US 6,887,867 B2Granted

5H-2,3-benzodiazepine antagonists of excitatory amino acid receptors

AssigneeTransgenomic, Inc.

InventorsXue-Feng Pei, Baoqing Li, Maria-Luisa Maccecchini

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Abstract

Substituted benzodiazepine compositions are provided which are active as non-NMDA ionotropic excitatory amino acid (EAA) receptor antagonists. The compounds are generally 7- or 8-mono substituted 5H-2,3-benzodiazepines. The compositions are useful for treating disorders associated with excessive activation of the non-NMDA subtype of the ionotropic EAA receptor. The compounds further are useful as testing agents to identify and characterize other compounds for the treatment of these disorders. The compounds are useful therapeutically as sedatives or for the treatment of neurosychopharmacological disorders such as stroke, ischemia and epilepsy. The compositions may be provided in combination with a suitable carrier for oral or parenteral administration. The compounds may be administered orally or parenterally for the treatment of a variety of disorders associated with non-NMDA EEA receptor function.

Claims12

Dependent claims

A compound of Formula I:

wherein
R1, R2, R3 and R4 are independently
H,
HO,
R13O—,
R13S—,
halogen,
C1-C3-alkyl,
CF3,
R14CO2—,
R14CO—
R14CONH—,
R14NHCO—,
R14NHCO2—,
R14OCONH—,
R14O2S—,
R14OS—, or
R15R16N—;
or
R1 and R2, or R2 and R3, or R3 and R4 taken together can be
—SCH2S—,
—SCH2O—,
—OCH2S—,
—SCH2CH2S—,
—SCH2CH2O—, or
—OCH2CH2S—;
wherein one of R1, R3 and R4 must be C1-C3-alkoxy or C1-C3-alkylthio group;
R5, R6, R7 and R8 are independently
H,
C1-C6-alkyl,
C3-C6-alkenyl,
C3-C6-cycloalkyl,
phenyl or substituted phenyl, wherein the phenyl is substituted with one or two substituents, C1-C3-alkyl, halogen, R13O—, CF3—, R14O2S—, R14OS—, R14CO—, R14CO2—, R14O2C—, R14CONH—, R14NHCO—;
or
R5 and R6 taken together can be C3-C6-cycloalkyl;
R7 and R8 taken together can be C3-C6-cycloalkyl;
R9 is
R15R16NCO—,
R15R16NCS—,
R17OCO—,
R15CO—,
R15R16NCH2CO—,
R14O2C—(CH2)n—,
R15R16NCO—(CH2)n—,
NC—(CH2)n—,
H
C1-C6-alkyl,
C3-C6-alkenyl, or
C3-C6-cycloalkyl;
or
R8 and R9 taken together can be
—(CH2)mCH2(R15)NCO—,
—(CH2)mCH2OCO—, or
—(CH2)mCH2CH2CO—;
R10 and R11 are independently
H,
R15R16N—,
R14HNCO—, or
R14CONH—;
R12 is
H,
halogen,
HO,
R13O—,
R15R16N—,
C1-C3-alkyl,
CF3,
R14CO2—,
R14CO—, or
R14CONH—;
R13 is C1-C3-alkyl;
R14 is H or C1-C3-alkyl;
R15 and R16 are independently
H,
C1-C10-alkyl,
C1-C6-perfluoroalkyl,
C3-C10-alkenyl, or
C3-C6-cycloalkyl;
or
R15 and R16 taken together can be C3-C6-cycloalkyl;
R17 is C1-C6-alkyl, C3-C6-alkenyl, or C3-C6-cycloalkyl;
n is 1 to 6;
m is 0 to 2;
and pharmaceutically acceptable salts thereof;
wherein R10 and H11 cannot be both H.

82 more elements

A method for treating a patient suffering from isohemia, epilepsy or stroke, the method comprising administering to the patient, in an effective amount to alleviate the symptoms of the isohemia, epilepsy or stroke, a compound of Formula I:

wherein
R1, R2, R3 and R4 are independently
H,
HO,
R13O—,
R13S—,
halogen,
C1-C3-alkyl,
CF3,
R14CO2—,
R14O2C—,
R14CO—,
R14CONH—,
R14NHCO—,
R14NHCO2—,
R14OCONH—,
R14O2S—,
R14 OS—, or
R15R16N—;
or
R1 and R2, or R2 and R3, or R3 and R4 taken together can be
—SCH2S—,
—SCH2O—,
—OCH2S—,
—SCH2CH2S—,
—SCH2CH2O—, or
—OCH2CH2S—;
wherein one of R1, R3 and R4 must be C1-C3-alkoxy or C1-C3-alkylthio group;
R5, R6, R7 and R8 are independently
H,
C1-C6-alkyl,
C3-C6-alkenyl,
C3-C6-cycloalkyl,
phenyl or substituted phenyl, wherein the phenyl is substituted with one or two substituents, C1-C3-alkyl, halogen, R13O—, CF3—, R14O2S—, R14OS—, R14CO—, R14CO2, R14O2C—, R14CONH—, R14NHCO—;
or
R5 and R6 taken together can be C3-C6-cycloalkyl;
R7 and R8 taken together can be C3-C6-cycloalkyl;
R9 is
R15R16NCO—,
R15R16NCS—,
R17OCO—,
R15CO—,
R15R16NCH2CO—,
R14O2C—(CH2)n—,
R15R16NCO—(CH2)n—,
NC—(CH2)n—,
H
C1-C6-alkyl,
C3-C6-alkenyl, or
C3-C6-cycloalkyl;
or
R8 and R9 taken together can be
—(CH2)mCH2(R15)NCO—,
—(CH2)mCH2OCO—, or
—(CH2)mCH2CH2CO—;
R10 and R11 are independently
H,
R15R16N—,
R14HNCO—, or
R14CONH—;
R12 is
H,
halogen,
HO,
R13O—,
R15R16N—,
C1-C3-alkyl,
CF3,
R14CO2—,
R14CO—, or
R14CONH—;
R13 is C1-C3-alkyl;
R14 is H or C1-C3-alkyl;
R15 and R16 are independently
H,
C1-C10-alkyl,
C1-C6-perfluoroalkyl,
C3-C10-alkenyl, or
C3-C6-cycloalkyl;
or
R15 and R16 taken together can be C3-C6-cycloalkyl;
R17 is C1-C6-alkyl, C3-C6-alkenyl, or C3-C6-cycloalkyl;
n is 1 to 6;
m is 0 to 2;
and pharmaceutically acceptable salts thereof;
wherein R10 an R11 cannot be both H,
in combination with a pharmaceutically acceptable carrier.

84 more elements

A compound of Formula II:

wherein
R1 and R4 are independently
H,
HO,
R13O—,
R13S—,
halogen,
C1-C3-alkyl,
CF3,
R14CO2—,
R14O2—,
R14CO—,
R14CONH—,
R14NHCO—,
R14NHCO2—,
R14OCONH—,
R14O2S—,
R14OS—, or
R15R16N—;
or
R2 is one of H, HO, R13O—, halogen, C1-C3-alkyl, CF3, R14CO2—, R14O2C—, R14CO—, R14CONH—, R14NHCO—, R14NHCO2—, R14OCONH—, R14O2S—, R14OS—, R13S— and R15R16N— when R3 is one of HO, halogen, C1-C3-alkyl, CR3, R14CO2—, R14O2C—, R14CO—, R14CONH—, R14NHCO—, R14NHCO2—, R-OCONH—, R14O2S—, R14OS—, R13S— and R15R16N—;
or
R2 is one of H, HO, halogen, C1-C3-alkyl, CF3, R14CO2—, R14O2C—, R14CO—, R14CONH—, R14NHCO—, R14NHCO2—, R14OCONH—, R14O2S—, R14OS—, R13S— and R15R16N— when R3 is one of H, HO, R13O—, halogen, C1-C3-alkyl, CF3, R14CO2—, R14O2C—, R14CO—, R14CONH—, R14NHCO—, R14NHCO2—, R14OCONH—, R14O2S—, R14OS—, R13S— and R15R16N—;
or
R1 and R2, or R2 and R3, or R3 and R4 taken together can be
—SCH2S—,
—SCH2O—,
—OCH2S—,
—SCH2CH2S—,
—SCH2CH2O—, or
—OCH2CH2S—;
wherein one of the substituents of R1, R3 and R4 must be C1-C3-alkoxy or C1-C3-alkylthio group;
R5, R6 and R7 are independently
H,
C1-C6-alkyl,
C3-C6-alkenyl,
C3-C6-cycloalkyl,
phenyl or substituted phenyl, wherein the phenyl is substituted with one or two substituents, C1-C3-alkyl, halogen, R13O—, CF3—, R14O2S—, R14OS—, R14CO—, R14CO2—, R14O2C—, R14CONH—, R14NHCO—;
or
R5 and R6 taken together can be C3-C6-cycloalkyl;
R13 is C1-C3-alkyl;
R14 is H or C1-C3-alkyl;
R15 and R16 are independently
H,
C1—C10-alkyl,
C1-C 6-perfluoroalkyl,
C3-C10-alkenyl, or
C3-C6-cycloalkyl;
or
R15 and R16 taken tog ether can be C3-C6-cycloalkyl;
R18 and R19 are independently
H,
halogen,
C1-C3-alkyl,
CF3—, or
R14CO2—;
R20 and R21 are independently
H,
R15R16N—,
R15HNC(NH)— or
R14CONH—;
and pharmaceutically acceptable salts thereof;
wherein R20 an R21 cannot both be H.

60 more elements

A method for treating a patient, the method comprising administering to the patient, in an effective amount to alleviate the symptoms of the ischemia, epilepsy or stroke, a compound of Formula II:

wherein
R1 and R4 are independently
H,
HO,
R13O—,
R13S—,
halogen,
C1-C3-alkyl,
CF3,
R14CO2—,
R14O2C—,
R14CO—,
R14CONH—,
R14NHCO—,
R14NHCO2—,
R14OCONH—,
R14O2S—,
R14OS—, or
R15R16N—;
or
R2 is one of H, HO, R13O—, halogen, C1-C3-alkyl, CF3, R14CO2—, R14O2C—, R14CO—, R14CONH—, R14NHCO—, R14NHCO2—, R14OCONH—, R14O2S—, R14OS— and R15R16N— when R3 is one of HO, halogen, C1-C3-alkyl, CF3, R14CO2—, R14O2C , R14CO—, R14CONH—, R14NHCO—, R14NHCO2—, R14OCONH—, R14O2S—, R14OS—, R13S— and R15R16N—;
or
R2 is one of H, HO, halogen, C1-C3-alkyl, CF3, R14CO2—, R14O2C—, R14CO—, R14CONH—, R14NHCO—, R14NHCO2—, R14OCONH—, R14O2S—, R14OS— and R15R16N— when R3 is one of H, HO, R13O—, halogen, C1-C3-alkyl, CF3, R14CO2—, R14O2C—, R14CO—, R14CONH—, R14NHCO—, R14NHCO2—, R14OCONH—, R14O2S—, R14OS—, R13S— and R15R16N—;
or
R1 and R2, or R2 and R3, or R3 and R4 taken together can be
—SCH2S—,
—SCH2O—,
—OCH2S—,
—SCH2CH2S—,
—SCH2CH2O—, or
—OCH2CH2S—,
wherein one of the substituents of R1, R3 and R4 must be C1-C3-alkoxy or C1-C3-alkylthio group;
R5, R6, and R7 are independently
H,
C1-C6-alkyl,
C3-C6-alkenyl,
C3-C6-cycloalkyl,
phenyl or substituted phenyl, wherein the phenyl is substituted with one or two substituents, C1-C3-alkyl, halogen, R13O—, CF3—, R14O2S—, R14OS—, R14CO—, R14CO2—, R14O2C—, R14CONH—, R14NHCO—;
or
R5 and R6 taken together can be C3-C6-cycloalkyl;
R13 is C1-C3-alkyl;
R14 is H or C1-C3-alkyl;
R15 and R16 are independently
H,
C1-C10-alkyl,
C1-C6-perfluoroalkyl,
C3-C10-alkenyl, or
C3-C6-cycloalkyl;
or
R15 and R16 taken together can be C3-C6-cycloalkyl;
R18 and R19 are independently
H,
halogen,
C1-C3-alkyl,
R14O—,
CF3—, or
R14CO2—;
R20 and R21 are independently
H,
R15R16N—,
R15HNC(NH)— or
R14CONH—;
and pharmaceutically acceptable salts thereof;
wherein R20 and R21 cannot both be H
in combination with a pharmaceutically acceptable carrier.

62 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/882,843Filed 15 Jun 2001 · us provisional application
Priority: 16 Jun 2000
Published: US 2002/0025958 A128 Feb 2002
Granted: 3 May 2005
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 243/02
Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms: having the nitrogen atoms in…
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…