked effect in 50% of the test cultures) (2). Control cultures receive compound or virus only. Five days after virus challenge, the cultures are visually examined for the frequency and distribution of virus-induced giant cell fusions. The% inhibition by test compound is determined by comparison with control values. The presence or absence of viral replication was confirmed by harvesting cell-free cultures from all test groups and infected progeny via induction of fusion cell formation in secondary human T cell cultures after 3 days. The presence or absence of.

Documents: (1) M. Somasundaran and HL Robinson, Scienc
e 242 , 1554 (1988) (2) GM Shaw, RH Hahn, SK Arya, JE Groo
pman, RC Gallo and F. Wong-Staal, Science 2
26 , 1165 (1984) In order to evaluate the specificity of the enzyme inhibitory activity of the compound of the present invention, a few compounds were used to analyze feline leukemia virus-derived reverse transcriptase and calf thymus-derived DNA using assay methods known per se. It was tested for its ability to suppress alpha polymerase. Thus none of the compounds tested were observed to have any inhibitory activity against these enzymes. These results indicate that the enzyme inhibiting activity of the compounds of the invention is rather specific for HIV-1RT.

To roughly estimate the cytotoxicity of the compounds of the present invention, several such compounds were tested in the MTT cytotoxicity assay described below. The results of this test are shown in Table 1 below. Compounds having a relatively high EC ₅₀ are preferred. MTT Assay for Cytotoxicity Assay Theory: The MTT [3- (4,5-dimethylthiazol-2yl] -2,5 diphenyltetrazolium bromide] assay is based on the division of tetrazolium bromide by metabolically active cells and is highly quantitative. Produces a sexual blue color, which has been previously disclosed (1),
It is most suitable for the purpose of this test. Assay method: H9 cell line (2), RPMI 1640 with 10% fetal bovine serum
Established human lymphocyte suspension cell lines grown in are used as target cell lines for this assay. Cells (100μ
l) is plated in microtest plate wells at a concentration of 10 ⁵ cells / ml in the presence of various concentrations of inhibitor. The cells are incubated at 37 ° C. in a warm CO ₂ incubator. After 5 days, 20 μl MTT (sonicated, 0.2 micron filtered, RPMI164 stored at 4 ° C.
5 mg / ml in 0) in each well. 4 more at 37 ° C
After incubation for 60 hours, 60 μl of Triton-X is added to each well and mixed well to promote dissolution of crystals. Absolute alcohol (5 μl) was added to each well and the resulting mixture was mixed with 6
Incubate for 30 minutes at 0 ° C and immediately read the plate reader (Dynatech) at a wavelength of 570 nm.

The data from this assay was used to generate E
A non-linear regression analysis giving the C ₅₀ , highest non-toxic concentration is performed. Document: 1. Mosmann, Tim, J. Immunol. Methods, 65:55,
1983 2. Jacobs. JP, J. Natl. Cancer Inst., 34: 2.
31, 1965 Table 1 Compound RT assay% inhibition T cell assay% inhibition Cytotoxicity assay (Example No.) (a) 10 μg / ml (a) 3 μg / ml (EC ₅₀ , μM) 10 100 NT NT 11 100 100 200 12 100 100 250 13 36 ^* NT NT 15 91 ⁺ 100 45 16 96 ⁺ 100 350 17 40 ^* NT NT 18 75 ^* NT NT 19 85 ^* NT NT 20 76 ^* NT NT 21 91 ^* NT NT 22 90 ^* NT NT 23 99 100 NT 24 87 NT NT 25 63 ^* NT NT

26 99 NT NT 27 99 NT NT 28 50 ^* NT NT 29 93 NT NT 30 85 NT NT 31 100 NT NT 32 88 NT NT 33 33 ^* NT NT 34 94 ^* NT NT 35 86 ^* NT NT 36 2 ^* NT NT 37 34 ^* NT NT 38 0 NT NT 39 100 NT NT 40 99 NT NT 41 100 NT NT 42 83 ^* NT NT 43 85 ^* NT NT 44 91 NT NT 45 64 ^* NT NT 46 70 ^* NT NT 47 34 ^* NT NT 48 0 ^* NT NT 49 0 ^* NT NT 50 43 43 ^* NT NT

51 90 ^* NT NT 52 44 NT NT 53 90 ^* NT NT 54 35 ^* NT NT 55 44 NT NT 56 100 100 NT 57 77 NT NT 58 52 ^* NT NT 59 44 ^* NT NT 60 20 ^* NT NT 61 72 ^* NT NT 62 17 ^* NT NT 63 30 ^# NT NT 64 61 ^* NT NT 65 68 ^* NT NT 66 66 ^* NT NT 67 37 ⁺ NT NT 68 8 ^* NT NT 69 90 ^* NT NT 70 75 ^* NT NT 71 0 ^* NT NT 72 98 ^* NT NT 73 94 ^* NT NT 74 74 82 ^* NT NT 75 100 NT NT 76 88 ^* NT NT ^* = (a) 1 μM ⁺ = (a) 1.25 μM ^# = (a) 0.5 μM NT = not tested

[0086]

The following examples further illustrate the present invention.
And those skilled in the art will more fully understand the invention.
Enable However, the present invention provides the following specific
It should be understood that it is not limited to the examples.
You. [Example 1]5,11-dihydro-6H-dipyrido
[3,2-b: 2 ', 3'-e] [1,4] diazepine
-6-on a)2-chloro-N- (2-chloro-3-pyridini
) -3-Pyridinecarboxamide Efficient reflux condenser, mechanical stirrer and
And a three-necked round bottom flask equipped with a dropping funnel.
0 ml dioxane, 500 ml cyclohexane and
215 g dissolved in a mixture with 130 ml pyridine
(1.672 mol) of 3-amino-2-chloropyridine
I put it in. 299.2 g (1.7 mol) of freshly prepared 2-
200 ml of chloro-3-pyridinecarboxylic acid chloride
Such as maintaining a vigorous reaction in a controlled solution in oxane
Added at speed. Then the reaction mixture is cooled to room temperature and obtained
The precipitated crystal precipitate was filtered off, and cyclohexane and ether were added.
It was washed continuously with.

The dark brown product was treated with 5 liters of sodium hydroxide.
It was dissolved in a 3% aqueous solution of um. The resulting solution is activated carbon
Treated, filtered with suction and the filtrate is acidified by adding 50% dilute acetic acid.
Sexualized. The precipitate obtained is collected by filtration and washed thoroughly with water.
did. After drying overnight in a stream of nitrogen at room temperature, almost nothing
The colored product has a m.p. of 156-159 ° C.
Was pure enough for the reaction. Yield is 376.0
Was (84% of theory). b)N- (2-chloro-3-pyridinyl) -2-
{[(4-methoxyphenyl) methyl] amino} -3-
Pyridine carboxamide 13.4 g (0.05 mol) of the product obtained in step a)
It was dissolved in 1 ml of xylene and the resulting solution was 13.8 g (0.
1 mol) of p-methoxybenzylamide. So
After that, the mixture was refluxed for 2 hours. Vacuum steam the reaction mixture
And the residue is filtered over silica gel (0.2-0.5 mm).
Dichloromethane / ethyl acetate by ram chromatography
Purified using 10/1 (v / v) as eluent. Dark
A colorless crystal that melts at 122 to 124 ° C.
After recrystallization from cetonitrile). Yield is 17.2g
(93% of theory).

C) 5,11-dihydro-11-[(4
-Methoxyphenyl) methyl] -6H-dipyrido [3,3
2-b: 2 ', 3'-e] [1,4] diazepine-6-
On 16.7 g (0.0453 mol) of the product obtained in step b) was dissolved in 150 ml of anhydrous dioxane and the resulting solution was added to 6.
Mixed with 7 g (0.14 mol) of a 50% sodium hydride dispersion in mineral oil. The mixture was then refluxed until the starting material could not be detected by TLC, protected by a low nitrogen stream against the external atmosphere. The excess sodium hydride was decomposed by careful addition of 10 ml of a mixture of methanol and tetrahydrofuran (50/50 v / v). The reaction mixture was neutralized by addition of acetic acid and then evaporated in vacuo. The residue was treated with silica gel (0.2-0.2).
Purification by column chromatography on 0.5 mm) using dichloromethane / ethyl acetate (10/1, v / v) and dichloromethane / ethyl acetate 1/1 (v / v) successively as eluents. The crystalline product obtained by evaporation of the appropriate fractions was recrystallized from acetonitrile and 2-propanol. The product has a m.p. of 213-215 ° C.
p.5,11-dihydro-11-[(4-methoxyphenyl) methyl] -6H-dipyrido [3,2-b:
It was identified as 2 ', 3'-e] [1,4] diazepin-6-one. The yield was 10.3 g (theoretical 68
%). d) 5,11-dihydro-6H-dipyrido [3,2-
b: 2 ', 3'-e] [1,4] diazepin-6-one 10.0 g (0.3 mol) of the product obtained in step c) in 50 ml.
Dissolved in trifluoroacetic acid, which caused the mixture to warm somewhat. Then the reaction mixture was stirred at 60 ° C. for 1 hour. The starting material was then undetectable by TLC. Then the mixture was evaporated in vacuo. The residue thus obtained was thoroughly stirred with 0.5% aqueous ammonia and then suction filtered. The crude product was recrystallized from 150 ml of dimethylsulfoxide to give colorless crystals with an mp of> 340 ° C. The yield was 4.8 g (theoretical value of 75).
%). The product was identified as 5,11-dihydro-6H-dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepin-6-one.

Example 2 5,11-Dihydro-11-
Propyl-6H-dipyrido [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
26.8 g (0.1 mol) of pyridinecarboxamide were dissolved in 200 ml of dioxane and the resulting solution was mixed with 21.4 g (0.362 mol) of propylamine. The mixture was then shaken in a stainless steel pressure vessel at 150 ° C for 6 hours. Then the reaction mixture is evaporated under reduced pressure, dichloromethane / ethyl acetate 10/1 (v / v) as eluent
And dichloromethane / cyclohexane / ethyl acetate 1 /
The residue was purified by chromatography on silica gel using 2/1 (v / v / v) successively. The product obtained by evaporation was a highly viscous resin of sufficient quality for the following reaction. b) 5,11-Dihydro-11-propyl-6H-dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepin-6-one with the procedure described in Example 1c). Using the same operation,
From the product obtained in step a) above and sodium hydride, 5,11-dihydro-11-propyl-6H-dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepine -6-one, mp 184-186 ° C (recrystallized with acetonitrile) was prepared. The yield was 74% of theory.

Example 3 5,11-Dihydro-5-me
Tyl-11-propyl-6H-dipyrido [3,2-b:
2 ', 3'-e] [1,4] -diazepin-6-one a) 2-chloro-N- (2-chloro-3-pyridinyl) -N-methyl-3-pyridinecarboxamide mechanical stirrer, A 4-neck round bottom flask equipped with a dropping funnel, thermometer and effective reflux condenser was charged with 2-chloro-N- (2
-Chloro-3-pyridinyl) -3-pyridinecarboxamide 268.1 g (1.0 mol), 50% aqueous sodium hydroxide 260 ml, toluene 1500 ml and benzyltriethylammonium chloride 8.0 g (0.0352 mol) were charged. It is. Stirring is begun and 134 ml of dimethylsulfate (178.5 g, 1.415 mol) in 1 liter of toluene.
Solution was added dropwise over a period of about 3 hours, which caused the temperature to rise to 50-60 ° C. After the addition of dimethylsulfate was completed, stirring at 60 ° C was continued for another 2 hours. The reaction mixture was cooled to room temperature and 1 liter of water was added. The layers were separated and the aqueous layer was extracted 3 times with 300 ml of toluene each time. The organic layers were combined and washed successively with 300 ml of water, 1% aqueous acetic acid and 300 ml of water. The combined organic extracts were dried over sodium sulfate and the solvent removed by distillation under reduced pressure. Toluene and ethyl acetate as eluent /
Cyclohexane / tetrahydrofuran 1/9/10 (v
/ V / v) in succession and the residue on silica gel (0.
2 to 0.5 mm) and purified by column chromatography. The product obtained by evaporation of the appropriate fractions is acetonitrile / tert-butyl methyl ether 1/1 (v / v)
It was recrystallized in. It is very soluble in dichloromethane, has a melting point of 98-101 ° C and is 2-chloro-N-
It was identified as (2-chloro-3-pyridinyl) -N-methyl-3-pyridinecarboxamide. Yield 2
It was 32.5 g (82.5% of theory).

B) N- (2-Chloro-3-pyridinyl) -N-methyl-2- (propylamino) -3-pyridinecarboxamide Using a procedure similar to that described in Example 2a, above. From the product obtained in the above step and propylamine to N-2
-Chloro-3-pyridinyl) -N-methyl-2- (propylamino) -3-piperidinecarboxamide was prepared. The yield was 91% of theory. c) 5,11-Dihydro-5-methyl-11-propyl-6H-dipyrido [3,2-b: 2 ', 3'-e]
[1,4] diazepin-6-one Using a procedure similar to that described in Example 1c except that tetrahydrofuran was used as the solvent instead of dioxane and only equimolar amounts of sodium hydride were applied. , A very viscous oil, 5,11-dihydro-5-methyl-11-propyl-
6H-dipyrido [3,2-b: 2 ', 3'-e] [1,
4] Diazepin-6-one was prepared from the product obtained in the above step. 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-dipyrido [3,2-b:
2 ', 3'-e] [1,4] diazepin-6-one 6.4
g (0.03 mol) 100 ml of anhydrous dimethylformamide
Of sodium hydride in mineral oil.
It was mixed with 3.4 g (0.071 mol) of a 50% dispersion. nitrogen
Mixing while protected against the external atmosphere by the flow
The product was stirred at 50-70 ° C for 1 hour. Hydrogen generation stopped
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. Fever
To complete the reaction, the mixture is heated at 80-90 ° C for another hour.
Heated. The solvent was removed by distillation under reduced pressure. The residue
Mix with water and suspend the suspension thus obtained in dichloromethane
Thoroughly extracted with. The product obtained after normal processing
Recrystallized with 150 ml of isooctane. The product has a melting point of 10
2 to 103 ° C., 5,11-diethyl-5,11-
Dihydro-6H-dipyrido [3,2-b: 2 ', 3'-
e] [1,4] diazepin-6-one
Was. The yield was 5.7 g (71% of theory).

Example 5 5,11-Dihydro-5-d
Tyl-6H-dipyrido [3,2-b: 2 ', 3'-e]
[1,4] diazepin-6-one a) N- (2-chloro-3-pyridinyl) -2-
[(Phenylmethyl) amino] -3-pyridinecarboxamide 2-chloro-N was prepared using the same procedure as described in Example 1b, except that diethylene glycol dimethyl ether was used as the solvent instead of xylene.
-(2-Chloro-3-pyridinyl) -3-pyridinecarboxamide and benzylamine to N- (2-chloro-3-pyridinyl) -2-[(phenylmethyl) amino] -3-pyridinecarboxamide, melting point 95 ~ 97
C. (recrystallized with diethylene glycol dimethyl ether) was prepared. The yield was 72% of theory. b) 5,11-dihydro-11- (phenylmethyl)
-6H-dipyrido [3,2-b: 2 ', 3'-e]
[1,4] diazepin-6-one Using the procedure similar to that described in Example 1c, except using diethylene glycol dimethyl ether instead of dioxane as the solvent, the product obtained in step a) and From sodium hydride to 5,11-dihydro-11- (phenylmethyl) -6H-dipyrido [3,2-b: 2 ', 3'-e]
[1,4] diazepin-6-one, melting point 212-213
C (recrystallized with 1-propanol) was prepared. The yield was 61% of theory.

C) 5,11-dihydro-5-ethyl-
11- (phenylmethyl) -6H-dipyrido [3,2-
b: 2 ', 3'-e] [1,4] diazepin-6-one Using a procedure similar to that described in Example 3a, the product obtained in step b) and diethyl sulphate 5 , 11
-Dihydro-5-ethyl-11- (phenylmethyl)-
6H-dipyrido [3,2-b: 2 ', 3'-e] [1,
4] Prepared diazepin-6-one, melting point 209-211 ° C (recrystallized with toluene / acetonitrile 1/1 v / v). The yield was 82% of theory. d) 5,11-Dihydro-5-ethyl-6H-dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepin-6-one A pressure vessel is used instead of the open vessel. Then, using a procedure similar to that described in Example 1d, except heating the mixture at 120 ° C. for 10 hours, from the product obtained in step c) 5,11-dihydro-5-ethyl-6H. Preparation of dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepin-6-one, melting point 161-163 ° C (recrystallized with isooctane / ethyl acetate 1/1 v / v) did. The yield was 57% of theory.

Example 6 5,11-Dihydro-5-me
Tyl-6H-dipyrido [3,2-b: 2 ', 3'-e]
[1,4] Diazepin-6-one a) N- (2-chloro-3-pyridinyl) -N-methyl-2-[(phenylmethyl) amino] -3-pyridinecarboxamide Described in Example 1b. Using the same operation as the operation, 2
-Chloro-N- (2-chloro-3-pyridinyl) -N-
Methyl-3-pyridinecarboxamide and benzylamine to N- (2-chloro-3-pyridinyl) -N-methyl-2-[(phenylmethyl) amino] -3-pyridinecarboxamide, melting point 114-116 ° C (tert. -Butyl methyl ether / dichloromethane / ethyl acetate 3 /
Was recrystallized at 1 v / v). The theoretical yield is 8
7%. b) 5,11-dihydro-5-methyl-11- (phenylmethyl) -6H-dipyrido [3,2-b: 2 ',
3'-e] [1,4] diazepin-6-one 5,11-dihydro-5-from the product obtained in step (a) using a procedure similar to that described in Example 3b.
Methyl-11- (phenylmethyl) -6H-dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepin-6-one, melting point 198-199 ° C (recrystallized with acetonitrile) Was prepared. The yield was 80% of theory.

C) 5,11-dihydro-5-methyl-
6H-dipyrido [3,2-b: 2 ', 3'-e] [1,
4] diazepin-6-one 75.5 g (0.239 mol) of the product obtained in step b),
A mixture consisting of 2.5 kg of polyphosphoric acid and 425 ml of anisole was stirred at 140-160 ° C. for 2 hours. The reaction mixture was stirred in crushed ice while still hot. After that, the mixture was made slightly alkaline by adding aqueous ammonia,
Then it was thoroughly extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. Dichloromethane / ethyl acetate 1/1 (v / v) as eluent
The residue was chromatographed on silica gel with. The product obtained by evaporation of the appropriate fractions was recrystallized from acetoniryl to give 21.6 g (40% of theory) of colorless crystals with a melting point of 236 ° -237 °.

Example 7 5,11-Dihydro-6H-
Dipyrido [3,2-b: 2 ', 3'-e] [1,4] di
Azepin-6-one 3.8 g (0.0126 mol) of the product obtained in Example 5b.
Was dissolved in 20 ml of trifluoroacetic acid, which caused the mixture to become slightly warm. Then the reaction mixture was refluxed for 8 hours. At that point no starting material could be detected by TLC. Then the mixture was evaporated under reduced pressure and the residue thus obtained was thoroughly stirred with 0.5% aqueous ammonia and then filtered by suction. The crude material was suspended in 20 ml of acetonitrile, refluxed for 15 minutes and suction filtered while hot. The filter cake is recrystallized with hot dimethylsulfoxide to give 1.2 g (45% of theory) of colorless crystals, having a melting point> 340 ° C., melting point, mixed melting point and UV spectrum, IR spectrum and MS. The spectrum was identified to be the same as the compound obtained in Example 1d.

[Embodiment 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-pyridini
Ru) -3-Pyridinecarboxamide using a procedure similar to that described in Example 1a, 2
-Chloro-N- (2-chloro-3-pyridinyl) -3-
Pyridinecarboxamide was prepared. Chamber the reaction mixture
By cooling to warm and decanting the supernatant from the precipitate
A purified product was obtained. Then dissolve the solid in methylene chloride
Solution, wash the solution with water, dry (anhydrous sodium sulfate), and dissolve.
The medium was removed under reduced pressure. Then wash the solid with ethyl acetate
7.24 g of product which is then dried and suitable for use in the next reaction
(84% of theory) was obtained. b) N- (2-chloro-3-pyridinyl) -2-
[[(4-Methoxyphenyl) methyl] amino] -3-
Pyridinecarboxamide Using a procedure similar to that described in Example 1b, N
-(2-chloro-3-pyridinyl) -2-[[(4-me
Toxyphenyl) methyl] amino] -3-pyridinical
Voxyamide was prepared. The solvent was removed under reduced pressure leaving water behind.
By adding to the residue and extracting the product with methylene chloride.
A purified product was obtained. This solution is dried (anhydrous sodium sulfate).
The solvent was removed to give a brown oil which was washed with ether.
Treated with 10 ml. The crystallized product is filtered off with ether
And washed successively with hexane and off-white powder (melting point 1
78.0 g (theoretical value) of the title compound as 21-122 ° C.
91% of) was obtained.

C) 5,11-dihydro-11-[(4
-Methoxyphenyl) methyl] -6H-dipyrido [3,3
2-b: 2 ', 3'-e] [1,4] diazepine-6-
50% dispersion of sodium hydride in on mineral oil 1.44
3.69 g (0.010 mol) of N- (2-chloro-3-pyridinyl) -2-[[(4-methoxyphenyl) methyl] amino] -3-pyridine-carboxamide in 100 ml of dimethylformamide. Added to the solution. After hydrogen evolution has stopped, heat the mixture for 16 hours (110 ° C)
And then refluxed for 8 hours. After the mixture has cooled,
Excess sodium hydride was destroyed by the gradual addition of ice. The mixture was further diluted with water and the product was extracted with ether and concentrated. The crystallized residue was filtered to give 5,11-dihydro- as an off-white powder (mp 209-210 ° C).
1.60 g (50% of theory) of 11-[(4-methoxyphenyl) methyl] -6H-dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepin-6-one Got d) 5,11-Dihydro-11-[(4-methoxyphenyl) methyl] -5-methyl-6H-dipyrido [3.
2-b: 2 ', 3'-e] [1,4] diazepine-6-
on

5,11-Dihydro-11-[(4-methoxyphenyl) methyl] -6H-dipyrido [3,2-
b: 2 ', 3'-e] [1,4] diazepin-6-one 10.0 g (0.030 mol), 2.16 g of a 50% dispersion of sodium hydride in mineral oil and 100 ml of dimethylformamide. Was added to the flask containing. The resulting mixture was stirred at room temperature for 30 minutes and then heated at 50 ° C. for 30 minutes. After cooling, 8.51 g (0.060 mol) of methyl iodide in 10 ml of dimethylformamide were added dropwise and the mixture was stirred at room temperature overnight. Excess sodium hydride was destroyed by careful addition of ice. Then add water, extract the product with ether and dry (anhydrous sodium sulfate)
, 11-dihydro-11-[(methoxyphenyl) methyl] -5-methyl-6H-dipyrido- [3,2 as a pale yellow oil, suitable for concentration and use in the next reaction.
-B: 2 ', 3'-e] [1,4] diazepin-6-one (10.3 g, 99% of theory) was obtained.

E] 5,11-dihydro-5-methyl-
6H-dipyrido [3,2-b: 2 ', 3'-e] [1,
4] Diazepin-6-one 50 ml of trifluoroacetic acid was added to 5,11-dihydro-11-
[(4-Methoxyphenyl) methyl] -5-methyl-6
H-dipyrido [3,2-b: 2 ', 3'-e] [1,
4] -diazepin-6-one 10.3 g (0.030 mol)
And the mixture was stirred at room temperature for 1 hour. The acid was removed under reduced pressure and the residue was stirred with 0.5% ammonia for 1 hour. The solid was filtered and dried to give pure 5,11-dihydro-5-methyl-6H-dipyrido [3,2-b: 2 ',
3'-e] [1,4] diazepin-6-one (melting point 23
6.70 g (98% of theory) were obtained.
f) 5,11-Dihydro-11-ethyl-5-methyl-6H-dipyrido [3,2-b: 2 ', 3'-e]
[1,4] diazepin-6-one 2.00 g of a 50% dispersion of sodium hydride in mineral oil was added to dimethylformamide 1
5,11-Dihydro-5-methyl-6H-dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepin-6-one 5.75 g (0.025 mol) in 00 ml Was added to the solution. When hydrogen evolution ceased, the mixture was heated to 50 ° C for 3
Heat for 0 minutes and then cool to room temperature. Then, 7.80 g of ethyl iodide (neat) was added dropwise over 15 minutes and the resulting mixture was stirred overnight at room temperature. Excess sodium hydride was decomposed by careful addition of ice followed by water. The product was extracted with ether, dried (anhydrous sodium sulfate) and evaporated to give 5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido [3,3.
2-b: 2 ', 3'-e] [1,4] diazepine-6-
ON (melting point 130-132 °) 4.5g (theoretical value 70
%) Was obtained.

[Embodiment 9]5,11-dihydro-11-
Ethyl-5-methyl-6H-dipyrido [3,2-b:
2 ', 3'-e] [1,4] diazepine-6-thione 5,11-Dihydro-11-ethyl in 50 ml of toluene
-5-methyl-6H-dipyrido [3,2-b: 2 ',
3'-e] [1,4] diazepin-6-one and Laue
Sussen reagent (2,4-bis (4-methoxyphenyl)-
1,3-dithia-2,4-diphosphetan-2,4-di
2.10 g (0.005 mol) of a mixture of 2¹/
₂Reflux for hours. Then the solvent is removed under reduced pressure and the water is removed.
Added to the residue. The product is extracted with ethyl acetate and dried
(Anhydrous sodium sulfate) and concentrated under reduced pressure. First elution
Methylene chloride was used as the agent, followed by ethyl acetate /
Purification on silica gel using xane (1: 4)
Was. The solvent was removed under reduced pressure to remove 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, which
Recrystallized with 10% hexane / ethyl acetate to give a yellow needle
Compound 1.1 as crystalline crystals (melting point 157-158 ° C)
g was obtained.

Example 10 5,11-Dihydro-11
-Ethyl-2-methyl-4-trifluoromethyl-6H
-Dipyrido [3,2-b: 2 ', 3'-e] [1,4]
Diazepin-6-one a) 3-cyano-2-hydroxy-6-methyl-4-
(Trifluoromethyl) pyridine A solution of 14.0 g of cyanoacetamide in 80 ml of ethanol was warmed to 50 ° C, after which 14 g of piperidine and 25 g of trifluoroacetylacetone were added. The resulting mixture was stirred at 70 ° C. for 30 minutes and then at room temperature overnight. The mixture was concentrated under reduced pressure and then diluted with 100 ml of water. Concentrated hydrochloric acid (15 ml) was added cautiously with stirring and after 15 minutes the precipitate was filtered and dried under reduced pressure overnight to give 27.8 g of the desired cyanopyridine. b) 3-Aminocarbonyl-2-chloro-6-methyl-4- (trifluoromethyl) pyricin 35 ml phosphorus oxychloride and the cyanopyridine obtained above
9.8 g of the mixture was refluxed for 5 hours. The reaction was stopped by the careful addition of the cooled mixture to 400 ml of ice water. The product was extracted with methylene chloride, washed with saturated sodium bicarbonate and dried (magnesium sulfate). After filtering and concentrating under reduced pressure, the crude chloro compound was added to concentrated sulfuric acid 50
It was dissolved in ml and heated to 140 ° C. for 20 minutes. The cooled mixture was carefully poured onto 600 ml of ice, the precipitate was filtered, washed with ice water and dried to give 7.6 g of the desired amide. The filtrate was extracted with 200 ml of ethyl acetate, dried (magnesium sulfate), filtered and concentrated to give an additional 1.7 g of product.

C) 3-Amino-2-chloro-6-methyl-4- (trifluoromethyl) pyricine To a solution of 6.6 g sodium hydroxide in 60 ml water at 5 ° C. was added 9.3 g bromine. When a clear solution was obtained, 9.2 g of 3-aminocarbonyl-2-chloro-6-methyl-4- (trifluoromethyl) pyricin was added rapidly and the temperature was adjusted to 5
Kept below ℃. The resulting mixture was stirred until the 3- (aminocarbonyl) pyridine was dissolved (about 30 minutes). The cooling bath was removed and then the mixture was warmed to 75 ° C. for 30 minutes. After cooling to room temperature, the 2-aminopyridine product is extracted with ethyl acetate and dried (magnesium sulfate).
, Filtered and evaporated to give 4.9 g of the desired product. d) 2-chloro-N- (2-chloro-6-methyl-4
-Trifluoromethyl-3-pyridinyl) -3-pyridinecarboxamide A cooled (-78 ° C) solution of 2.1 g of 3-amino-2-chloro-6-methyl-4- (trifluoromethyl) pyridine in 10 ml of THF. To this was added 7 ml of lithium diisopropylamine (LDA, 1.5M in cyclohexane) dropwise over 3 minutes. The mixture was stirred for 5 minutes and 0.9 g of 2-chloronicotinoyl chloride in 3 ml of THF was added over 1 minute. After 5 minutes, another 3 ml of LDA solution was added and then T
Another 0.5 g of acid chloride in 1 ml of HF was added. The resulting mixture was stirred for 10 minutes and then quenched with 100 ml of water. After partitioning with 30 ml of ethyl acetate, the organic phase is extracted with water, the combined aqueous phases are extracted with methylene chloride, dried (magnesium sulfate), filtered and evaporated to give the crude product. This was washed with a small amount of ethyl acetate and dried to obtain 1.3 g of the title compound.

E] N- (2-chloro-6-methyl-4)
-Trifluoromethyl-3-pyridinyl) -2-ethylamino-3-pyridinecarboxamide ethylamine (0.4 g) in 2-chloro-N- (2-chloro-6-methyl-4-trifluoro) in 5 ml xylene. Methyl-3-pyridinyl) -3-pyridinecarboxamide was added to a suspension of 1.3 g and the resulting mixture was heated in a pressure tube at 160 ° C. for 30 minutes. The cooled mixture was diluted with ethyl acetate, washed, dried and concentrated. Column chromatography on silica gel (ethyl acetate / hexane, 1: 1) yielded 0.5 g of the title compound. f) 5,11-Dihydro-11-ethyl-2-methyl-4-trifluoromethyl-6H-dipyrido [3,2-
b: 2 ', 3'-e] [1,4] diazepin-6-one N- (2-chloro-6-methyl-4-in 3 ml of pyridine.
A solution of 0.5 g of trifluoromethyl-3-pyridinyl) -2-ethylamino-3-pyridinecarboxamide was added to 0.2 g of a 50% dispersion of sodium hydride in oil. The mixture was heated to 150 ° C. then cooled and concentrated under reduced pressure. Water was added to the residue and the product was extracted with ethyl acetate, dried (magnesium sulfate), filtered and concentrated.
The product was purified by column chromatography on silica gel (methylene chloride then methylene chloride / methanol). After concentrating under reduced pressure, the residue was crystallized from hexane to obtain 0.09 g of the title compound (melting point: 150-151 ° C).

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-hydroxy-4-methyl-3-nitropyridine 25
g, 12.5 g of phosphorus pentachloride, and 62 ml of phosphorus oxychloride were refluxed for 2 hours. After cooling, the mixture was poured onto crushed ice and stirred until precipitation occurred. The product was extracted with methylene chloride, dried (sodium sulfate), concentrated to a brown oil, which was washed with hot hexane. Concentration under reduced pressure gave 16.2 g of the title compound (mp 45-47 ° C). b) 3-Amino-2-chloro-4-methylpyridine 2-chloro-4-methyl-3-nitropyridine 16.2 g
Was added to 470 ml of acetic acid and the resulting mixture was stirred at room temperature for 15 minutes.
Stir for minutes. Then a solution of 160 g stannic chloride dihydrate in 200 ml concentrated hydrochloric acid was added in one portion and the resulting mixture was stirred at room temperature overnight. This mixture was then diluted to 1 liter with water and 10N sodium hydroxide was added slowly until the white precipitate of tin hydrochloride dissolved. The product is extracted with methylene chloride and dried (sodium sulfate)
And concentrated to give 12.8 g of a yellow oil, which is almost pure 3-amino-2-chloro-, suitable for use in the next reaction.
It was an oil of 4-methylpyridine and solidified on standing. c) 2-chloro-N- (2-chloro-4-methyl-3
-Pyridinyl) -3-pyridinecarboxamide using a procedure similar to that described in Example 1a, 3
-Amino-2-chloro-4-methylpyridine 12.8 g,
2-chloronicotinoyl chloride 15.8 g, pyridine 7.
The carboxamide was prepared from 1 g, 30 ml cyclohexane and 60 ml dioxane. After removal of the solvent, the product was dissolved in methylene chloride, washed with water and dried (sodium sulfate). After removing the solvent, the residue was washed with ethyl acetate to obtain 1.2 g of the title compound (melting point 193-194 ° C.).

D) N- (2-chloro-4-methyl-3)
-Pyridinyl) -2-ethylamino-3-pyridinecarboxamide Ethylamine (12.7 g) was added to xylene 15 in steel hombe.
2-chloro-N- (2-chloro-4-methyl- in 0 ml
3-pyridinyl) -3-pyridinecarboxamide 21.
Added to 0 g of suspension. Then the mixture is 1 in an oil bath.
Heat to 65 ° C. for 6 hours and then stir at room temperature overnight. The solvent was removed under reduced pressure and water was added to the residue. The product was extracted with ether, dried (sodium sulfate) and concentrated to give an oil. This was dissolved in ethyl acetate and then hexane was added, at which time precipitation occurred. The solid was filtered and dried to give 16.5 g of the title compound (mp 122-124 ° C). e] 5,11-Dihydro-11-ethyl-4-methyl-6H-dipyrido [3,2-b: 2 ', 3'-e]
[1,4] diazepin-6-one A 50% suspension of sodium hydride (7.9 g) in N- (2-chloro-4-methyl-3-pyridinyl) obtained above in 200 ml of dimethylformamide. ) -2-Ethylamino-3-pyridinecarboxamide (16.0 g) was added to the solution and stirred for 30 minutes. The mixture was then refluxed for 2 hours, cooled and carefully treated with crushed ice. The solvent was removed under reduced pressure and water was added to the residue. The product was extracted with ether, dried (sodium sulfate) and concentrated. The residue was boiled with ethyl acetate / cyclohexane (1: 1) and filtered to give 4.1 g of almost pure product. 2.0 g of this product was recrystallized from dichloroethane for further purification to give pure 5,11-
1.0 g of dihydro-11-ethyl-4-methyl-6H-dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepin-6-one (melting point 212-214 ° C) was obtained. It was

[Embodiment 12]11-cyclopropyl-
5,11-dihydro-4-methyl-6H-dipyrido
[3,2-b: 2 ', 3'-e] [1,4] diazepine
-6-on Use cyclopropylamine instead of ethylamine
Except that the same operation as that described in Example 11 was used.
To give the title compound (mp 247 ° -249 ° C.)
Was.

[Example 13]11-cyclopropyl-
5,11-dihydro-5-hydroxy-4-methyl-6
H-dipyrido [3,2-b: 2 ', 3'-e] [1,
4] diazepin-6-one 11-Cyclopropyl-in 25 ml of tetrahydrofuran
5,11-dihydro-4-methyl-6H-dipyrido
[3,2-b: 2 ', 3'-e] [1,4] diazepine
-6-one (Example 12) 0.5 g of a mixture of 5 in mineral oil
0.12 g of 0% sodium hydride was added. Reaction mixture
The mixture was stirred at room temperature for 1 hour, then cooled to 0 ° C, at which time
Oxodiperoxymolybdenum (pyridine) -hex at the point
Add 0.9 g of samethylphosphoramide (MoOPH) at once
Was. Then the reaction mixture was warmed to room temperature and stirred overnight.
The mixture was quenched with water and the solvent removed under reduced pressure. The rest
The residue is extracted with warm ethyl acetate, concentrated under reduced pressure, and concentrated with silica gel.
Pure column 11 (eluent: ethyl acetate)
-Cyclopropyl-5,11-dihydro-5-hydroxy
Ci-4-methyl-6H-dipyrido [3,2-b: 2 ',
3'-e] [1,4] diazepin-6-one (melting point 23
0.05 g (9-241 ° C.) was obtained. Yield is 9.5% of theory
Met.

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-methoxypyridine Sodium acetate (1.6g) was added to a solution of 5-amino-2-methoxypyridine (2.5g) in acetic acid (15ml). . Bromine (3.0 g) was added dropwise to the resulting solution,
The mixture was stirred for 20 minutes and then added to a solution of sodium hydroxide (10g) in water (100ml). The product was extracted with ethyl acetate (50 ml), dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The product was purified on a silica gel column (ethyl acetate / hexane, 1: 4) to give 2.7 g of the title compound suitable for use in the next reaction. b) N- (2-Bromo-6-methoxy-3-pyridinyl) -2-chloro-3-pyridinecarboxamide 3--in methylene chloride (20 ml) and pyridine (1 ml).
Amino-2-bromo-6-methoxypyridine (2.7g)
2-Chloronicotinoyl chloride (2.2 g) was added to the solution of and the resulting mixture was stirred for 20 minutes. afterwards,
After mixing, dilute with methylene chloride (100 ml) and mix with water (10 ml).
It was washed with 0 ml), dried (anhydrous magnesium sulfate) and concentrated. The semi-solid residue was saturated with hexanes, filtered and dried to give 4.1 g of product suitable for use in the next reaction.

C) N- (2-bromo-6-methoxy-
3-Pyridinyl) -2-chloro-N-methyl-3-pyridinecarboxamide Sodium hydride (0.3 g of 50% dispersion in mineral oil) was added to dimethyl sulfoxide (10 ml) and warmed to 50 ° C. After cooling the mixture to room temperature, N- (2-bromo-6
-Methoxy-3-pyridinyl) -2-chloro-3-pyridinecarboxamide (2.0 g) was added and the resulting solution was stirred for 10 minutes. Then, methyl iodide (0.4 ml)
Was added and the mixture was stirred for 30 minutes. The reaction mixture was quenched by the addition of water (10 ml), then ethyl acetate (100 ml) was added. The organic phase is water (4 x 100 m
l) washed, dried (anhydrous magnesium sulfate), concentrated and a silica gel column (methylene chloride followed by methylene /
Purification with ethanol, 98: 2) gave 1.9 g of the title compound suitable for use in the next reaction. d) N- (2-Bromo-6-methoxy-3-pyridinyl) -2-ethylamino-N-methyl-3-pyridinecarboxamide Ethylamine (0.7g) in N- in xylene (5ml).
(2-Bromo-6-methoxy-3-pyridinyl) -2-
Chloro-N-methyl-3-pyridinecarboxamide (1.9 g) was added to the solution and the resulting mixture was sealed in a pressure bottle and heated at 150 ° C for 4 hours. Dilute the solution with ethyl acetate, wash with water, and dry (anhydrous magnesium sulfate).
, Concentrated and purified by silica gel column (ethyl acetate / hexane, 1: 4) to give 1.5 g of the title compound suitable for use in the next reaction.

E] 5,11-Dihydro-11-ethyl-2-methoxy-5-methyl-6H-dipyrido [3,2]
-B: 2 ', 3'-e] [1,4] diazepin-6-one Sodium hydride (0.9 g of a 50% dispersion in mineral oil) was added to N- (2-bromo) in xylene (20 ml). -6-Methoxy-3-pyridinyl) -2-ethylamino-N-methyl-3-pyridinecarboxamide (1.4 g) was added and the mixture was refluxed for 2 hours. After cooling, the mixture was quenched with methanol, diluted with ethyl acetate and washed with water. The organic phase is dried (anhydrous magnesium sulfate), concentrated and a silica gel column (ethyl acetate / hexane, 1:
Purification in 4) gave a fairly pure product which was then recrystallized twice from ethyl acetate / hexane to give pure 5,11
-Dihydro-11-ethyl-2-methoxy-5-methyl-6H-dipyrido [3,2-b: 2 ', 3'-e]
[1,4] diazepin-6-one (melting point 116-118
C.) 0.52 g was obtained.

Example 15 5,11-Dihydro-11
-Ethyl-5-methyl-2- (N-pyrrolidino) -6H
-Dipyrido [3,2-b: 2 ', 3'-e] [1,4]
Diazepin- 6-one a) 5,11-dihydro-11-ethyl-2-hydroxy-5-methyl-6H-dipyrido [3,2-b:
2 ', 3'-e] [1,4] diazepin-6-one Hydrobromic acid (48%, 2 ml) in acetic acid (2 ml)
1-dihydro-11-ethyl-2-methoxy-5-methyl-6H-dipyrido [3,2-b: 2 ', 3'-e]
Add to a solution of [1,4] diazepin-6-one (0.3 g) and heat the resulting mixture to reflux for 5 minutes. The reaction mixture was quenched with 10% sodium hydroxide (10 ml), the product was extracted with ethyl acetate, dried (anhydrous magnesium sulfate) and concentrated to give a solid which was recrystallized from ethyl acetate to yield. Substance (melting point 215 to 218 ° C.)
08 g were obtained. b) 5,11-Dihydro-11-ethyl-5-methyl-2-trifluoromethanesulfonyloxy-6H-dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepine-6- 5,11-Dihydro-11-ethyl-2-hydroxy-5-methyl-6H- in methylene chloride (4 ml) under nitrogen.
A solution of dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepin-6-one (0.2 g) was added to diisopropylethylamine (0.2 ml) followed by trifluoromethanesulfonic anhydride ( 0.2 ml) was added. The resulting mixture was stirred for 1 hour then diluted with methylene chloride (20 ml) and washed with water. Dry the organic phase (anhydrous magnesium sulfate)
, Concentrated and purified on silica gel column (ethyl acetate / hexane, 1: 3) to give a fairly pure product suitable for use in the next reaction.

C) 5,11-Dihydro-11-ethyl-5-methyl-2- (N-pyrrolidino) -6H-dipyrido [3,2-b: 2 ', 3'-e] [1,4] Diazepin-6-one 5,11-dihydro-11-ethyl-5-methyl-2-
Trifluoromethanesulfonyloxy-6H-dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepin-6-one (0.25 g) was dissolved in pyrrolidine (1 ml) and refluxed for 30 minutes. It was The colored solution was diluted with ethyl acetate, washed with water, the organic phase was dried (anhydrous magnesium sulfate) and concentrated. The obtained oily residue was crystallized from ethyl acetate / hexane to give 5,11-dihydro-11-ethyl-5-methyl-2-N- (pyrrolidino) -6H-dipyrido [3,3.
2-b: 2 ', 3'-e] [1,4] diazepine-6-
0.11 g of on (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-nitropyridine sodium methoxide (26.1 g) was added to methanol (10
1-chloro-4-methyl-5-nitropyridine (19.0 g) in 0 ml) and the resulting mixture was added to 12 ml.
Reflux for hours. After cooling, the mixture was poured 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, the residue was dissolved in hot ether and filtered. Crystallization with ether gave 10.2 g of the title compound suitable for use in the next reaction. b) 5-Amino-2-methoxy-4-methylpyridine stannous chloride dihydrate (41 g) and concentrated hydrochloric acid (40 ml).
Was slowly added to a solution of 2-methoxy-4-methyl-5-nitropyridine (5.1 g) in acetic acid (40 ml) keeping the temperature below 35 ° C. The resulting mixture was stirred at room temperature for 2 hours and then left in the refrigerator overnight. The solid was collected and both the solid and the supernatant were basified separately with 20% sodium hydroxide solution. The products were extracted with chloroform, combined, dried (anhydrous magnesium sulfate) and concentrated to give 3.9 g of the title compound as a solid suitable for use in the next reaction.

C) 3-Amino-2-bromo-6-methoxy-4-methylpyridine Bromine (4.8 g) in 5-amino-2-methoxy-in acetic acid (25 ml) and sodium acetate (4.0 g). Added to a mixture of 4-methylpyridine (3.9 g) in one portion. The resulting mixture was stirred for 20 minutes and then added to a solution of sodium hydroxide (15g) in water (200ml). The product is extracted with chloroform, dried (anhydrous magnesium sulphate), concentrated and purified on a silica gel column (methylene chloride / ethyl acetate, 19: 1 → 4: 1) suitable for use in the next reaction. There was obtained 4.5 g of the title compound. d) N- (2-bromo-6-methoxy-4-methyl-
3-Pyridinyl) -2-chloro-3-pyridinecarboxamide 2-chloronicotinoyl chloride (3.5 g) was added to 3-amino-2-bromo-6-methoxy-4- in methylene chloride.
Methylpyridine (4.5 g) was added and the resulting mixture was stirred at room temperature overnight and triturated with diisopropyl ether. The solid that precipitated was filtered to give 6.0 g of the title compound suitable for use in the next reaction. e] N- (2-bromo-6-methoxy-4-methyl-
3-pyridinyl) -2-ethylamino-3-pyridinecarboxamide N- (2-bromo-6-methoxy-4-methyl-3-pyridinyl) -2-chloro-3-pyridinecarboxamide (2.1 g), Mix a mixture of dioxane (10 ml) and ethylamine (0.5 g) at 140 ° C. in a sealed tube at 5 ° C.
Heated for hours. Dilute the cooled mixture with ethyl acetate,
It was washed with water, the organic phase was dried (anhydrous magnesium sulfate) and concentrated. The product was purified by silica gel column (methylene chloride / ethyl acetate, 99: 1) and crystallized by trituration with diisopropyl ether to give 0.95 g of the title compound.

F) 5,11-Dihydro-11-ethyl-2-methoxy-4-methyl-6H-dipyrido [3,2
-B: 2 ', 3'-e] [1,4] diazepin-6-one sodium hydride (0.14 g of a 50% dispersion in mineral oil)
Was added to a solution of N- (2-bromo-6-methoxy-4-methyl-3-pyridinyl) -2-ethylamino-3-pyridinecarboxamide (0.54 g) in pyridine (4 ml), resulting The mixture was refluxed for 1.5 hours. The cooled mixture was diluted with ethyl acetate, washed with water, the organic phase was dried (anhydrous magnesium sulfate) and concentrated. The residue was washed with diisopropyl ether and then hot ethyl acetate and then crystallized from ethanol to give 5,11-dihydro-11-ethyl-2-methoxy-4-methyl-6H-dipyrido [3,3].
2-b: 2 ', 3'-e] [1,4] diazepine-6-
0.2 g of on (melting point 249-251 ° C.) was obtained.

Examples 17-73 The compounds of Examples 17-73 shown below in Table II were prepared using procedures similar to those described above.

Table II The compounds in this table are of the formula:

[0120]

Embedded image

(In the formula, R ^{1 to} R ⁸ are as follows and Z is an enzyme atom unless otherwise stated to be a sulfur atom.) Example R ¹ R ² Others Melting point (° C.) 17 Methyl ethyl 3- Chloro, 2-nitro 215-216 18 H cyclobutyl 4-methyl 214-215 19 H cyclopropyl 2,4-dimethyl> 300 20 H cyclopropyl 4-ethyl 228-230 21 H ethyl 2-chloro, 4-methyl 224- 228 22 H cyclopropyl 2-chloro, 4-methyl 310-320 23 H ethyl 211-212 24 methyl t-butyl 192-194 25 methyl ethyl 8-azide 265-266 26 H isopropyl 204-206 27 H cyclopropyl 240- 250 28 Methyl cyclopropyl 4-methyl 244-245 29 Methyl cyclopropyl 138-139-Methyl

30 H (R) -2-Butyl 172-174 31 Methyl ethyl 2,3-Dimethyl 143-145 32 H (S) -2-Butyl 173-175 33 H Cyclopentyl 225-228 34 Methyl ethyl 2- ( Pyrrolidine-1-yl 244-246), 4-methyl 35 methyl ethyl 2- (3-pyrroline-1-153-156yl) 36 H ethyl 7,9-dimethyl 245-247 37 methyl cyclopentyl 38 methoxy methoxy-methyl 4-Methyl 135-137-Methyl 39 H Ethyl 2-chloro, 4-tri-158-160 Fluoromethyl 40 H Cyclobutyl 241-243 41 Methyl Cyclobutyl 144-146 42 H Cyclopropyl 4-Chloro NA 43 Methyl Ethyl 2- ( Tetrahydro-138-140 pyridin-1-yl)

44 H cyclopropyl 4-methoxy 185-187 45 methyl ethyl 2- (p-methoxy-ben 83-85 dimethyl-amino) 46 methyl ethyl 2-allylamino 167-170 47 H cyclopropyl 4-hydroxymethyl 243- 246 48 Methyl ethyl 3,8-dinitro 167-169 49 Methyl ethyl 2,8-dinitro, 3-chloro 215-216 50 H cyclopropyl 4-methyl, 7-hydroxy 225-227 51 H cyclopropyl 4-methyl, ( Z = S) 189-194 52 Methyl cyano 274-277 53 Methyl cyclohexyl 145-146 54 H Cyclohexyl 199-201 55 H Ethyl 7,9-dimethyl, 8-chloro 160-162 56 Methyl cyclopropyl 163-166 57 Methyl methyl Sulfonyl 239-241 58 Methyl ethyl 2-amino, 3-chloro 160-162 59 Allyl cyclopropyl 4-methyl 146-149 60 Methyl ethyl 3,8-diamino 240-250 61 Vinyl oxycyclopropyl 4- Methyl 140-143 C-Carbonyl

62 methoxy cyclopropyl 4-methyl 169-171 63 acetyl cyclopropyl 4-methyl 176-179 64 methyl ethyl 2- (p-methoxy-benzyl 133-135 luamino) 65 methyl ethyl 2- (morpholin-1-yl ) 158-160 66 Methyl ethyl 2- (piperidin-1-yl) 164-166 67 H Cyclopropyl 4-cyano 243-245 68 Dimethyl-cyclopropyl 88-89 Aminoethyl 69 Methyl ethyl 2-dimethylamino 118-120 70 Methyl ethyl 2-ethylamino 154-157 71 Methyl ethyl 8-nitro 148-149 72 H ethyl 2-dimethylamino, 209-211 4-Methyl 73 H ethyl 2- (pyrrolidin-1-yl), 215-218 3- Chloro, 4-methyl NA = not available

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-chloro-3-nitropyridine (8.60 g, 0.054)
Mol), ethylamine (5.37 g, 0.12 mol), and
1 x stirred mixture of xylene (10 ml) in a sealed tube
Heated at 00 ° 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
Dried (sodium sulphate) and concentrated under reduced pressure to
10.0 g of the title compound, which is suitable for use in the reaction,
Obtained as an oil. b) 3-Amino-2-ethylaminopyridine Using a procedure similar to that described in Example 11b,
2-Ethylamino-3-nitropyridine 9.1 g to the title
6.5 g of compound was prepared. c) 2-chloro-N- (2-ethylamino-3-pyri
Dinyl) -5-nitro-3-pyridinecarboxamide 2-chloro-5-nitro in 10 ml of tetrahydrofuran
2.21 g of nicotinoyl chloride (2-hydroxynicotine
Nitrate the acid followed by 2-chloro-5-nitronico
Convert to tinic acid, then treat it with thionyl chloride
The resulting solution of 3-amino-2-ethyl
Luminopyridine 1.34 g, diisopropylethylami
1.29 g of tetrahydrofuran and 40 ml of tetrahydrofuran with cooling.
Gradually added to the stirred mixture over 15 minutes. Profit
Stir the resulting mixture at room temperature overnight then concentrate under reduced pressure.
did. Title precipitated when the residue was treated with methylene chloride
Compound (2.30g, melting point 185-186 ° C)
Was suitable for use in.

D) 5,11-Dihydro-11-ethyl-8-nitro-6H-dipyrido [3,2-b: 2 ',
3'-e] [1,4] diazepin-6-one A solution of 1.80 g of 2-chloro-N- (2-ethylamino-3-pyridinyl) -5-nitro-3-pyridinecarboxamide in 25 ml of xylene. Was refluxed for 4 hours. After concentrating under reduced pressure, the residue was purified by silica gel column liberating with 50% ethyl acetate / hexane to give the title compound 0.93.
g was obtained. e] 5,11-dihydro-11-ethyl-5-methyl-8-nitro-6H-dipyrido [3,2-b: 2 ',
3'-e] [1,4] diazepin-6-one 5,11-in a manner similar to that described in Example 8d.
Dihydro-11-ethyl-8-nitro-6H-dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepin-6-one 0.93 g to the title compound (0.72 g, melting point) 1
48-149 ° C) was prepared. f) 8-amino-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido [3,2-b: 2 ',
3'-e] [1,4] diazepin-6-one hemihydrate Following a procedure similar to that described in Example 11b,
5,11-dihydro-11-ethyl-5-methyl-8-
Nitro-6H-dipyrido [3,2-b: 2 ', 3'-
e] [1,4] diazepin-6-one is reduced to give 1,2
-After recrystallization from dichloroethane / hexane, 0.060 g of the title compound is a tan powder (mp 193-194 ° C).
Got as.

Example 75 6-Cyanoimino-5,1
1-dihydro-11-ethyl-2,4-dimethyl-6H
-Dipyrido [3,2-b: 2 ', 3'-e] [1,4]
Diazepine 5,11-Dihydro-11-ethyl-6-methanesulfonyloxy-2,4-dimethyl -6H- dipyrido [3,
2-b: 2 ', 3'-e] [1,4] diazepine (0.2
5 g, 0.63 mmol), cyanamide (0.034 g, 0.03 g).
8 mmol), 1,4-dioxane 5 ml, and potassium carbonate (0.11 g, 0.8 mmol) at room temperature for 10 min.
It was stirred for a day. Then the mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was dried, filtered and concentrated under reduced pressure. The residue was chromatographed on silica with 10% ethyl acetate / methylene chloride to give 0.025 g of the title compound (mp 230-233 ° C).

Example 76!5,11-dihydro-11
-Ethyl-6-methoxyimino-2,4-dimethyl-6
H-dipyrido [3,2-b: 2 ', 3'-e] [1,
4] Diazepine a) 5,11-dihydro-11-ethyl-6-methane
Sulfonyloxy-2,4-dimethyl-6H-dipyrido
[3,2-b: 2 ', 3'-e] [1,4] diazepine trifluoromethanesulfonic anhydride (0.24 ml, 14
0.25 ml of diisopropylethylamine
5,1 in 15 ml of methylene chloride containing (14 mmol)
1-dihydro-11-ethyl-2,4-dimethyl-6H
-Dipyrido [3,2-b: 2 ', 3'-e] [1,4]
Dissolution of 0.314 g (1.2 mmol) of diazepin-6-one
Add to liquid and reflux the resulting mixture under argon for 3 hours.
Let Then, add ethyl acetate (about 200 ml) and dissolve.
The solution was washed 3 times with water and 4 times with saline. Dry (sulfuric acid mug
Solution) and concentrated the solution under reduced pressure and the residue under high vacuum.
It was dried for 2 hours. Dissolve the residue in 20 ml of methylene chloride,
Tetraethylammonium cyanide 0.23 g (14 mm
Mol) was added. The resulting solution was stirred at room temperature overnight
Afterwards, the reaction mixture was concentrated under reduced pressure. The residue is ethyl acetate 1
It was dissolved in 00 ml and the solution was washed with water and brine. Dry
The solution (magnesium sulfate) was concentrated under reduced pressure and the residue was
Chromatograph on silica using 5% ethyl acetate / hexane.
I went to the graph. Crystallize the obtained solid with heptane
Then 0.033 g of the title compound was obtained as red crystals (melting point 154-
155 ° C). b) 5,11-dihydro-11-ethyl-6-methoxy
Symino-2,4-dimethyl-6H-dipyrido [3,2
-B: 2 ', 3'-e] [1,4] diazepine chloride
5,11-Dihydro-11-ethyl-6-meta in len
Sulfonyloxy-2,4-dimethyl-6H-dipyroxy
[3,2-b: 2 ', 3'-e] [1,4] diazepi
(0.3 g, 0.75 mmol), methoxylamine hydrochloric acid
Salt (0.15 g, 1.8 mmol) and diisopropylami
A solution of benzene (0.3 g, 2 mmol) was stirred at room temperature for 4 days.
Was. The organic phase was washed with water, dried and filtered. Solution under reduced pressure
Concentrate and residue with 20% ethyl acetate / hexane
Chromatography on silica title compound (mp 1
(64-166 ° C.) 0.07 g was obtained.

Example 77 5,11-dihydro-6H
-11-Cyclopropyl-4-methyl-dipyrido [3,3
2-b: 2 ', 3'-e] [1,4] diazepine-6-
Thione 5,11-dihydro-11-cyclopropyl-4-methyl-dipyrido [3,2-b: 2 ′, 3′-e] [1,
4] 5.0 g (18.77 mmol) of diazepin-6-one
And p-methoxyphenylthienophosphine sulfide dimer (Lawsson's reagent) 3.8g
A mixture of (9.40 mmol) was refluxed in 100 ml of toluene for 2.5 hours. The solution was cooled to room temperature and left overnight.
Toluene is removed by downward distillation and the residue is chromatographed through fresh silica gel (methylene chloride /
Ethyl acetate 6: 1) gave a yellow oil which became a solid on standing. Recrystallized from ethyl ether / petroleum ether and dried at 80 ° C. under high vacuum for 12 hours to give a melting point of 1
Obtained 1.7 g (32%) of a bright yellow solid at 89-194 ° C.

[0130]

[0131] Example A] a capsule or tablet A-1 A-2 of Compound 50mg Example 12 Ingredient Quantity Ingredient Quantity Example 12 50mg Starch 160mg dicalcium phosphate 160mg microcrystalline cellulose 90mg microcrystalline cellulose 90mg Sodium Sodium Starch Gluc 10 mg Stearic Acid 5 mg Tate Magnesium Stearate 2 mg Sodium Starch Glyco 10 mg Rate Fumed Colloidal Silica 1 mg Fumed Colloidal Silica 1 mg Mix with the drug substance to form a powder mixture. The lubricant is then mixed and the resulting mixture is either pressed into tablets or filled into hard gelatin capsules.

[0132] The Example B] The amount excipient materials reaching the parenteral solutions the compound of Ingredient Quantity Example 12 500 mg tartaric acid 1.5g Benzyl Alcohol 0.1% by weight water for injection 100mg were mixed with water, then carried Add the compound of Example 12. Mixing is continued until the solution is clear. The pH of this solution is adjusted to 3.0 and then filtered into suitable vials or ampoules and sterilized by autoclaving.

[0133] Example C] amount to achieve a compound 100mg Citric acid 1.92g Benzalkonium chloride 0.025% by weight EDTA 0.1% by weight of polyvinyl alcohol 10 wt% Water 100mg of Nasal solutions Ingredient Quantity Example 12 The excipient material is mixed with water, then the compound of Example 12 is added and mixing is continued until the solution is clear. The pH of this solution is adjusted to 4.0 and then filtered into suitable vials or ampoules.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Güntelschmitt Germany Day 8000 München 19 Nünfenburger Strasse 155 (72) Inventor Wolfhard Engel German Republic Day 7950 Biberach 1 Mozartstrasse 13 (72) ) Inventor Güntel Torumlitz Germany Day 7951 Waldhausen Buchenweg 27 (72) Inventor Wolfgang Eberlein Germany Day 7950 Biberach 1 Ober Au 6 (72) Inventor Karl Die Hague Rave United States Connecticut 06805 Brookfield Edna Drive 4

Claims (9)

(57) [Claims] 1. A compound of formula I or a pharmaceutically acceptable acid addition salt thereof. Embedded image [In the formula, Z is oxygen, = NCN, or a group of the formula = NOR ⁹ (wherein R ⁹ is alkyl of 1 to 3 carbon atoms); R ¹ is hydrogen and 1 to 6 Alkyl of carbon atoms, alkenyl of 2 to 6 carbon atoms, alkanoyl of 2 to 4 carbon atoms, dialkylaminoethyl (each alkyl moiety contains 1 to 2 carbon atoms), 2 to 4 carbon atoms Is an alkoxyalkyl of carbon atoms, an alkenyloxycarbonyl of 2 to 4 carbon atoms, a hydroxyl or an alkyloxy of 1 to 4 carbon atoms; R ² is hydrogen (provided R ¹ is not hydrogen). ,
Alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkoxyalkyl of 2 to 5 carbon atoms, cyano or benzyl (phenyl moiety is optionally 1
Be to three may be substituted by alkyl carbon atoms); R ³ is hydrogen, halogen, hydroxyl, nitro, 1-6
Alkyl of 1 carbon atom, alkoxy of 1 to 5 carbon atoms or —NR ¹⁰ R ¹¹ (R ¹⁰ and R ¹¹ are each independently hydrogen, alkyl of 1 to 4 carbon atoms, 2 to 4 carbons. Atom alkenyl or methoxybenzyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom form a 5, 6 or 7 membered saturated or monounsaturated ring (which may contain one oxygen atom). R ⁴ is hydrogen, halogen, nitro, amino or alkyl of 1 to 6 carbon atoms; R ⁵ is hydrogen, halogen, cyano, trihalomethyl, 1
R ⁶ is alkyl of 6 carbon atoms, alkoxy of 1 to 5 carbon atoms or hydroxyalkyl of 1 to 6 carbon atoms; R ⁶ is hydrogen, hydroxyl or alkyl of 1 to 4 carbon atoms; R ⁷ is hydrogen, halogen, azide, nitro or amino; R ⁸ is hydrogen or alkyl of 1 to 6 carbon atoms]
And a compound of formula I wherein a) Z is oxygen, R ¹ is methyl, R ² is methylsulfonyl, R ^{3 to} R ⁸ are each hydrogen, or b) Z is oxygen. R ¹ is methyl, R ² is cyclopropylmethyl, R ^{3 to} R ⁸ are each hydrogen, provided that (i) Z is oxygen and R ² is 1-5 carbons. An alkyl of atoms or a cycloalkyl of 3 to 6 carbon atoms, R ³ is hydrogen or an alkyl of 1 to 4 carbon atoms, R ⁴ is hydrogen and R ⁵ is 1 to 4 carbons. When the atom is alkyl or trifluoromethyl and R ⁶ , R ⁷ and R ⁸ are each hydrogen, then R ¹ cannot be hydrogen; and (ii) Z is oxygen and R ² Is hydrogen, alkyl having 1 to 5 carbon atoms or unsubstituted benzyl, and (1) R ³ , R ⁴ , R ⁵ , and R ⁶ , R ⁷ and R ⁸ are each a hydrogen atom, or (2) one of R ³ , R ⁴ and R ⁵ is halogen, 1 to 4
Alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- or di-alkylamino (each alkyl moiety contains 1 to 2 carbon atoms), nitro, hydroxyl or amino, R ³ ~ The other 5 substituents of R ⁸ are each hydrogen, or (3) one of R ⁶ , R ⁷ and R ⁸ is halogen or 1 to
Alkyl of 4 carbon atoms, the other 5 of R ^{3 to} R ⁸
Each of the two substituents is hydrogen, or (4) one of R ³ , R ⁴ and R ⁵ is hydrogen and R
The other two of ^{3 to} R ⁵ are independently hydrogen or alkyl of 1 to 3 carbon atoms, or one of R ³ , R ⁴ and R ⁵ is butyl, and R ³ to
The other two R ⁵ are hydrogen, R ⁶ is hydrogen or alkyl of 1 to 3 carbon atoms, R ⁷ is hydrogen, R ⁸ is hydrogen or alkyl of 1 to 3 carbon atoms. And
Or, when both R ⁶ and R ⁷ are hydrogen and R ⁸ is butyl, R ¹ is hydrogen, alkyl of 1 to 5 carbon atoms, or alkanoyl of 2 to 3 carbon atoms. Furthermore, (iii) Z is oxygen, R ¹ is hydrogen or linear or branched alkyl (containing 1 to 5 carbon atoms), and R ² is hydrogen ( R ¹ is not hydrogen) or R is straight or branched chain alkyl (containing 1 to 5 carbon atoms)
^At least one of ^{3 to} R ⁸ is other than hydrogen)] 2. The formula I according to claim 1, wherein Z is oxygen or a group of the formula ═NOR ⁹ (wherein R ⁹ is alkyl of 1 to 2 carbon atoms); R ¹ is Hydrogen, alkyl of 1 to 4 carbon atoms, alkenylmethyl of 3 to 4 carbon atoms, alkanoyl of 2 to 3 carbon atoms, alkoxyalkyl of 2 to 3 carbon atoms or 1 to 4 carbons An atom alkyloxy; R ² is hydrogen (provided R ¹ is not hydrogen), 1
~ Alkyl of 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, alkoxyalkyl of 2 to 4 carbon atoms or benzyl (wherein the phenyl moiety is optionally of 1 to 3 carbon atoms). R ³ is hydrogen, halogen, hydroxyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 3 carbon atoms, amino, 1 to 4 carbon atoms. A monoalkylamino, a dialkylamino (each alkyl moiety containing from 1 to 4 carbon atoms), pyrrolin-1-yl, pyrrolidin-1-yl, pyrazolin-1-yl, pyrazolidin-1-yl,
Imidazolin-1-yl, imidazolidin-1-yl,
Tetrahydropyridin-1-yl, piperidin-1-yl, morpholin-1-yl or piperazin-1-yl; R ⁴ is hydrogen, halogen, amino or alkyl of 1 to 4 carbon atoms; R ⁵ Is hydrogen, halogen, trifluoromethyl, alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms or hydroxyalkyl of 1 to 2 carbon atoms; R ⁶ is hydrogen, hydroxyl or 1 Is alkyl of 2 to 2 carbon atoms; R ⁷ is hydrogen, halogen or amino; R ⁸ is hydrogen or alkyl of 1 to 2 carbon atoms; provided that (i) Z is oxygen; R ² is alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, R ³ is hydrogen or alkyl of 1 to 4 carbon atoms, R ⁴ is hydrogen, 1-2 R ⁵ Is alkyl or trifluoromethyl of the carbon atom of and R ⁶ , R ⁷ and R ⁸ are each hydrogen, then R ¹ cannot be hydrogen; and (ii) Z is oxygen, R ² is hydrogen, alkyl having 1 to 5 carbon atoms or unsubstituted benzyl, and (1) R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each a hydrogen atom, or , (2) one of R ³ , R ⁴ and R ⁵ is halogen, 1 to 4
Alkyl of 1 carbon atom, alkoxy of 1 to 3 carbon atoms, mono- or di-alkylamino (each alkyl moiety contains 1 to 2 carbon atoms), hydroxyl or amino, and R ^3- The other five substituents of R ⁸ are each hydrogen, or (3) one of R ⁶ , R ⁷ and R ⁸ is halogen or 1 to
An alkyl of 2 carbon atoms, the other 5 of R ^{3 to} R ⁸
Each of the four substituents is hydrogen, or (4) one of R ³ , R ⁴ and R ⁵ is hydrogen and R
Two other of ^{3 to} R ⁵ are independently hydrogen or alkyl of 1 to 3 carbon atoms, or one of R ³ and R ⁴ is butyl and the other 2 of R ^{3 to} R ⁵ are One is hydrogen and R ⁶ is hydrogen or alkyl of 1 to 2 carbon atoms, R ⁷ is hydrogen and R ⁸ is hydrogen or alkyl of 1 to 2 carbon atoms, R ¹ is hydrogen, alkyl of 1 to 4 carbon atoms and 2
~ 3 carbon atoms cannot be alkanoyl; further, (iii) Z is oxygen and R ¹ is hydrogen or straight or branched chain alkyl (containing 1 to 4 carbon atoms). And R ² is hydrogen (provided R ¹ is not hydrogen) or straight or branched chain alkyl (including 1 to 5 carbon atoms), R ^{3 to} R
^A compound or a pharmaceutically acceptable acid addition salt thereof, wherein at least one of ⁸ is other than hydrogen. 3. In formula I according to claim 1, Z is oxygen; R ¹ is hydrogen, alkyl of 1 to 3 carbon atoms or allyl; R ² is 2 to 3 carbon atoms. R ³ is hydrogen or cycloalkyl having 3 to 4 carbon atoms; R ³ is hydrogen, methyl, alkoxy having 1 to 3 carbon atoms, chloro, amino, monoalkylamino having 1 to 3 carbon atoms, dialkyl. Amino (containing 1 to 3 carbon atoms), pyrrolin-1-yl, pyrrolidin-1-yl, pyrazolin-1-yl, pyrazolidin-1-yl, imidazolin-1-yl, imidazolidin-1-yl, tetrahydropyrazine-1-yl, piperidin-1-yl, it is morpholin-1-yl or piperazin-1-yl; R ⁴ is hydrogen, methyl or chloro; R ⁵ is hydrogen, methyl, ethyl, chloro Is trifluoromethyl; R ⁶ is hydrogen; R ⁷ is hydrogen or amino; and, R ⁸ is hydrogen; provided that a (i) Z is oxygen, R ² is 1-3 Is alkyl of 3 to 4 carbon atoms or cycloalkyl of 3 to 4 carbon atoms, R ³ is hydrogen or methyl, R ⁴ is hydrogen,
R ⁵ is methyl, ethyl or trifluoromethyl,
And R ⁶ , R ⁷ and R ⁸ are each hydrogen, R
¹ cannot be hydrogen; and (ii) Z is oxygen, R ² is alkyl of ² to 3 carbon atoms, and (1) R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each a hydrogen atom, or (2) one of R ³ , R ⁴ and R ⁵ is chloro, methyl, ethyl, alkoxy having 1 to 3 carbon atoms, mono- or dialkylamino. (Each alkyl moiety contains 1 to 2 carbon atoms) or amino and the other 5 substituents of R ^{3 to} R ⁸ are hydrogen, or (3) R ³ , R ⁴ and R ^{One of 5} is hydrogen and R ³ ~
The other two of R ⁵ are independently hydrogen or methyl (R ⁵
Can also be ethyl) and R ^{6 to} R ⁸ are each hydrogen, R ¹ cannot be hydrogen and alkyl of 1 to 3 carbon atoms; and (iii) Z Is oxygen, R ¹ is hydrogen or linear or branched alkyl (containing 1 to 3 carbon atoms), and R ² is linear or branched alkyl (each alkyl moiety is Containing 2-3 carbon atoms)
When at least one of R ^{3 to} R ⁸ is other than hydrogen, the compound or a pharmaceutically acceptable acid addition salt thereof. 4. A compound selected from the group consisting of the following and a pharmaceutically acceptable acid addition salt thereof: 2-chloro-
5,11-dihydro-11-ethyl-4-methyl-6H
-Dipyrido [3,2-b: 2 ', 3'-e] [1,4]
Diazepin-6-one; 2-chloro-11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b: 2 ',
3′-e] [1,4] diazepin-6-one; 5,11-dihydro-11-ethyl-2-methoxy-4
-Methyl-6H-dipyrido- [3,2-b: 2 ', 3'
-E] [1,4] diazepin-6-one; 11-cyclopropyl-5,11-dihydro-2-methoxy-4-methyl-6H-dipyrido [3,2-b:
2 ', 3'-e] [1,4] diazepin-6-one; 8-amino-5,11-dihydro-11-ethyl-2-
Methoxy-4-methyl-6H-dipyrido [3,2-b:
2 ', 3'-e] [1,4] diazepin-6-one; 8-amino-11-cyclopropyl-5,11-dihydro-2-methoxy-4-methyl-6H-dipyrido [3.
2-b: 2 ′, 3′-e] [1,4] diazepine-6-
ON; 11-cyclopropyl-5,11-dihydro-2-methoxy-5-methyl-6H-dipyrido [3,2-b:
2 ', 3'-e] [1,4] diazepin-6-one; 5,11-dihydro-11-ethyl-4-methyl-2-
(N-pyrrolidino) -6H-dipyrido [3,2-b:
2 ', 3'-e] [1,4] diazepin-6-one; 11-cyclopropyl-5,11-dihydro-4-methyl-2- (N-pyrrolidino) -6H-dipyrido [3,2]
-B: 2 ', 3'-e] [1,4] diazepin-6-one; 5,11-dihydro-11-ethyl-5-methyl-2-
(N-pyrrolidino) -6H-dipyrido [3,2-b:
2 ', 3'-e] [1,4] diazepin-6-one; 11-cyclopropyl-5,11-dihydro-5-methyl-2- (N-pyrrolidino) -6H-dipyrido [3,2]
-B: 2 ', 3'-e] [1,4] diazepin-6-one; 5,11-dihydro-11-ethyl-4-methyl-2-
(N, N-Dimethylamino) -6H-dipyrido [3,2
-B: 2 ', 3'-e] [1,4] diazepin-6-one; 11-cyclopropyl-5,11-dihydro-4-methyl-2- (N, N-dimethylamino) -6H-. Dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepin-6-one; 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; 8-amino-11-cyclopropyl -5,11-Dihydro-4-methyl-2- (N, N-dimethylamino) -6
H-dipyrido [3,2-b: 2 ′, 3′-e] [1,
4] Diazepin-6-one. 5. 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 a pharmaceutically acceptable acid thereof Addition salt. 6. 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 a pharmaceutically acceptable acid addition salt thereof. 7. 5,11-Dihydro-11-ethyl-2
-Methoxy-4-methyl-6H-dipyrido [3,2-
b: 2 ′, 3′-e] [1,4] diazepin-6-one or a pharmaceutically acceptable acid addition salt thereof. 8. 11-Cyclopropyl-5,11-dihydro-2-methoxy-4-methyl-6H-dipyrido [3,2-b: 2 ′, 3′-e] [1,4] diazepine-6 -One or a pharmaceutically acceptable acid addition salt thereof. 9. A prophylactically or therapeutically effective amount of claim 1
A pharmaceutical composition suitable for the prevention or treatment of HIV-1 infection, which comprises the compound of formula I as defined in claim 8 or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.