AP179A - 5 11-Dihydro-6H-Dipyrido (3, 2-b:2', 3'-e) (1,4) Diazepines and their use in the prevention and treatment of HIV infection. - Google Patents

Abstract

Disclosed are novel 5,11

Description

5,ll-DrHTORO-6H-DIPYRIDOf32-b:2’J’-e]fl.41DlAZEPINES AND THEIR USE IN THE PREVENTION OR TREATMENT OF HTV INFECTION

Feld of the Invention

I

The invention relates to novel 5,ll-dihydro-6H-dipyrido[3,2-b:2’,3^,-e][l,4]diazepines and pharmaceutically acceptable acid addition salts thereof, methods for preparing thesecompounds, the use of these compounds in the prevention or treatment of HIV infection, andto pharmaceutical compositions containing these compounds.

AP 0 0 0 1 7 9

Background of the Invention

The human disease, Acquired Immune Deficiency Syndrome (AIDS), is caused by the Human Immunodeficiency Virus (HIV), particularly the strain known as HIV-1.

9/038-4-C6

Like other viruses, HIV-1 cannot replicate without commandeering the biosynthetic apparatus of the host cell it infects. It causes this apparatus to produce the structural proteins which make up the viral progeny. These proteins are coded for by ±e genetic material contained within the infecting virus particle, or virion. Being a retrovirus, however, the genetic material of HTV is RNA, not DNA as in the host cell’s genome. Accordingly, the viral RNA must first be converted into DNA, and then integrated into the host cell’s genome, in order for the host cell to produce the required viral proteins. The conversion of the RNA to DNA is accomplished through the use of the enzyme reverse transcriptase (RT), which is included within the infecting virion along with the RNA. Reverse transcriptase has three enzymatic functions; it acts as an RNA-dependent DNA polymerase, as a ribonuclease, and as a DNAdependent DNA polymerase. Acting first as an RNA-dependent DNA polymerase, RT makes a single-stranded DNA copy of the viral RNA. Next, acting as a ribonuclease, RT frees the

DNA just produced from the original viral RNA and then destroys the original RNA. Finally, acting as a DNA-dependent DNA polymerase, RT makes a second, complementary DNA strand, using the first DNA strand as a template. The two strands form double-stranded DNA, which is integrated into the host cell’s genome by another enzyme called an integrase.

Compounds which inhibit the enzymatic functions of HTV-1 reverse transcriptase will inhibit replication of HIV-1 in infected cells. Such compounds arc useful in the prevention or treatment of HIV-1 infection in human subjects.

9/038-4-C6

Description of the Invention

In one of its composition of matter aspects, the invention comprises 5,11-dihydro-6Hdipyrido[3,2-b:2’,3’-e][l,4]diazepines of the formula I

wherein,

Z is oxygen, sulfur, =NCN or a group of the formula =NOR* wherein R’ is alkyl of 1 to 3 carbon atoms;

R^! 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 or alkynyl of 2 to 6 carbon atoms, 2-halo-2-propen-l-yI, mono- or di-halovinyl, aryl or arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyL, which is either unsubstituted or substituted by methyl, methoxy or halogen), alkanoyl of 2 to 4 carbon atoms, aminoethyl, mono- or di-alky laminoe thyl wherein

AP 0 0 0 1 7 9

9/038-4-C6 each alkyl moiety contains 1 to 2 carbon atoms, aikyloxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms, alkyloxycarbonyl wherein the alkyl moiety contains 1 to 4 carbon atoms, alkenyloxy- or alkynyloxycarbonyl wherein each alkenyl or aikynyl moiety contains 2 to 4 carbon atoms, hydroxy, alkyloxy of 1 to 4 carbon atoms, amino, mono- or di-alkylamino wherein each alkyl moiety contains 1 to 4 carbon atoms, aminocarbonylmethyl, or cyanoalkyl wherein the alkyl moiety contains 1 to 4 carbon atoms;

R² is hydrogen (with the proviso that R¹ is not 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, oxetanyl, thietanyl, tetrahydrofuranyl or tetrahydrothienyl, alkenyl or aikynyl of 2 to 6 carbon atoms, aikyloxyalkyl or alkylthioalkyl of 2 to 5 carbon atoms,' alkanoyl of 2 to 5 carbon atoms, cyano, hydroxyalkyl of 2 to 6 carbon atoms, aryl or arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, which is either unsubstituted or substituted by alkyl or alkyloxy of 1 to 3 carbon atoms, hydroxyl or halogen), or alkyloxycarbonylmethyl wherein the alkyl moiety contains 1 to 5 carbon atoms;

one of R³, R⁴ and R⁵ is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or aikynyl of 2 to 6 carbon atoms, trihalomethyl, hydroxyalkyl of 1 to 6 carbon atoms, aikyloxyalkyl or alkylthioalkyl of 2 to 5 carbon atoms, alkyloxycarbonylalkyl wherein the alkyl moieties each contain 1 to 2 carbon atoms, hydroxyl, alkyloxy or alkylthio of 1 to 5 carbon atoms, hydroxyalkyloxy of 2 to 4 carbon atoms, alkanoyloxy of 2 to 4 carbon atoms, alkyisulfinyl or alkylsulfonyl of 1 to 4 carbon atoms, alkanoyl of 2 to 6 carbon atoms,

9/038-4-C6 alkyloxycarbonyl wherein the alkyl moiety contains 1 to 3 carbon atoms, mono- or dialkylaminocarbonyl wherein each alkyl moiety contains 1 to 3 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, mono- or di-alkylaminoalkyl wherein each alkyl moiety contains 1 to 3 carbon atoms, aryl or arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, which is either unsubstituted or substituted by alkyl or alkyloxy of 1 to 3 carbon atoms, hydroxyl or halogen), a group of the formula -NR^1OR^U, halogen, cyano, nitro, azido or carboxyl, with the other two substituents being hydrogen, methyl or chloro; or, two of R³, R⁴ and R⁵ are independently alkyl or hydroxyalkyl of 1 to 2 carbon atoms, trihalomethyl, alkyloxy or alkylthio of 1 to 2 carbon atoms, halogen or a group of the formula -NR¹⁰R¹¹, with the remaining substituent being hydrogen or methyl; or,

R³, R⁴ and R⁵ are each hydrogen;

one of R\ R’ and R* 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 moieties each contain 1 to 2 carbon atoms, hydroxyl, alkyloxy or alkylthio of 1 to 4 carbon atoms, hydroxyalkyloxy of 2 to 4 carbon atoms, alkanoyloxy of 2 to 4 carbon atoms, alkylsulfinyl or alkylsulfonyl of 1 to 4 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkoxycarbonyl wherein the alkyl moiety contains 1 to 3 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, mono- or dialkylaminoalkyl wherein each alkyl moiety contains 1 to 2 carbon atoms, a group of the

AP o 0 0 1 7 9

9/038-4-C6 formula -NR^I2R¹³, halogen, cyano, nitro, azido or carboxyl, with the other two substituents being hydrogen; or, two of R⁶, R⁷ and R* are independently alkyl of 1 to 2 carbon atoms, trihalomethyl, alkyloxy or alkylthio of 1 to 2 carbon atoms, halogen or a group of the formula -NR^:2R^U, with the remaining substituent being hydrogen; or,

R⁴, R⁷ and R* are each hydrogen; and,

R¹⁰, R”, R¹² and R¹³ are each independently hydrogen, alkyl of 1 to 4 carbon atoms, alkenylmethyl or alkynylmethyl of 2 to 4 carbon atoms, aryl or arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, which is either unsubstituted or substituted by methyl, methoxy or halogen), mono- or dihydroxyalkylmethyl of 2 to 4 carbon atoms, alkyloxy of 1 to 3 carbon atoms, hydroxy, alkyloxyethyl or alkylthioethyl of 3 to 4 carbon atoms, aminoalkylmethyl of 1 to 4 carbon atoms, mono- or dialky laminoalkylmethyl wherein each alkyl moiety contains 1 or 2 carbon atoms, or alkanoyl of 1 to 4 carbon atoms; or,

R’° and Rⁿ, and R¹² and R¹³, together with the nitrogen atoms between them, respectively and independently form azetidin-l-yl or a 5, 6 or 7-membered ring which is either saturated or unsaturated, which optionally contains up to one additional hetcroatom which may be selected from O, S or N, or which optionally contains in place of a carbon atom a group of the formula =NR¹⁴ wherein R¹⁴ is hydrogen or alkyl of 1 to 2 carbon atoms, and which ring is

9/038-4-C6 optionally and independently substituted with hydroxymethyl, aminomethyl, 1 to 4 methyl groups and 1 to 2 hydroxy groups.;

subject to the proviso that when

a) z is oxygen or sulphur

b) R is hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl or alkinyl of 2 to 5 carbon atoms, alkoxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms, alkanoyl of 2 to 4 carbon atoms, hydroxyalkyl of 2 to 5 carbon atoms, phenyl (optionally substituted by alkyl or alkoxy of 1 to 3 carbon atoms, hydroxyl or halogen), or alkoxycarbonylmethyl wherein the alkyl moiety contains 1 to 5 carbon atoms,

C)	i)	R3, R4, R5, R6, R7 hydrogen or	and	R8 are	each
	ii)	3 4 5 one of R , R , R ,	R6,	R7 and	R8 is
		alkyl of 1 to 4 carbon	atoms,	hydroxyalkyl of 1

AP 0 0 0 1 7 9 to 4 carbon atoms alkyloxycarbonylalkyl wherein the alkyl moieties each contain 1 or 2 carbon atoms, hydroxyl, alkoxy or alkylthio of 1 to 4 carbon atoms, alkanoyloxy of up to 4 carbon atoms, alkanoyl of up to 4 carbon atoms, amino, aminoalkyl of up to 4 carbon atoms, mono- or di-alkylaminoalkyl wherein each alkyl moiety contains 1 to 2 carbon atoms, halogen, cyano, nitro, azido, or carboxyl, and the remaining five of R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each hydrogen, or

4 5 iii) R , R and R are each independently hydrogen or alkyl of 1 to 3 carbon atoms, provided at least one is hydrogen, or one of 3 4 5

R , R and R is butyl with the remaining two being hydrogen and

7 8

R , R and R are each independently hydrogen or alkyl of 1 to 3 carbon atoms, provided at least one is hydrogen, or

7 8 one of R , R and R is butyl with the remaining two being hydrogen, then R¹ cannot be hydrogen, alkyl of 1 to 5 carbon ^toms, alkenyl or alkinyl of 3 to 5 carbon atoms, 2-halo-2propen-l-yl, arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, which is either unsubstituted or substituted by methyl, methoxy or halogen), alkanoyl containing 2 or 3 carbon atoms, alkoxyalkyl or alkylthio alkyl of 2 to 4 carbon atoms;

or a compound of formula I wherein Z is oxygen and

2

i) R is methyl, R is ethyl and either

R ⁷ is azido, amino or nitro and to R^ and g

R are hydrogen, or

4

R is ethylamino or diethylamino and R to

Q

R are hydrogen, or

BAD ORIGINAL r ο o 5 7

R and R are methyl and R to R and R are hydrogen, or

8

R³ and R are methyl and R³ to R are

3 4 6 7 8 hydrogen, or R is methyl and R , R , R , R and R are hydrogen, ii) R¹ is methyl, R² is ethyl, t-butyl, s-butyl or 3 8 isopropyl and R to R are hydrogen,

5 iii) R and R are methoxymethyl, R is methyl and R³, R⁴ and R⁶, R⁷ and R⁸ are hydrogen, or

2 3 8 iv) R^x is hydrogen, R is ethyl and R to R are hydrogen;

or a compound of Formula I wherein Z is sulfur and 2 3 5 either a) R is ethyl, R and R are both methyl and

R¹ , R⁴ and R⁶ to R⁸ are hydrogen, or b) R¹ is methyl,

3 4 8

R is ethyl, R is methoxy and R to R are hydrogen.

AP 0 0 0 1 7 9

6C

-—5

BAD ORIGINAL

A subgeneric aspect of the invention comprises compounds of formula I, wherein,

Z is oxygen, sulfur or a group of the formula =NOR’ wherein R’ is alkyl of 1 to 2 carbon atoms;

R* is hydrogen, alkyl of 1 to 4 carbon atoms, fluoroalkyl of 1 to 4 carbon atoms, cyclopropyl, alkenylmethyl or alkynylmethyl of 3 to 4 carbon atoms, 2-halo-2-propen-l-yl, alkanoyl of 2 to 3 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 3 carbon atoms, or cyanoalkyl wherein the alkyl moiety contains 1 to 3 carbon atoms;

R¹ is hydrogen (with the proviso that R^l is not hydrogen), alkyl of 1 to 5 carbon atoms, fluoroalkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, oxetanyl, thietanyl, alkenylmethyl or alkynylmethyl of 3 to 5 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms, alkanoyl of 2 to 4 carbon atoms, hydroxyalkyl of 2 to 5 carbon atoms, aryl or arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, which is either unsubstituted or substituted by alkyl or alkyloxy of 1 to 3 carbon atoms, hydroxyl or halogen), or alkyloxycarbonylmethyl wherein the alkyl moiety contains 1 to 4 carbon atoms;

z - ’ ~

9/038-4-C6, one of R^J, R⁴ and R³ 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 to 4 carbon atoms, alkyloxycarbonylalkyl wherein the alkyl moieties each contain 1 to 2 carbon atoms, hydroxyl, alkyloxy or alkylthio of 1 to 3 carbon atoms, hydroxyalkyloxy of 2 to 3 carbon atoms, alkanoyloxy of 2 to 3 carbon atoms, alkylsulfinyl or alkylsulfonyl of J^to carbon atoms, alkanoyl of 2 to 4 carbon atoms, alkyloxycarbonyl wherein the alkyl moiety contains 1 to 2 carbon atoms, aminoalkyl of 1 to 3 carbon atoms, mono- or dialkylaminoalkyl wherein each alkyl moiety contains 1 to 2 carbon atoms, amino, mono- or dialkylamino wherein each alkyl moiety contains 1 to 4 carbon atoms, azetidin-l-yl, pyrrol-1-yl, pyrrolin-l-yl, pyirolidin-l-yl, pyrazol-l-yl, pyrazolin-l-yl, pyrazolidin-l-yl, imidazol-l-yl, imidazolin-l-yl, imidazolidin-l-yl, tetrahydropyridin-l-yl, piperidin-l-yl, morpholin-l-yl, (4methyl)piperazin-l-yl, piperazin-l-yl, N,N-bis(2-hydroxyethyl)amino, N,N-bis(2methoxyethyl)amino, or halogen, with the other two substituents being hydrogen, methyl or chloro; or,

AP 0 0 0 1 7 9 two of R³, R⁴ and R³ are independently alkyl of 1 to 2 carbon atoms, alkyloxy or alkylthio of 1 to 2 carbon atoms, amino, mono- or di-alkylamino wherein each alkyl moiety contains 1 to 3 carbon atoms, azetidin-l-yl, pyrrol-1-yl, pyrrolin-l-yl, pyrrolidin-l-yl, pyrazol-l-yl, pyrazolin-l-yl, pyrazolidin-l-yl, imidazol-l-yl, imidazolin-l-yl, imidazolidin-l-yl, tetrahydropyridin-l-yl, piperidin-l-yl, morpholin-l-yl, (4-methyl)piperazin-l-yl, piperazin-l-yl, N,N-bis(2-hydroxyethyl)amino, N,N-bis(2-methoxyethyl)amino, or halogen, with the remaining substituent being hydrogen, methyl or chloro; or,

9/038-4-C6

R’, R⁴ and R⁵ are each hydrogen;

one of R⁴, R⁷ and R* is alkyl of 1 to 2 carbon atoms, vinyl, trifluoromethyl, hydroxyalkyl of 1 to 2 carbon atoms, hydroxyl, alkyloxy or alkylthio of 1 to 2 carbon atoms, hydroxyalkyloxy of 2 to 3 carbon atoms, alkanoyloxy of 2 to 3 carbon atoms, amino, mono- or di-alkylamino wherein each alkyl moiety contains 1 to 2 carbon atoms, azetidin-l-yl, pyrrol-l-yl, pyrrolin-1yl, pyrrolidin-l-yl, pyrazol-l-yl, pyrazolin-l-yl, pyrazolidin-l-yL, imidazol- 1-yl, imidazolin-1yl, imidazolidin-l-yl, tetrahydropyridin-l-yl, piperidin-l-yl, morpholin-l-yl, (4methyl)piperazin-l-yl, piperazin-l-yl, NJ^si-bis(2-hydroxyethyI)amino, N,N-bis(2methoxyethyl)amino, or halogen, with the other two substituents being hydrogen; or,

R⁴, R⁷ and R* are each hydrogen.

A particular subgeneric aspect of the invention comprises compounds of formula I wherein,

Z is oxygen or sulfur,

R¹ is hydrogen, alkyl of 1 to 3 carbon atoms or allyl;

R^J is alkyl of 2 to 3 carbon atoms, or cycloalkyl of 3 to 4 carbon atoms;

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R³ is hydrogen, methyl, alkyloxy or alkylthio of 1 to 3 carbon atoms, chloro, amino, mono- or di-alkylamino wherein each alkyl moiety contains 1 to 3 carbon atoms, allylamino, azeddin-1yl, pyrrol-1-yl, pyrrolin-l-yl, pyrrolidin-l-yl, pyrazol-l-yl, pyrazolin-l-yl, pyrazolidin-l-yl, imidazol-l-yl, imidazolin-l-yl, imidazolidin-l-yl, tetrahydropyridin-l-yl, piperidin-l-yl.

t morpholin-l-yl, (4-methyl)piperazin-l-yl, piperazin-l-yl, or N,N-bis(2-hydroxyethyl)amin0;

R⁴ is hydrogen, methyl or chloro;

R³ is hydrogen, methyl, ethyl, chloro, or trifluoromethyl;

R* and R* are hydrogen; and

R⁷ is hydrogen or amino.

A more particular subgeneric aspect of the invention comprises compounds of formula I wherein,

Z is oxygen or sulfur,

R’ is hydrogen, alkyl of 1 to 3 carbon atoms or allyl;

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R² is alkyl of 2 to 3 carbon atoms, or cycloaikyl of 3 to 4 carbon atoms;

R³ is hydrogen, methyl, chloro, methoxy, ethoxy, amino, mono- or di-alkylamino wherein each alkyl moiety contains 1 to 2 carbon atoms, allylamino, allylmethylamino, pyrrolin-l-yl, p\iTolidin-1-yl, tetrahydropyridin-l-yl, piperidin-1 -yl or morpholin-1-yl;

R⁴ is hydrogen;

R³ is hydrogen, methyl, ethyl, chloro, or trifluoromethyl;

R⁴ and R* are hydrogen; and

R⁷ is hydrogen or amino.

Preferred compounds of formula I are:

5,11-dihydro-1 l-ethyl-4-methyl-6H-dipyrido(3,2-b:2’,3’-e][l,4]diazepin-6-one

-cyclopropyl-5,11 -dihydro-4-methyl-6H-dipyrido(3,2-b:2’,3’-e][ 1,4]diazepin-6-one or

-thione;

5,11 -dihydro-1 l-ethyl-2,4-dimethyl-6H-dipyrido[3,2-b:2’,3’-e][l,4]diazepin-6 -thione;

11-cyclopropyl-5,1 l-dihydro-2,4-dimethyl-6H-dipyrido{3,2-b:2’,3’-e][l,4]diazepin-6-one or thione;

2-chloro-5,l 1-dihydro-1 l-ethyl-4-methyl-6H-dipyrido(3,2-b:2’,3’-e][l,4]diazepin-6-one or 9/038-4-C6

BAD ORIGINAL ]

thinne;

2- chloro-11 -cyclopropyl-5,1 l-d±hydro-4-methyl-6H-dipyndo[3,2-b:2’,3’-e]( l,4]diazepin-6-one or -thione;

5.1 l-dihydro-l l-ethyl-2-methoxy-4-methyl-6H-dipyndo[3,2-b:2’,3’-e](l,4]diazcpin-6-one or thione;

11-cyclopropyl-5,1 l-dihydro-2-methoxy-4-methyl-0H-dipyrido(3,2-b:2’,3^,-e)(l,4]diazepin-6one or -thione;

3- ainino-5,l l-dihydro-l l-ethyl-2-methoxy-4-methyl-6H-dipyrido[3,2-b:2’,3’-e][l,4]diazepin-6one or -thione;

8-amino-l 1 -cyclopropyl-5,11 -dihydro-2-methoxy-4-methyl-6H-dipyrido[3,2-b:2’, 3’s][ 1,4]diazepin-6-one or -thione;

5.1 l-dihydro-l l-ethyl-2-methoxy-5-methyl-6H-dipyrido(3,2-b:2’,3^,-e][l,4]diazepin-6thione;

11-cyclopropyl-5,1 l-dihydro-2-methoxy-5-methyl-6H-dipyrido[3,2-b:2’,3’-e][l,4]diazepin-6one or -thione;

5,11 -dihydro-1 l-ethyl-4-methyl-2-(N-pyTTolidino)-6H-dipyndo[3,2-b:2’,3’-e](l,4]diazepin-6one or -thione;

-cyclopropyl-5,11 -dihydro-4-methyl-2-(N-pyTrolidino)-6H-dipyrido[3,2-b:2’,3’e](! ,4]diazepin-b-one or -thione;

5,11 -dihydro-11 -ethyl-5-methyl-2-(N-pyrrolidino)-6H-dipyrido[3,2-b:2’,3’-e][l,4]diazepin-6one or -thione;

11-cyclopropyl-5,1 l-dihydro-5-methyl-2-(N-pyrrolidino)-6H-dipyrido[3,2-b:2’,3’9/038-4-C6

BAD ORIGINAL

e][l,4]diazepin-6-one or -thione;

5,11-dihydro-l l-ethyl-4-me thyl-2-(N,N-dimethylamino)-6H-dipyrido[3,2-b:2’,3’e][l,4]diazepin-6-one or -thione;

11-cyclopropyl-5,1 l-dihydro-4-methyl-2-(N,N-dimethylamino)-6H-dipyrido(3_>2-b:2’,3’e][l,4]diazepin-6-one or -thione;

8-amino-5,l 1-dihydro-l l-e^yl-^methyl^-iN^i-dimethylaminoJ-eH-dipyridotS^-b^’.S’e][l,4]diazepin-6-one or -thione; and,

8-amino-11-cyclopropyl-5,1 l-dihydro-4-methyl-2-(N,N-dimethylannno)-6H-dipyrido{3,2b:2’,3’-e][l,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 modifications thereof. Methods A-H, described below, are illustrative of the methods for preparing the compounds.

Method A

Compounds of the formula la

(la)

9/038/4»€6 wherein R¹ and R³ through R* are defined as above and R^r has the same definitions as R² with the exception of hydrogen, can be obtained by cyclizing carboxylic acid amides of formula II,

(Π) wherein R¹, R³ through R* and R²’ have the same definitions set forth with respect to Formula Ia and Hal represents fluorine, chlorine, bromine or iodine.

L I 0 0 0 dV

A variant of this method, which is preferably used to prepare compounds of formula Ia wherein R⁴, R⁷, or R’, especially R⁷, are electron withdrawing groups, such as nitro, involves cyclizing carboxylic acid amides of formula Ha,

(Da)

9/038-4-C6 wherein R³ through R* are defined as above and R^r has the same definitions as R^J with the exception of hydrogen, and Hal represents fluorine, chlorine, bromine or iodine.

Cyclization is conveniently carried out by the conversion of compounds of formula Π or Ila into their alkaline metal salts and subsequent condensation at temperatures between O°C and the boiling point of the reaction mixture. If, in the starting compounds of formula Π or Ha, R* is different from hydrogen, metallation requires at least 1 mole of the metallating agent If, on the other hand, R^l is hydrogen, at least 2 moles of this agent must be used. For metallation, lithium, sodium and potassium hydrides or lithium alkyls, such as n-butyl lithium, are preferably used.

The cyclization reaction is usually carried out in inert solvents, e.g. in tetrahydrofuran, 1,4dioxane, glycoldimethyl ether, diethylene-glycoldimethyl ether, triethyleneglycoldimethyl ether, dimethylf ormamide, benzene or anisole. Cyclization may also be effected by heating carboxylic acid amides of formula Π or Ha in dipolar aprotic solvents, preferably in sulfolane or dimethylsulfone. Catalytic quantities of strong acids, e.g. sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, methanesulfonic acid or ptoluencsulfonic acid, have proved to be of use. The necessary reaction temperature is usually between 110 and 220°C.

9/038-4-C6

Method Β

Compounds of formula lb

(lb) wherein R’ and R^J through R* are defined as above, can be prepared by hydrolytic cleavage of the arylmethyl group in compounds of formula HI,

AP 0 0 0 1 7 9

(HI) _s

9/038,-4-C6 wherein R* and R³ through R* are defined as mentioned above and Ar can be, for example, a phenyl or 4-methoxyphenyl group. Hydrolysis is effected by moderate to strong acids or Lewis-acids at temperatures between -20 and +150°C. Such acids can be, for example, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, phosphoric or polyphosphoric acid. When using phosphoric or polyphosphoric acid, the addition of solvents such as benzene, toluene, phenol, anisole or veratrole has proved to be of advantage.

If Lewis acids, such as aluminum chloride or bromide are used to eliminate the arylmethyl group, solvents such as aromatic hydrocarbons, e.g. benzene, toluene, anisole, or mixtures thereof with dichloromethane are suitable.

It will be obvious to those skilled in the an that Method B is not preferred in those cases wherein any of R* and R³ through R* are readily hydrolyzable substituents, for example, wherein R* is alkanoyl or any of R³ through R* are alkanoylamino or alkoxycarbonyl. In cases wherein R¹ is alkanoyl or any of R³ through R* are alkoxycarbonyl, for example, it is preferable to utilize method A described above; when R* is hydrogen two equivalents of base must be used. In cases wherein any of R³ through R* are alkanoylamino, for example, it is preferable to carry out the hydrolysis (and subsequent acylation) on the corresponding nitro derivative, and then reduce the nitro moiety to the amine, followed by acylation to yield the desired product

9/038-4-C6

Method C

A compound of formula Ic

He) wherein R*‘ has the same definitions as R¹ with the exception of hydrogen and R^a through R are defined as above, may be obtained by converting a 5,ll-dihydro-6H-dipyrido[3,2-b:2’,3’· e](l,4]diazepin-6-one of the formula IV

AP 0 0 0 1 7 9

wherein R^J through R* are defined as above, into the corresponding 5-alkali or alkaline earth

9/038-4-C6 metal compound and subsequently reacting the alkali metal compound with a compound of the formula V

R^rX (V) wherein R¹’ has the same meanings as in formula Ic and X is the radical of a reactive ester, a halogen atom, the group OSOjOR¹', the methanesulfonyloxy or ethanesulfonyloxy group or an aromatic sulfonyloxy group. Instead of converting the compound of the formula IV into its corresponding alkali metal salt in the first step, the alkylation of a compound of formula IV may also be performed by reaction with a compound of formula V in the presence of amines, such as triethylamine, diazabicycloundecene or 4-(dimethylamino)pyridine, or of alkali carbonates or bicarbonates, such as sodium and potassium carbonate or sodium bicarbonate.

The conversion of a compound of formula IV into the corresponding alkali metal or alkaline earth metal compound may be effected by reacting a compound of formula IV with an alkali metal or alkaline earth metal hydroxide, such as lithium hydroxide, barium hydroxide, sodium hydroxide or potassium hydroxide, with an alkali metal alcoholate, such as sodium methoxide or potassium tert-butoxide, with an alkali metal amide, such as sodium amide or potassium amide, or with an alkali metal hydride such as sodium hydride or potassium hydride. The reaction is preferably carried out at elevated temperatures and in the presence of a suitable organic solvent. Inert organic solvents, such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran or glycoldimethyl ether are preferred if alkali metal hydrides are used as the

9/038-4-C6 metalladng agents, whereas, if an alkali or alkaline earth metal hydroxide is used, an aqueous mixture with an organic solvent, such as methanol or tetrahydrofuran, may also be employed. For conversion of the alkali or alkaline earth metal-substituted 5,ll-dihydro-6H-dipyrido[3,2b:2’,3’-ej[l,4]diazepin-6-one thus obtained into a compound of general formula Ic, the solution or suspension of the alkali or alkaline earth metal compound is reacted directly, i.e. without isolation, with a compound of formula V at -20°C or at elevated temperatures, up to the boiling point of the solvent or reaction medium, whichever is lower. The substitution takes place almost exclusively at the nitrogen atom in the 5-position of the dihydrodipyridodiazepinone, even if R^J in the starting material of formula IV is a hydrogen atom, provided that one equivalent of base and one equivalent of a compound of formula V are used.

It will be obvious to those skilled in the art that the presence of nucleophilic substituents in the compounds of formula Ic may require the use of an intermediate of formula Ic having substituents which are, other than the 11-position nitrogen, not nucleophilic but which can be derivatized to yield the required group. For example, amino or monoalkylamino substituents at any of R³ through R* are preferably obtained by alkylating or acylating an intermediate of formula Ic having a nitro group at any of R³ through R*, and subsequently reducing the nitro group, and alkylating, if appropriate, to yield the final product

9/038-4-C6

Method D

wherein Z is oxygen and R¹ through R* represent the groups mentioned above, can be obtained by converting a 5,1 l-dihydro-6H-dipyrido[3,2-b:2’,3’-e][l,4]diazepin-6-one of formula lb, as described above, into the corresponding metal salt of formula Via or - in the case of R¹ in the compound of formula lb being hydrogen - into a compound of formula VIb

9/038-4-C6 ο

(Vib) wherein M represents an alkali metal, such as lithium, sodium, potassium, rubidium or cesium, or M represents the group MgHal+, wherein Hal is a chlorine, bromine or iodine atom, and subsequently alkylating with a compound of formula VII ‘

R*X (VH)

AP o 0 0 1 7 a wherein R² and X are as hereinbefore defined.

The conversion of a compound of formula lb into the corresponding alkali metal compound of formulae Via or Vib may be effected by reacting a compound of formula lb with a lithium alkyl (e.g. n-butyl lithium, or t-butyl lithium) optionally in the presence of tetramethylethylenediamine, a lithium dialkylamide, (e.g. lithium diisopropylamide, lithium dicyclohexylamide and lithium isopropyl-cyclohexylamide), a lithium aryl (e.g. phenyl lithium), an alkali metal hydroxide (e.g. lithium, sodium or potassium hydroxide), an alkali metal hydride (e.g. sodium or potassium hydride), an alkali metal amide (e.g. sodium or

9/038-4-C6 potassium amides) or a Grignard reagent (e.g. methyl magnesium iodide, ethyl magnesium bromide or phenyl magnesium bromide). One equivalent of base is required for the formation of compounds of formula Via, whereas two equivalents of base are required for the formation of compounds of formula VIb. The metallation is conveniently carried out in an inert organic solvent at temperatures of between -78°C and the boiling point of the reaction mixture in question. If a lithium alkyl, lithium aryl, lithium dialkylamide or Grignard reagent is used for the metallation, the preferred solvents are ethers such as tetrahydrofuran, diethyl ether or dioxane, optionally in a mixture with aliphatic or aromatic hydrocarbons, such as hexane or benzene, and the operation may be carried out at temperatures of between -20 and +80°C. When metallation is effected with an alkali metal hydride or alkali metal amide, in addition to the solvents mentioned hereinbefore it is also possible to use xylene, toluene, acetonitrile, dimethylformamide and dimethylsulfoxide, while if an alkali metal hydroxide is used it is also possible to use alcohols such as ethanol, methanol and aliphatic ketones,such as acetone, as well as mixtures of these solvents with water.

For conversion of the alkali metal salt thus obtained into a compound of formula I, the solution or suspension of the alkali metal compound is reacted directly, i.e. without isolation of the reaction product, with a compound of formula VH at temperatures of between -20° and the boiling point of the reaction mixture, preferably at room temperature.

It will be obvious to those skilled in the art that the presence of nucleophilic substituents in the compounds of formula I may require the use of an intermediate of formula I having

9/038-4-C6 substituents which are, other than the 11-position nitrogen, not nucleophilic but which can be derivatized to yield the required group. For example, amino or monoalkylamino substituents at any of R’ through R* are preferably obtained by alkylating or acylating an intermediate of formula Ic having a nitro group at any of R^J through R*. and subsequently reducing the nitro group, and alkylating, if appropriate, to yield the final product *

Starting Materials For Methods A-D

The carboxylic acid amides of formula Π used as starting materials are obtained, for example, by amination of 2-chloro-nicotinic acid amides of formula VIH

(vm)

AP 0 0 0 1 7 9 wherein R¹ through R* and Hal are as hereinbefore defined, with primary amines of formula EX

H₂N-R^r (IX) wherein R² is as hereinbefore defined.

The reaction can also be carried out in the presence

9/038-4-C6 of inorganic or organic auxiliary bases, such as triethylamine, Ν,Ν-dimethylaniline, or sodium or potassium carbonate. The reaction can be carried out without using a solvent; it is of some advantage, however, to use inert organic solvents at temperatures of between 0°C and 175°C, preferably at reflux temperature. Suitable inert solvents that can be used include an excess of the primary amine of general formula IX, open chain or cyclic ethers, such as tetrahydrofuran,

1,4-dioxane, glycoldimethyl ether, diethyleneglycoldimethyl ether, aromatic hydrocarbons, such as benzene, toluene, xylene, chlorobenzene or pyridine; alcohols such as methanol, ethanol, isopropanol; dipolar aprotic solvents such as dimethylformamide; l,3-dimethyl-2imidazolidinone, l,3-dimethyl-tetrahydro-2(lH)-pyrimidinone and sulfolane.

Carboxylic acid amides of formula Da can be prepared by condensation of an appropriately substituted 2-chloronicotinic acid chloride with an appropriately substituted 3-amino-2(aikylamino)pyridine, under well known reaction conditions.

Starting materials of formula VHI, wherein R¹ is different from hydrogen, can be prepared from 2-chloronicotinic acid amides of formula X

9/038-4-C6 by reaction with alkylating agents of formula V in the presence of proton acceptors, for example of amines, such as triethylamine, diazabicycloundecene, 4-(dimethylamino)pyridine, or alkali or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, of alkali carbonates, or alkaline earth metal carbonates or hydrogen carbonates, such as sodium carbonate or potassium carbonate, or potassium hydrogen carbonate.

2-Chloronicotinic acid amides of general formula X can be obtained by condensation of an appropriately substituted 2-chloronicotinic acid chloride with an appropriately substituted 3amino-2-halopyridine, under well known reaction conditions.

All the other starting materials are known from the literature or may be purchased or may be obtained by procedures known from the literature.

Method E

In Method E, a compound of Formula I, wherein Z is sulfur, is obtained by reacting a compound of Formula I, wherein Z is oxygen, with a sulfurating agent, such as 2,4-bis(4methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide; bis(tricyclohexyltin)sulfide; bis(trin-butyltin)sulfide; bis(tri-phenyltin)sulfide; bis(trimethylsilyl)sulfide or phosphorous pentasulfide. The reaction is carried out in an inert organic solvent such as carbon disulfide, benzene or toluene, at room temperature or higher, preferably at an elevated temperature up to the boiling point of the reaction mixture, and preferably under anhydrous conditions. When

Lt 0 0 0 dV

9/038-4-C6 using the above mentioned tin or silyl sulfides, it is preferable to carry out the sulfurization reaction in the presence of a Lewis acid such as boron trichloride.

It will be obvious to those skilled in the art that the presence of another carbonyl moiety in a compound of formula I, for example, a compound wherein Z is oxygen and any of R³ through R* is alkanoyl, will require that the ketone carbonyl be protected via known methods by a suitable protecting group prior to the sulfurization reaction; deprotection subsequent to the sulfurization reaction provides the desired compound. Similarly, in cases wherein R² is, for example, alkanoyl, it will be obvious that the sulfurization reaction is best performed prior to the acylation of the 11-position nitrogen. In those cases wherein the substituents at any of R¹ through R* can be derived from nitro, for example, alkanoylamino, the sulfurization reaction can be performed on the corresponding nitro derivative, followed by an appropriate (known) reduction and finally acylation to yield the desired product

Method F

Compounds of formula I, wherein R* is hydrogen and R² through R* are as defined above and Z is a group of formula =NCN, can be obtained by reacting a compound of the formula XI

9/038-4-C6 wherein R² through R* are as defined above, with cyanamide. The reaction is carried out in the presence of a base such as potassium carbonate, sodium carbonate, triethylamine, or diisopropylethylamine, and in an inert solvent such as methylene chloride, 1,4-dioxane, tetrahydrofuran, diethylether, chloroform, or dimethylformamide at a temperature between 0°C up to the boiling point of the reaction mixture.

Method G

Compounds of formula I, wherein R* is hydrogen and R² through R* are as defined above and Z is a group of formula =NOR’, can be obtained, in a manner analogous to that of Method F, by reacting a compound of formula XL wherein R² through R* are as defined above with the

O>

appropriate alkoxylamine ((9-alkylhydroxylamine) or their salts (for example, methoxylamine hydrochloride). The reaction is carried out under conditions analogous to those described for the treatment of compounds of formula XI with cyanamide. θ

0.

<

Starting Materials For Methods F and G

Compounds of the formula XI wherein R² through R* are as defined above, can be obtained by reacting a compound of formula I, wherein R¹ is hydrogen, R² through R* are as defined above and Z is oxygen, with trifluoromethanesulfonic anhydride. The reaction is preferably carried out in an inert solvent using one to two equivalents of trifluoromethanesulfonic anhydride and in the presence of one to two equivalents of a base. The base may be; for example, a tertiary amine such as triethylamine or diisopropylethylamine, and the inert solvent used may include, for example, methylene chloride, chloroform, diethylether, tetrahydrofuran,

9/038-4-C6 or toluene. Addition of the reagents is generally earned nut at or below ambient temperature, and the mixture is then allowed to react, at or near room temperature.

The alkoxy lam ine starting materials may be purchased or are known from the literature or may be obtained by procedures known from the literature.

Formation Of Salts And Other Derivatives

Compounds of formula I may, if desired, be converted into their non-toxic, pharmaceutically acceptable acid addition salts by conventional methods; for example, by dissolving a compound of formula I in a suitable solvent and acidifying the solution with one or more molar equivalents of the desired acid. The invention also comprises such salts.

Examples of inorganic and organic acids which may form nontoxic, pharmaceutically acceptable acid addition salts with a compound of the formula I are the following: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, and the like. Compounds of formula I may form acid addition salts with one molar equivalent of the acid.

BAD ORIGINAL

9/038-4-C6

Those skilled in the art will realize that it will at times be more convenient to make certain compounds of formula I by derivatization of other compounds of formula I, rather than by making them directly, using one of the above-described Methods A-G. Such derivatizations will employ known reaction techniques. As non-limiting examples, where R’ is hydrogen it can be oxidized to yield hydroxy; a nitro group can be reduced to yield an amine; a methoxy * group can converted to hydroxy by standard demethylation procedures and hydroxy can, in appropriate settings, be in turn replaced with amine via the trifluoromethanesulfonyloxy derivative; an amine can be acylated to yield an alkanoylamine or can be alkylated to yield the mono- or dialkylamine; a halogen can be replaced, in appropriate settings, by an amine;

and a protecting group can be removed. ⁰⁷

Γ*·»

Biological Properties

The above described compounds of formula I possess inhibitory activity against HIV-1 reverse transcriptase. When administered in suitable dosage forms, they are useful in the prevention or treatment of AIDS, ARC and related disorders associated with HIV-1 infection. Another aspect of the invention, therefore, is a method for preventing or treating HIV-1 infection which comprises administering to a human being, exposed to or infected by HIV-1, a prophylactically or therapeutically effective amount of a novel compound of Formula I, as described above.

AP 0 0 0 1

The compounds of formula I may be administered in single or divided doses by the oral, parenteral or topical routes. A suitable oral dosage for a compound of formula I would be in

9/038-4-C6 the range of about 0.5 mg to 1 g per day. In parenteral formulations, a suitable dosage unit may contain from 0.1 to 250 mg of said compounds, whereas for topical administration, formulations containing 0.01 to 1% active ingredient are preferred. It should be understood, however, that the dosage administration from patient to patient will vary and the dosage for any particular patient will depend upon the clinician’s judgement, who will use as criteria for fixing a proper dosage the size and condition of the patient as well as the patient’s response to the drug.

When the compounds of the present invention are to be administered by the oral route, they may be administered as medicaments in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier material. Such carrier material can be an inert organic or inorganic carrier material suitable for oral administration. Examples of such carrier materials are water, gelatin, talc, starch, magnesium stearate, gum arabic, vegetable oils, polyalkylcne-glycols, petroleum jelly and the like.

The pharmaceutical preparations can be prepared in a conventional manner and finished dosage forms can be solid dosage forms, for example, tablets, dragees, capsules, and the like, or liquid dosage forms, for example solutions, suspensions, emulsions and the like. The pharmaceutical preparations may be subjected to conventional pharmaceutical operations such as sterilization. Further, the pharmaceutical preparations may contain conventional adjuvants such as preservatives, stabilizers, emulsifiers, flavor-improvers, wetting agents, buffers, salts for varying the osmotic pressure and the like. Solid carrier material which can be used

9/038-4-C6 include, for example, starch, lactose, mannitol, methyl cellulose, microcrystalline cellulose, talc, silica, dibasic calcium phosphate, and high molecular weight polymers (such as polyethylene glycol).

For parenteral use, a compound of formula I can be administered in an aqueous or non- _T aqueous solution, suspension or emulsion in a pharmaceutically acceptable oil or a mixture of liquids, which may contain bacteriostatic agents, antioxidants, preservatives, buffers or other solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Additives of this type include, for example, tartrate, citrate and acetate buffers, ethanol, propylene glycol, polyethylene glycol, complex formers (such as EDTA), antioxidants (such as sodium bisulfite, sodium metabisulfite, and ascorbic acid), high molecular weight polymers (such as liquid polyethylene oxides) for viscosity regulation and polyethylene derivatives of sorbitol anhydrides. . Preservatives may also be added if necessary, such as benzoic acid, methyl or propyl parabcn, benzalkonium chloride and other quaternary ammonium compounds.

The compounds of this invention may also be administered as solutions for nasal application and may contain in addition to the compounds of this invention suitable buffers, tonicity » adjusters, microbial preservatives, antioxidants and viscosity-increasing agents in an aqueous vehicle. Examples of agents used to increase viscosity are polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone, polysorbates or glycerin. Microbial preservatives added may include benzalkonium chloride, thimerosal, chloro-butanol or phenylethyl alcohol.

L I 0 0 0 dV

9/038-4-C6

Additionally, the compounds provided by the invention can be administered by suppository.

As stated before, the compounds provided by the invention inhibit the enzymatic activity of HIV-1 RT. Based upon testing of these compounds, as described below, it is known that they inhibit the RNA-depcndent DNA polymerase activity of HIV-1 RT. It is known (data not shown) that they also inhibit the DNA-dependent DNA polymerase activity of HIV-1 RT.

Utilizing the Reverse Transcriptase (RT) Assay described below, compounds can be tested for their ability to inhibit the RNA-dependent DNA polymerase activity of HIV-1 RT. Certain specific compounds described in the Examples which appear below, were so tested. The results of this testing appear in Table I, below.

REVERSE TRANSCRIPTASE (RT) ASSAY

Assay Theory:

.Among the enzymes for which Human Immunodeficiency Virus (HIV-1) encodes is a reverse transcriptase (1), so-named because it transcribes a DNA copy from an RNA template. This activity can be quantitatively measured in a cell-free enzyme assay, which has been previously described (2), and is based upon the observation that reverse transcriptase is able to use a synthetic template [poly r(C) primed with oligo d(G)] to transcribe a radio-labelled, acid-precipitable DNA strand utilizing ³H-dGTP as a substrate.

9/038-4-C6

Materials;

a) Preparation of the enzyme

Reverse transcriptase enzyme from the LAV strain of Human Immunodeficiency Virus (HTV1) (1) was isolated from the bacterial strain JM109 (3) expressing the DNA clone pBRTprtl+ (2) which is under the control of the lac promotor in the expression vector ρΠ3Ι21 (4). An overnight culture grown in 2XYT medium (37°C, 225 rpm) (5) supplemented with 100 pg/ml ampiciiiin for positive selection is inoculated at a 1:40 dilution into M9 medium supplemented with lO^g/ml thiamine, 0.5% casamino acids, and 50 pg/ml ampiciiiin (5). The culture is incubated (37°C, 225 rpm) until it reaches an OD540 of 0.3-0.4. At that time the repressor inhibitor IPTG (isopropyl β-D-thiogalactopyranoside) is added to 0_5mM, and the mixture is incubated for 2 additional hours. Bacteria are pelleted, resuspended in a 50mM Tris, 0.6mM EDTA, 0.375M NaCl buffer and digested by the addition of lysozyme (lmg/ml) for 30 minutes on ice. The cells are lysed by the addition of 0.2% NP-40 and brought to 1M

NaCl.

L I 0 0 0 dV

After removal of the insoluble debris by centrifugation, the protein is precipitated by the addition of 3 volumes of saturated aqueous ammonium sulfate. The enzyme is pelleted, resuspended in RT buffer (50mM Tris pH 7.5, ImM EDTA, 5mM DTT, 0.1% NP-40, 0.1M NaCl, and 50% glycerol), and stored at -70°C for further use.

9/038-4-C6

b) Composition of 2X concentrated stock reaction mixture

Stock Reagent	2X Mix Concentration
l.M Tris pH 7.4	lOOmM
IM Dithiothrietol	40m M
IM S’aCl	120mM
1% Nonidet P-40	0.1%
IM MgCl	4mM
[poly r(C)/oligo d(G)](5:1)	2μg/ml
3H-dGTP (81μΜ)	0.6μΜ
Assay Procedure:

The 2X concentrated stock reaction mixture is aliquoted and stored at -20°C. The mixture is stable and thawed for use in each assay. This enzyme assay has been adapted to a 96 well microtiter plate system, and has been previously described (6). Tris buffer (50 mM, pH 7.4), vehicle (solvent diluted to match the compound dilution), or compounds in vehicle are dispensed into 96-well microtiter plates (ΙΟμΙ/well; 3 wells/ compound). The HIV-1 RT enzyme is thawed, diluted in 50mM Tris pH 7.4 so that fifteen μ] of diluted enzyme contain 0.001 Unit (one unit is that amount of enzyme to transform 1 micromole of substrate per minute at 25³C), and fifteen μΐ are dispensed per well. Twenty μΐ of 0.12-0.5M EDTA are added to the first three wells of the microdter plate. EDTA chelates th* .Mg** present and prevents reverse transcription. This group serves as background polymerization which is subtracted from all other groups. Twenty-five ul of the 2X reaction mixture are added to all

9/038-4-C6 wells and the assay is allowed to incubate at room temperature for 60 minutes. The assay is terminated by precipitating the DNA in each well with 50μ1 of 10% trichloracetic acid (TCA) (10% w/v) in sodium pyrophosphate (1% w/v). The microtiter plate is incubated for 15 minutes at 4⁵C and the precipitate is fixed onto #30 glass fiber paper (Schleicher & Schuell) using a Skatron semi-automatic harvester. The filters are then washed with additional TCA (5%) containing sodium pyrophosphate (1%), rinsed with aqueous ethanol (70%), dried, and transferred to scintillation vials (6). Each vial receives 2 mis of scintillation cocktail and is counted in a Beckman beta counter.

The calculation for percent inhibition is as follows:

% inhibition = CPM Mean Test Value - CPM Mean Control Value X100

CPM Mean Control Value

AP 0 0 0 1 7 9

References:

1. Benn, S., et al., Science 230:949, 1985

2. Farmerie, W.G. et. al., Science 236:305, 1987

3. Yanisch-Pcrron, C., Viera, I, and Messing, J., Gene 33:103, 1985

4. International Biotechnologies, Inc., New Haven, CT 06535

5. Maniatis, T, Fritsch, E.F., and J. Sambrook, eds. Molecular

Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory,

1982

6. Spira, T., et. al. J. Clinical Microbiology, 25:97, 1987.

9/038-4-C6

In order to confirm that compounds which are active in the RT Assay also have the ability to inhibit HTV replication in a living system, compounds according to the invention were also tested in the human T-Cell Culture Assay described below. The results of this testing appear in Table I.

HUMAN T-CELL CULTURE ASSAY

Assay Theory; Formation of syncytia is a feature of in vitro cultures of CD4+ T-cells infected with HTV-1. In this assay, T-cells are treated with a putative replication inhibiting compound and then infected with HTV-1. After incubation, the culture is checked for the formation of syncytia. The absence or reduction in the number of syncytia is used as a measure of the test compound’s ability to inhibit HTV replication.

Assay Method; The target cells, designated c8166, are a subclone of human lymphoma cells of T-cell origin and are established at an initial density of 5x1ο⁴ per 100 ul in RPMI 1640 (+ 10% fetal bonne serum) culture medium in 96 well flat bottom plates. A selected amount of test compound, dissolved in DMSO, is included. After 24 hours, 50-100 TCID/s (the dose that results in induced effect in 50% of test cultures) of the HTLV-IHB strain of HTV-1 (2) are inoculated into each culture. Control cultures receive compound or virus only. Four days after virus challenge, cultures are visually examined for the frequency and distribution of virus-induced giant cell syncytia. The percent inhibition by the test compound is determined by comparison with control values. Confirmation of the presence or absence of virus f------ —>

9/038-4-C6 37BAD ORIGINAL replication is accomplished by harvesting the cell free culture fluids from all experimental groups to determine the presence or absence of infectious progeny through the induction of syncytia formation in secondary human T-cell cultures after 3 days.

References:

(1) M. Somasundaran and H.L. Robinson, Science 242, 1554 (1988).

(2) G.M. Shaw, R.H. Hahn, S.K. Arya, J.E. Groopman, R.C. Gallo and F.

Wong-Staal, Science 226, 1165 (1984)

In order to assess the specificity of the enzyme inhibitory activity of the compounds provided by the invention, a few were tested, using known per se assay methods, for their ability to inhibit Feline Leukemia Virus-derived reverse transcriptase and Calf Thymus-derived DNA alpha-polymerase. None of the compounds so tested was observed to possess any inhibitory activity against these enzymes. These results indicate that the enzyme inhibitory activity of the compounds provided by the invention is directed rather specifically against HTV-1 RT.

In order to roughly assess the cytotoxicity of the compounds provided by the invention, several such compounds were tested in the MTT Cellular Cytotoxicity Assay described below. The results of this testing are reported in Table I, below. Compounds having a relatively high ECjo are preferred.

AP 0 0 0 1 7 9

9/038-4-C6

BAD ORIGINAL

MTT ASSAY FOR CELLULAR CYTOTOXICITY

Assay Theory:

The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide) assay is based on cleavage of tetrazolium bromide by metabolically active cells, resulting in a highly quantitative blue color. This assay has been previously described (1) but has been optimized for the purposes of the testing reported herein.

Assay Method:

The H9 cell line (2), an established human lymphoma suspension cell line grown in RPMI 1640 supplemented with 10% fetal bovine serum, is used as the target cell line in the assay. Cells (ΙΟΟμΙ) are plated in microtest plate wells al a concentration of 10³ cells per ml in the presence of varying concentrations of inhibitor. The cells are incubated at 37°C in a humidified COj incubator. Five days later, 20μ1 of MTT (5mg/ml in RPMI 1640, sonicated, 0.2 micron filtered, and stored at 4°C) is added to each welL After 4 hours additional incubation at 37°C, 60μ1 of Triton-X is added to each well and thoroughly mixed to aid the solubilization of the crystals. Absolute ethanol (5μ1) is added to each well and the resulting mixture is incubated for 30 minutes at 60°C and immediately read on a plate reader (Dynatech) at a wavelength of 570nm.

9/038-4-0*.··

Data from this assay are used to generate a nonlinear regression analysis which yields an

EC^

References:

1. Mosmann, Tim, J. Immunol. Methods, 65:55, 1983.

2. Jacobs, J.P., Z Natl. Cancer Inst., 34:231, 1965.

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9/038-4-C6

BAO ORIGINAL

TABLE ί

Compound of	RT Assay	T-Ccll Assay	Cytotoxicity .·
Example No.	% inhibition	% inhibition	(ECjo,pM)
	@ 10 pg/ml	@ 3 pg/ml

3.	94	NT	-----NT
3	94	NT	NT
4	98	100	92
5	44	9 NT	NT
6	50	NT -	NT
8	100	100	140
---------_	100	100
10	100	NT	NT
11	100	100	200
12	100	100	250
13	36*	NT	NT
H----------- ...	-------------
	1 to
15	91'	100	45
16	961	100	350
47—	100— — -	- TOO --- -	-NT-

9/038-4-C6

Ί8----	100
19	31
20	94
54=^-'-	100
17 ?i	40*
	75*
24	78*
A	85*
26-	100
7C Zf	76*
-28.--------	100
	91*
2‘λ 30	90’
-31,,-------	66
—— - - -
Λ7 xi	45
33 --	96
& a.s	99 T1

NT	NT
NT	NT
NT	NT
100 - -----	- NT
NT	NT
NT	NT
NT	- NT
NT	NT
—NT - - -	----NT
NT	NT

Μ 98

2L W 87

NT-----------------NT

NT	NT
NT	NT
NT	.....ΧΓΓ
NT	NT
NT-
100	NT
----NT	----NT
NT	NT
NT	2 NT
NT	NT

AP 0 0 0 1 7 9

9/038-4-C6

	100
4ο i	93
J 4ι	86
! 42	91
i 43	95
44	60
45	98
46 1	100
47--------	96
Λ	63*
tl9	99
i
50 1	96
54------	96
..;c- xi	99
5i-------	99
54	92.
55	.^9-
*' .	- 37-
	99
*	50’
59--------	-----89--

ST	----
ST	ST
NT	NT
ST	NT
ST	NT
ST	NT
ST	NT
100	St
NT	-
NT NT	NT • _vrr
_________-—*7
ST	NT 1
NT	- -_ I -NT
NT	NT
NT	ΧΓΤ
. £*·
NT	NT
NT -ST	NT 'MT
NT	NT
NT	NT
NT	----- - ----NT

9/038-4-C6

η		93	NT	NT
SC 6ΐ		85	NT	NT
62 - -·		99	NT	--------------2vr
63		96	NT	-----NT
Si X		100	NT	NT
ST J65		S3	VT	NT
;s &		35*	NT	NT
67 -	-	94 ------	-NT-	- --------------
68-------	—	100	. -NT	---—
S^r rf		94’	NT	NT
53		36*	NT	NT
SC rf		2’	NT	NT
S7 72		34*	NT	NT
		0	NT	NT
74-		80	NT	NT
75 -		42	NT	-- ------NT
V		100	NT	NT
4-0 rf		99	N'T	NT
L+< rf		100	NT	NT
ύ-Ζ^		83*	NT	NT
s3xr		85*	NT	NT

9/038-4-C6

		91		NT	NT
-33-		96		NT	---------—NT
*		64’		NT	NT
		70*		NT	NT
ul		34*		NT	NT
36--		14*		NT	-----------NT
67 -		7*		NT	----------NT
us		0*		NT	NT
89---------	—	-38’ -	. — ._....	-----NT-	-NT
90		0*		NT	NT
5C *		43’		NT	NT
92----		72*		NT -------	------NT
S-, M		90*		NT	NT
62-94		44		NT	NT
S S		90*		NT	NT
.95		35*		NT	NT
TS -97		44		NT	NT
5'C 9<		100		100	NT
5'^-97-		77		NT	NT
		52*		NT	NT
>9 -K>T		44*		NT	NT

9/038-4-C6

BAD ORIGINAL

	102	17’	NT	NT
	103	94'	NT	-- - - NT
	104·	44*	NT	NT
£c·		20’	NT	NT
	W6-	42’	NT	---NT
	107	96’	NT	-------- -NT
L·'	V&	7>*	.NT	NT
		17’	NT	NT
i-3	ΤΚΓ	30*	NT	NT
		61’	NT	NT
		68’	NT	NT
		66*	NT	NT
	114-------	53*	NT ---------	- NT
6’7	.-K5	37’	NT	NT
0-¾		8*	NT	NT
	4-17----	75’	NT- -----	-----------NT-
n	.H5	90’	NT	NT
	-44-9	75’	NT	NT
~7i	4^r	0’	NT	xNT
	J2T	98*	NT	NT

L 1 0 0 0 dV

9/038-4-C6

	94'	NT	NT
— 1 , -t	82’	N'T	NT
5	100	NT	NT
76	88'	N'T	NT

• =@ ΙμΜ ' = @ 1.25μΜ * = @ 0.5μΜ

NT = not tested

Examples

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited to the particular examples given below.

Example 1

5J l-Dihvdp>6H-dipvridof3.2-b:2^,.3'-clfl.4jdiazepin-6-one

a) 2-Ch]oro-.N-(2-chJoro-3-pyridinyl)-3-pyridinecarboxamide

In a three-necked round-bottomed flask, fitted with an efficient reflux condenser, mechanical stirrer and dropping funnel, were placed 215 g (1.672 mol) of 3-amino-2-chloropyridine, dissolved in a mixture of 400 ml dioxane, 500 ml cyclohexane and 130 ml pyridine. The

9/038-4-C6 solution of 299.2 g (1.7 mol) of freshly prepared 2-chloro-3-pyridinecarboxylic acid chloride in 200 ml dioxane was added at such a rate as to keep the vigorous reaction under control. Thereafter, the reaction mixture was allowed to cool to room temperature and the resulting crystalline precipitate was filtered off and washed successively with cyclohexane and ether.

The dark brown product was dissolved in 5 1 of a 3% aqueous solution of sodium hydroxide.

The resulting solution was treated with charcoal, suction filtered, and the filtrate was acidified by addition of 50% aqueous acetic acid. The resulting precipitate was collected by filtration and thoroughly washed with water. After being dried overnight in a stream of nitrogen at room temperature the almost colorless product had a m.p. of 156-159®C and was sufficiently pure for further reactions. The yield was 376.0 g (84% of theory).

Q.

b) N-(2-Chloro-3-pyridinyl)-2-([(4-methoxyphenyl)methyl]amino]-3’pyridinecarboxamide

13.4 g (0.05 mol) of the product obtained in step a) were dissolved in 20 ml of xylene, and the resulting solution was admixed with 13.8 g (0.1 mol) of p-methoxybenzylamine.

Thereafter, the mixture was refluxed for two hours. The reaction mixture was then evaporated in vacuo, and the residue was purified by column chromatography on silica gel (0.2-0.5 mm) using dichloromethane/ethyl acetate 10/1 (v/v) as an eluent Concentration afforded colorless crystals, melting at 122-124°C (after recrystallization from acetonitrile).

The yield was 17.2 g (93% of theory).

0179

9/038-4-C6

c) 5,1 l-Dihydro-ll-[(4-methoxyphenyl)methyl]-6H-dipyrido(3,2-b:2^,,3’-e][l,4]diazepin-6-one 16.7 g (0.0453 mol) of the product obtained in step b) were dissolved in 150 ml of absolute dioxane, and the resulting solution was admixed with 6.7 g (0.14 mol) of a 50% dispersion of sodium hydride in mineral oil. Thereafter, the mixture - while protected against the external atmosphere by a low flow of nitrogen - was refluxed until no starting material could be detected by TLC. The surplus of sodium hydride was decomposed by cautious 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 was evaporated in vacuo. The residue was purified by column chromatography on silica gel (0.2-0.5 mm) using successively dichloromethane/ethyl acetate 10/1 (v/v) and dichloromethane/echyl acetate 1/1 (v/v) as eluents. The crystalline product obtained by evaporation of suitable fractions was recrystallized from acetonitrile and 2-propanoL The product had a m.p. of 213-215°C and was identified as 5,11-dihydro-1 l-[(4-methoxyphenyl)-methyl]-6H-dipyrido(3,2-b:2*,3’e][l,4]diazepin-6-one. The yield was 10.3 g (68% of theory).

d) 5,1 l-Dihydro-6H-dipyrido{3,2-b:2’,3’-e][l,4]diazepin-6-one

10.0 g (0.3 mol) of the product obtained in step c) were dissolved in 50 ml of trifluoroacetic acid, whereby the mixture became slightly warm. Thereafter, the reaction mixture was stirred at 60°C for 1 hour. No starting material could be detected by TLC at that time. The mixture was then evaporated in vacuo. The residue thus obtained was thoroughly stirred with 0.5% aqueous ammonia and then was filtered by suction. The raw product was recrystallized from 150 ml of dimethyl sulfoxide to provide colorless crystals of m.p. > 340°C. The yield was

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4.8 g (75% of theory). The product was identified as 5_Ill-dihydro-6H-dipyrido(3,2-b:2^,,3’e][l,4]diazepin-6-one.

Example 2

5.11-Dihvdro-l l-groovl-6H-dipvridof3.2-b:2’.3‘-eU1.4'!diazgpin-6-one

a) N-(2-Chloro-3-pyridinyl)-2-(propyIamino)-3-pyridinecarboxamide

26.8 g (0.1 mol) of 2-<hIoro-N-(2-chloro-3-pyridinyl)-3-pyridinecarboxamide were dissolved in 200 ml of dioxane, and the resulting solution was admixed with 21.4 g (0.362 mol) of propylamine. Thereafter, the mixture was shaken in a stainless steel pressure vessel at 150°C for 6 hours. The reacdon mixture was then evaporated in vacua, and the residue was purified by column chromatography on silica gel, successively using dichloromethane/ethyl acetate 10/1 (v/v) and dichloromethane/cyclohexane/ethyl acetate 1/2/1 iy/v/v} as eluents. The product obtained by evaporadon was a highly viscous resin that had a satisfactory quality for the following reacdon.

b) 5,11-Dihydro-ll-propyl-6H-dipyrido(3-2-b:2^,,3^,-e][l,4]diazepin-6--one

Using a procedure analogous to that described in Example lc), 5,11-dihydro-11-propy!-6Hdipyrido(3,2-b:2’,3’-e][l,4]diazepin-6~one, m.p. 184-186³C (recrystall!zed from acetonitrile), was prepared from the product obtained in the above step a) and sodium hydride. The yield was 74% of theory.

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Example 3

5.1 l-Dihvdro-5-methvl-l l-propvl-6H-dipvridof3.2-b:2^,.3^,-elfl.41-diazepin-6-one

a) 2-Chloro-N-(2-chloro-3-pyridinyl)-N-methyl-3-pyridinecarboxamide A four-necked round-bottomed flask, equipped with a mechanical stirrer, a dropping funnel, a thermometer and an efficient reflux condenser, was charged with 268.1 g (1.0 mol) of 2chloro-N-(2-chlon>3-pyridinyl)-3-pyridinecarboxamide, 260 ml of 50% aqueous sodium hydroxide, 1500 ml of toluene and 8.0 g (0.0352 mol) of benzyltriethylammonium chloride. Stirring was begun and a solution of 134 ml (178.5 g, 1.415 mol) of dimethyl sulphate in 1 1 of toluene was added dropwise over a period of about 3 hours, whereby the temperature rose to 50-60°C. After the addition of dimethyl sulfate was complete, stirring at 60°C was continued for a further 2 hours. The reaction mixture was cooled to room temperature and 1 1 of water was added. The layers were separated, and the aqueous phase was extracted three times with 300-ml portions of toluene. The organic layers were combined and washed successively with 300 ml of water, 300 ml of 1% aqueous acetic acid and 300 ml of water. The combined organic extracts were dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography on silica gel (0.2-0.5 mm) using as eluents successively toluene and ethyl acetate/cyclohexane/tetrahydrofuran 1/9/10 (v/v/v). The product obtained by evaporation of suitable fractions was recrystallized from acetonitrile/tert-butyl methyl ether 1/1 (v/v). It was highly soluble in dichloromethane, had a m.p. of 98-101°C, and was identified to be 2-chloroN-(2-chloro-3-pyridinyl)-N-methyl-3-pyridinecarboxamide. The yield was 232.5 g (82.5% of theory).

9/0^M-C6 51

I

b) N-(2-Chloro-3-pyridinyl)-N-methyl-2-(propylamino)-3-pyridinecarboxamide

Using a procedure analogous to that described in Example 2a, N-2-(chloro-3-pyridinyl)-Nmethyl-2-(propylamino)-3-piperidinecarboxamide was prepared from the product obtained in the preceding step and propylamine. 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 analogous to that described in Example lc, except employing tetrahydrofuran instead of dioxane as a solvent and applying only equimolar quantities of sodium hydride, 5,1 l-dihydro-5-raethyl-ll-propyl-6H-dipyrido-[3,2-b;2’,3’-e][l,4]diazepin-6one, a highly viscous oil, was prepared from the product obtained in the above step. The yield was 75% of theory.

Example 4

5.1 l-Diethvl-5,1 l-dihvdro-6H-dipvridof3.2-b:2^>.3^,-e1fl,41-diazepin-6-one

6.4 g (0.03 mol) of 5,ll-dihydro-6H-dipyrido(3,2-b:2’,3’-e][l,4]diazepin-6-one were dissolved in 100 ml of absolute dimethylformamide, and the resulting solution was admixed with 3.4 g (0.071 mol) of a 50% dispersion of sodium hydride in mineral oil. While protected against the external atmosphere by a flow of nitrogen, the mixture was stirred at 50-70°C for 1 hour. After the evolution of hydrogen had ceased, the mixture was cooled to 30°C and 10.9 g (0.07 mol) of ethyl iodide were added dropwise within 15 minutes. For completion of the exothermic reaction, the mixture was heated at 8O-9O°C for a further hour. The solvent was removed by distillation under reduced pressure. The residue was admixed with water and the

9/038-4-C6 52

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BAD ORIGINAL suspension thus obtained was exhaustively extracted with dichloromethane. The product obtained after usual work-up was recrystallized from 150 ml of isooctane. The product had a m.p. of 102-103°C and was identified as 5,11-diethyl-5,11-dihydro- 6H-dipyrido[3,2-b:2’,3’e][l,4]diazepin-6-one. The yield was 5.7 g (71% of theory).

Example 5

5,1 l-Dihvdro-5-ethvl-6H-dipvridof3.2-b:2’.3‘-eiri.41diazepin-6-one

a) N-(2-Chloro-3-pyridinyl-2-[(phenylmcthyl)amino]-3-pyridinecarboxamide

Using a procedure analogous to that described in Example lb, except employing die±yleneglycoldimethyl ether as a solvent instead of xylene, N-(2-chIoro-3-pyridinyI)-2-[(phcnylmethyl)amino]-3-pyridine carboxamide, m.p. 95-97°C (recrystallized from diethyleneglycoldimethyl ether), was prepared from 2-chloro-N-(2-chloro-3-pyridinyl)-3-pyridinecarboxamide and benzylamine. The yield was 72% of theory.

b) 5,11-Dihydno-ll-(phenylmethyl)-6H-dipyrido(3,2-b:2’,3’-e][l,4]diazepin-6-one

Using a procedure analogous to that described in Example lc except employing diethyleneglycoldimethyl ether as a solvent instead of dioxane, 5,ll-dihydro-ll-(phenylmethyl)-6Hdipyrido[3,2-b:2’,3^,-e][l,4]-diazepin-6-one, m.p. 212-213°C (recrystallized from 1-propanol), was prepared from the product obtained in step a) and sodium hydride. The yield was 61% of theory.

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c) 5,11 -Dihydro-5-ethyl-11 -(phcnylmethyl)-6H-dipyrido-[3,2-b:2’,3’-e][ 1,4]diazepin-6-onc Using a procedure analogous to that described in Example 3a, 5,ll-dihydro-5-ethyl-ll(phenyImethyi)-6H-dipyrido[3,2-b:2’,3’-e](l_t4]diazepln-6-one, m.p. 209-21 l^eC (recrystallized from toluene/acetonitrile 1/1 v/v), dichloromethane/methanol 99/1 v/v), was prepared from the product obtained in step b) and diethyl sulfate. The yield was 82% of theory.

d) 5,1 l-Dihydro-5-ethyl-6H-dipyrido[3,2-b:2’,3’-e][l,4]diazepin-6-one

Using a procedure analogous to that described in Example Id, except employing a pressure vessel instead of an open one and heating the mixture at 120°C for 10 hours, 5,ll-dihydio-5ethyl-6H-dipyrido(3,2-b:2’,3’-e][l,4]dia2epin-6-one, m.p. 161-163°C (recrystallized from isooctane/ethyl acetate 1/1 v/v), was prepared from the product obtained in step (c). The yield was 57% of theory.

Example 6

5,ll-Dihvdro-5-methvl-6H-dipvridof3,2-b:2^,.3^,-ein.41diazepin-6-one

a) N-(2-Chloro-3-pyridinyl)-N-methyl-2-[(phenylmethyl)emino]-3-pyridinccarboxamide Using a procedure analogous to that described in Example lb, N-(2-chloro-3-pyridinyI)-Nmethyl-2-[(phenylmethyl)amino]-3-pyridinecarboxamide, m.p. 114-116^eC (recrystallized from tert-butyl methyl ether), dichloromethane/ethyl acetate 3/1 v/v), was prepared from 2-chloroN-(2-chloro-3-pyridinyl)-N-methyl-3-pyridinecarboxaroide and benzylamine. The yield was 87% of theory.

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b) 5,11 -Dihydro-5-methyl-11 -(phenylmethyl)-6H-dipyrido(3,2-b:2’,3’-e][ 1,4]diazepin-6-one Using a procedure of analogous to that described in Example 3b, 5,ll-dihydro-5-methyl-l 1(phenylmethyl)-6H-dipyrido[3_>2-b:2’,3’-e][l₁4]diazepin-6-one, m.p. 198-199°C (recrystallized from acetonitrile), was prepared from the product obtained in step (a). The yield was 80% of theory.

c) 5,1 l-Dihydro-5-methyl-6H-dipyrido[3,2-b:2’,3’-e][l,4]diazepin-6-one

A mixture consisting of 75.5 g (0.239 mol) of the product obtained in step b), 2.5 kg of polyphosphoric acid, and 425 ml of anisole was stiiTed at 140-160°C for 2 hours. While still hot, the reaction mixture was stirred into crushed ice. Thereafter, the mixture was made slightly alkaline by addition of aqueous ammonia and was then exhaustively extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using dichloromethane/ ethyl acetate 1/1 (v/v) as an eluent. The product obtained by evaporation of suitable fractions was recrystallized from acetonitrile, yielding 21.6 g (40% of theory) of colorless crystals having a m.p. of 236-237°C.

Example 7

5,11-Dihvdro-6H-dipyridof3.2-b:2\3^,-elil.4]diazepin-6-one

3.8 g (0.0126 mol) of the product obtained in Example 5b were dissolved in 20 ml of trifluoroacetic acid whereby the mixture became slightly warm. Thereafter, the reaction mixture was refluxed for 8 hours. No starting material could be detected by TLC at that

9/038-4-C6 point of time. The mixture was then evaporated in vacuo, the residue thus obtained was thoroughly stirred with 0.5% aqueous ammonia and then filtered by suction. The raw material was suspended in 20 ml of acetonitrile, refluxed for 15 minutes and suction filtered while hot The filter cake was recrystallized from hot dimethyl sulfoxide yielding 1.2 g (45% of theory) of colorless crystals which had a m.p. > 340°C and were identified by m.p., mixed m.p. and UV-, IR- and MS spectra to be identical with the compound obtained in Example

Id.

Example 8

5.11-Dihvdro-l l-ethvl-5-mcthyl-6H-dipvridof3.2-b:2^,.3*-ein.4IdiazepIh-6-one

a) 2-Chloro-N-(2-chloro-3-pyridinyl)-3-pyridinecarboxamide

Using a procedure analogous to that described in Example la, 2-chloro-N-(2-chloro-3pyridinyl)-3-pyridinecarboxamide was prepared. The purified product was obtained by cooling the reaction mixture to room temperature and decanting the supernatant from the precipitate. The solid was then dissolved in methylene chloride, and the solution washed with water, dried (anhydrous sodium sulfate), and the solvent removed in vacuo. The solid was then washed with ethyl acetate and dried to provide 7.24g (84% of theory) of product suitable for use in the next reaction.

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b) N-(2-Chloro-3-pyridinyl)-2-[[(4-methoxyphenyl)methyl]amino]-3-pyridinccarboxamide Using a procedure analogous to that described in Example lb, N-(2-chloro-3-pyridinyl)-2-[[(4mcthoxyphenyl)methyl]amino]-3-pyridinecarboxamide was prepared. The purified product

9/038-4-C6 was obtained by removing the solvent in vacuo, adding water to the residue, and extracting the product with methylene chloride. This solution was dried (anhydrous sodium sulfate) and the solvent removed to give a brown oil which was treated with 10 ml of ether. The product which crystallized was filtered and washed sequentially with ether and hexane to give 78.0 g (91% of theory) of the title compound as an off-white powder, m.p. 121-122°C. ·<

c) 5,1 l-Dihydro-ll-[(4-tnethoxyphenyl)methyl]-6H-dipyrido(3,2-b:2’,3’-e][l,4]diazepin-6-one 1.44 g of a 50% dispersion of sodium hydride in mineral oil was added to a solution of 3.69g (0.010 mol) N-(2-chloro-3-pyridinyl)-2-[[(4-methoxyphenyl)mcthyl]amino]-3-pyridinecarboxamide in 100 ml of dimethylformamide. After the evolution of hydrogen stopped, the mixture was heated (110°C) for 16 hours and then refluxed for eight hours. After the mixture had cooled, the excess sodium hydride was decomposed by the slow addition of ice. The mixture was further diluted with water, and the product was extracted with ether and concentrated. The crystallized residue was filtered and washed with ether to give 1.60 g of

5,ll-dihydro-ll-[(4-methoxyphenyl)methyl]-6H-dipyrido(3_r2-b:2’,3’-eJ[l,4]diazepin-6”One (50% of theory) as an off-white powder, m.p. 209-210°C.

d) 5,1 l-Dihydro-ll-[(4-methoxyphenyl)methyl]-5-methyl-6H-dipyrido [3,2-b:2’,3’-e][l,4]diazepin-6-one

10.0 g (0.030 mol) of 5,ll-dihydro-ll-[(4-methoxyphenyl)methyl]-6H-dipyrido-[3,2-b:2’,3’e) (l,4]diazepin-6-one was added to a flask containing 2.16 g of a 50% dispersion of sodium hydride in mineral oil and 100 ml of dimethylformamide. The resulting mixture was stirred

9/038-4-C6 at room temperature for 30 min. and then heated to 50°C for 30 min. After cooling, 8,51 g (0.060 mol) of methyl iodide in 10 ml of dimethylformamide was added dropwise and the mixture was allowed to stir at room temperature overnight. Excess sodium hydride was decomposed by the careful addition of ice. Water was then added, and the product was extracted with ether, dried (anhydrous sodium sulfate), and concentrated to give 10.3 g (99% of theory) of 5,11-dihydro-l l-[(4-methoxy-phenyl)-methyl]-5-methyl-6H-dipyrido-[3,2-b:2’,3’e][l,4]diazepin-6-one as a light yellow oil suitable for use in the next reaction.

e) 5,1 l-Dihydro-5-methyl-6H-dipyrido[3,2-b:2’3’-e](l,4]diazepin-6-one 50 ml of trifluoroacetic acid was added to 10.3 g (0.030 mol) of 5,11-dihydro-l 1-((4methoxyphenyl)methyl]-5-methyl-6H-dipyrido [3,2-b:2’,3’-e][l,4]-diazepin-6-one, and the mixture was stirred for one hour at room temperature. The acid was removed in vacuo and the residue was stirred for one hour with 0.5% ammonia. The solid was filtered and dried to give 6.70 g (98% of theory) of pure 5,ll-dihydro-5-methyl-6H-dipyrido [3^-b:2’,3’e] [l,4]diazepin-6-one, m.p. 230-232^eC.

f) 5,ll-Dihydro-ll-ethyl-5-methyl-6H-dipyrido[3,2-b:2’,3’-e][l,4]diazepin-6-one

2.00 g of a 50% dispersion of sodium hydride in mineral oil was added to a solution of 5.75 g (0.025 mol) of 5,1 l-dihydro-5-me±yl-6H-dipyrido[3_r2-b:2’,3’-e][l,4]diazepin-6-one in 100 ml of dimethylformamide. When the evolution of hydrogen ceased, the mixture was heated to 50°C for 30 min. and then cooled to room temperature. Then,7.80 g of ethyl iodide (neat) was added dropwise over 15 minutes, and the resulting mixture was allowed to stir overnight

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9/038-4-C6 at room temperature. The excess sodium hydride was decomposed by the careful addition of ice, followed by water. The product was extracted with ether, dried (anhydrous sodium sulfate), and evaporated to yield 4.5 g (70% of theory) of 5,11-dihydro-11-ethyl-5-methyl-6H dipyrido(3,2-b:2’,3’-e][l,4]diazepin-6-one, m.p. 130-132°C.

Example 9

5,11-Dihvdro-l l-ethvl-5-methvl-6H-dipyridof3.2-b:2^,,3^,.-e1f l,41diazepin-6-thione

A mixture of 2.66g (0.01 mol) of 5,ll-dihydro-ll-ethyl-5-methyl-6H-dipyrido-[3,2-b:2’3’e][l,4]diazepin-6-one and 2.10g (0.005 mol) of Lawesson’s reagent (2,4-bis(4methoxyphenyl)-13-dithia-2,4-diphosphetane-2,4-disulfide) in 50ml of toluene was refluxed for 2 1/2 h. The solvent was then removed in vacuo and water was added to the residue.

The product was extracted with ethyl acetate, dried (anhydrous sodium sulfate), and concentrated in vacuo. Purification was effected on a silica gel column· using methylene chloride as the first eluent, followed by ethyl acetate/hexane (1:4). Removal of the solvent in vacuo gave 2.20g (74% of theory) of 5,ll-dihydro-ll-ethyl-5-methyl-6H-dipyrido[3,2-b:2’,3’e][l,4]diazepin-6-thione as a yellow powder, which was recrystallized from 10% hexane/ethyl acetate to provide 1.1 g of the title compound as yellow needles, m.p. 157-158°C.

Example 10

5,11-Dihvdro-l 1-e thvl-2-methvl-4-tri fIuoromethvI-6H-dipyrido-f3.2-b:2*,3’-eiri,4]djazepin-6one

a) 3-Cyano-2-hydroxy-6-methyI-4-(trifluoromethyl)pyridine

9/038-4-C6

A solution of 14.0g of cyanoacetamide in 80 ml of ethanol was warmed to 50°C, and then

14g of piperidine and 25g of trifluoroacety lace tone were added. The resulting mixture was stirred at 70° for 30 min. and then allowed to stir overnight at room temperature. The mixture was concentrated in vacuo and then diluted with 100 ml of water. Concentrated hydrochloric acid (15 ml) was cautiously added with stirring and after 15 min. the precipitate was filtered and dried in vacuo overnight to give 27.8 g of the desired cyanopyridine.

b) 3-Aminocarbonyl-2-chloro-6-methyl-4-(trifluoromethyl)pyridine

A mixture of 35 ml of phosphorous oxychloride and 9.8g of the cyanopyridine obtained above was refluxed for 5 hrs. The cooled mixture was quenched by cautiously adding 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 in vacuo, the crude chloro compound was dissolved in 50 ml of concentrated sulfuric, acid and heated to 140°C for 20 min. The cooled mixture was carefully poured over 600 ml of ice and the precipitate filtered, washed with ice water, and dried to give 7.6g of the desired amide. The filtrate was extracted with 200 ml of ethyl acetate, dried (magnesium sulfate), filtered and concentrated to give an additional 1.7g of product

c) 3-Amino-2-chloro-6-methyl-4-(trifluoromethyl)pyridine

To a solution of 6.6g of sodium hydroxide in 60 ml of water at 5°C was added 9.3g of bromine. When a clear solution was obtained, 9.2g of 3-aminocarbonyl-2-chloro-6-me±yl-4(trifluoromethyl)pyridine was added quickly, maintaining the temperature below 5°C. The

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BAD ORIGINAL resulting mixture was stirred until the 3-(aminocarbonyl)pyridine dissolved (-30 min). The cooling bath was removed and the mixture was then warmed to 75°C for 30 min. After cooling to room temperature, the 3-aminopyridine product was extracted with ethyl acetate, dried (magnesium sulfate), filtered, and evaporated to give 4.9g of the desired product ·»'

d) 2-Chloro-N-(2-chloro-6-methyl-4-trifluoromethyl-3-pyridinyl)-3-pyridinecarboxamide To a cooled (-78°C) solution of 2.1g of the 3-amino-2-chloro-6-methyl-4-(trifluoromethyl)pyridine in 10 mi of THF was added dropwise over 3 min. 7 ml of lithium diisopropylamine (LDA, 1.5 M in cyclohexane). The mixture was stirred 5 min., and 0.9g of 2-chloronicotinoyl chloride in 3 ml of THF was added over 1 min. After 5 min. an additional 3 ml of LDA solution was added followed by an additional 0.5 g of the acid chloride in 1 ml of THF. The resulting mixture was stirred 10 min. and then quenched with 100 ml of water. After partitioning with 30 ml of ethyl acetate, the organic phase was extracted with water and the combined aqueous phases 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 give 1.3g of the title compound.

e) N-(2-Chloro-6-methyl-4-trifluoromethyl-3-pyridinyl)-2-ethylamino-3-pyridinecarboxamide Ethylamine (0.4g) was added to a suspension of 1.3g of 2-chloro-N-(2-chloro-6-methyl-4trifIuoromethyl-3-pyridinyl)-3-pyrid^;necarboxamide in 5 ml of xylene, and the resulting mixture heated in a pressure tube for 30 min. at 160°C. The cooled mixture was diluted with ethyl acetate, w’ashed, dried, and concentrated. Column chromatography over silica gel (ethyl

9/038>€6 acetate/hexane, 1:1) gave 0.5g of the title compound.

f) 5,11 -Dihydro-ll-ethyl-2-methyl-4-trifluoromethyl-6H-dipyrido-[3,2-b:2*_>3’-e]£l,4]diazepin6-one

A solution of 0.5 g of N-(2-chloro-6-methyl-4-trifluoromethyl-3-pyridinyl)-2-ethylamino-3· pyridinecarboxamide in 3 ml of pyridine was added to 0.2g of a 50% dispersion of sodium hydride in oil. The mixture was heated to 150°C and then cooled and concentrated in vacuo. 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 over silica gel (methylene chloride, then methylene chloride/methanol). After concentrating in vacuo, the residue was crystallized from hexane to give 0.09g of the title ^C

P compound, m.p. 150-151°C.

o

Example 11 Q5,11 -Dihvdro-11 -ethyl-4-methvl-6H-dipyridof 3,2-5:2^3,-eH 1,41diazcpin-6-one

a) 2-Chloro-4-methyl-3-nitropyridine

A mixture of 25g of 2-hydroxy-4-methyl-3-nitropyridine, 12.5g of phosphorous pentachloride, and 62 ml of phosphorous oxychloride was refluxed for 2 hrs. After cooling, the mixture was poured onto crushed ice and stirred until a precipitate formed. The product was extracted with methylene chloride, dried (sodium sulfate) and concentrated to a brown oil, which was washed with hot hexane. Concentration in vacuo provided 16.2g of the the title compound, m.p. 45-47°C.

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b) 3-Amino-2-chloro-4-methylpyridine

16.2g of 2-chloro-4-methyl-3-nitropyridine was added to 470 ml of acetic acid and the resulting mixture stirred at room temperature for 15 min. A solution of 160 g of stannic chloride dihydrate in 200 ml of concentrated hydrochloric acid was then added in one portion and the resulting mixture stirred overnight at room temperature. This mixture was then diluted to 1 liter with water and ION sodium hydroxide was added slowly with cooling until the white precipitate of tin hydrochloride dissolved. The product was extracted with methylene chloride, dried (sodium sulfate) and concentrated to give 12.8g of a yellow oil, which solidified on standing, of almost pure 3-amino-2-chloro-4-methylpyridine suitable for use in the next reaction.

c) 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide

Using a procedure analogous to that described in Example la, the carboxamide was prepared from 12.8g of 3-amino-2-chloro-4-methyl pyridine, 15.8g of 2-chloronicotinoyl chloride, 7.lg of pyridine, 30ml of cyclohexane and 60 ml of dioxane. After removal of the solvent, the product was dissolved in methylene chloride, washed with water and dried (sodium sulfate). After removal of the solvent, the residue was washed with ethyl acetate to give 1.2g of the title compound, m.p. 193-194°C. _v

d) N-(2-Chloro-4-methyl-3-pyridinyl)-2-ethylamino-3-pyridinecarboxamide

Ethylamine (12.7g) was added to a suspension of 21.Og of the 2-chloro-N-(2-chloro-4-methyl3-pyridinyl)-3-pyridinecarboxamide in 150ml of xylene in a steel bomb. The mixture was

9/038-4-C6 then heated in an oil bath to 165°C for 6 hrs. and then stirred overnight at room temperature.

The solvent was removed in vacuo and water 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 followed by hexane at which time a precipitate formed. The solid was filtered and dried to give 16.5g of the title compound, m.p. 122-124°C.

e) 5,ll-Dihydro-ll-ethyl-4-mcthyl-6H-dipyrido[3,2-b:2’,3’-e][l,4]diazepin-6-one A 50% suspension of sodium hydride (7.9g) was added to a solution of l6.0g of N-(2-chloro4-methyl-3-pyridinyl)-2-ethylamino-3-pyridinecarboxamide obtained above in 200 ml of dimethylformamide and stirred for 30 min. The mixture was then refluxed for 2 hrs., cooled and carefully treated with crushed ice. The solvent was removed in vacuo 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 2.0g of this product was further purified by recrystallization from dichloroethane to give l.Og of pure 5,ll-dihydro-ll-ethyl-4-methyl-6H-dipyrido[3,2b:2’,3’-e][l,4]diazepin-6-one, m.p. 212-214°C.

Example 12 l-Cyclopropvl-5.1 l-dihvdro-4-methvl-6H-dipvridof3.2-b:2^,,3^,-e]|'l,41diazepin-6-one

Using a procedure analogous to that employed in Example 11, but using cyclopropylamine instead of ethylamine, yielded the title compound, m.p. 247-249 °C.

Lt 0 0 0 dV

9/038-4-C6

Example 13 ll-Cvclopropyl-5.1 l-dihvdro-5-hvdiOxv-4-methvl-6H-dipvridof3,2-b:2’,3^,-e1fl.4'|diazepin-6one

To a mixture of 0.5g of ll-cyclopropyl-5,ll-dihydro-4-methyl-6H-dipyrido(3,2-b:2’,3’e][l,4]diazepin-6-one (Example 12) in 25 ml of tetrahydrofuran was added 0.12g of 50% sodium hydride in mineral oiL The reaction mixture was stirred at room temperature for one hour and then cooled to 0°C, at which time 0.9g of oxodiperoxymolybdenum(pyridine)hexamethylphosphoramide (MoOPH) was added in one portion. The reaction mixture was then allowed to warm to room temperature and was allowed to stir overnight. The mixture was quenched with water and the solvents removed in vacuo. The residue was extracted with warm ethyl acetate, concentrated in vacuo and purified on a silica gel column (eluent: ethyl acetate) to give 0.05 g of pure 11-cyclopropyl-5,11-dihydro-5-hydroxy-4-methyl-6Hdipyrido[3,2-b:2’,3’-e](l,4]diazepin-6-one, m.p. 239-241°C. The yield was 9.5% of theory.

EXAMPLE 14

5,ll-Dihvdro-ll-ethvI-2-methoxv-5-methvl-6H-dipvridof3.2-b:2^,,3’-eiri,41diazepin-6-one

a) 3-Amino-2-bromo-6-methoxypyridine

Sodium acetate (1.6 g) was added to a solution of 5-amino-2-methoxypyridine (2.5 g) in acetic acid (15 ml). To the resulting solution bromine (3.0 g) was added dropwise, and the mixture was stirred for 20 min., and then added to a solution of sodium hydroxide (10 g) in water (100 ml). The product was extracted with ethyl acetate (50 ml), dried (anhydrous magnesium sulfate), and concentrated in vacuo. The product was purified over a silica gel

9/038-4-C6 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

To a solution of 3-amino-2-bromo-6-methoxypyridine (2.7 g) in methylene chloride (20 ml) and pyridine (1 ml) was added 2-chloronicotinoyl chloride (2.2 g), and the resulting mixture was stirred 20 min. The mixture was then diluted with methylene chloride (100 ml), washed with water (100 ml), dried (anhydrous magnesium sulfate), and concentrated. The semisolid residue was saturated with hexane, 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 a 50% dispersion in mineral oil) was added to.dimethylsulfoxide (10 ml) and warmed to 50°C. After cooling the mixture to room temperature, N-(2-bromomethoxy-3-pyridinyl)-2-chloro-3-pyridinecarboxamide (2.0 g) was added and the resulting solution was stirred for 10 min. Methyl iodide (0.4 ml) was then added and the mixture was stirred for 30 min. The reaction mixture was quenched by the addtion of water (10 ml) and ethyl acetate (100 ml) was then added. The organic phase was washed with water (4 x 100 ml), dried (anhydrous magnesium sulfate), concentrated, and purified on a silica gel column (methylene chloride followed by methylene chloride/ethanol, 98:2) to give 1.9 g of the title compound, suitable for use in the next reaction.

9/038-4-C6

d) N-(2-Bromo-6-methoxy-3-pyridinyl)-2-ethylamino-N-methyl-3-pyridinecarboxamide Ethylamine (0.7 g) was added to a solution of N-(2-bromo-6-methoxy-3-pyridinyl)-2-chloroN-methyl-3-pyridinecarboxamide (1.9 g) in xylene (5 ml), and the resulting mixture was sealed in a pressure bottle and heated at 150°C for 4 hours. The solution was diluted with ethyl acetate, washed with water, dried (anhydrous magnesium sulfate), concentrated, ahd purified on a 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-1 l-ethyl-2-methoxy-5-methyl-6H-dipyrido[3,2-b:2’,3’-e][l,4]diazepin-6-one Sodium hydride (0.9 g of a 50% dispersion in mineral oil) was added to a solution of N-(2bromo-6-methoxy-3-pyridinyl)-2-ethylamino-N-methyl-3-pyridinecarboxamide (1.4 g) in xylene (20 ml) and the mixture refluxed for 2 hours. After cooling, the mixture was quenched with methanol, diluted with ethyl acetate, and washed with water. The organic phase was dried (anhydrous magnesium sulfate), concentrated, and purified on a silica gel column (ethyl acetate/hexane, 1:4) to give fairly pure product, which was then recrystallized twice from ethyl acetate/hexane to give 0.52 g of pure 5,11-dihydro-11-ethyl-2-methoxy-5methyl-6H-dipyrido(3,2-b:2’,3’-e][l,4]diazepin-6-one, m.p. 116-118°C.

EXAMPLE 15

5,1 l-Dihvdro-ll-ethvl-5-methvI-2-(N-pvrrolidino')-6H-dipyridof3,2-b:2\3^,-elfl.41diazepin-6one

a) 5,11-Dihydro-ll-ethyl-2-hydroxy-5-methyl-6H-dipyrido(3,2-b:2’,3’-e][l,4]diazepin-6-one

9/038-4-C6

Hydrobromic acid (48%, 2 ml) was added to a solution of 5,ll-dihydro-ll-ethyl-2-methoxy5- methyl-6H-dipyrido[3,2-b:2’,3’-e][l,4]diazepin-6-one (0.3 g) in acetic acid (2 ml), and the resulting mixture was rapidly heated to reflux for 5 min. The reaction mixture was quenched with 10% sodium hydroxide (10 ml) and the product was extracted with ethyl acetate, dried (anhydrous magnesium sulfate) and concentrated to give a solid which was recrystallized from ethyl acetate to give 0.08 g of product, m.p. 215-218°C.

b) 5,11-Dihydro-ll-ethyl-5-methyl-2-trifluoromethanesulfonyloxy-6H-dipyrido[3,2-b:2’,3’e] [ 1,4]diazepin-6-one

To a solution of 5,11-Dihydro-l l-ethyl-2-hydroxy-5-methyl-6H-dipyrido(3,2-b:2’,3’e][l,4]diazepin-6-one (0.2 g) in methylene chloride (4 ml) under nitrogen was added diisopropylethylamine (0.2 ml) followed by trifluoromethanesulfonic anhydride (0.2 ml). The resulting mixture was stirred for one hour, and then diluted with methylene chloride (20 ml), and washed with water. The organic phase was dried (anhydrous magnesium sulfate), concentrated, and purified on a silica gel column (ethyl acetate/hexane, 1:3) to give 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]diazepin6- one

5,11-Dihydro-1 l-ethyl-S-methyl^-trifluoromethanesulfonyloxy-tiH-dipyridolO^-b^’.S’e][l,4]diazepin-6-one (0.25 g) was dissolved in pyrrolidine (1 ml) and refluxed 30 min. The cooled solution was diluted with ethyl acetate, washed with water, and the organic phase was

Z I· 0 0 0 d V

9/038-4-C6 bad original dried (anhydrous magnesium sulfate) and concentrated. The resulting oily residue was crystallized from ethyl acetate/hexane to provide 0.11 g of 5,ll-dihydro-ll-ethyl-5-methyl-2N-(pynOlidino)-6H-dipyrido(3,2-b:2’,3’-e][l,4]diazepin-6-one, m.p. 185-188°C.

EXAMPLE 16 <

5,11-Dihydro-1 l-ethvl-2-methoxv-4-methvl-6H-dipyridof3.2-b:2^,,3^,-e1fl.41diazcpin-6-one

a) 2-Methoxy-4-methyl-5-nitropyridine

Sodium methoxide (26.1 g) was added to a solution of 2-chloro-4-methyl-5-nitropyridine (19.0 g) in methanol (100 ml) and the resulting mixture was refluxed for 12 hours. Upon cooling, the mixture was poured over water (1 L), and the product was extracted with ethyl acetate and washed with water. The organic phase was dried (anhydrous magnesium sulfate) and concentrated, and the residue dissolved in hot ether and filtered. Crystallization from ether provided 10.2 g of the title compound, suitable for use in the next reaction.

b) 5-Amino-2-methoxy-4-methylpyridine

A mixture of stannous chloride dihydrate (41 g) and concentrated hydrochloric acid (40 ml) was added slowly to a solution of 2-methoxy-4-methy!-5-nitropyridinc (5.1 g) in acetic acid (40 ml), maintaining the temperature below 35°C. The resulting mixture was stirred at foom temperature for 2 hours, and then allowed to stand overnight in the refrigerator. The solid was collected and both solid and supernatant were separately basified with a 20% sodium hydroxide solution. The product was extracted with chloroform, combined, dried (anhydrous magnesium sulfate) and concentrated to give 3.9 g of the title compound as a solid, suitable

9/038-4-C6 for use in the next reaction.

c) 3-Amino-2-bromo-6-methoxy-4-methylpyridine

Bromine (4.8 g) was added in one portion to a mixture of 5-amino-2-methoxy-4methylpyridine (3.9 g) in acetic acid (25 ml) and sodium acetate (4.0 g). The resulting mixture was stirred for 20 min. and then added to a solution of sodium hydroxide (15 g) in water (200 ml). The product was extracted with chloroform, dried (anhydrous magnesium sulfate), concentrated, and purified on a silica gel column (methylene chloride/ethyl acetate, 19:1 —> 4:1) to give 4.5 g of the title compound, suitable for use in the next reaction.

d) N-(2-Bromo-6-methoxy-4-methyl-3-pyridinyl)-2-chlon>3-pyridinecarboxamide 2-Chloronicotinoyl chloride (3.5 g) was added to a solution of 3-amino-2-bromo-6-methoxy-4methylpyridine (4.5 g) in methylene chloride, and the resulting mixture was stirred overnight at room temperature, and triturated with diisopropyl ether. The precipitated solid 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

A mixture of N-(2-bromo-6-methoxy-4-methyl-3-pyridinyl)-2-chloro-3-pyridinecarboxamide (2.1 g), dioxane (10 ml), and ethylamine (0.5 g) was heated to 140°C in a sealed tube for 5 hours. The cooled mixture was diluted with ethyl acetate, washed with water, and the organic phase was dried (anhydrous magnesium sulfate) and concentrated. The product was purified on a silica gel column (methylene chloride/ethyl acetate, 99:1) and crystallized by trituration

L I 0 0 0 dV

9/038-4-C6 with diisopropyl ether to give 0.95 g of the title compound.

f) 5,11-Dihydro-ll-ethyl-2-methoxy-4-methyl-6H-dipyrido[3,2-b:2’,3’-c][l,4]diazepin-6-one Sodium hydride (0.14 g of a 50% dispersion in mineral oil) was added to a solution of N-(2bromo-6-methoxy-4-methyl-3-pyridinyl)-2-ethylamino-3-pyridinecarboxamide (0.54 g) in* pyridine (4 ml), and the resulting mixture was refluxed for 1.5 hours. The cooled mixture was diluted with ethyl acetate, washed with water, and the organic phase was dried (anhydrous magnesium sulfate) and concentrated. The residue was washed with diisopropyl ether and hot ethyl acetate, and then crystallized from ethanol to provide 0.2 g of 5,11dihydro-1 l-ethyl-2-methoxy-4-methyl-6H-dipyrido[3,2-b:2’,3*-e][l,4]diazepin-6-one, m.p. 249

251°C.

EXAMPLES 17-122

Using procedures analogous to those described above, the compounds of Examples 17-122, which are described below in Table Π, were made.

9/038-4-C6

TABLE Π

Compounds in this table are of the formula

wherein R'-R* are as defined below and Z is an oxygen atom unless noted to be a sulfur atom.

Ex.	R1	R2	Other	m.p (°C)
17	H-----------	ethyl -	4-chloro	---U4-L86·
18	H	ethyl	4-ethyl	218-219
19	H	4-methoxybcnzvl -		209-210
20	methyl	ethyl	8-chloro	105-106
-2T'-	H----- -	ethyl- -	2,4-dimethyl	---------
p	methyl	ethyl	3-chloro, 2-nitro	215-216
P 25	H	cyclobutyl	4-methyl	214-215

9/038-4-C6

BAD ORIGINAL

24	H
!<-, 2i	H
26-	H
π c. 27	H
28	H
Jd &	H
'^2.	H
-31	methyl
-32-	methyl
-33-	—methyl-----

isopropyl cyclopropyl ethyl cyclopropyl ethyl ethyl cyclopropyl benzyl

4-methoxybenzvl

----2-fluoroethyl

4-methyl

2.4- dimethyl

3.4- dimethyl

4-ethyl

2,4,9-trimethyl

2-chloro, 4-methyl

2-chloro, 4-methyl

X	H	ethyl	*
-35—	—B---------	phenyl	—
36--	methyl---------	ethyl	4-methyl
33-	- methyl	acetyl -	—
X	methyl	t-butyl
39—	H	ethyl	2,3-dimethyl
40-	methyl- - tniomethyl	ethyl
41--	H- ---	ethyl	9-methyl ---
42-	H	ethyl - -	2-methyl
4-3—	H ------------	ethyl— -	-- 3-methyl—
44—	H .. _ .	acetyl—

-. 188-189 >300

-------265-266

228-230

-------228-230

224-228

310-320

-------NA

---120-121

--11-7-118211-212

-220 222

--4-57-159---188-443

192-194

-----------242-244 — 418-120

---344-247

263-266 >215(dee>

bad ORIGINAL

9/038-4-C6

45— methyl	ethyl	2,9-dimethyl
46- - -methyl· —	ethyl	2-methyl
.47----methyl -	ethyl	3-methyl—
25 methyl	ethyl	8-azido
49—- -methyl------	ethyl	3,4-di methyl
50-----methyl·-.......	ethyl ---	9-methyl —
51 - acetyl	ethyl
A- # h 6-3----methyl-----	isopropyl methylthio- methyl·-
54--H -	ethyl	3-chloro
55 ----methyl·—...... 56 ----benzyl-----	ethyl--- acetyl----- -	-3-chlore---
Λ7 >7 H	cyclopropyl
methyl	cyclopropyl	4-methyl
59- -H------------	ethyl------	8-methyl-
?c\ methyl	cyclopropyl- methyl
sc >r h	(7?)-2-butyl
62----methyl	allyl	—
63-- H---------	ethyl -	— 2-chloro
3i methyl	ethyl	2,3-dimethyl

--100-402

----124-126

-94-96265-266

----149-420

--79-93-----123-424204-206 inn ι in ----------1W-1 Iv

--217-218

-124-125--169-170

240-250

244-245

-----182-183

138-139

172-174

--93-95

-252-254

143-145

AP 0 0 0 1 7 9

9/038-4-C6

V-		H	(S)-2-butyl	173-175
S'-)	is6	H	cyclopentyl		225-228
	67	methyl	propargyl		------- 169-170
	68-	methyl	ethly	2-chloro	125-126
3 k-	69	methyl	ethyl	2-(pyrrolidin-	244-246
				1-yl), 4-methyl
.r~t '	X5	methyl	ethyl	2-(?-pyrrolin-	153-156
				l-yi)
	74	H	ethyl	7,9-dimethyl	245-247
S'7	72	methyl	cyclopentyl
33	75	methoxy-	methoxy-	4-methyl	135-137
		methyl	methyl
	.74--	-- H	ethyl	7-methy4-	---------493-494
	75—	44 ----	ethyl	8,9-dimethyl -- --
3Ί	76	H	ethyl	2-chloro, 4-tri-	158-160
				Huoromethyl
4c	7<	H	cyclobutyl		241-243
4»	.75	methyl	cyclobuty!		144-146
	79	H	cyclopropyl	4-ch!oro	NA
	44-	methyl	ethyl	2-(tetrahydro-	138-140
				pyri din-1-yl)
	4T	H	cyclopropyl	4-methoxy	185-187

ΒΑΌ ORIGINAL

9/038-4-C6

H ethyl 4-methoxy methyl ethyl 2-(p-methoxy- 83-85 benzylmethylamino)

- -156-157

	methyl	' ethyl	2-allylamino	167-170
i+Ί *	H	cyclopropyl	4-hydroxymethyl	243-246
86-	- H	ethyl	8-bromo ------	- 233-235
87	methyl	ethyl	3-nitro	-154-156
	methyl	ethyl	3,8-dinitro	167-169
89_	- methyl---	ethyl-	-3-amino — - ----	235 240
	methyl	ethyl	2,8-dinitro, 3-	215-216
			chloro
5c *	H	cyclopropyl	4-methyl, 7-hydroxy	225-227
92 -	-methyl —	ethyl	2,4-dimethyl - - ------—	-453-353
5Ί #5	H	cyclopropyl	4-methyl, (Z=S)	189-194
5C	methyl	cyano		274-277
73	methyl	cyclohexyl		145-146
33*.	H	cyclohexyl		199-201
55	H	ethyl	7,9-dimethyl, 8-	160-162
			chloro
5L· -98	methyl	cyclopropyl		163-166
57 *	methyl	methylsulfonyl		239-241

AP 0 0 0 1 7 9

9/O38-4-C6

53	jetf	methyl	ethyl	2-amino, 3-chloro	160-162
53	ιοί	allyl	cyclopropyl	4-methyl	146-149
	-102	methyl	ethyl	7-methyl	------422-494
	103	H	ethyl	4-methyl, (Z=S)	--158-459
	104	H	ethyl	4-hydroxy	---295-296
L-c	405	methyl	ethyl	3,8-diamino	240-250
	W6	methyl	ethyl	2-hydroxy	----215-248
	107	H	ethyl	2,4-dimethyl, (Z^=S> -	--—499-204
	JO8	vinyloxy- car bonyl	cyclopropyl	4-methyl	140-143
(=2	409	methoxy	cyclopropyl	4-methyl	169-171
43	no	acetyl	cyclopropyl	4-mcthyl	176-179
	541	methyl	ethyl	2-(p-mcthoxy- benzylamino)	133-135
L-S-	.442	methyl	ethyl	2-(morpholin- 1-yl)	158-160
	145	methyl	ethyl	2-(piperidin-l-yl)	164-166
	444	methyl — -	ethyl	2-amino------ —	-497-499
	445	H	cyclopropyl	4-cyano	243-245
	445	timethyl- aminocthyl	cyclopropyl		88-89
	417	methyl -	ethyl	2-methylamino ----	--486-489
	>43	methyl	ethyl	2-dimethylamino	118-120

9/038-4-C6 77

BAD ORIGINAL

yc		methyl	e Lhyl
7/		methyl	ethyl
7λ		H	ethyl
73	127	H	ethyl

154-157

2-ethylamino

8-nitro 148-149

2-dimethyiamino, 209-211

4-methyl

2-(pyrrolidin-l- 215-218 yl),3-chloro, 4methyl

ΝΑ = not available

7A

Example 4-2T

8-Amino-5 J1-dihvdro-1 l-ethvl-5-methyl-6H-dipyridof3.2-b:2^,,3^,-elf l,41diazepin-6-one hemihvdrate

a) 2-Ethylamino-3-nitropyridine

A stirred mixture of 2-chloro-3-nitropyridine (8.60 g, 0.054 mol), ethylamine (5.37 g, 0.12 mol), and xylene (10 ml) was heated at 100°C in a scaled tube for three hours. After cooling, the solvent was removed in vacuo, and water was added to the residue. The product was extracted with methylene chloride, dried (sodium sulfate), and concentrated in vacuo to give 10.0 g of the title compound as a yellow oil, suitable for use in the next reaction.

AP o 0 0 1 7 9

9/038-4-C6

BAD ORIGINAL

b) 3-Amino-2-ethyIaminopyridine

Using a procedure analogous to that described in Example lib, 6.5 g of the title compound was prepared from 9.1 g of 2-ethylamino-3-nitropyridine.

c) 2-Chloro-N-(2-ethylamino-3-pyridinyl)-5-nitro-3-pyridinecarboxamide

A solution of 2.21 g of 2-chloro-5-nitronicotinoyl chloride (obtained by nitrating 2hydroxynicotinic acid, followed by conversion to 2-chloro-5-nitronicotinic acid, which was then treated with thionyl chloride) in 10 ml of tetrahydrofuran was slowly added over 15 minutes to a cooled, stirred mixture of 1.34 g of 3-Amino-2-ethylaminopyridine, 1.29 g of diisopropylethylamine, and 40 ml of tetrahydrofuran. The resulting mixture was allowed to stir overnight at room temperature, and then concentrated in vacuo. The title compound (2.30 g, m.p. 185-186°C), which precipitated out when the residue was treated with methylene chloride, was suitable for use in the next reaction.

%

d) 5,11-Dihydro-ll-ethyl-8-nitro-6H-dipyrido[3,2-b:2’,3’-e][l,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 four hours. After concentrating in vacuo, the residue was purified on a silical gel column eluting with 50% ethyl acetate/hexane to give 0.93 g of the title compound.

e) 5,11-Dihydro-ll-ethyl-5-methyl-8-nitro-6H-dipyrido{3,2-b:2’,3’-e][l,4]diazepin-6-one The title compound (0.72 g, m.p. 148-149°C) was prepared from 0.93 g of 5,11-dihydro-119/038-4-C6 * 79 ethyl-8-nitro-6H-dipyrido[3,2-b:2’,3’-e][1.4]diazepin-6-one in a manner analogous to that described in Example 8d.

f) 8-Amino-5,l 1-dihydro-l l-ethyl-5-methyl-6H-dipyrido(3,2-b:2’,3‘-e](l,4]diazepin-6-one hemi-hydrate

Following a procedure analogous to that described in Example lib, 0.23 g of 5,11-dihydro1 l-ethyl-5-methyl-8-nitro-6H-dipyrido[3,2-b:2^,,3'-e](l,4]diazepin-6-one reduced to give, after recrystallization from 1,2-dichloroethane/hexane, 0.060 g of the title compound as a yellowbrown powder, m.p. 193-194°C.

Example t

6-Cyanoimino-5,l 1-dihydro-l 1 -ethyl-2,4-dimethyI-6H-dipyridof 3,2-b:2',3'-elfl,41diazepine

A mixture of 5,11-dihydro-l l-elhyl-6-methanesulfonyloxy-2,4-dimethyl-6H-dipyrido(3,2b:2’,3’-e](1.4]dia2epine (0.25g, 0.63 mmol), cyamamide (0.034g, 0.8 mmol), 5 ml of 1,4dioxane, and potassium carbonate (0.1 lg, 0.8 mmol) was stirred at room temperature for 10 days. The mixture was then concentrated in vacuo, and the was residue partitioned between ethyl acetate and water. The organic phase was dried, filtered and concentrated in vacuo. The residue was chromatographed over silica with 10% ethyl acetate/methylene chloride to provide 0.025 g of the title compound, m.p. 230-233°C.

9/038-4-C6 ' 80

BAD ORIGINAL

7C

Exam

5,11-Dihydro-1 l-ethvl-6-methoxyimino-2,4-(limethvl-6H-dipvridoi3.2-b:2^,.3^,-elfl,41diazcpine

a) 5,11-Dihydro-l l-ethyl-6-methanesulfonyloxy-2,4-dimethyl-6H-dipyndo(3,2-b:2’,3’-e](l,4]diazepine

Trifluoromethancsulfonic anhydride (0.24 ml, 14 mmol) was added to a solution of 0.314 g (1.2 mmol) 5,11-dihydro-l l-ethyl-2,4-dimethyl-6H-dipyrido(3,2-5:2’,3’-e](l,4]diazepin-6rone in 15 ml of methylene chloride containing 0.25 ml (14 mmol) of diisopropylethylamine, and the resulting mixture was refluxed under argon for three hours. Ethyl acetate (-200 mL) was then added and the solution was washed three times with water and four times with brine.

After drying (magnesium sulfate), the solution was concentrated in vacuo and the residue dried under high vacuum for 2 hr. The residue was dissolved in 20 ml of methylene chloride, and 0.23 g (14 mol) of tetraethylammonium cyanide was added. After stirring the resulting solution overnight at room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate, and the solution was washed with water and brine. The dried (magnesium sulfate) solution was concentrated in vacuo and the residue was chromatographed over silica with 5% ethyl acetate^exane. The resulting solid was crystallized from heptane to provide 0.033 g of the title compound as red crystals, m.p. 154155°C. ·;

b) 5,11 -Dihydro-11 -ethyl-6-methoxyimiro-2,4-dimethyl-6H-dipyrido(3,2-b:2’,3’c) [l,4]diazepine

A solution of 5,11 -dihydro-1 l-cthyl-6-methanesulfonyloxy-2,4-dimeihyl-6H-dipyrido{3,29/038-4-C6

BAD ORIGINAL b:2’,3’-e][l,4]diazepine (0.3g, 0.75 mmol), methoxylamine hydrochloride (0.15g, 1.8 mmol) and diisopropylethylamine (0.3g, 2 mmol) in methylene chloride was stirred at room temperature for 4 days. The organic phase was washed with water, dried, and filtered. The solution was concentrated in vacuo and the residue was chromatographed over silica with 20% ethyl acetate/hexane to give 0.07 g of the title compound, m.p. 164-166°C.

Example 77 (See page 82 a)

EXAMPLE A

Capsules or Tablets

A-l		A-2
Ingredients	Ouantitv	Ingredients	Quantity
Compound of Ex. 2	250 mg	Compound of Ex. 2	50 mg
Starch	160 mg	Dicalcium Phosphate	160 mg
Microcrys. Cellulose	90 mg	Microcrys. Cellulose	90 mg
Na Starch Glycolate	10 mg	Stearic acid	5 mg
Magnesium Stearate	2 mg	Sodium Starch Glycolate	10 mg
Fumed colloidal silica	1 mg	Fumed colloidal silica	1 mg

AP 0 0 0 1 7 9

The compound of Examplel2 is blended into a powder mixture with the premixed excipient materials as identified above with the exception of the lubricant. The lubricant is then blended in and the resulting blend compressed into tablets or rilled into hard gelatin capsules.

9/038-4-C6

-—

BAD ORIGINAL

Example 77 ί ,_1 1 -Dihydro-6H- 1 I -eye Lopropy 1 -4 -niethy 1 -d .py r i do ( 3,2 -b :

' , 3 ¹ -e) ( 1 , 4) diazepm A ~thione

A. niixture of 5.0 g ( 1 3 . ⁷ 7 oropv1-4-me thyl-diuyr ide (3,2-b : 2' a n 3 3.8 g (9.40 mm ; 1 ) if p-;me t noxypheny 1 -..-. i·. nophosphine suiph liner (Lawes son'= reaoent) was refluxed in '00 ml of toluene fnr 2.5 hrs. The solution was cooled to room temperature and mmol) of 5,11-Dihydro-6H-11-cycloi'-e) * 1 ,4) J iazepin-6-one :e wan allowed to sta:

•wmwarc l rat ion •might. The toluene was removed by .d or.rimatography rf toe residue over ash s i11: a .oride/ethvi icetate - 6:1 ave a yellow oil wnich solidified on standing.

Recrystallization from ethyl ether/petroleum ether gave a bright yellow solid which was dried 12 hrs. in high vacuum at 80°C, 1.7 g ( 32 . 0% , mp = 189-1?4°C.)

Ar.al,

Ca 1 ' d Found

C

63.31

63.75

H > .00

:.10

N

19.84

19.83 s

11.36

11.24

2 a _1ίΒ bad ORIGINAL

EXAMPLE Β

Parenteral Solutions

Ingredients Quantity

Compound of Example 2 500mg

Tartaric acid 1.5g

Benzyl Alcohol 0.1% by weight

Water for injection q.s. to 100ml

The excipient materials are mixed with the water and thereafter the compound of Example 2 is added. Mixing is continued until the solution is clear. The pH of this solution is adjusted to 3.0 and is then filtered into the appropriate vials or ampoules and sterilized by autoclaving.

EXAMPLE C

Nasal Solutions

AP 0 0 0 1 7 9

Ingredients	Ouandtv
Compound of Example 2	lOOmg
Citric acid	1.92g
Benzalkonium chloride	0.025% by weight
EDTA	0.1 % by weight
Polyvinylalcohol	10% by weight
Water	q.s. to 100ml

9/038-4-C6

The excipient materials are mixed with the water and thereafter the compound of Example 2 is added and mixing is continued until the solution is clear. The pH of this solution is adjusted to 4.0 and is then filtered into the appropriate vials or ampoules.

Claims (2)

Wc Cairn:

1 ’ 1 (wherein R is as hereinbefore defined for R with the exception of hydrogen and X is the radical of a reactive ester, ι · a halogen atom, a group OSO₂OR , a methanesulphonyloxy or ethanesulphonyloxy group or an aromatic sulphonyloxy group);

(C') (for preparing compounds of Formula I wherein R¹ is other than hydrogen and Z is oxygen) by reacting a compound of Formula I wherein R¹ is hydrogen and Z is oxygen with a compound of Formula V (as defined above) in the presence of an amine or an alkali metal carbonate or bicarbonate;

(D) (for preparing a compound of Formula I wherein Z is oxygen) converting a compound of rormula I wherein R is hydrogen into a corresponding metal salt of Formula Via or, where R^ represents hydrogen, VIb

6 L I· 0 0 0 dV ' BAD ORIGIN*?

(Via) (VIb) (wherein M represents an alkali metal, such as lithium, sodium, potassium, rubidium or cesium, or M represents the group MgHal+, wherein Kai is chlorine, bromine or iodine) and subsequently alkylating with a compound of Formula VII

R²X (VII) (wherein X is as hereinbefore defined and R is as defined for R²)

BAD ORIGINAL (E) (to prepare a compound of Formula I, wherein Z is sulphur) reacting a compound of Formula I, wherein Z is oxygen with a sulphurating agent, (F) (to prepare a compound of formula I wherein R^ is

2 8 hydrogen, R to R are as hereinbefore defined and Z is a group of the formula =NCN) reacting a compound of the formula XI

AP 0 0 0 1 7 9 with cyanamide, (G) (to prepare a compound of formula I wherein R¹ is 2 8 hydrogen and R to R are as hereinbefore defined and Z is 9 a group of the formula =NOR ) reacting a compound of formula XI as defined with an appropriate alkcxylamine (O-alkylhydroxylamine) or salt thereof:

and isolating the compound of Formula I as such or as an acid addition salt thereof.

BAD ORIGINAL

14. A method of preparing a pharmaceutical composition which comprises mixing a compound of Formula I as set forth in any one of claims 1 to 10 or a pharmaceutically acceptable acid addition salt with a pharaceutically acceptable carrier or excipient.

15. A compound of Formula I as set forth in any one of claims 1 to lOor a pharmaceutically acceptable acid addition salt thereof for use in the treatment or prevention of HIV-infection.

15. Use of a compound of Formula I or a physiologically acceptable acid addition salt thereof as claimed in claim 6 for the manufacture of a therapeutic agent for combatting HIV-infection.

101

ABSTRACT

Disclosed are novel 5,ll-dihydro-6H-dipyrido[3,2-b;

1 4 6 8 1 and R , R⁴ and R to R° are hydrogen, or b) R ? 3 4 is methyl, R is ethyl, R is methoxy and R to g

R are hydrogen, or a pharmaceutically acceptable acid addition salt thereof.

AP 0 0 0 1 7 9

3 8C

BAD ORIGINAL

2. A compound of formula I, as set forth in claim 1, wherein,

Z is oxygen, sulfur or a group of the formula =NOR* wherein R* is alkyl of 1 to 2 carbon atoms;

R¹ is hydrogen, alkyl of I to 4 carbon atoms, fluoroalkyl of 1 to 4 carbon atoms, cyclopropyl, alkenylmethyl or alkynylmethyl of 3 to 4 carbon atoms, 2-halo-2-propen-l-yl, alkanoyl of 2 to 3 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 3 carbon atoms, or cyanoalkyl wherein the alkyl moiety contains 1 to 3 carbon atoms;

R² is hydrogen (with the proviso that R’ is not hydrogen), alkyl of 1 to 5 carbon atoms, fluoroalkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, oxetanyl, thietanyl, alkenylmethyl or alkynylmethyl of 3 to 5 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms, alkanoyl of 2 to 4 carbon atoms, hydroxyalkyl of 2 to 5 carbon atoms, aryl or arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, which is either unsubstituted or substituted by alkyl or alkyloxy of 1 to 3 carbon atoms, hydroxyl or halogen), or alkyloxycarbonylmethyl wherein the alkyl moiety contains 1 to 4 carbon atoms;

one of R³, R⁴ and R^s 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 moieties each contain 1 to 2

9/038-4-C6 carbon atoms, hydroxyl, alkyloxy or alkylthio of I to 3 carbon atoms, hydroxyalkyloxy of 2 to 3 carbon atoms, alkanoyloxy of 2 to 3 carbon atoms, alkylsulfinyl or alkylsulfonyl of 1 to 3 carbon atoms, alkanoyl of 2 to 4 carbon atoms, alkyloxycarbonyl wherein the alkyl moiety contains 1 to 2 carbon atoms, aminoalkyl of 1 to 3 carbon atoms, mono- or dialkylaminoaikyl wherein each alkyl moiety contains 1 to 2 carbon atoms, amino, mono- or dialkylamino wherein each alkyl moiety contains 1 to 4 carbon atoms, azeridin-l-yl, pyrrol-l-yl, pyrrolin-l-yl, pyirolidin-1-yl, pyrazol-l-yl, pyrazolin-l-yl, pyrazolidin-l-yl, imidazol-l-yl, imidazolin-l-yl, imidazolidin-l-yl, tetrahydropyridin-l-yl, piperidin-l-yl, morpholin-l-yl, (4mcthyl)piperazin-l-yl, piperazin-l-yl, N,N-bis(2-hydroxyethyl)amino, N,N-bis(2methoxyethyOamino, or halogen, with the other two substituents being hydrogen, methyl or chloro; or,

6lI 0 0 0 dV two of R³, R⁴ and R^s are independently alkyl of 1 to 2 carbon atoms, alkyloxy or alkylthio of 1 to 2 carbon atoms, amino, mono- or di-alkylamino wherein each alkyl moiety contains 1 to 3 carbon atoms, azetidin-l-yl, pyrrol-l-yl, pyrrolin-l-yl, pyrrolidin-l-yl, pyrazol-l-yl, pyrazolin-l-yl, pyTazolidin-l-yl, imidazol-l-yl, imidazolin-l-yl, imidazolidin-l-yl, tetrahydropyridin-l-yl, piperidin-l-yl, morpholin-l-yl, (4-methyl)piperazin-l-yl, piperazin-l-yl, N,N-bis(2-hydroxyethyl)amino, N,N-bis(2-methoxyethyl)amino, or halogen, with the remaining substituent being hydrogen, methyl or chloro; or,

R³, R⁴ and R⁵ are each hydrogen;

9/038-4-C6 one of R⁴, R⁷ and R* is alkyl of 1 to 2 carbon atoms, vinyl, trifluoromethyl, hydroxyalkyl of I to 2 carbon atoms, hydroxyl, alkyloxy or alkylthio of I to 2 carbon atoms, hydroxyalkyloxy of 2 to 3 carbon atoms, alkanoyloxy of 2 to 3 carbon atoms, amino, mono- or di-alkylamino wherein each alkyl moiety contains 1 to 2 carbon atoms, azetidin-l-yl, pyrrol-l-yl, pyrrolin-lyl, pyrrolidin-l-yl, pyrazol-l-yl, pyrazolin-l-yl, pyrazolidin-l-yl, imidazol-l-yl, imidazolin-lyl, imidazolidin-l-yl, tetrahydropyridin-l-yl, piperidin-l-yl, morpholin-l-yl, (4methyl)piperazin-l-yl, piperazin-l-yl, N,N-bis(2-hydroxyethyl)amino, N,N-bis(2methoxyethyl)amino, or halogen, with the other two substituents being hydrogen; or,

R⁴, R⁷ and R* are each hydrogen;

or a pharmaceutically acceptable acid addition salt thereof.

3. A compound of formula I, as set forth in claim 1, wherein,

Z is oxygen or sulfur,

R¹ is hydrogen, alkyl of 1 to 3 carbon atoms or allyl;

R^J is alkyl of 2 to 3 carbon atoms, or cycloalkyl of 3 to 4 carbon atoms;

R³ is hydrogen, methyl, alkyloxy or alkylthio of 1 to 3 carbon atoms, chloro, amino, mono- or

9/038-4-C6 di-alkylamino wherein each alkyl moiety contains 1 to 3 carbon atoms, allylamino, azctidin-1 yl, pyrrol-1-yl, pyrrolin-l-yl, pyrrolidin-l-yl, pyrazol-l-yl, pyrazolin-l-yl, pyrazolidin-l-yl.

imidazol-l-yl, imidazolin-l-yl, imidazolidin-l-yl, tetrahydropyridin-l-yl, piperidin-l-yl.

morpholin-l-yl, (4-methyl)piperazin-l-yl, piperazin-l-yl, N,N-bis(2-hydroxyethyl)amino;

R⁴ is hydrogen, methyl or chloro;

R³ is hydrogen, methyl, ethyl, chloro, or trifluoromethyl;

R* and R* are hydrogen; and.

R⁷ is hydrogen or amino;

or a pharmaceutically acceptable acid addition salt thereof.

AP 0 0 0 1 7 9

4. A compound of formula I, as set forth in claim 1, wherein,

Z is oxygen or sulfur,

R‘ is hydrogen, alkyl of 1 to 3 carbon atoms or allyl;

R² is alkyl of 2 to 3 carbon atoms, or cycloalkyl of 3 to 4 carbon atoms;

9/038-4-C6

R^J is hydrogen, methyl, chloro, methoxy, ethoxy, amino, mono- or di-alkylamino wherein each alkyl moiety contains 1 to 2 carbon atoms, allylamino, allylmethylamino, pyrrolin-l-yl, pyrrolidin-l-yl, tetrahydropyridin-l-yl, piperidin-l-yl or morpholin-l-yl;

R⁴ is hydrogen;

R^J is hydrogen, methyl, ethyl, chloro, or trifluoromethyl;

R⁴ and R* are hydrogen; and

R⁷ is hydrogen or amino;

or a pharmaceutically acceptable salt thereof.

5. A compound selected from the group consisting of:

5.11- dihydro-ll-ethyl-4-methyl-6H-dipyrido(3,2-b:2^,,3’-e][l,4]diazepin-6-one or -thione;

11-cyclopropyl-5,1 l-dihydro-4-methyl-6H-dipyrido[3,2-b:2’,3’-e][l,4]diazepin-6-one or

-thione;

5.11- dihydro-ll-ethyl-2,4-djmethyl-6H-<lipyTido(3,2-b:2’,3’-e](l,4]diazepin-6-one or -thione; 1 l-cyclopropyl-5,1 l-dihydro-2,4-dimethyl-6H-dipyrido[3,2-b:2’,3^,-e][l,4]diazepin-6-one or thione;

2-chloro5,11-dihydro-1 l-ethyl-4-methyl-6H-dipyrido[3,2-b:2’,3’-e][l,4]diazepin-6-one or 9/038-4-C6 thione;

2-chloro-11-cyclopropyl-5,1 l-dihydro-4-methyl-6H-dipyrido{3^-b:2’,3’-e][l,4]diazepin-6-one or -thione;

5,1 l-dihydro-l l-ethyl-2-methoxy-4-rnethyl-6H-dipyrido(3,2-b:2’3’-«][l,4]diazepin-6-one or thione;

11 -cyclopropyl-5,1 l-dihydro-2-methoxy-4-methyl-6H-dipyrido(3,2-b:2’,3’-c][ l,4]diazepin-6one or -thione;

8-amino-5,l 1-dihydro-1 l-ethyl-2-methoxy-4-methyl-6H-dipyndo[32-b:2^,,3^,-e][l,4]diazepm-6one or -thione;

8-amino-11-cyclopropyl-5,1 l-dihydro-2-methoxy-4-methyl-6H-dipyrido(3,2-b:2’,3’e][l,4]diazepin-6-one or -thione;

5.11- dihydro-ll-ethyl-2-methoxy-5-methyl-6H-dipyrido{3^-b:2*J^,-e][l,4]dia2epin-6-one or thione;

11-cyclopropyl-5, ll-dihydro-2-methoxy-5-methyl-6H-dipyrido(3,2-b:2’J’-e][l,4]diazepin-6one or -thione;

5.11- dihydro-l l-€thyl-4-methyl-2-(N-pynolidino)-6H-dipyrido(3,2-b:2’,3’-e][l,4]diazepin-6one or -thione;

11-cyclopropyl-5,1 l-dihydΓO-4-methyl-2-(N-pyπϋlidino)-6H-dipyrido(3,2-b:2^,,3^,e](l,4]diazepin-6-one or -thione;

5.11- dihydro-1 l-ethyl-5-njethyl-2-(N-pyTrolidino)-6H-dipyrido(3,2-b:2^,,3’-e][l,4]diazepin-6one or -thione;

11-cyclopropyl-5,1 l-dihydro-5-methyl-2-(N-pynolidino)-6H-dipyrido[3^-b:2’,3’AP 0 0 0 1 7 9

9/038-4-C6

e][l,4]diazepin-6-one or -thione;

5,11-dihydro-1 l-ethyl-4-methyl-2-(N,N~dimethylamlno)-6H-<lipyrido(3,2-b:2’,3’e][l,4]diazepin-6-one or -thione;

11-cyclopropyl-5,1 l-dihydro-4-metbyl-2-(N,N-dimethylamino)-6H-dipyrido(3 J2-b:2’,3’e][l,4]diazepin-6-one or -thione;

8-am ino-5,11-dihydro-11-c thyl-4--methyl-2-(N,Ν-dimethylam ino)-6H-dipyrido[3,2-b:2'J’e][l,4]diazepin-6-one or -thione;

8-amino- 1 l-cyclopropyi-5,1 l-dihydro-4-mcthyl-2-(N ,N-dimethylamino)-6H-dipyrido(3,2b:2’,3'-e][l,4]diazepin-6-one or -thione; and pharmaceutically acceptable salts thereof

6. 1 l-Cyclopropyl-5,1 l-dihydro-4-methyl-6H-dipyrido(3^-b:2^,,3’-«][l,4]diazepin-6-one or -thione, or a pharmaceutically acceptable acid addition salt thereof.

7. 5,11-Dihydro-1 l-ethyl-4-methyl-2-(N,N-dimethylamino)-6H-dipyrido[3,2-b:2^,,3’e][l,4]diazepin-6-one or -thione, or a pharmaceutically acceptable acid addition salt thereof.

8. 1 l-Cyclopropyl-5,1 l-dihydro-4-methyl-2-(N₁N-dimethylamino)-6H-<iipyrido{3_r2-b:2’,3’e][l,4]diazepin-6-one or -thione, or a pharmaceutically acceptable acid addition salt thereof.

9. 5,1 l-Dihydro-ll-ethyl-2-methoxy-4-methyl-6H-dipyrido(3,2-b:2’,3’-e][l,4]diazepin-6-one or -thione, or a pharmaceutically acceptable acid addition salt thereof.

9/038-4-C6

IQ. 11-Cyclopropyl-5, J l-dihydro-2-mc±oxy-T-mcthyI-6H-dipyri£io(3,2-b:2’J’· ej[l,4]ciazepifl-6-one or -thione, or a pharmaceutically acceptable acid, addition salt thereof.

11. Use of a compound of Formula I or a physiologically acceptable acid addition salt thereof as claimed in any of claims 1 to 10 for the manufacture of a therapeutic agent for combatting HIV-infection.

12. A pharmaceutical composition suitable for preventing or treating HIV-l infection which comprises a prophylactically or therapeutically effective amount of a compound of formula I, as set forth in claims 1,2, 3, 4, 5, 6, 7, 8, 9 or 10, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.

6 L I 0 0 0 dV

13. A process for preparing a compound as defined in any of claims 1 to 10, said process comprising at least one of the following steps:

(A) (for preparing compounds of Formula I wherein R^ is other than hydrogen and Z is oxygen) cyclizing a carboxylic acid amide of general Formula II

BAD ORIGINAL (II)

HN

133 2 ’ (wherein R*, R to R are as hereinbefore defined, R is as defined for R with the exception of hydrogen, and Hal represents a fluorine, chlorine, bromine or iodine atom);

(3) (for producing compounds of Formula I wherein R is hydrogen and Z.is oxygen) hydrolytically cleaving an arylmethyl group from a compound of Formula III (wherein R represents

Ar an aryl group);

(III) (C) (for preparing compounds of Formula I wherein R is ether than hydrogen and Z is oxygen)

BAD ORIGINAL converting a compound of Formula I wherein R is hydrogen and Z is oxygen into a corresponding 5-alkali or alkaline earth metal compound and subsequently reacting said alkali or alkaline earth metal compound with a compound of Formula V

R^X (V)

1 2 3 8 iv) R is hydrogen, R is ethyl and R to R are hydrogen;

or a compound of Formula I wherein Z is sulfur and

2 3 either a) R is ethyl, R and R³ are both methyl

1 2

l) R is methyl, R is ethyl and either

R7 is azido, amino or nitro and to and g

R are hydrogen, or

3 ..4

R is ethylamino or diethylamino and R to g

R are hydrogen, or and r8 are methyl and R^ to R^ and R^ are hydrogen, or

BAD ORIGINAL ii) or and R⁴ are methyl and R^ to R& are hydrogen, or R^ is methyl and r\ R⁴ , R^ , R⁷ and P/ are hydrogen,

R¹ is methyl, R⁰ 3 isopropyl and R is ethyl, t-butyl, s-butyl or

Q to R are hydrogen,

12 5

m) R and R are methoxymethyl, R is methyl and r\. R⁴ and r\ R⁷ and R^ are hydrogen, or

1 % then R cannot be hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl or alkinyl of 3 to 5 carbon atoms, 2-halo-2prcpen-l-yl, arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, which is either unsubstituted or substituted by methyl, methoxy or halogen), alkanoyl containing 2 or 3 carbon atoms, alkoxyalkyl or alkylthio alkyl of 2 to 4 carbon atoms;

or a compound of formula I wherein Z is oxygen and

1. A compound of the formula I wherein,

Z is oxygen, sulfur, =NCN, or a.group of the formula =NOR’ wherein R* is alkyl of I to 3 carbon atoms;

AP 0 0 0 1 7 9

R‘ is hydrogen, alkyl of 1 to 6 carbon atoms, fluoroalkyl of 1 to 6 carboa atoms and 1 to 3 fluorine atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, 2-haio-2-propen-l-yl, mono- or di-halovinyl, aryl or arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyL, which is either unsubsrituted or substituted by methyl, methoxy or halogen), alkanoyl of 2 to 4 carbon atoms, iminoethyL, mono- or di-alkylaminoethyl wherein each alkyl moiety contains 1 to 2 carbon atoms, aikyloxyalkyl or alkylthioaikyl of 2 to 4 carbon atoms, alkyloxycarbonyl wherein the alkyl moiety contains 1 to 4 carbon atoms, alkcnyloxy- or alkynyloxycarbonyl wherein each alkenyl or alkynyl moiety contains 2 to 4 carbon atoms, or is hydroxy, alkyloxy of 1 to 4 carbon atoms, amino, mono- or di-alkylamino

9/038-4-C6

BAD ORIGINAL wherein each alkyl moiety contains 1 to 4 carbon atoms, aminocarbonylmethyl, or cyanoaikyl wherein the alkyl moiety contains 1 to 4 carbon atoms;

R^: is hydrogen (with the proviso that R* is not 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, oxetanyl, thietanyl, tetrahydrofuranyl or tetrahydrothienyl, alkenyl or alkynyl of 2 to 6 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 5 carbon atoms, alkanoyl of 2 to 5 carbon atoms, cyano, hydroxyalkyl of 2 to 6 carbon atoms, aryl or arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, which is either unsubstituted or substituted by alkyl or alkyloxy of 1 to 3 carbon atoms, hydroxyl or halogen), or alkyloxycarbonylmethyl wherein the alkyl moiety contains 1 to 5 carbon atoms; and, one of R³, R⁴ and R³ 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 moieties each contain 1 to 2 carbon atoms, hydroxyl, alkyloxy or alkylthio of 1 to 5 carbon atoms, hydroxyalkyloxy of 2 to 4 carbon atoms, alkanoyloxy of 2 to 4 carbon atoms, alkylsulfinyl or alkylsulfonyl of 1 to 4 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkyloxycarbonyl wherein the alkyl moiety contains 1 to 3 carbon atoms, mono- or di- ·-, alkylaminocarbonyl wherein each alkyl moiety contains 1 to 3 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, mono- or di-alkylaminoalkyl wherein each alkyl moiety contains 1 to 3 carbon atoms, aryl or arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, which _BAn original

9/038-4-C6 is either unsubstituted or substituted by alkyl or alkyloxy of 1 to 3 carbon atoms, hydroxyl or halogen), a group of the formula -NR^1(>Rⁿ, halogen, cyano, nitro, azido or carboxyl, with the other two substituents being hydrogen, methyl or chloro; or, two of R³, R⁴ and R⁵ are independently alkyl or hydroxyalkyl of 1 to 2 carbon atoms.

trihalomethyl, alkyloxy or alkylthio of 1 to 2 carbon atoms, halogen or a group of the formula -NR^IOR^U, with the remaining substituent being hydrogen or methyl; or,

R³, R⁴ and R⁵ are each hydrogen;

one of R⁴, R⁷ and R* is alkyl of 1 to 4 carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms, trihalomethyl, hydroxy alkyl of 1 to 4 carbon atoms, alkyloxy alkyl or alkylthioalkyl of 2 to 4 carbon atoms, alkyloxycarbonylalkyl wherein the alkyl moieties each contain 1 to 2 carbon atoms, hydroxyl, alkyloxy or alkylthio of 1 to 4 carbon atoms, hydroxyalkyloxy of 2 to 4 carbon atoms, alkanoyloxy of 2 to 4 carbon atoms, alkylsulfinyl or alkylsulfonyl of 1 to 4 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkoxycarbonyl wherein the alkyl moiety contains 1 to 3 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, mono- or dialkylaminoalkyl wherein each alkyl moiety contains 1 to 2 carbon atoms, a group of the formula -NR^I2R¹³, halogen, cyano, nitro, azido or carboxyl, with the other two substituents being hydrogen; or, two of R^s, R⁷ and R* are independently alkyl of 1 to 2 carbon atoms, trihalomethyl, alkyloxy

AP 0 0 0 1 7 9

9/038-4-C6

BAD ORIGINAL or alkylthio of 1 to 2 carbon atoms, halogen or a group of the formula -NR¹²R¹³, with the remaining substituent being hydrogen; or,

R⁴, R⁷ and R* are each hydrogen; and,

R¹⁰, Rⁿ, R¹² and R¹³ are each independently hydrogen, alkyl of 1 to 4 carbon atoms, alkenylmethyl or alkynylmethyl of 2 to 4 carbon atoms, aryl or arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, which is either unsubstituted or substituted by methyl, methoxy or halogen), mono- or dihydroxyalkylmethyl of 2 to 4 carbon atoms, alkyoxy of 1 to 3 carbon atoms, hydroxy, alkyloxyethyl or alkylthiocthyl of 3 to 4 carbon atoms, aminoalkylmethyl of 2 to 4 carbon atoms, mono- or dialkylaminoalkylmethyl wherein each alkyl moiety contains 1 or 2 carbon atoms, or alkanoyl of 1 to 4 carbon atoms; or,

R^!0 and R, and R^u and R¹³, together with the nitrogen atoms between them, respectively and independently form azetidin-l-yl or a 5, 6 or 7-mernbered ring which is either saturated or unsaturated, which optionally contains up to one additional heteroatom which may be selected from O, S or N, or which optionally contains in place of a carbon atom a group of the formula =NR¹⁴ wherein R^!4 is hydrogen or alkyl or 1 to 2 carbon atoms, and which ring is optionally and independently substituted with hydroxymethyl, aminomethyl, 1 to 4 methyl groups and 1 to 2 hydroxy groups;

subject to the proviso that when

a) Z is oxygen or sulphur bad original

b) R is hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl or alkinyl of 2 to 5 carbon atoms, alkoxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms, alkanoyl of 2 to 4 carbon atoms, hydroxyalkyl of 2 to 5 carbon atoms, phenyl (optionally substituted by alkyl or alkoxy of 1 to 3 carbon atoms, hydroxyl or halogen), or alkoxycarbonylmethyl wherein the alkyl moiety contains 1 to 5 carbon atoms,

c) i) R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each hydrogen or ii) one of R³, R⁴, R⁵, R⁶, R⁷ and R⁸ is alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms alkyloxycarbonylalkyl wherein the alkyl moieties each contain 1 or 2 carbon atoms, hydroxyl, alkoxy or alkylthio of 1 to 4 carbon atoms, alkanoyloxy of up to 4 carbon atoms, alkanoyl of up to 4 carbon atoms, amino, aminoalkyl of up to 4 carbon atoms, mono- or di-alkylaminoalkyl wherein each alkyl moiety contains 1 to 2 carbon atoms, halogen, cyano, nitro, azido, or carboxyl, and the remaining five of R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each hydrogen, or

3 4 5 iii) R , R and R are each independently hydrogen or alkyl of 1 to 3 carbon atoms, provided at least one is hydrogen, or one of 3 4 5

R , R and R is butyl with the remaining two being hydrogen and

AK 0 0 0 1 7 9

83A

Ί 3

R , R and R are each independently hydrogen or alkyl cf 1 to 3 carbon atoms, provided at least one is hydrogen, or

6 V 8 one of R , R and R is butyl with the remaining two being hydrogen,

2’,3’-e][1,4Jdiazepines. These are useful in the prevention or treatment of HIV infection and have the general formula I: