# US 5,707,988 A · Benzo›d! isoxazole derivatives, compositions containing them and their use in therapy

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- Number: US 5,707,988 A
- Document ID: US5707988A
- Status: Granted
- Kind: A
- Application number: 08/464,709
- Filed: 1995-07-11
- Granted: 1998-01-13
- Earliest claimed: 1992-12-23
- Assignees: British Technology Group Limited
- Inventors: Edward Andrew Boyd; Brenda Costall; Mary Elizabeth Kelly; Philip James Parsons
- Web page: https://patentgrep.com/patent/US5707988A

## CPC

- C07D 498/04: Ortho-condensed systems
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of formula (I) ##STR1## in which X represents a group >O, >S, >C.dbd.O or >NR wherein R is hydrogen, C.sub.1-6 alkyl, phenyl or C.sub.7-12 phenalkyl, R.sub.1 and R.sub.2 each represent hydrogen or together represent an oxo group and R.sub.3, R.sub.4 and R.sub.5 each represent hydrogen or R.sub.1 represents hydrogen and two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 together represent the second bond of a double bond joining positions 7 and 8, 8 and 9 or 9 and 10 with the remaining two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 representing hydrogen, the compound optionally being in the form of a salt thereof formed with a physiologically acceptable inorganic or organic acid, are of value for the treatment of anxiety and in the improvement of learning ability and/or the reversal of amnesia.

## Claims

### Claim 1

A compound of formula (I) ##STR6## in which X represents a group >O, >S, >C.dbd.O or >NR wherein R is hydrogen, C.sub.1-6 alkyl, phenyl or C.sub.7-12 phenalkyl, R.sub.1 and R.sub.2 each represent hydrogen or together represent an oxo group and R.sub.3, R.sub.4 and R.sub.5 each represent hydrogen or R.sub.1 represents hydrogen and two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 together represent the second bond of a double bond joining positions 7 and 8, 8 and 9 or 9 and 10 with the remaining two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 representing hydrogen, but with the proviso that when each of R.sub.1 to R.sub.5 is hydrogen X is not >O, the compound optionally being in the form of a salt thereof formed with a physiologically acceptable inorganic or organic acid.

### Claim 2 (depends on 1)

A compound according to claim 1, in which X is >NR wherein R is methyl or phenyl.

### Claim 3 (depends on 1)

A compound according to claim 1, in which X is >O.

### Claim 4 (depends on 1)

A compound according to claim 1, in which R.sub.1, R.sub.4 and R.sub.5 are each hydrogen and R.sub.2 and R.sub.3 are the second bond of a double bond joining positions 9 and 10.

### Claim 5 (depends on 1)

A compound according to claim 1, in which R.sub.1 and R.sub.2 are an oxo group and R.sub.3, R.sub.4 and R.sub.5 are each hydrogen.

### Claim 6 (depends on 1)

A compound according to claim 1 being ›cis-1,2,3,4,5,6a,7,8,9,10,10a,10b-dodecahydro-1,4-oxazino›3',4':2,3!benzo -›d!isoxazol-4-one! cis-1,3,4,6a,7,8,9,10,10a,10b-decahydro-1,4-oxazino-›4,3-b!benz›d!isoxazol -10-one or a salt thereof.

### Claim 7 (depends on 1)

A compound according to claim 1 being ›cis-1,2,3,4,5,6a,7,8,10a,10b-decahydro-1,4-oxazino›3',4':2,3!benzo›d!isox azole! cis-1,3,4,6a,7,8,10a,10b-octahydro-1,4-oxazino›4,3-b!benz›d!isoxazol or a salt thereof.

### Claim 8 (depends on 1)

A compound according to claim 1, in which the hydrogen atom at the 10b position is in the cis configuration relative to the hydrogen atoms at positions 6a and 10a.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 together with a pharmaceutically acceptable diluent or carrier.

### Claim 10 (depends on 1)

A pharmaceutical composition for treating anxiety or effecting improvement of learning ability and/or the reversal of amnesia comprising a compound of formula (I) as defined in claim 1.

### Claim 11

A method for treating a patient suffering from a condition requiring an improvement in learning ability or the alleviation of anxiety which comprises administering to said patient a therapeutically effective mount of a compound of a formula (I) ##STR7## in which X represents a group >O, >S, >C.dbd.O or >NR wherein R is hydrogen, C.sub.1-6 alkyl, phenyl or C.sub.7-12 phenalkyl, R.sub.1 and R.sub.2 each represent hydrogen or together represent an oxo group and R.sub.3, R.sub.4 and R.sub.5 each represent hydrogen or R.sub.1 represents hydrogen and two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 together represent the second bond of a double bond joining positions 7 and 8, 8 and 9 or 9 and 10 with the remaining two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 representing hydrogen, the compound optionally being in the form of a salt thereof formed with a physiologically acceptable inorganic or organic acid.

### Claim 12

A method for treating a patient suffering from anxiety which comprises administering to said patient a therapeutically effective amount of a compound of formula I. ##STR8## in which X represents a group >O, >S, >C.dbd.O or >NR wherein R is hydrogen, C.sub.1-6 alkyl, phenyl or C.sub.7-12 phenalkyl, R.sub.1 and R.sub.2 each represent hydrogen or together represent an oxo group and R.sub.3, R.sub.4 and R.sub.5 each represent hydrogen or R.sub.1 represents hydrogen and two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 together represent the second bond of a double bond joining positions 7 and 8, 8 and 9 or 9 and 10 with the remaining two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 representing hydrogen, the compound optionally being in the form of a salt thereof formed with a physiologically acceptable inorganic or organic acid.

### Claim 13

A method for the treatment of a patient requiring improvement of learning ability and/or the reversal of amnesia which comprises the step administering to said patient a therapeutically effective amount of a compound of formula (I) ##STR9## in which X represents a group >O, >S, >C.dbd.O or >NR wherein R is hydrogen, C.sub.1-6 alkyl, phenyl or C.sub.7-12 phenalkyl, R.sub.1 and R.sub.2 each represent hydrogen or together represent an oxo group and R.sub.3, R.sub.4 and R.sub.5 each represent hydrogen or R.sub.1 represents hydrogen and two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 together represent the second bond of a double bond joining positions 7 and 8, 8 and 9 or 9 and 10 with the remaining two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 representing hydrogen, the compound optionally being in the form of a salt thereof formed with a physiologically acceptable inorganic or organic acid.

### Claim 14

A method of preparing an anxiolytic agent or an agent for effecting improvements in learning behavior, which comprises the steps of:
reacting a compound of formula (II): ##STR10## in which R.sub.1 and R.sub.2 each represent hydrogen or together represent an oxo group and R.sub.3, R.sub.4 and R.sub.5 each represent hydrogen or R.sub.1 represents hydrogen and two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 together represent the second bond of a double bond joining positions 7 and 8, 8 and 9 or 9 and 10 with the remaining two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 representing hydrogen, with a compound of formula (III): ##STR11## wherein X represents a group >O, >S, >C.dbd.O or >NR wherein R is hydrogen, C.sub.1-6 alkyl, phenyl or C.sub.7-12 phenalkyl, with the proviso that when each of R.sub.1 to R.sub.5 is hydrogen, X is not O.

### Claim 15

A method of preparing an anxiolytic agent, which comprises the steps of:
reacting a compound of formula (II): ##STR12## in which R.sub.1 and R.sub.2 each represent hydrogen or together represent an oxo group and R.sub.3, R.sub.4 and R.sub.5 each represent hydrogen or R.sub.1 represents hydrogen and two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 together represent the second bond of a double bond joining positions 7 and 8, 8 and 9 or 9 and 10 with the remaining two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 representing -hydrogen, with a compound of formula (III): ##STR13## wherein X represents a group >O, >S, >C.dbd.O or >NR wherein R is hydrogen, C.sub.1-6 alkyl, phenyl or C.sub.7-12 phenalkyl, with the proviso that when each of R.sub.1 to R.sub.5 is hydrogen, X is not O.

### Claim 16

A method of preparing an agent for effecting improvements in learning behavior, which comprises the steps of:
reacting a compound of formula (II): ##STR14## in which R.sub.1 and R.sub.2 each represent hydrogen or together represent an oxo group and R.sub.3, R.sub.4 and R.sub.5 each represent hydrogen or R.sub.1 represents hydrogen and two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 together represent the second bond of a double bond joining positions 7 and 8, 8 and 9 or 9 and 10 with the remaining two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 representing hydrogen, with a compound of formula (III): ##STR15## wherein X represents a group >O, >S, >C.dbd.O or >NR wherein R is hydrogen, C.sub.1-6 alkyl, phenyl or C.sub.7-12 phenalkyl, with the proviso that when each of R.sub.1 to R.sub.5 is hydrogen, X is not O.

### Claim 17 (depends on 14, 20)

A method according to claim 14, wherein the compound of formula (III) is formed in situ from a compound of formula (IIIa): ##STR16## wherein X is as defined in claim 20, and converting the compound of formula (IIIa) to the compound of formula (III) by a tungstate catalyzed oxidation.