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Details for Patent: 5,620,974

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Details for Patent: 5,620,974

Title: 5,11-dihyro-6H-dipyrido[3,2-B:2',3'-e][1,3]diazepines and their use in the prevention or treatment of HIV infection
Abstract:Disclosed are novel 5,11-dihydro-6H-dipyrido[3,2-b; 2',3'-e][1,4]diazepines. These are useful in the prevention or treatment of HIV infection.
Inventor(s): Hargrave; Karl D. (Brookfield, CT), Proudfoot; John R. (Newtown, CT), Adams; Julian (Ridgefield, CT), Grozinger; Karl G. (Ridgefield, CT), Schmidt, deceased; Gunther (late of Munich, DE), Engel; Wolfhard (Biberach, DE), Trummlitz; Gunther (Warthausen, DE), Eberlein; Wolfgang (Biberach, DE)
Assignee: Boehringer Ingelheim Pharmaceuticals, Inc. (Ridgefield, CT)
Filing Date:Jul 22, 1994
Application Number:08/279,464
Claims:1. A compound of the formula I ##STR15## wherein, Z is oxygen, sulfur, .dbd.NCN or a group of the formula .dbd.NOR.sup.9 wherein R.sup.9 is alkyl of 1 to 3 carbon atoms;

R.sup.1 is hydrogen, alkyl of 1 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms and 1 to 3 fluorine atoms, cycloalkyl of 3 to 6 carbon atoms, alkenylmethyl or alkynylmethyl of 3 to 6 carbon atoms, 2-halo-2-propen-1-yl, 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 or thioalkanoyl of 2 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, aminocarbonyl, mono- or di-alkylaminocarbonyl wherein each alkyl moiety contains 1 to 2 carbon atoms, aminoethyl, mono- or di-alkylaminoethyl wherein each alkyl moiety contains 1 to 2 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms, alkyloxycarbonyl wherein the alkyl moiety contains 1 to 4 carbon atoms, alkenyloxycarbonyl wherein the alkenyl moiety contains 2 to 4 carbon atoms, hydroxy, alkyloxy of 1 to 4 carbon atoms, cyano, amino, mono- or di-alkylamino wherein each alkyl moiety contains 1 to 4 carbon atoms, aminocarbonylmethyl, mono- or di-alkylaminocarbonylmethyl wherein the alkyl moiety contains 1 to 2 carbon atoms, or cyanoalkyl wherein the alkyl moiety contains 1 to 4 carbon atoms;

R.sup.2 is hydrogen (with the proviso that R.sup.1 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 carbon atoms, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, alkenylmethyl or alkynyl methyl of 3 to 6 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 5 carbon atoms, alkanoyl or thioalkanoyl of 2 to 5 carbon atoms, cyano, cyanoalkyl of 2 to 5 carbon atoms, hydroxyalkyl or acyloxyalkyl wherein the alkyl moiety contains 2 to 6 carbon atoms and the acyl moiety contains 2 to 3 carbon atoms, oxazolyl, isoxazolyl, thiazolyl, 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 R.sup.3, R.sup.4 and R.sup.5 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, trihalomethyl, hydroxyalkyl of 1 to 6 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 5 carbon atoms, alkyloxycarbonylalkyl wherein the alkyl moieties each contain 1 to 2 carbon atoms, carboxyalkyl or cyanoalkyl wherein the alkyl moieties each contain 1 to 5 carbon atoms, mono- or di-alkylaminocarbonylalkyl wherein the alkyl moieties each contain 1 to 2 carbon atoms, hydroxyl, mercapto, 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 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, imidazol-2-yl, imidazol-4-yl, aryl or arylalkyl (wherein the aryl moiety is phenyl, thienyl, furanyl, or pyridyl, which is either unsubstituted or substituted by alkyl or alkyloxy of 1 to 3 carbon atoms, hydroxyl, amino, or halogen, and the alkyl moiety contains 1 to 3 carbon atoms which may be unsubstituted or substituted with a methyl, hydroxyl, or amino groups), a group of the formula --NR.sup.10 R.sup.11, halogen, cyano, nitro, azido or carboxyI, with the other two substituents being hydrogen, methyl or halogen; or,

two of R.sup.3, R.sup.4 and R.sup.5 are independently alkyl of 2 to 3 carbon atoms, hydroxyalkyl of 1 to 3 carbon atoms, trihalomethyl, alkyloxy or alkylthio of 1 to 2 carbon atoms, or a group of the formula --NR.sup.10 R.sup.11, with the remaining substituent being hydrogen, methyl, or halogen; or,

two of R.sup.3 and R.sup.4 or R.sup.4 and R.sup.5 are joined to form a cycloalkyl with a 3 or 4 carbon bridge, or a fused pyridine ring; or,

R.sup.3, R.sup.4 and R.sup.5 are each hydrogen;

one of R.sup.6, R.sup.7 and R.sup.8 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 I to 3 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, mono- or di-alkylaminoalkyl wherein each alkyl moiety contains 1 to 2 carbon atoms, a group of the formula --NR.sup.12 R.sup.13, halogen, cyano, nitro, azido or carboxyl, with the other two substituents being hydrogen; or,

two of R.sup.6, R.sup.7 and R.sup.8 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.sup.12 R.sup.13, with the remaining substituent being hydrogen; or,

R.sup.6, R.sup.7 and R.sup.8 are each hydrogen; and,

R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are each independently hydrogen, alkyl of 1 to 4 carbon atoms, alkenylmethyl or alkynylmethyl of 3 to 4 carbon atoms, aryl or arylalkyl (wherein the aryl moiety is phenyl, thienyl, furanyl, or pyridyl which is either unsubstituted or substituted by methyl, methoxy, hydroxyl, or halogen, and the alkyl moiety contains 1 to 3 carbon atoms), mono- or dihydroxy(or acetoxy)alkylmethyl wherein the alkyl moiety contains 1 to 3 carbon atoms, alkyloxyethyl or alkylthioethyl 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.sup.10 and R.sup.11 and R.sup.12 and R.sup.13 together with the nitrogen atoms between them, respectively and independently form azetidin-1-yl , pyrrol-1-yl, pyrrolin-1-yl, pyrrolidin-1-yl, pyrazol-1-yl, pyrazolin-1-yl, pyrazolidin-1-yl, imidazol-1-yl, imidazolin-1-yl, imidazolidin-1-yl, tetrahydropyridin-1-yl, piperidin-1-yl, morpholin-1-yl, (4-methyl)piperazin-1-yl, piperazin-1-yl, (2-hydroxy(or acetoxy)ethyl)amino, N-methyl-N-(2-hydroxy(or acetoxy)ethyl)amino, N-methyl-N-(2-methoxyethyl)amino;

or a pharmaceutically acceptable salt thereof.

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

Z is oxygen, sulfur or a group of the formula .dbd.NOR.sup.9 wherein R.sup.9 is alkyl of 1 to 2 carbon atoms;

R.sup.1 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-1-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;

R.sup.2 is hydrogen (with the proviso that R.sup.1 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 R.sup.3, R.sup.4 and R.sup.5 is alkyl of 1 to 4 carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms, trihalomethyl, hydroxyalkyl of 1 to 4 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms, alkyloxycarbonylalkyl wherein the alkyl 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 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 di-alkylaminoalkyl wherein each alkyl moiety contains 1 to 2 carbon atoms, amino, mono- or di-alkylamino wherein each alkyl moiety contains 1 to 4 carbon atoms, azetidin-1-yl, pyrrol-1-yl, pyrrolin-1-yl, pyrrolidin-1-yl, pyrazol-1-yl, pyrazolin-1-yl, pyrazolidin-1-yl, imidazol-1-yl, imidazolin-1-yl, imidazolidin-1-yl, tetrahydropyridin-1-yl, piperidin-1-yl, morpholin-1-yl, (4-methyl)piperazin-1-yl, piperazin-1-yl, (2-hydroxy(or acetoxy)ethyl)amino, N-methyl-N-(2-hydroxy(or acetoxy)ethyl)amino, N-methyl-N-(2-methoxyethyl)amino, or halogen, with the other two substituents being hydrogen, methyl or chloro; or,

two of R.sup.3, R.sup.4 and R.sup.5 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-1-yl, pyrrol-1-yl, pyrrolin-1-yl, pyrrolidin-1-yl, pyrazol-1-yl, pyrazolin-1-yl, pyrazolidin-1-yl, imidazol-1-yl, imidazolin-1-yl, imidazolidin-1-yl, tetrahydropyridin-1-yl, piperidin-1-yl, morpholin-1-yl, (4-methyl)piperazin-1-yl, piperazin-1-yl, (2-hydroxy(or acetoxy)ethyl)amino, N-methyl-N-(2-hydroxy(or acetoxy)ethyl)amino, N-methyl-N-(2-methoxyethyl)amino, with the remaining substituent being hydrogen, methyl or chloro; or,

R.sup.3, R.sup.4 and R.sup.5 are each hydrogen;

one of R.sup.6, R.sup.7 and R.sup.8 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-1-yl, pyrrol-1-yl, pyrrolin-1-yl, pyrrolidin-1-yl, pyrazol-1-yl, pyrazolin-1-yl, pyrazolidin-1-yl, imidazol-1-yl, imidazolin-1-yl, imidazolidin-1-yl, tetrahydropyridin-1-yl, piperidin-1-yl, morpholin-1-yl, (4-methyl)piperazin-1-yl, piperazin-1-yl, (2-hydroxy(or acetoxy)ethyl)amino, N-methyl-N-(2hydroxy(or acetoxy)ethyl)amino, N-methyl-N-(2-methoxyethyl)amino, or halogen, with the other two substituents being hydrogen; or,

R.sup.6, R.sup.7 and R.sup.8 are each hydrogen;

or a pharmaceutically acceptable salt thereof.

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

Z is oxygen or sulfur;

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

R.sup.2 is alkyl of 2 to 3 carbon atoms, or cycloalkyl of 3 to 4 carbon atoms;

R.sup.3 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, azetidin-1-yl, pyrrol-1-yl, pyrrolin-1-yl, pyrrolidin-1-yl, pyrazol-1-yl, pyrazolin-1-yl, pyrazolidin-1-yl, imidazol-1-yl, imidazolin-1-yl, imidazolidin-1-yl, tetrahydropyridin-1-yl, piperidin-1-yl, morpholin-1-yl, (4-methyl)piperazin-1-yl, piperazin-1-yl, or N-methyl-N-(2-hydroxy(or acetoxy)ethyl)amino;

R.sup.4 is hydrogen, methyl or chloro;

R.sup.5 is hydrogen, methyl, ethyl, chloro, or trifluoromethyl;

R.sup.6 and R.sup.8 are hydrogen; and

R.sup.7 is hydrogen or amino;

or a pharmaceutically acceptable salt thereof.

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

Z is oxygen or sulfur;

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

R.sup.2 is alkyl of 2 to 3 carbon atoms, or cycloalkyl of 3 to 4 carbon atoms;

R.sup.3 is hydrogen, methyl, chloro, methoxy, ethoxy, amino, mono- or di-alkylamino wherein each alkyl moiety contains 1 to 2 carbon atoms, allylamino, allylmethylamino, pyrrolin-1-yl, pyrrolidin-1-yl, tetrahydropyridin-1-yl, piperidin-1-yl or morpholin-1-yl;

R.sup.4 is hydrogen;

R.sup.5 is hydrogen, methyl, ethyl, chloro, or trifluoromethyl;

R.sup.6 and R.sup.8 are hydrogen; and

R.sup.7 is hydrogen or amino;

or a pharmaceutically acceptable salt thereof.

5. A compound selected from the group consisting of:

5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-on e or -thione;

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

11-cyclopropyl-5,11-dihydro-2,4-dimethyl-6H-dipyrido[3,2-b:2',3'-e][1,4]dia zepin-6-one or -thione;

2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diaz epin-6-one or -thione;

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

5,11-dihydro-11-ethyl-2-methoxy-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]dia zepin-6-one or -thione;

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

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

2-chloro-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diaz epin-6-one or -thione;

2-bromo-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diaze pin-6-one or -thione;

5,11-dihydro-11-ethyl-4-methyl-2-(N,N-dimethylamino)-6H-dipyrido[3,2-b:2',3 '-e][1,4]diazepin-6-one or -thione; and,

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

or pharmaceutically acceptable salts thereof.

6. A method for treating HIV-1 infection which comprises administering, to a human being infected by HIV-1, a therapeutically effective amount of a compound of formula I, as set forth in claims 1, 2, 3, 4, or 5, or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition suitable for treating HIV-1 infection which comprises a therapeutically effective amount of a compound of formula I, as set forth in claims 1, 2, 3, 4, or 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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