# US 5,708,168 A · Azepine compounds

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- Number: US 5,708,168 A
- Document ID: US5708168A
- Status: Granted
- Kind: A
- Application number: 08/544,107
- Filed: 1995-10-17
- Granted: 1998-01-13
- Earliest claimed: 1994-11-16
- Assignees: State of Oregon, acting by and through The Oregon State Board of Higher Education, acting for and on behalf of The Oregon Health Sciences University and The University of Oregon, Eugene Oregon; Acea Pharmaceuticals, Inc.
- Inventors: John F. W. Keana; Anthony P. Guzikowski; Daniel F. Nogales; Sui Xiong Cai
- Web page: https://patentgrep.com/patent/US5708168A

## CPC

- C07D 223/16: Benzazepines; Hydrogenated benzazepines
- C07D 223/32: containing carbocyclic rings other than six-membered
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Disclosed are methods of preparing azepines by a multistep synthesis including a Diels-Alder reaction. Also disclosed are methods of treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome, treating or preventing the adverse consequences of the hyperactivity of the excitatory amino acids, as well as treating anxiety, chronic pain, convulsions, inducing anesthesia and treating or preventing opiate tolerance are disclosed by administering to an animal in need of such treatment an azepine which has high binding to the NMDA glycine site.

## Claims

### Claim 1

A compound of the Formula ##STR157## or a tautomer thereof or a pharmaceutically acceptable salt thereof; wherein
R.sub.1, R.sub.3, R.sub.4 and R.sub.6 are independently hydrogen, halo, C.sub.1 -C.sub.4 haloalkyl, C.sub.6 -C.sub.14 aryl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, C.sub.6 -C.sub.14 aryl(C.sub.1 -C.sub.4)alkyl, (C.sub.6 -C.sub.14)aryl(C.sub.1 -C.sub.4)alkenyl, C.sub.6 -C.sub.14 aryl(C.sub.1 -C.sub.4)alkynyl, C.sub.1 -C.sub.4 hydroxyalkyl, nitro, amino, cyano, C.sub.1 -C.sub.6 alkanoylamino, hydroxy, thiol, C.sub.1 -C.sub.6 alkanoyloxy, azido, C.sub.1 -C.sub.4 alkoxy, carboxy, carbonylamido, C.sub.1 -C.sub.4 alkylthiol, C.sub.3 -C.sub.18 trialkylsilyloxy, or C.sub.8 -C.sub.18 phenyldialkylsilyloxy;
Q is OR.sub.7 or NR.sub.12 R.sub.13, wherein R.sub.12 and R.sub.13 are independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl(C.sub.1 -C.sub.6)alkyl, C.sub.6 -C.sub.14 aryl, C.sub.6 -C.sub.14 aryl(C.sub.1 -C.sub.6)alkyl, and CH.sub.2 Y wherein Y is selected from (CHOH).sub.n CH.sub.2 OH and (CH.sub.2).sub.m R.sup.c where m is 0 to 5, n is 1 to 5 and R.sup.c is selected from hydroxy, C.sub.1 -C.sub.6 alkoxycarbonyl, and NR.sup.d R.sup.e in which R.sup.d and R.sup.e are independently selected from hydrogen and C.sub.1 -C.sub.6 alkyl or R.sup.d and R.sup.e, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered heterocyclic ring which, in addition to said nitrogen atom, optionally contains one additional heteroatom selected from nitrogen, oxygen and sulfur; or R.sub.12 and R.sub.13, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered heterocyclic ring which is bonded to said compound through said nitrogen atom, said heterocyclic ring optionally containing, in addition to said nitrogen atom, one additional heteroatom selected from nitrogen, oxygen and sulfur; R.sub.7 is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.6 alkanoyl; and
T is selected from hydrogen, halo, hydroxy, C.sub.1 -C.sub.6 alkanoyloxy, C.sub.1 -C.sub.4 alkyl which may optionally bear a substituent selected from amino, C.sub.1 -C.sub.4 alkanoylamino, carboxy and carboxamido; and C.sub.6 -C.sub.14 aryl(C.sub.1 -C.sub.4)alkyl.

### Claim 2

A compound of the Formula ##STR158## or a tautomer thereof or a pharmaceutically acceptable salt thereof; wherein
R.sub.1, R.sub.3, R.sub.4 and R.sub.6 are independently hydrogen, halo, C.sub.1 -C.sub.4 haloalkyl, C.sub.6 -C.sub.14 aryl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, C.sub.6 -C.sub.14 aryl(C.sub.1 -C.sub.4)alkyl, C.sub.6 -C.sub.14 aryl(C.sub.1 -C.sub.4)alkenyl, C.sub.6 -C.sub.14 aryl(C.sub.1 -C.sub.4)alkynyl, C.sub.1 -C.sub.4 hydroxyalkyl, nitro, amino, cyano, C.sub.1 -C.sub.6 alkanoylamino, hydroxy, thiol, C.sub.1 -C.sub.6 alkanoyloxy, azido, C.sub.1 -C.sub.4 alkoxy, carboxy, carbonylamido, C.sub.1 -C.sub.4 alkylthiol, C.sub.3 -C.sub.18 trialkylsilyloxy, or C.sub.8 -C.sub.18 phenyldialkylsilyloxy;
X' and Y' are independently hydrogen, halogen; hydroxy and hydrogen; nitro and hydrogen; C.sub.1 -C.sub.6 alkanoylamido and hydrogen; X' and Y' together form an oxirane ring; X' and Y' are vicinal C.sub.1 -C.sub.6 alkanoylamido C.sub.1 -C.sub.6 alkanoyloxy groups; or X' and Y' together form a double bond;
Q is OR.sub.7 or NR.sub.12 R.sub.13, wherein R.sub.12 and R.sub.13 are independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl(C.sub.3 -C.sub.6)alkyl, C.sub.6 -C.sub.14 aryl, C.sub.6 -C.sub.14 aryl(C.sub.1 -C.sub.6)alkyl, and CH.sub.2 Y wherein Y is selected from (CHOH).sub.n CH.sub.2 OH and (CH.sub.2).sub.m R.sup.c where m is 0 to 5, n is 1 to 5 and R.sup.c is selected from hydroxy, C.sub.1 -C.sub.6 alkoxycarbonyl, and NR.sup.d R.sup.e in which R.sup.d and R.sup.e are independently selected from hydrogen and C.sub.1 -C.sub.6 alkyl or R.sup.d and R.sup.e, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered heterocyclic ring which, in addition to said nitrogen atom, optionally contains one additional heteroatom selected from nitrogen, oxygen and sulfur; or R.sub.12 and R.sub.13, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered heterocyclic ring which is bonded to said compound through said nitrogen atom, said heterocyclic ring optionally containing, in addition to said nitrogen atom, one additional heteroatom selected from nitrogen, oxygen and sulfur; R.sub.7 is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.6 alkanoyl; and
T is selected from hydrogen, halo, hydroxy, C.sub.1 -C.sub.6 alkanoyloxy, C.sub.1 -C.sub.4 alkyl which may optionally bear a substituent selected from amino, C.sub.1 -C.sub.4 alkanoylamino, carboxy and carboxamido; and C.sub.6 -C.sub.14 aryl(C.sub.1 -C.sub.4)alkyl.

### Claim 3

A compound of the Formula ##STR159## or a tautomer thereof or a pharmaceutically acceptable salt thereof; wherein
R.sub.1, R.sub.3, R.sub.4 and R.sub.6 are independently hydrogen, halo, C.sub.1 -C.sub.4 haloalkyl, C.sub.6 -C.sub.4 aryl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, C.sub.6 -C.sub.14 aryl(C.sub.1 -C.sub.4)alkyl, C.sub.6 -C.sub.14 aryl(C.sub.1 -C.sub.4)alkenyl, C.sub.6 -C.sub.4 aryl(C.sub.1 -C.sub.4)alkynyl, C.sub.1 -C.sub.4 hydroxyalkyl, nitro, amino, cyano, C.sub.1 -C.sub.6 alkanoylamino, hydroxy, thiol, C.sub.1 -C.sub.6 alkanoyloxy, azido, C.sub.1 -C.sub.4 alkoxy, carboxy, carbonylamido, C.sub.1 -C.sub.4 alkylthiol, C.sub.3 -C.sub.18 trialkylsilyloxy, or C.sub.8 -C.sub.18 phenyldialkylsilyloxy;
X' and Y' are independently hydrogen, halogen; hydroxy and hydrogen; nitro and hydrogen; C.sub.1 -C.sub.6 alkanoylamido and hydrogen; X' and Y' together form an oxirane ring; X' and Y' are vicinal C.sub.1 -C.sub.6 alkanoylamido C.sub.1 -C.sub.6 alkanoyloxy groups; or X' and Y' together form a double bond;
one of A' and B' is hydrogen and the other of A' and B' is C.sub.1 -C.sub.4 alkyl or C.sub.6 -C.sub.14 ar(C.sub.1 -C.sub.4)alkyl;
Q is OR.sub.7 or NR.sub.12 R.sub.13, wherein R.sub.12 and R.sub.13 are independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl(C.sub.1 -C.sub.6)alkyl, C.sub.6 -C.sub.14 aryl, C.sub.6 -C.sub.14 aryl(C.sub.1 -C.sub.6)alkyl, and CH.sub.2 Y wherein Y is selected from (CHOH).sub.n CH.sub.2 OH and (CH.sub.2).sub.m R.sup.c where m is 0 to 5, n is 1 to 5 and R.sup.c is selected from hydroxy, C.sub.1 -C.sub.6 alkoxycarbonyl, and NR.sup.d R.sup.e in which R.sup.d and R.sup.e are independently selected from hydrogen and C.sub.1 -C.sub.6 alkyl or R.sup.d and R.sup.e, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered heterocyclic ring which, in addition to said nitrogen atom, optionally contains one additional heteroatom selected from nitrogen, oxygen and sulfur; or R.sub.12 and R.sub.13, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered heterocyclic ring which is bonded to said compound through said nitrogen atom, said heterocyclic ring optionally containing, in addition to said nitrogen atom, one additional heteroatom selected from nitrogen, oxygen and sulfur; R.sub.7 is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.6 alkanoyl; and
T is selected from hydrogen, halo, hydroxy, C.sub.1 -C.sub.6 alkanoyloxy, C.sub.1 -C.sub.4 alkyl which may optionally bear a substituent selected from amino, C.sub.1 -C.sub.4 alkanoylamino, carboxy and carboxamido; and C.sub.6 -C.sub.14 aryl(C.sub.1 -C.sub.4)alkyl.

### Claim 4

A compound of the Formula ##STR160## or a tautomer thereof or a pharmaceutically acceptable salt thereof; wherein
R.sub.1, R.sub.3, R.sub.4 and R.sub.6 are independently hydrogen, halo, C.sub.1 -C.sub.4 haloalkyl, C.sub.6 -C.sub.4 aryl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, C.sub.6 -C.sub.14 aryl(C.sub.1 -C.sub.4)alkyl, C.sub.6 -C.sub.14 aryl(C.sub.1 -C.sub.4)alkenyl, C.sub.6 -C.sub.4 aryl(C.sub.1 -C.sub.4)alkynyl, C.sub.1 -C.sub.4 hydroxyalkyl, nitro, amino, cyano, C.sub.1 -C.sub.6 alkanoylamino, hydroxy, thiol, C.sub.1 -C.sub.6 alkanoyloxy, azido, C.sub.1 -C.sub.4 alkoxy, carboxy, carbonylamido, C.sub.1 -C.sub.4 alkylthiol, C.sub.3 -C.sub.18 trialkylsilyloxy, or C.sub.8 -C.sub.18 phenyldialkylsilyloxy;
A is (CH.sub.2).sub.n, wherein n is 1 to 4;
X' and Y' are independently hydrogen, halogen; hydroxy and hydrogen; nitro and hydrogen; C.sub.1 -C.sub.6 alkanoylamido and hydrogen; X' and Y' together form an oxirane ring; X' and Y' are vicinal C.sub.1 -C.sub.6 alkanoylamido C.sub.1 -C.sub.6 alkanoyloxy groups; or X' and Y' together form a double bond;
Q is OR.sub.7 or NR.sub.12 R.sub.13, wherein R.sub.12 and R.sub.13 are independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl(C.sub.1 -C.sub.6)alkyl, C.sub.6 -C.sub.14 aryl, C.sub.6 -C.sub.14 aryl(C.sub.1 -C.sub.6)alkyl, and CH.sub.2 Y wherein Y is selected from (CHOH).sub.n CH.sub.2 OH and (CH.sub.2).sub.m R.sup.c where m is 0 to 5, n is 1 to 5 and R.sup.c is selected from hydroxy, C.sub.1 -C.sub.6 alkoxycarbonyl, and NR.sup.d R.sup.e in which R.sup.d and R.sup.e are independently selected from hydrogen and C.sub.1 -C.sub.6 alkyl or R.sup.d and R.sup.e, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered heterocyclic ring which, in addition to said nitrogen atom, optionally contains one additional heteroatom selected from nitrogen, oxygen and sulfur; or R.sub.12 and R.sub.13, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered heterocyclic ring which is bonded to said compound through said nitrogen atom, said heterocyclic ring optionally containing, in addition to said nitrogen atom, one additional heteroatom selected from nitrogen, oxygen and sulfur; R.sub.7 is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.6 alkanoyl; and
T is selected from hydrogen, halo, hydroxy, C.sub.1 -C.sub.6 alkanoyloxy, C.sub.1 -C.sub.4 alkyl which may optionally bear a substituent selected from amino, C.sub.1 -C.sub.4 alkanoylamino, carboxy and carboxamido; and C.sub.6 -C.sub.14 aryl(C.sub.1 -C.sub.4)alkyl.

### Claim 5 (depends on 1, 2, 3, 4)

A compound of any of claims 1-4, wherein T is hydrogen.

### Claim 6 (depends on 1, 2, 3, 4)

A compound of any of claims 1-4, wherein Q is OR.sub.7 and R.sub.7 is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.6 alkanoyl.

### Claim 7 (depends on 6)

A compound of claim 6, where R.sub.7 is hydrogen.

### Claim 8 (depends on 1, 2, 3, 4)

A compound of any of claims 1-4, wherein Q is NR.sub.12 R.sub.13, wherein NR.sub.12 R.sub.13 represents a heterocyclic ring selected from the group consisting of morpholino; imidazolyl; pyrrolidinyl; pyrrolo; pyrazolyl; piperidinyl optionally substituted at the 4-position by one of C.sub.1 -C.sub.6 alkyl, phenyl(C.sub.1 -C.sub.6)alkyl, phenoxy or phenyl; piperazinyl optionally substituted at the 4-position by one of C.sub.1 -C.sub.6 alkyl, phenyl(C.sub.1 -C.sub.6)alkyl or phenyl; and perhydroazepinyl.

### Claim 9 (depends on 1, 2, 3, 4)

A compound of any of claims 1-4, wherein wherein Q is NR.sub.12 R.sub.13, and NR.sub.12 R.sub.13 represents amino, methylamino, dimethylamino, diethylamino, phenethylamino, 4-morpholino, allylamino, .alpha.-methylbenzylamino, t-butoxycarbonylmethylamino, 1-perhydroazepinyl, 1-pyrrolidinyl, anilino, pyrrolo, 4-phenylpiperazin-1-yl, 4-benzylpiperazin-1-yl, piperidino, 4-(N,N-diethylamino)ethylamino, glucamino, 4-phenoxypiperidine, benzylamino, cyclopropylmethylamino, 3,4-dibenzyloxyphenethylamino, 2-(4-imidazolyl)ethylamino, N,N-bis(2-hydroxyethyl)amino and N-(2-hydroxyethyl)amino.

### Claim 10 (depends on 1, 2, 3, 4)

A compound of any of claims 1-4, wherein R.sub.6 is hydrogen.

### Claim 11 (depends on 1)

A compound of claim 1, wherein R.sub.1, R.sub.3 and R.sub.4 are other than hydrogen, and R.sub.6 is hydrogen.

### Claim 12 (depends on 1)

A compound of claim 1, which is one of:
3-methoxy-6,7,8,9-tetrahydro-1H-1-benzazepine-2,5-dione);
3-hydroxy-6,7,8,9-tetrahydro-1H-1-benzazepine-2,5-dione;
3-methoxy-7,8-dichloro-6,7,8,9-tetrahydro-1H-1-benzazepine-2,5-dione;
3-hydroxy-7,8-dichloro-6,7,8,9-tetrahydro-1H-1-benzazepine-2,5-dione;
7,8-dimethyl-3-methoxy-6,7, 8,9-tetrahydro-1H-1-benzazepine-2,5-dione;
7,8-dimethyl-3-hydroxy-6,7,8,9-tetrahydro-1H-1-benzazepine-2,5 , dione;
7,8-dichloro-6-methyl-3-methoxy-6,7,8,9-tetrahydro-1H-1-benzazepine-2,5-dio ne;
7,8-dichloro-3-hydroxy-6-methyl-6,7,8,9-tetrahydro-1H-1-benzazepine-2,5-dio ne; and
6,7,8,9-tetrahydro-7,8-dichloro-6-ethyl-3-hydroxy-1H-1-benzazepine-2,5-dion e.

### Claim 13 (depends on 4)

A compound of claim 4, which is one of:
3-hydroxy-6,9-methano-6,7,8,9-tetrahydro-1H-1-benzazepine-2,5-dione;
6,9-methano-3-methoxy-6,7,8,9-tetrahydro-1H-1-benzazepine-2,5-dione;
6,9-ethano-3-methoxy-6,7,8,9-tetrahydro-1H-1-benzazepine-2,5-diione; and
6,9-ethano-3-hydroxy-6,7,8,9-tetrahydro-1H-1-benzazepine-2,5-dione.