SEROTONERGIC 5HT7 RECEPTOR COMPOUNDS FOR TREATING OCULAR AND CNS DISORDERS

COMPOSES A AFFINITE POUR LE RECEPTEUR DE 5HT7 SEROTONINERGIQUE, DESTINES AU TRAITEMENT DE TROUBLES OCULAIRES ET DU SYSTEME NERVEUX CENTRAL

English Abstract

Compounds with 5HT7 receptor affinity (some of which are novel) useful for
lowering IOP, improving blood flow to the optic nerve head and the retina,
providing neuroprotection, and treating retinal diseases are disclosed. The
Compounds are also useful for treating sleep disorders, depression, and other
psychiatric disorders, such as, schizophrenia, anxiety, obsessive compulsive
disorder, circadian rhythm disorders, and centrally and peripherally mediated
hypertension. Compositions and methods for their use are also disclosed.

French Abstract

L'invention concerne des composés possédant une affinité à l'égard du récepteur de 5HT¿7? (dont certains sont nouveaux), utiles pour abaisser la tension intra-oculaire, pour améliorer l'écoulement sanguin vers la tête du nerf optique et la rétine, pour apporter une protection neurologique et traiter des maladies de la rétine. Ces composés sont également utiles pour traiter les troubles du sommeil, la dépression ainsi que d'autres troubles psychiatriques tels que la schizophrénie, l'anxiété, les troubles obsessifs impulsifs, les troubles du rythme circadien, ainsi que l'hypertension d'origine centrale ou périphérique. L'invention concerne encore des compositions et des procédés destinés à l'emploi de ces composés.

Claims

We Claim:

1. A compound of the formula:
Image

Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, OH, OC1-3alkyl, C1-3alkyl, C1-3alkyl substituted optionally with OH,
or OC1-3alkyl;
R2 is H, halogen, C1-3alkyl, CONR5R6, S(=O)mC1-3alkyl, S(=O)2 NR5R6, C1-3alkyl
substituted
optionally with OH, or OC1-3alkyl;
R3, R4 are independently H, C1-3alkyl, C1-3alkyl substituted optionally with
OH or OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl, or
R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
m is 0,1 or 2
and any pharmaceutically acceptable salts and solvates.
-25-



2. A compound of the formula:
Image

Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, C1-5alkyl, C3-5alkenyl, an aromatic ring such as phenyl, thienyl,
pyridyl, and
imidazoyl which is either unsubstituted or substituted optionally with OH,
OC1-3alkyl, S(=O)mC1-3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2-5alkyl
substituted optionally with OH, OC1-3alkyl, S(=O)mC1-3alkyl or an aromatic
ring
such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted
or
substituted optionally with OH, OC1-3alkyl, S(=O)mC1-3alkyl, halogen, CF3,
S(=O)2
NR5R6; or C3-5alkenyl substituted optionally with OH, OC1-3alkyl,
or S(=O)mC1- 3alkyl;
R2 is H, halogen, C1-3alkyl, S(=O)mC1-3alkyl, S(=O)2 NR5R6, or C1-3alkyl
substituted
optionally with OH, or OC1-3alkyl;
R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl,
or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or
6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
-26-



optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
m is 0,1 or 2
and any pharmaceutically acceptable salts and solvates.
3. A compound of the formula:
Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or
substituted
with C1-4alkyl, halogen, OC1-4alkyl;
R10 is C1-4alkyl, or R10 can be joined to R9 to form a fused bicyclic ring
system such as
indoline;
n is 2 to 4
and any pharmaceutically acceptable salts and solvates.
-27-



4. A Compound of the formula:
Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1 -3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
R11 is C1-3alkyl, phenyl or a monocyclic heteroaromatic ring which can be
unsubstituted or
substituted with C1-4alkyl, halogen, OC1-4alkyl;
R12 is C1-4alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-
1,2-thiazine, or
1,2-benzothiazine, or R12 can be joined to R11 to form a fused bicyclic ring
system
such as 2,3-dihydro-benzo[c]isoxazole;
n is 2 to 4
and any pharmaceutically acceptable salts and solvates.
-28-



5. A method for lowering IOP which comprises administering to a person in need
thereof, a composition comprising an effective amount of a compound of the
formula:
Image

Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, OH, OC1-3alkyl, C1-3alkyl, C1-3alkyl substituted optionally with OH,
or OC1-3alkyl;
R2 is H, halogen, C1-3alkyl, CONR5R6, S(=O)mC1-3alkyl, S(=O)2 NR5R6 , C1-
3alkyl substituted
optionally with OH, or OC1-3alkyl;
R3, R4 are independently H, C1-3alkyl, C1-3alkyl substituted optionally with
OH or OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl, or
R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
m is 0, 1 or 2
and any pharmaceutically acceptable salts and solvates.
-29-



6. A method for lowering IOP which comprises administering to a person in need
thereof, a composition comprising an effective amount of a compound of the
formula:
Image

Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, C1-5alkyl, C3-5alkenyl, an aromatic ring such as phenyl, thienyl,
pyridyl, and
imidazoyl which is either unsubstituted or substituted optionally with OH,
OC1-3alkyl, S(=O)mC1-3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2-5alkyl
substituted optionally with OH, OC1-3alkyl, S(=O)mC1-3alkyl or an aromatic
ring
such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted
or
substituted optionally with OH, OC1-3alkyl, S(=O)mC1-3alkyl, halogen, CF3,
S(=O)2
NR5R6; or C3-5alkenyl substituted optionally with OH, OC1-3alkyl, or
S(=O)mC1-3alkyl;
R2 is H, halogen, C1-3alkyl, S(=O)mC1-3alkyl, S(=O)2 NR5R6, or C1-3alkyl
substituted
optionally with OH, or OC1-3alkyl;
R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl,
or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or
6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
-30-


more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
m is 0, 1 or 2
and any pharmaceutically acceptable salts and solvates.
7. A method for lowering IOP which comprises administering to a person in need
thereof, a composition comprising an effective amount of a compound of the
formula:
Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or
substituted
with C1-4alkyl, halogen, OC1-4alkyl;
R10 is C1-4alkyl, or R10 can be joined to R9 to form a fused bicyclic ring
system such as
indoline;
n is 2 to 4
-31-



and any pharmaceutically acceptable salts and solvates.
8. A method for lowering IOP which comprises administering to a person in need
thereof, a composition comprising an effective amount of a compound of the
formula:
Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
R11 is C1-3alkyl, phenyl or a monocyclic heteroaromatic ring which can be
unsubstituted or
substituted with C1-4alkyl, halogen, OC1-4alkyl;
R12 is C1-4alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-
1,2-thiazine, or
1,2-benzothiazine, or R12 can be joined to R11 to form a fused bicyclic ring
system
such as 2,3-dihydro-benzo[c]isoxazole;
n is 2 to 4
and any pharmaceutically acceptable salts and solvates.
-32-



9. A method for improving blood flow to the optic nerve head and the retina
which
comprises administering to a person in need thereof, a composition comprising
an effective
amount of a compound of the formula:
Image

Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, OH, OC1-3alkyl, C1-3alkyl, C1-3alkyl substituted optionally with OH,
or OC1-3alkyl;
R2 is H, halogen, C1-3alkyl, CONR5R6, S(=O)m C1-3alkyl, S(=O)2 NR5R6, C1-
3alkyl substituted
optionally with OH, or OC1-3alkyl;
R3, R4 are independently H, C1-3alkyl, C1-3alkyl substituted optionally with
OH or OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl, or
R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
m is 0, 1 or 2
and any pharmaceutically acceptable salts and solvates.
-33-



10. A method for improving blood flow to the optic nerve head and the retina
which
comprises administering to a person in need thereof, a composition comprising
an effective
amount of a compound of the formula:
Image

Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, C1-5alkyl, C3-5alkenyl, an aromatic ring such as phenyl, thienyl,
pyridyl, and
imidazoyl which is either unsubstituted or substituted optionally with OH,
OC1-3alkyl, S(=O)mC1-3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2-5alkyl
substituted optionally with OH, OC1-3alkyl, S(=O)mC1-3alkyl or an aromatic
ring
such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted
or
substituted optionally with OH, OC1-3alkyl, S(=O)mC1-3alkyl, halogen, CF3,
S(=O)2
NR5R6; or C3-5alkenyl substituted optionally with OH, OC1-3alkyl, or S(=O)mC1-
3alkyl
R2 is H, halogen, C1-3alkyl, S(=O)mC1-3alkyl, S(=O)2 NR5R6, or C1-3alkyl
substituted
optionally with OH, or OC1-3alkyl;
R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl,
or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or
6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
-34-



or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
m is 0, 1 or 2
and any pharmaceutically acceptable salts and solvates.
11. A method for improving blood flow to the optic nerve head and the retina
which
comprises administering to a person in need thereof, a composition comprising
an effective
amount of a compound of the formula:
Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
-35-



R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or
substituted
with C1-4alkyl, halogen, OC1-4alkyl;
R10 is C1-4alkyl, or R10 can be joined to R9 to form a fused bicyclic ring
system such as
indoline;
n is 2 to 4
and any pharmaceutically acceptable salts and solvates.
12. A method for improving blood flow to the optic nerve head and the retina
which
comprises administering to a person in need thereof, a composition comprising
an effective
amount of a compound of the formula:
Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
R11 is C1-3alkyl, phenyl or a monocyclic heteroaromatic ring which can be
unsubstituted or
substituted with C1-4alkyl, halogen, OC1-4alkyl;
R12 is C1-4alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-
1,2-thiazine, or
1,2-benzothiazine, or R12 can be joined to R11 to form a fused bicyclic ring
system
such as 2,3-dihydro-benzo[c]isoxazole;
-36-



n is 2 to 4
and any pharmaceutically acceptable salts and solvates.
13. A method for treating retinal diseases which comprises administering to a
person
in need thereof, a composition comprising an effective amount of a compound of
the formula:
Image

Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, OH, OC1-3alkyl, C1-3alkyl, C1-3alkyl substituted optionally with OH,
or OC1-3alkyl;
R2 is H, halogen, C1-3alkyl, CONR5R6, S(=O)mC1-3alkyl, S(=O)2 NR5R6 , C1-
3alkyl substituted
optionally with OH, or OC1-3alkyl;
R3, R4 are independently H, C1-3alkyl, C1-3alkyl substituted optionally with
OH or OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl, or
R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
-37-



m is 0, 1 or 2
and any pharmaceutically acceptable salts and solvates.
14. A method for treating retinal diseases which comprises administering to a
person
in need thereof, a composition comprising an effective amount of a compound of
the formula:
Image

Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, C1-5alkyl, C3-5alkenyl, an aromatic ring such as phenyl, thienyl,
pyridyl, and
imidazoyl which is either unsubstituted or substituted optionally with OH,
OC1-3alkyl, S(=O)mC1-3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2-5alkyl
substituted optionally with OH, OC1-3alkyl, S(=O)mC1-3alkyl or an aromatic
ring
such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted
or
substituted optionally with OH, OC1-3alkyl, S(=O)mC1-3alkyl, halogen, CF3,
S(=O)2
NR5R6; or C3-5alkenyl substituted optionally with OH, OC1-3alkyl, or S(=O)mC1-
3alkyl
R2 is H, halogen, C1-3alkyl, S(=O)mC1-3alkyl, S(=O)2 NR5R6, or C1-3alkyl
substituted
optionally with OH, or OC1-3alkyl;
R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl,
or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or
6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;
R7,R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
-38-



from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
m is 0,1or2
and any pharmaceutically acceptable salts and solvates.
15. A method for treating retinal diseases which comprises administering to a
person
in need thereof, a composition comprising an effective amount of a compound of
the formula:

Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or
substituted
with C1-4alkyl, halogen, OC1-4alkyl;
-39-



R10 is C1-4alkyl, or R10 can be joined to R9 to form a fused bicyclic ring
system such as
indoline;
n is 2 to 4
and any pharmaceutically acceptable salts and solvates.
16. A method for treating retinal diseases which comprises administering to a
person
in need thereof, a composition comprising an effective amount of a compound of
the formula:
Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N,O,S, such as pyrrolidine, piperidine, .DELTA.3-piperidein, piperazine,
morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
R11 is C1-3alkyl, phenyl or a monocyclic heteroaromatic ring which can be
unsubstituted or
substituted with C1-4alkyl, halogen, OC1-4alkyl;
R12 is C1-4alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-
1,2-thiazine, or
1,2-benzothiazine, or R12 can be joined to R11 to form a fused bicyclic ring
system
such as 2,3-dihydro-benzo[c]isoxazole;
n is 2 to 4
and any pharmaceutically acceptable salts and solvates.
-40-



17. A composition for lowering IOP comprising a pharmaceutically effective
amount
of a compound of the formula:
Image
Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, OH, OC1-3alkyl, C1-3alkyl, C1-3alkyl substituted optionally with OH,
or OC1-3alkyl;
R2 is H, halogen, C1-3alkyl, CONR5R6, S(=O)mC1-3alkyl, S(=O)2 NR5R6 , C1-
3alkyl substituted
optionally with OH, or OC1-3alkyl;
R3, R4 are independently H, C1-3alkyl, C1-3alkyl substituted optionally with
OH or OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl, or
R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
m is 0,1 or 2
and any pharmaceutically acceptable salts and solvates.
-41-



18. A composition for lowering IOP comprising a pharmaceutically effective
amount
of a compound of the formula:
Image

Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, C1-5alkyl, C3-5alkenyl, an aromatic ring such as phenyl, thienyl,
pyridyl, and
imidazoyl which is either unsubstituted or substituted optionally with OH,
OC1-3alkyl, S(=O)mC1-3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2-5alkyl
substituted optionally with OH, OC1-3alkyl, S(=O)mC1-3alkyl or an aromatic
ring
such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted
or
substituted optionally with OH, OC1-3alkyl, S(=O)mC1-3alkyl, halogen, CF3,
S(=O)2
NR5R6; or C3-5alkenyl substituted optionally with OH, OC1-3alkyl,
or S(=O)mC1-3alkyl;
R2 is H, halogen, C1-3alkyl, S(=O)mC1-3alkyl, S(=O)2 NR5R6, or C1-3alkyl
substituted
optionally with OH, or OC1-3alkyl;
R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1 -3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl,
or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or
6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
-42-



more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
m is 0, 1 or 2
and any pharmaceutically acceptable salts and solvates.
19. A composition for lowering IOP comprising a pharmaceutically effective
amount
of a compound of the formula:
Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or
substituted
with C1-4 alkyl, halogen, OC1-4alkyl;
R10 is C1-4alkyl, or R10 can be joined to R9 to form a fused bicyclic ring
system such as
indoline;
-43-



n is 2 to 4
and any pharmaceutically acceptable salts and solvates.
20. A composition for lowering IOP comprising a pharmaceutically effective
amount
of a compound of the formula:
Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
R11 is C1-3alkyl, phenyl or a monocyclic heteroaromatic ring which can be
unsubstituted or
substituted with C1-4alkyl, halogen, OC1-4alkyl;
R12 is C1-4alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-
1,2-thiazine, or
1,2-benzothiazine, or R12 can be joined to R11 to form a fused bicyclic ring
system
such as 2,3-dihydro-benzo[c]isoxazole;
n is 2 to 4
and any pharmaceutically acceptable salts and solvates.
21. A composition for improving blood flow to the optic nerve head and the
retina
comprising a pharmaceutically effective amount of a compound of the formula:
-44-


Image

Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, OH, OC1-3alkyl, C1-3alkyl, C1-3alkyl substituted optionally with OH,
or OC1-3alkyl;
R2 is H, halogen, C1-3alkyl, CONR5R6, S(=O)mC1-3alkyl, S(=O)2 NR5R6 , C1-
3alkyl substituted
optionally with OH, or OC1-3alkyl;
R3, R4 are independently H, C1-3alkyl, C1-3alkyl substituted optionally with
OH or OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl, or
R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
m is 0,1 or2
and any pharmaceutically acceptable salts and solvates.
22. A composition for improving blood flow to the optic nerve head and the
retina
comprising a pharmaceutically effective amount of a compound of the formula:
-45-




Image

Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, C1-5alkyl, C3-5alkenyl, an aromatic ring such as phenyl, thienyl,
pyridyl, and
imidazoyl which is either unsubstituted or substituted optionally with OH,
OC1-3alkyl, S(=O)mC1-3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2-5alkyl
substituted optionally with OH, OC1-3alkyl, S(=O)mC1-3alkyl or an aromatic
ring
such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted
or
substituted optionally with OH, OC1-3alkyl, S(=O)mC1-3alkyl, halogen, CF3,
S(=O)2
NR5R6; or C3-5alkenyl substituted optionally with OH, OC1-3alkyl, or
S(=O)mC1-3alkyl;
R2 is H, halogen, C1-3alkyl, S(=O)mC1-3alkyl, S(=O)2 NR5R6, or C1-3alkyl
substituted
optionally with OH, or OC1-3alkyl;
R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl,
or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or
6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
-46-



with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
m is 0, 1 or 2
and any pharmaceutically acceptable salts and solvates.
23. A composition for improving blood flow to the optic nerve head and the
retina
comprising a pharmaceutically effective amount of a compound of the formula:
Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or
substituted
with C1-4alkyl, halogen, OC1-4alkyl;
R10 is C1-4alkyl, or R10 can be joined to R9 to form a fused bicyclic ring
system such as
indoline;
n is 2 to 4
and any pharmaceutically acceptable salts and solvates.
-47-



24. A composition for improving blood flow to the optic nerve head and the
retina
comprising a pharmaceutically effective amount of a Compound of the formula:
Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
R11 is C1-3alkyl, phenyl or a monocyclic heteroaromatic ring which can be
unsubstituted or
substituted with C1-4alkyl, halogen, OC1-4alkyl;
R12 is C1-4alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-
1,2-thiazine, or
1,2-benzothiazine, or R12 can be joined to R11 to form a fused bicyclic ring
system
such as 2,3-dihydro-benzo[c]isoxazole;
n is 2 to 4
and any pharmaceutically acceptable salts and solvates.
25. A composition for treating retinal diseases comprising a pharmaceutically
effective amount of a compound of the formula:
-48-



Image

Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, OH, OC1-3alkyl, C1-3alkyl, C1-3alkyl substituted optionally with OH,
or OC1-3alkyl;
R2 is H, halogen, C1-3alkyl, CONR5R6, S(=O)mC1-3alkyl, S(=O)2 NR5R6, C1-3alkyl
substituted
optionally with OH, or OC1-3alkyl;
R3, R4 are independently H, C1-3alkyl, C1-3alkyl substituted optionally with
OH or OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl, or
R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
m is 0,1 or2
and any pharmaceutically acceptable salts and solvates.
26. A composition for treating retinal diseases comprising a pharmaceutically
effective amount of a compound of the formula:
-49-



Image

Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, C1-5alkyl, C3-5alkenyl, an aromatic ring such as phenyl, thienyl,
pyridyl, and
imidazoyl which is either unsubstituted or substituted optionally with OH,
OC1-3alkyl, S(=O)mC1-3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2-5alkyl
substituted optionally with OH, OC1-3alkyl, S(=O)mC1-3alkyl or an aromatic
ring
such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted
or
substituted optionally with OH, OC1-3alkyl, S(=O)mC1-3alkyl, halogen, CF3,
S(=O)2
NR5R6; or C3-5alkenyl substituted optionally with OH, OC1-3alkyl,
or S(=O)mC1-3alkyl;
R2 is H, halogen, C1-3alkyl, S(=O)mC1-3alkyl, S(=O)2 NR5R6, or C1-3alkyl
substituted
optionally with OH, or OC1-3alkyl;
R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl,
or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or
6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
-50-



with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
m is 0,1 or 2
and any pharmaceutically acceptable salts and solvates.
27. A composition for treating retinal diseases comprising a pharmaceutically
effective amount of a compound of the formula:
Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or
substituted
with C1-4 alkyl, halogen, OC1-4alkyl;
R10 is C1-4alkyl, or R10 can be joined to R9 to form a fused bicyclic ring
system such as
indoline;
n is 2 to 4
and any pharmaceutically acceptable salts and solvates.
-51-



28. A composition for treating retinal diseases comprising a pharmaceutically
effect amount of a compound of the formula:
Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
R11 is C1-3alkyl, phenyl or a monocyclic heteroaromatic ring which can be
unsubstituted or
substituted with C1-4alkyl, halogen, OC1-4alkyl;
R12 is C1-4alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-
1,2-thiazine, or
1,2-benzothiazine, or R12 can be joined to R11 to form a fused bicyclic ring
system
such as 2,3-dihydro-benzo[c]isoxazole;
n is 2 to 4
and any pharmaceutically acceptable salts and solvates.
29. A method for improving blood flow to the optic nerve head or the retina
which
comprises administering to a person in need thereof, a composition comprising
a
pharmaceutically effective amount of a compound with 5HT7 receptor affinity.
-52-



30. A composition for improving blood flow to the optic nerve head or the
retina
comprising a pharmaceutically effective amount of a compound with 5HT7
receptor affinity.
31. A method for providing neuroprotection to the optic nerve head or the
retina
which comprises administering to a person in need thereof, a composition
comprising a
pharmaceutically effective amount of a compound with 5HT7 receptor affinity.
32. A composition for providing neuroprotection to the optic nerve head or the
retina
comprising a pharmaceutically effective amount of a compound with 5HT7
receptor affinity.
33. A method for treating retinal diseases which comprises administering to a
person
in need thereof, a composition comprising a pharmaceutically effective amount
of a
compound with 5HT7 receptor affinity.
34. The method of Claim 1 wherein the retinal disease is selected from the
group
consisting of glaucoma, age related macular degeneration, optic neuritis,
ischemic disorders,
and retinal edema.
35. A composition for treating retinal diseases comprising a pharmaceutically
effective amount of a compound with 5HT7 receptor affinity.
36. The composition of Claim 35 wherein the retinal diseases are selected from
the
group consisting of glaucoma, age related macular degeneration, optic
neuritis, ischemic
disorders, diabetic retinopathy, and retinal edema.
37. A method for lowering IOP which comprises administering to a person in
need
thereof, a composition comprising a pharmaceutically effective amount of a
compound with
5HT7 receptor affinity.
38. A composition for lowering IOP comprising a pharmaceutically effective
amount
of a compound with 5HT7 receptor affinity.
-53-



39. A method for treating persons suffering from a sleeping disorder,
depression,
schizophrenia, anxiety, circadian rhythm disorders, and centrally and
peripherally mediated
hypertension, which comprises, administering a composition comprising a
pharmaceutically
effective amount of a compound of the formula:
Image

Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, OH, OC1-3alkyl, C1-3alkyl, C1-3alkyl substituted optionally with OH,
or OC1-3alkyl;
R2 is H, halogen, C1-3alkyl, CONR5R6, S(=O)mC1-3alkyl, S(=O)2 NR5R6 , C1-
3alkyl substituted
optionally with OH, or OC1-3alkyl;
R3, R4 are independently H, C1-3alkyl, C1-3alkyl substituted optionally with
OH or OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl, or
R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
m is 0,1 or 2
-54-





and any pharmaceutically acceptable salts and solvates.
40. A method for treating persons suffering from a sleeping disorder,
depression,
schizophrenia, anxiety, obsessive compulsive disorder, circadian rhythem
disorders, and
centrally and peripherally mediated hypertension which comprises,
administering a
composition comprising a pharmaceutically effective amount of a compound of
the formula:

Image

Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, C1-5alkyl, C3-5alkenyl, an aromatic ring such as phenyl, thienyl,
pyridyl, and
imidazoyl which is either unsubstituted or substituted optionally with OH,
OC1-3alkyl, S(=O)m C1-3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2-5alkyl
substituted optionally with OH, OC1-3alkyl, S(=O)m C1-3alkyl or an aromatic
ring
such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted
or
substituted optionally with OH, OC1-3alkyl, S(=O)m C1-3alkyl, halogen, CF3,
S(=O)2
NR5R6; or C3-5alkenyl substituted optionally with OH, OC1-3alkyl, or S(=O)m C1-
3alkyl;
R2 is H, halogen, C1-3alkyl, S(=O)m C1-3alkyl, S(=O)2 NR5R6, or C1-3alkyl
substituted
optionally with OH, or OC1-3alkyl;
R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl,
or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or
6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;



-55-




R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
m is 0, 1 or 2
and any pharmaceutically acceptable salts and solvates.
41. A method for treating persons suffering from a sleeping disorder,
depression,
schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm
disorders, and
centrally and peripherally mediated hypertension which comprises,
administering a
composition comprising a pharmaceutically effective amount of a compound of
the formula:

Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen



-56-



with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or
substituted
with C1-4 alkyl, halogen, OC1-4alkyl;
R10 is C1-4alkyl, or R10 can be joined to R9 to form a fused bicyclic ring
system such as
indoline;
n is 2 to 4
and any pharmaceutically acceptable salts and solvates.
42. A method for treating persons suffering from a sleeping disorder,
depression,
schizophrenia, anxiety, obsessive compulsive disorder, circadian rhythm
disorders, and
centrally and peripherally mediated hypertension which comprises,
administering a
composition comprising a pharmaceutically effective amount of a compound of
the formula:

Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;



-57-




R11 is C1-3alkyl, phenyl or a monocyclic heteroaromatic ring which can be
unsubstituted or
substituted with C1-4alkyl, halogen, OC1-4alkyl;
R12 is C1-4alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-a]-
1,2-thiazine, or
1,2-benzothiazine, or R12 can be joined to R11 to form a fused bicyclic ring
system
such as 2,3-dihydro-benzo[c]isoxazole;
n is 2 to 4
and any pharmaceutically acceptable salts and solvates.
43. A composition comprising a pharmaceutically effective amount of a compound
of the formula:

Image

Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, OH, OC1-3alkyl, C1-3alkyl, C1-3alkyl substituted optionally with OH,
or OC1-3alkyl;
R2 is H, halogen, C1-3alkyl, CONR5R6, S(=O)m C1-3alkyl, S(=O)2 NR5R6, C1-
3alkyl substituted
optionally with OH, or OC1-3alkyl;
R3, R4 are independently H, C1-3alkyl, C1-3alkyl substituted optionally with
OH or OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl, or
R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted



-58-




optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
m is 0, 1 or 2
and any pharmaceutically acceptable salts and solvates in a pharmaceutically
acceptable
career.
44. A composition comprising a pharmaceutically effective amount of a compound
of the formula:

Image

Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, C1-5alkyl, C3-5alkenyl, an aromatic ring such as phenyl, thienyl,
pyridyl, and
imidazoyl which is either unsubstituted or substituted optionally with OH,
OC1-3alkyl, S(=O)m C1-3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2-5alkyl
substituted optionally with OH, OC1-3alkyl, S(=O)m C1-3alkyl or an aromatic
ring
such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted
or
substituted optionally with OH, OC1-3alkyl, S(=O)m C1-3alkyl, halogen, CF3,
S(=O)2
NR5R6; or C3-5alkenyl substituted optionally with OH, OC1-3alkyl, or S(=O)m C1-
3alkyl;
R2 is H, halogen, C1-3alkyl, S(=O)m C1-3alkyl, S(=O)2 NR5R6, or C1-3alkyl
substituted
optionally with OH, or OC1-3alkyl;
R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with
OH, OC1-3alkyl,
or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or
6



-59-




membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-
3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
n is 2 to 4;
m is 0, 1 or 2
and any pharmaceutically acceptable salts and solvates in a pharmaceutically
acceptable
carrier.
45. A composition comprising a pharmaceutically effective amount of a compound
of the formula:

Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen



-60-




with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or
substituted
with C1-4 alkyl, halogen, OC1-4alkyl;
R10 is C1-4alkyl, or R10 can be joined to R9 to form a fused bicyclic ring
system such as
indoline;
n is 2 to 4
and any pharmaceutically acceptable salts and solvates in a pharmaceutically
acceptable
carrier.
46. A composition comprising a pharmaceutically effective amount of a compound
of the formula:

Image

R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally
with OH or
OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, .DELTA.3-piperidein,
piperazine, morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted
optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on
nitrogen
with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC1-3alkyl, or C1-3alkyl;
R11 is C1-3alkyl, phenyl or a monocyclic heteroaromatic ring which can be
unsubstituted or
substituted with C1-4alkyl, halogen, OC1-4alkyl;



-61-




R12 is C1-4alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-
1,2-thiazine, or
1,2-benzothiazine, or R12 can be joined to R11 to form a fused bicyclic ring
system
such as 2,3-dihydro-benzo[c]isoxazole;
n is 2 to 4
and any pharmaceutically acceptable salts and solvates in a pharmaceutically
acceptable
carrier.
47. The Compound of Claim 1 selected from the group consisting of:
6-Chloro-2-[4-[4-(2H benzimidazo-2-oxo-1-yl)piperidin-1-yl]butyl]-2H-
thieno[3,2-e]-1,2-thiazine
1,1-dioxide;
6-Chloro-2-[4-(4-phenylpiperazin-1-yl)butyl]-2H-thieno[3,2-e]-1,2-thiazine 1,1-
dioxide;
6-Chloro-2-[4-[4-(2-fluorophenyl)piperazin-1-yl]butyl]-2H-thieno[3,2-e]-1,2-
thiazine
1,1-dioxide;
6-Chloro-2-[3-[4-(3-trifluoromethylphenyl)piperazin-1-yl]propyl]-2H-thieno[3,2-
e]-1,2-thiazine
1,1-dioxide;
6-Chloro-2-[3-[4-(2H-benzimidazol-2-oxo)piperidin-1-yl]propyl]-2H-thieno[3,2-
e]-1,2-thiazine
1,1-dioxide.
48. The Compound of Claim 3 selected from the group consisting of:
3-[4-(3-Chlorophenyl)piperazin-1-yl]propylsulfonyl-2,3-dihydro-1H-indole;
3-(1,2,3,4-Tetrahydroisoquinolin-2-yl)propylsulfonyl-2,3-dihydro-1H-indole;
3-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]propylsulfonyl-2,3-dihydro-1H-
indole;
3-[4-(2-Methoxyphenyl)piperazin-1-yl]propylsulfonyl-2,3-dihydro-1H-indole;
3-(1,2,3,4-Tetrahydroisoquinolin-2-yl)-N methyl-N-phenyl-propylsulfonamide;
49. The Compound of Claim 4 selected from the group consisting of:
N-[3-[4-(3-Chlorophenyl)piperazin-1-yl]propyl]-N-(4-methoxyphenyl)-
propanesulfonamide;
N-(3-(1,2,3,4-Tetrahydroisoquinolin-2-yl)propyl]-N-(4-methoxyphenyl)-
propanesulfonamide;
N-[3-[4-(3-Chlorophenyl)piperazin-1-yl]propyl]-N-(4-methoxyphenyl)-
propanesulfonamide;
N-[3-[4-(2-Methoxyphenyl)piperazin-1-yl]propyl]-N-(4-methoxyphenyl)-
propanesulfonamide;
N-[3-[4-(2-Chlorophenyl)piperazin-1-yl]propyl]-N-(4-methoxyphenyl)-
propanesulfonamide.



-62-

Description

CA 02332505 2000-11-17
WO 99/59499 PCT/US99/10179
SEROTONERGIC SHT~ RECEPTOR COMPOUNDS
FOR TREATING OCULAR AND CNS DISORDERS
s The present invention is directed to the use of compounds with serotonergic
SHT~
receptor affinity (Compound) (some of which are novel), to improve blood flow
to the optic
nerve head and the retina, provide neuroprotection, lower intraocular pressure
(IOP), and treat
retinal diseases, such as, glaucoma, age related macular degeneration (ARMD),
optic neuritis,
ischemic disorders, diabetic retinopathy, and retinal edema. The Compounds are
also useful
io for treating sleep disorders, depression, and other psychiatric disorders,
such as,
schizophrenia, anxiety, obsessive compulsive disorder, circadian rhythm
disorders, and
centrally and peripherally mediated hypertension.
is
Backeround of the Invention
Serotonin (5-hydroxy tryptamine; SHT) is an endogenous biogenic amine with a
well
defined neurotransmitter function in many tissues of the body including the
eye [Zifa and
Fillion, Pharmacol. Rev., 44:401-458, 1992; Hoyer et al., Pharmacol. Rev.,
46:157-203,
1994; Tobin et al., J. Neurosci., 8:3713-3721, 1988].
SHT can interact with at least seven major SHT receptors (SHT1 - SHT~) and
additional subtypes within these families to initiate intracellular
biochemical events such as
stimulation of second messengers (e.g. cAMP, inositol trisphosphate)
eventually leading to
the final biological response, for example, tissue contraction or hormone
release, etc. [Hoyer
2s et al., supra; Martin et al., Trends Pharmacol. Sci., 19:2-4, 1998].
Receptor subtypes within
the SHTi family are negatively coupled to adenylyl cyciase (AC) and cause
inhibition of
cAMP production, while SHT4, SHT6, and SHT~ receptors are positively coupled
to AC and
thus stimulate cAMP production when activated by SHT [Martin et al., supra].
The
receptors in the SHTZ family are positively coupled to phospholipase C (PLC)
and thus
so generate inositol phosphates and mobilize intracellular calcium when
activated to mediate the
effects of SHT. The SHT3 receptor is unique in that it couples to an ion
channel which gates
sodium, potassium, and calcium [Hoyer et al., supra].


CA 02332505 2000-11-17
WO 99/59499 PCT/US99/10179
The human and animal SHT7 receptor has only recently been cloned, expressed,
and
shown to be present in various brain areas and peripheral tissues [Eglen et
al., Trend
Pharmacol. Sci., 18:104-107, 1997]. Recent studies have shown there to be four
splice
variants of the SHT~ receptor [Heidmann et al., J. Neurochem., 68:1372-1381,
1997]. It has
s been proposed that the SHT~ receptor may be involved in the pathophysiology
of sleep
disorders, depression, and other psychiatric disorders [Eglen et al., supra].
In the periphery,
stimulation of SHT~ receptors results in relaxation of blood vessels and hence
vasodilation
[Eglen et al., supra]. Improving blood flow to the back of the eye, including
the retina, the
macula, and the optic nerve head is believed to be beneficial in the treatment
of a number of
~o retinal diseases, for example, glaucoma, ARMD, and diabetic retinopathy
[Chiou, et al.,
J. Ocular Pharmacol. 9:13-24 (1993)].
Serotonergic nerves innervate the eye [Tobin et al., J. Neurosci., 8:3713-
3721, 1988]
and SHT has been found in the aqueous humor of human eyes [Martin et al.,
Ophthalmol.,
is 95:1221-1226, 1988]. In addition, receptor binding sites for [3H]SHT have
been
demonstrated and pharmacologically characterized in the iris-ciliary body
(ICB) of rabbits
[Mallorga and Sugrue, Curr. Eye Res., 6:527-532, 1987 and Chidlow et al.,
Invest.
Ophthalmol. Vis. Sci., 36:2238-2245, 1995]. These SHT binding sites have been
shown to be
functionally coupled to second messenger generation in rabbits [Tobin and
Osborne,
2o J. Neurochem., 53:686-601, 1989 and Tobin et al., J. Neurosci, supra]. In
the human ICB
these binding sites are characterized as SHT~A and SHT2 receptors [Barnet and
Osborne, Exp.
Eye Res., 57:209-216, 1993]. In addition, the presence of mRNAs for SHT,a and
SHT~
receptors in the rabbit ICB have been reported [Chidlow et al., Invest.
Ophthalmol.
Vis. Sci., supra and Osborne and Chidlow, Ophthalmologica, 210:308-314, 1996].
The
2s precise functions of these receptors in the eye are unknown, especially the
SHT~ subtype(s).
SHT or 5-carboxamidotryptamine (5-CT) topically applied to the rabbit eye
raise
intraocular pressure in the anterior chamber of the eye [Meyer-Bothling et
al., Invest.
Ophthalmol. Vis. Sci., 34:3035-3042, 1993]. By contrast, it has been shown
that topically
3o applied SHT lowers IOP [Krootila et al., J. Ocular Pharmacol., 3:279-290,
1987
{intracamerally SHT raised IOP and caused breakdown of the blood-aqueous
barrier)]. In
addition, the SHT uptake inhibitor, fluoxetine (Prozac~, also raises IOP in
human.subjects
-2-


CA 02332505 2000-11-17
WO 99/59499 PCT/US99/10179
upon oral administration [Costagliola et al., Br. J. Ophthalmol., 80:678,
1996] and may cause
glaucoma [Ahmad, Ann. Pharmacother., 25:436, 1992]. However, the SHT receptor
subtypes) involved in the IOP-elevating effects of SHT, 5-CT and fluoxetine
are unknown.
s Studies conducted in rabbits with 8-hydroxy DPAT and MKC-242 (SHT1A
agonists)
have shown these compounds lower IOP [Osborne and Chidlow, Ophthalmologica,
210:308-319, 1996, and EP 0771563-A2]. In addition, 5-methylurapidil (SHTiA
agonist)
lowered IOP in glaucomatous monkeys [Wang, et al., Curr. Eye Res., 16:679-775,
1997].
Both MKC-242 and 5-methylurapidil are relatively potent al receptor
antagonists
~o (al antagonists are known to lower IOP in rabbits, monkeys, and man). The
mechanism of
action for lowering IOP by 5-methylurapidil has been attributed to its al
antagonist activity
and not its SHT~A agonist activity [Wang, et al., Invest. Ophthal. Vis. Sci.,
39(Suppl):2236-
488, 1998]. U.S. Patent No. 5,693,654, discloses SHT1 receptor agonists for
lowering IOP.
W092/20333 discloses certain SHT1A agonists for the treatment of glaucoma.
is
Methysergide (SHT2 antagonist) lowered IOP in rabbits [Krootila, et al., Esp.
Eye
Res., supra]. Ketanserin (SHT2~~ antagonist), also with significant al
antagonist activity,
lowers IOP in rabbits and man [Char, et al., J. Ocular Pharmacol., 1:137-147,
1985 and
Costagliola, et al., Ex. Eye Res., 52:507-510, 1991]. Saprogrelate (SHT2A
antagonist) lowers
2o IOP in rabbits and in man when dosed topically or orally [Mann, et al.,
Invest. Ophthal. Vis.
Sci., 36(Suppl):3322-309, 1995, and Takenaka, et al., Invest Ophthal. Vis.
Sci.,
36(Suppl):3390-377, 1995]. EP 522226 and U.S. Patent No. 5,290,781 disclose
the use of
ketanserin and its derivatives for treating ocular hypertension. U.S. Patent
Nos. 5,290,781
and 5,106,555 discloses the use of certain SHT2 antagonists for lowering IOP.
U.S. Patent
2s No. 5,652,272 discloses saprogrelate for reducing IOP. U.S. Patent No.
5,538,974 discloses
opthalmic compositions of certain SHT2 antagonists for lowering IOP.
U.S. Patent No. 5,011,846 discloses certain SHT3 receptor antagonists for
treating
glaucoma.
-3-


CA 02332505 2000-11-17
WO 99/59499 PCT/US99/10179
WO 97/17345 discloses that particular compounds with SHT4 serotonergic
receptor
s
agonist or antagonist activity are useful for treating psychiatric,
gastrointestinal, lower
urinary, and cardiovascular disorders. The publication mentions the compounds
may also be
useful for glaucoma.
As evidenced by the previous discussion, it is not clear which serotonergic
receptor
activity is responsible for lowering IOP. Moreover, a number of these
compounds are known
to have activity at other receptors which are known to be involved in lowering
IOP.
Furthermore, it has not been cleared which receptors) might be responsible for
increasing
to blood flow and providing neuroprotection in the eye.
Summary of the Invention
The present invention is directed to Compounds, some of which are novel, that
have
is SHT~ receptor affinity, and the use of compounds with SHT? receptor
affinity to lower IOP,
improve blood flow to the optic nerve head and the retina, provide
neuroprotection, and
control damage associated with diseases, such as, glaucoma, ARMD, optic
neuritis, ischemic
disorders, and retinal edema by functioning as neuroprotectants. Compositions
of the
compounds are contemplated for such uses. The Compounds are also useful for
treating sleep
2o disorders, depression, and other psychiatric disorders, such as,
schizophrenia, anxiety,
obsessive compulsive disorder, circadian rhythm disorders, and centrally and
peripherally
mediated hypertension.
Detailed Description Preferred Embodiments
2s
It has been unexpectedly discovered that SHT~ receptors are present in the
retina,
choroid, and possibly the optic nerve head. Furthermore, sertonergic Compounds
which
possess a relatively high affinity (K; = 0.01 - 200nM) for SHT~ receptors
effectively lower
elevated IOP. It is believed that these Compounds can improve blood flow, and
provide
3o neuroprotection to the optic nerve head and the retina. The Compounds'
(preferrably
Compounds that are agonists or partial agonists) ability to improve blood flow
to the optic
nerve head and the retina and other characteristics are believed to render
them


CA 02332505 2000-11-17
WO 99/59499 PCT/US99/10179
neuroprotective. The novel Compounds disclosed herein are also useful for
treating sleep
disorders, depression, and other psychiatric disorders.
Compounds found in the following applications are useful according to the
present
invention and are incorporated herein by reference: EP 738513-A1; WO 97/29097;
WO 97/48681; WO 97/49695; and WO 98/00400. Specific Compounds include:
LY-215840, SB-258719, and DR-4004.
The following novel Compounds and their pharmaceutically acceptable salts and
to solvates are useful for treating persons with the diseases and disorders
previously described.
Formula 1
R
Aryl I ~ Rs
yN yCR3R,~ nwN r\ ~7
R
~s
Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
2o R' is H, OH, OC,_3alkyl, Ci_3alkyl, C,_3alkyl substituted optionally with
OH, or OC,_3alkyl;
R2 is H, halogen, Ci_3alkyl, CONRSR6, S(=O)mC~_3alkyl, S(=O)2 NRSR6 ,
C,_3alkyl substituted
optionally with OH, or OC,_3alkyl;
R3, R4 are independently H, C,_3alkyl, C,_3alkyl substituted optionally with
OH or OC1_3alkyl;
R5, R6 are independently H, C~_3alkyl, C2_3alkyl substituted optionally with
OH, OCI_3alkyl, or
2s RS and R6 can be joined together with saturated carbon atoms to form a 5 or
6
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C1_3alkyl, C2_3alkyl substituted optionally with OH or
OC,_3alkyl;
R', R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
so from N, O, S, such as pyrrolidine, piperidine, 03-piperidein, piperazine,
morpholine
-5-


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WO 99/59499 PCT/US99/10179
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C~_3alkyl, C,_3alkyl substituted
optionally with OH, OCi.3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC~_3alkyl, or Ci.3alkyl, or substituted on
nitrogen
with C,.aalkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OCi_3alkyl, or Ci_3alkyl;
nis2to4;
m is 0, 1 or 2.
Formula II
~o
a
R CR3R~ --N
n \~
qry~ ~ R
O O
Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
is R~ is H, C1_salkyl, C3_Salkenyl, an aromatic ring such as phenyl, thienyl,
pyridyl, and
imidazoyl which is either unsubstituted or substituted optionally with OH,
OC,_3alkyl, S(=O)mCl_3alkyl, halogen, CF3, or S(=O)2 NRSR6; or C2_Salkyl
substituted optionally with OH, OCl.3alkyl, S(=O)mCl.3alkyl or an aromatic
ring
such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted
or
2o substituted optionally with OH, OC~_3alkyl, S{=O)mCl_3alkyl, halogen, CF3,
S(=O)2
NRSR6; or C3_Salkenyl substituted optionally with OH, OC!_3alkyl, or S(=O)mCl_
3alkyl;
R2 is H, halogen, C,.3alkyl, S(=O)mC,.3alkyl, S(=O)2 NRSR6, or C~_3alkyl
substituted
optionally with OH, or OC ~ _3alkyl;
2s R3 & R4 are independently H, C~_3alkyl, or C1_3alkyl substituted optionally
with OH or
OC 1_3alkyl;
R5, R6 are independently H, C,_3alkyl, C2_3alkyl substituted optionally with
OH, OC~_3alkyl,
or RS and R6 can be joined together with saturated carbon atoms to form a 5 or
6
-6-


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WO 99/59499 PCT/US99/10179
membered ring and said carbon atoms can be either unsubstituted or substituted
optionally with C~_3alkyl, C2.3alkyl substituted optionally with OH or
OC1_3alkyl;
R', R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
s from N, O, S, such as pyrrolidine, piperidine, D3-piperidein, piperazine,
morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents .optionally selected from C1_3alkyl, C,_3alkyl substituted
optionally with OH, OC,_3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC~_3alkyl, or C,_3alkyl, or substituted on
nitrogen
io with Cl~alkoxy or phenyl which can be unsubstituted or substituted
optionally with
halogen, CF3, OC,_3alkyl, or C,_3alkyl;
nis2to4;
m is 0, 1 or 2.
Formula III
R~ o Rs
s~N~ ~~CR3R4)n
R
R OS O
is
R3 & R4 are independently H, CI_3alkyl, or C1_3alkyl substituted optionally
with OH or
OC i _3alkyl;
R', R$ are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
2o from N, O, S, such as pyrrolidine, piperidine, t13-piperidein, piperazine,
morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C,_3alkyl, C,_3alkyl substituted
optionally with OH, OC~.3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC~_3alkyl, or C~.3alkyl, or substituted on
nitrogen
2s with C»alkoxy or phenyl which can be unsubstituted or substituted
optionally with
halogen, CF3, OC,_3alkyl, or C~.3alkyl;
-7-


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WO 99/59499 PCT/US99/10179
R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or
substituted
with C,_a alkyl, halogen, OC,~alkyl;
R'° is C»alkyl, or R'° can be joined to R9 to form a fused
bicyclic ring system such as
indoline;
nis2to4.
Formula IV
~~S~ R~2
R'vN/
Rs
i
(CR3Ra)n
R
R3 & R4 are independently H, C~_3alkyl, or C1_3alkyl substituted optionally
with OH or
to OCi_3alkyl;
R', R8 are together with the nitrogen atom to which they are attached
incorporated into a
heterocyclic ring of 5 to 8 atoms which may include a second heteroatom
selected
from N, O, S, such as pyrrolidine, piperidine, 03-piperidein, piperazine,
morpholine
or thiomorpholine which can be unsubstituted or substituted on carbon with one
or
more substituents optionally selected from C,_3alkyl, C~_3alkyl substituted
optionally with OH, OC,_3alkyl, phenyl which can be unsubstituted or
substituted
optionally with halogen, CF3, OC1_3alkyl, or C,_3alkyl, or substituted on
nitrogen
with C~_aalkoxy or phenyl which can be unsubstituted or substituted optionally
with
halogen, CF3, OC,_3alkyl, or C,_~alkyl;
2o Ril is C1_3alkyl, phenyl or a monocyclic heteroaromatic ring which can be
unsubstituted or
substituted with C1.~ alkyl, halogen, OC,.~alkyl;
Rl2 is Cl~alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-a]-
1,2-thiazine, or
1,2-benzothiazine, or R'2 can be joined to Rt ~ to form a fused bicyclic ring
system
such as 2,3-dihydro-benzo[c)isoxazole;
nis2to4.
_g_


CA 02332505 2000-11-17
WO 99/59499 PCT/US99/10179
The compounds of the present invention can be prepared using chemical
synthesis procedures
herein described. The preferred method for preparing compounds of Formula I is
illustrated
in Scheme I. For example, the thiazine alcohols 1, which can be prepared by
methods
described in U.S.Patents 5,344,929 and 5,470,973, or in J. Org. Chem. 31, 162
(1966), can be
s selectively alkylated on the nitrogen atom at position two with, for
example, a dihaloalkane
using procedures known to the art to give 2, where X is a halogen atom such as
chlorine,
bromine, or iodine. Compounds 2 can be treated with amines by known procedures
to
provide compounds of Formula I (3) where R' is hydroxyl, further these
alcohols 3 can be
treated with an alkylhalide to effect alkylation on oxygen to provide the
ethers, Rl is alkoxy.
Alternately, 2 can be dehydrated by using methods described in U.S. Patent
5,538,966 to give
compounds 4 which can be further reacted with amines to give compounds of
Formula I
where R' is hydrogen and the thiazine ring contains a double bond (5).
Scheme I
OH OH OH
Rz R~ HNR~R~ R2 a
Aryl ~ .~ A~Y~ I ~Y~ ~ . N /R
S'N~H S' N~(CH~,; X S~ ~(CHs)~ N
O, 00 O ~O O O \R,
MszOIDBN
R~ \ HNR~RB RZ \ a
nryi ~ ~N\ AM ~ S,N\ /R
S (CHz),; X , '~ (CHz)~ N
O~ °O O O \Rr
is Procedures for preparing compounds of Formula II are illustrated in Scheme
II. For example,
the 3-hydroxymethyl thiazine compounds 7 can be prepared from the esters 6 by
methods
described in U.S. Patent 5,538,966 [Equation (a)]. Further, compounds 7 can be
aminated
using a variety of well known procedures, such as initial activation of the
hydroxyl group by
forming a sulfonate ester, followed by reaction of this intermediate with the
desired primary
20 or secondary amine to give compounds 8 of Formula II where R3 and R4 are
hydrogen and n
is 1 [Equation (b)]. Additionally, using 7 as an intermediate with which to
initiate a suitable
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CA 02332505 2000-11-17
WO 99/59499 PCT/US99/10179
homologation sequence, compounds of Formula II wherein R3 and R4 are hydrogen
and n is 2
or 3 can be prepared; an example of such a homologation sequence employing 7
is illustrated
in Equations (c) and (d), respectively.
Scheme II
z
Rz \ C02Et DIBAL-H R ~,~ ( \ OH
(a) ~ S~N~R, THF ~S'' N~R~
O~ O
6
Rz Rz Re
~y, ' \ OH 1. MszOITEA _ my I \ N
S~N~R~ 2. HNR~ReIfHF S~N~R~
p~ ~O O~ ~O
7 8
Rz
Rz \ COZH
~yi ~ \ OH 1. TsCIffEA nay
(C) S~N~R~ 2. NaCN S~NwR'
O O
O~ ~O 3. Hydrolysis
9
1. Bo~ane
2. MszO/TEA
3. Amine
R°
z
R \
S~N~R~
0~ ~O
10
-10-


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WO 99/59499 PCTNS99/10179
z z
R ~ OH R
(d) a,ry' I PBr3 ~ ~ Br
S~ 'rt, -3~- S~N'R'
O~ ~O O~ ~O
11
1. Mg/THF
2. Ethylene Oxide
RZ R 2
R ~ OH
my I ~ ~~ E 1. Ms,O/TEA ,4,y~
O g O 'R' 2. Amine S~N'R,
O~ ~O
13 12
The preparation of compounds of Formula III can be readily accomplished by
procedures
herein described. For example, reaction of the desired amine 14 with the
appropriate
haloalkylsulfonyl chloride 15 in an inert solvent in the presence of a
suitable base [see e.g., J.
s Med. Chem. 40, 3217 (1997)] to give the haloalkylsulfonamide intermediate
16. Subsequent
reaction of 16 with the appropriate primary or secondary amine employing known
procedures,
provides compounds 17 of Formula III.
Scheme III
,° '°
R CI~ /(CR'R4)~ CI R
EtNH(iPr)2 s 4
acetone R9/N~S/(CR R )~ CI
R H O O
O O 16
14 15
HNR~Re
DMF/heat
R'o
Ra
R9/N~S/(CR3R4)~ NR~
O/\O 17
-~ 1-


CA 02332505 2000-11-17
WO 99/59499 PCT/US99/10179
The preparation of compounds of Formula N can be readily accomplished by
procedures
herein described. For example, reaction of the desired primary amine 18 with
the appropriate
sulfonyl chloride in an inert solvent in the presence of a suitable base
provides the
intermediate secondary sulfonamide 19 which can be alkylated by known
procedures with the
s appropriately substituted alkyldibromide to give the haloalkylsulfonamide
intermediate 20.
Subsequent reaction of 20 with the appropriate primary or secondary amine
employing well
known procedures provides compounds 21 of Formula IV.
Scheme IV
9
' (CR R
R~N'H R~ogOZCI O-g H Br-(CR3R4)o-Br R~N~ 3 4~n Br
H TF~ O~ ~R,o NaH/DMF O ~ S\
O R
I8 19
HNR~Re
DMF/heat
R'
R\N~(CR3R4~" \
Re
O=S
O/ ~R,o 21
It is evident that some of the Compounds of Formula I - IV will include
asymmetric atoms, all
enantiomers and diastereomers are contemplated.
is The term heteroaromatic ring refers to thiophene, furan, pyrrole, pyridine,
pyrimidine,
pyridazine and pyrazine.
The Compounds can be administered systemically or locally to the eye {e.g.,
topically,
intracamerally, or via an implant). The Compounds are preferrably incorporated
into topical
ophthalmic formulations for delivery to the eye. The Compounds may be combined
with
ophthalmologically acceptable preservatives, surfactants, viscosity enhancers,
penetration
enhancers, buffers, sodium chloride, and water to form an aqueous, sterile
ophthalmic
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CA 02332505 2000-11-17
WO 99/59499 PCT/US99/10179
suspension or solution. Ophthalmic solution formulations may be prepared by
dissolving a
Compound in a physiologically acceptable isotonic aqueous buffer. Further, the
ophthalmic
solution may include an ophthalmologically acceptable surfactant to assist in
dissolving the
Compound. Furthermore, the ophthalmic solution may contain an agent to
increase viscosity,
s such as, hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylmethylcellulose,
methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention
of the formulation
in the conjunctiva) sac. Gelling agents can also be used, including, but not
limited to, gellan
and xanthan gum. In order to prepare sterile ophthalmic ointment formulations,
the active
ingredient is combined with a preservative in an appropriate vehicle, such as,
mineral oil,
io liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations
may be prepared by
suspending the active ingredient in a hydrophilic base prepared from the
combination of, for
example, carbopol-940, or the like, according to the published formulations
for analogous
ophthalmic preparations; preservatives and tonicity agents can be
incorporated. The
Compounds can be formulated for systemic (e.g. oral, LV., LM., subcutaneous)
delivery
~s according to methods known to one skilled in the art. For systemic delivery
the Compounds
are delivered at concentrations of 0.005 - 1000 mg. per dose, preferrably 0.05
- 20.0, most
preferrably 0.2 - 5 mg. per dose. The Compounds will,be dosed 1-4 times per
day according
to the discretion of a skilled clinician.
2o For ophthalmic medications the Compounds are preferably formulated as
topical
ophthalmic suspensions or solutions, with a pH of about 5 to 8. The Compounds
will
normally be contained in these formulations in an amount .O1% to 5% by weight,
but
preferably in an amount of .25% to 2% by weight. Thus, for topical
presentation 1 to 2 drops
of these formulations would be delivered to the surface of the eye 1 to 4
times per day
as according to the routine discretion of a skilled clinician. The preferred
Compounds are those
set forth in Examples l, 1.1, 1.2, 1.6, 1.8, 2.3, 2.7, 2.10, 2.1, 2.4, 3, 3.1,
3.11, 3.5, and 3.10.
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WO 99/59499 PCT/US99/10179
Example 1
6-Chloro-2-[4-[4-(2H benzimidazo-2-oxo-1-yl)piperidin-1-yl]butyl]
2Hthieno[3,2-e]-1,2-thiazine 1,1-dioxide Hydrochloride
0
cl ''
S ~ S.N N ~N
~. o
O 0 HCI --
Step 1. A solution 6-chloro-3,4-dihydro-2H thieno[3,2-a]-1,2-thiazine-4-of 1,1-
dioxide
(9.0 g, 37.6 mmol) in dimethylformamide (200 mL, anhydrous) and sodium hydride
(60% in
oil, 1.66 g, 41.5 mmol) was reacted with 1,4-dibromobutane at 0°. The
reaction was stirred in
an ice bath for 30 min and then it was allowed to warm to room temperature and
stir for three
days. The mixture was poured into ice water (400 mL) and extracted with
diethyl ether (2 x
to 200 mL). The combined organic layers were washed with water (200 mL), brine
(200 mL)
and then were dried over magnesium sulfate and evaporated. The resulting
residue was
purified by silica gel flash chromatography with hexane/ethyl acetate (7:3) to
give 6-chloro-
3,4-dihydro-2-(4-bromobutyl)-2H thieno[3,2-e]-1,2-thiazine-4-of 1,1-dioxide as
a colorless
oil (10.62 g, 75%); the'H NMR was consistent with the structure.
is
Step 2. The product from Step 1 (10.6 g, 28.3 mmol) was dissolved in
tetrahydrofuran
(anhydrous, 400 mL) and treated with triethyl amine (9.88 mL, 70.9 mmol) and
methane
sulfonic anhydride (9.86 g, 56.6 mmol) at room temperature and stirred for one
hour. The
suspension was concentrated and taken up in dimethylformamide (anhydrous, 120
mL). This
zo mixture was heated at 160° for 45 min. The reaction mixture was
poured into ice water (300
ml) and extracted with dichloromethane (300 mL). The organic layer was washed
with water
(2 x 200 mL), dried over magnesium sulfate and evaporated to a brown oil.
After silica flash
chromatography with hexane/ethyl acetate 6-chloro-2-(4-bromobutyl)-2H
thieno[3,2-a]-1,2-
thiazine 1,1-dioxide was obtained as a yellow oil (4.97 g, 49%); the'H NMR.
was consistent
is with the structure.
Step 3. A solution of 4-(2H benzimidazo-2-oxo-1-yl)piperidine (0.30 mmol) in
DMF (1.6
mL, anhydrous) and triethyl amine (0.5 mL) was treated with the product of
Step 2 (0.103 g,
-14-


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WO 99/59499 PCTNS99/10179
0.29 mmol) and stirred at 70° for 20 hours and then at room temperature
for two days. The
reaction mixture was diluted with ethyl acetate (3 mL) and water (4 mL).
Saturated sodium
bicarbonate ( 1 mL) was added and the layers were mixed followed by removal of
the aqueous
layer. The organic layer was washed with water (6 mL) and evaporated to give a
residue that
was dissolved in ethanol and treated with 1 N hydrochloric acid in ether.
After evaporation
the desired product was obtained as a white solid (69.2 mg, 45%): 'H NMR and
MS (M + H
493) were consistent with the structure.
By following the procedures of Example 1, but replacing 4-(2H benzimidazo-2-
oxo-1-
io yl}piperidine in Step 3 with the appropriate amine, the following compounds
were prepared.
The 1H NMR spectrum and the mass spectrum for each of these compounds were
consistent
with the assigned structure.
1. 6-Chloro-2-[4-(4-phenylpiperazin-1-yl)butyl]-2H thieno[3,2-a]-1,2-thiazine
1,1-dioxide
is hydrochloride;
2. 6-Chloro-2-[4-[4-(2-fluorophenyl)piperazin-1-yl]butyl]-2H thieno[3,2-a]-1,2-
thiazine 1,1-
dioxide hydrochloride;
3. 6-Chloro-2-[4-[4-hydroxy-4-(4-chlorophenyl)piperidin-1-yl]butyl]-2H
thieno[3,2-a]-1,2-
thiazine 1,1-dioxide hydrochloride;
Zo 4. b-Chloro-2-[4-[4-hydroxypiperidin-1-yl]butyl]-2Hthieno[3,2-a]-1,2-
thiazine 1,1-dioxide
hydrochloride.
By following the procedures of Example l, but replacing the 1,4-dibromobutane
in Step 1
with 1,3-dibromopentane and 4-(2H benzimidazo-2-oxo-1-yl)piperidine in Step 3
with the
2s appropriate amine, the following compounds were prepared. The 1H NMR
spectrum and the
mass spectrum for each of these compounds were consistent with the assigned
structure.
5. 6-Chloro-2-[3-[4-phenylpiperazin-1-yl]propyl]-2Hthieno[3,2-a]-1,2-thiazine
1,1-dioxide
hydrochloride;
30 6. 6-Chloro-2-[3-[4-(3-trifluoromethylphenyl)piperazin-1-yl]propyl]-2H
thieno[3,2-a]-1,2-
thiazine 1,1-dioxide hydrochloride;
-15-


CA 02332505 2000-11-17
WO 99/59499 PCT/US99/10179
7. 6-Chloro-2-[3-[4-(2-fluorophenyl)piperazin-1-yl]propyl]-2H thieno[3,2-a]-
1,2-thiazine
1,1-dioxide hydrochloride;
8. 6-Chloro-2-[3-[4-(2H benzimidazol-2-oxo)piperidin-1-yl]propyl]-2H
thieno[3,2-e]-1,2-
thiazine 1,1-dioxide hydrochloride.
Example 2
3-(4-Methylpiperidin-1-yl)propylsulfonyl-2,3-dihydro-1H indole Hydrochloride
CH3
I / N ,~
pi~~HCI
O
Step 1. To a solution of indoline (4.00 g, 33.6 mmol) in 100 mL of acetone at
O~C was
to added 3-chloropropanesulfonyl chloride (5.95 g, 33.6 mmol) with stirring. A
solid
precipitated from the solution. Diisopropylethylamine (4.33 g, 33.6 mmol) was
added in
two portions and the reaction mixture became a homogenous solution. The
mixture was
stirred for 30 min, warmed to ambient temperature, and evaporated to dryness.
The crude
mixture was combined with a saturated aqueous solution of sodium bicarbonate
and extracted
><s with ethyl acetate (2 x 100 mL). Chromatography on silica (10% to 25%
ethyl
acetate/hexane) gave an oil which solidified on standing (7.68 g, 77%, mp 53-
53 ~C ).
Step 2. A mixture of the product of Step 1 (200 mg, 0.77 mmol) and 0.5 M
solution of 4-
methylpiperidine (4 mL, 2.0 mmol) was heated at 35 ~C for 60 h. The reaction
mixture was
2o combined with a saturated aqueous solution of sodium bicarbonate and
extracted with ethyl
acetate (2 x 10 mL). The extracts were dried and evaporated to dryness. The
crude product
was filtered though a short silica column and treated with a 1.0 M solution of
hydrogen
chloride gas in ether. The solid was filtered and dried to give the
hydrochloride salt (220 mg,
80 %): MS(ES) 323 (M+H).
2s
By following the procedures of Example 2, but replacing 4-methylpiperidine in
Step 2 with
the appropriate amine, the following compounds were prepared. The'H NMR
spectrum and
the mass spectrum for each of these compounds were consistent with the
assigned structure.
-16-


CA 02332505 2000-11-17
WO 99!59499 PCT/US99/10179
1. 3-[4-(3-Chlorophenyl)piperazin-1-yl]propylsulfonyl-2,3-dihydro-1H indole;
2. 3-(3-Methylpiperidin-1-yl)propylsulfonyl-2,3-dihydro-1H indole;
3. 3-(1,2,3,4-Tetrahydroisoquinolin-2-yl)propylsulfonyl-2,3-dihydro-1H indole;
s 4. 3-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]propylsulfonyl-2,3-dihydro-
1H indole;
5. 3-(4-Phenylpiperazin-1-yl)propylsulfonyl-2,3-dihydro-1H indole;
6. 3-[4-(2-Fluorophenyl)piperazin-1-yl]propylsulfonyl-2,3-dihydro-1H indole;
7. 3-[4-(2-Methoxyphenyl)piperazin-1-yl]propylsulfonyl-2,3-dihydro-1H indole;
8. 3-[4-(4-Methoxyphenyl)piperazin-1-yl]propylsulfonyl-2,3-dihydro-1H indole;
~0 9. 3-[4-(2-Chlorophenyl)piperazin-1-yl]propylsulfonyl-2,3-dihydro-1H
indole.
By following the procedures of Example 2, but replacing the indoline in Step 1
with N
methylaniline and the 4-methylpiperidine in Step 2 with the appropriate amine,
the following
compounds were prepared. The ~H NMR spectrum and the mass spectrum for each of
these
~s compounds were consistent with the assigned structure.
10. 3-(1,2,3,4-Tetrahydroisoquinolin-2-yl)-N methyl-N phenyl-
propylsulfonamide;
11. N Methyl-N phenyl-3-[4-(3-trifluoromethylphenyl)piperazin-1-
yl]propylsulfonamide;
12. N Methyl-N phenyl-3-(4-phenylpiperazin-1-yl)propylsulfonamide;
20 13. 3-[4-(2-Fluorophenyl)piperazin-1-yl]- N methyl-N phenyl-
propylsulfonamide;
14. N Methyl-3-[4-(2-methoxyphenyl)piperazin-1-yl]-N phenyl-propylsulfonamide;
15. 3-[4-(2-Chlorophenyl)piperazin-1-yl]- N methyl-N phenyl-propylsulfonamide
By following the procedures of Example 2, but replacing the 3-
chloropropanesulfonyl
zs chloride in Step 1 with 2-chloroethanesulfonyl chloride and the 4-
methylpiperidine in Step 2
with 3-methylpiperidine, the following compound was prepared. The'H NMR
spectrum and
the mass spectrum for this compound were consistent with the assigned
structure.
16. 2-(3-Methylpiperidin-1-yl)ethylsulfonyl-2,3-dihydro-1H indole.
-17-


CA 02332505 2000-11-17
WO 99/59499 PCT/US99/10179
Example 3
N [3-[4-(3-Chlorophenyl)piperazin-1-yl]propyl]-N (4-methoxyphenyl)-
propanesulfonamide Hydrochloride
CHs
O~~ /~/
N S~ O
Ha P ~N N
HCI
CI
Step 1. To a solution ofp-anisidine (6.00 g, 48.7 mmol) and triethylamine
(5.91 g, 58.4
mmol) in methylene chloride (200 mL) at 0 C was added propylsulfonyl chloride
(7.64 g,
53.6 mmol) with stirring under nitrogen atmosphere. The reaction mixture was
allowed to
warm to room temperature and stirred overnight. The mixture was washed with a
saturated
aqueous solution of sodium bicarbonate (100 mL), water, and dried over
magnesium sulfate.
io The organic layer was evaporated to give an oil that was mixed with a
solution of hexane and
ethyl acetate (3:1 ) to afford a crystalline solid (7.97 g). The mother liquid
was
chromatographed on silica (hexane/ethyl acetate, 4:1 ) to give a solid (2.27
g, 92%): mp 72°C;
MS(-ES) 228 (M-H).
~s Step 2. To the product of Step 1 (3.50 g, 15.3 mmol) in anhydrous
dimethylformamide (80
mL) at O~C was added sodium hydride (60 % suspension in mineral oil, 0.672 g,
16.8 mmol)
under a nitrogen atmosphere. The suspension was stirred for 30 min and 1,3-
dibromopropane
(9.27 g, 45.9 mmol) was added over 1 min. The reaction was stirred for 3 h,
mixed with a
saturated aqueous solution of sodium bicarbonate (200 mL) and extracted with
ethyl acetate
20 (3 x 100 mL). The combined extracts were dried and evaporated to dryness.
Chromatography on silica (20% ethyl acetate in hexane) gave a colorless oil
(4.33 g, 81%):
MS(+ES) 352 (M+H).
Step 3. To a solution of the product of Step 2 (0.175 g, 0.50 mmol) in
anhydrous
is dimethylformamide (1 mL} was added a 0.5 M solution of 1-(3-
chlorophenyl)piperazine in
dimethylformamide (I.1 mL, 0.55 mmol) and triethylamine (0.20 mL); this
mixture was
heated at 60 C for 18 h. The cooled reaction mixture was extracted with ethyl
acetate (2 x 1
mL) and the combined extracts were washed with a saturated aqueous solution of
sodium
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WO 99/59499 PCT/US99/10179
bicarbonate, dried and evaporated to an oil which was treated with a 1.0 M
solution of
hydrogen chloride gas in ether to give the corresponding salt (0.11 g, 44%):
MS(ES) 466
(M+).
By following the procedures of Example 3, but replacing 1-(3-
chlorophenyl)piperazine in
Step 3 with the appropriate amine, the following compounds were prepared. The
~H NMR
spectrum and the mass spectrum for each of these compounds were consistent
with the
assigned structure.
io 1. N [3-(1,2,3,4-Tetrahydroisoquinolin-2-yl)propyl]-N (4-methoxyphenyl)-
propanesulfonamide;
2. N [3-(3-Hydroxymethylpiperidin-1-yl)propyl]-N (4-methoxyphenyl)-
propanesulfonamide;
3. N (4-Methoxyphenyl)-N [3-(morpholin-4-yl)propyl]-propanesulfonamide;
4. N (4-Methoxyphenyl)-N [3-(2-methylpiperidin-1-yl)propyl]-
propanesulfonamide;
is 5. N [3-[4-(3-Chlorophenyl)piperazin-1-yl]propyl]-N (4-methoxyphenyl)-
propanesulfonamide;
6. N (4-Methoxyphenyl)-N [3-[4-(3-trifluoromethylphenyl)piperazin-1-yl]propyl]-

propanesulfonamide;
7. N [3-(4-phenylpiperazin-1-yl)propyl)-N (4-methoxyphenyl)-
propanesulfonamide;
20 8. N (3-[4-(2-Fluorophenyl)piperazin-1-yl]propyl]-N (4-methoxyphenyl)-
propanesulfonamide;
9. N [3-[4-(4-Methoxyphenyl)piperazin-1-yl]propyl]-N (4-methoxyphenyl)-
propanesulfonamide;
10. N [3-[4-(2-Methoxyphenyl)piperazin-1-yl)propyl)-N (4-methoxyphenyl)-
2s propanesulfonamide;
11. N [3-[4-(2-Chlorophenyl)piperazin-1-yl]propyl]-N (4-methoxyphenyl)-
propanesuifonamide;
12. N [3-[4-(2H Benzimidazo-2-oxo-1-yl)piperidin-1-yl]propyl]-N (4-
methoxyphenyl)-
propanesuifonamide.
By following the procedures of Example 3, but replacing the 1,3-dibromopropane
in Step 2
with 1,4-dibromobutane and the 1-(3-chlorophenyl)piperazine in Step 3 with
1,2,3,4-
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WO 99/59499 PCT/US99/10179
tetrahydroisoquinoline, the following compound was prepared. The ~H NMR
spectrum and
the mass spectrum for this compound were consistent with the assigned
structure.
I3. N [4-(1,2,3,4-Tetrahydroisoquinolin-2-yl)butyl]-N (4-methoxyphenyl)-
methanesulfonamide.
The following topical ophthalmic formulations are useful according to the
present
invention administered 1-4 times per day according to the discretion of a
skilled clinician.
1o EXAMPLE 4
Ingredients Amount (wt %)


SHT~ Compound 0.01 - 2%


Hydroxypropyl methylcellulose 0.5%


Dibasic sodium phosphate (anhydrous)0.2%


Sodium chloride 0.5%


Disodium EDTA (Edetate disodium)0.0I


Polysorbate 80 0.05%


Benzalkonium chloride 0.01


Sodium hydroxide / HydrochloricFor adjusting pH to 7.3 - 7.4
acid


Purified water q.s. to I00%


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WO 99/59499 PCT/US99/10179
EXAMPLE 5
Ingredients Amount (wt %)


SHT~ Compound 0.01- 2%


Hydroxypropyl methylcellulose 0.5%


Cremophor EL 0.1


Tromethamine, USP, AR 0.64%


Mannitol, USP 3.0%


Boric acid, USP 0.3%


Dibasic sodium phosphate (anhydrous)0.2%


Sodium chloride 0.5%


Disodium EDTA (Edetate disodium)0.01


Polysorbate 80 0.05%


Benzalkonium chloride 0.01


Sodium hydroxide / HydrochloricFor adjusting pH to 7.3 - 7.4
acid


Purified water q.s. to 100%


EXAMPLE 6
Ingredients Amount (wt %)


_
SHT~ Compound 0.01 - 2%


Methyl cellulose 4.0%


Dibasic sodium phosphate (anhydrous)0.2%


Sodium chloride 0.5%


Disodium EDTA (Edetate disodium)0.01


Polysorbate 80 0.05%


Benzalkonium chloride 0.01


Sodium hydroxide l HydrochloricFor adjusting pH to 7.3 - 7.4
acid


Purified water q.s. to 100%


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WO 99/59499 PCTNS99/10179
EXAMPLE 7
Ingredients Amount (wt %)


SHT~ Compound 0.01 - 2%


Hydroxypropyl-~i-cyclodextrin 4.0%


Dibasic sodium phosphate (anhydrous)0.2%


Sodium chloride 0.5%


Disodium EDTA (Edetate disodium)0.01


Polysorbate 80 0.05%


Benzalkonium chloride 0.01%


Sodium hydroxide / HydrochloricFor adjusting pH to 7.3 - 7.4
acid


Purified water ~ q.s. to 100%


EXAMPLE 8
Ingredients Amount (wt %)


SHT~ Compound 0.01- 2%


Xanthan gum 0.5-6.0%


Dibasic sodium phosphate (anhydrous)0.2%


Sodium chloride 0.5%


Disodium EDTA (Edetate disodium)0.01


Polysorbate 80 0.05%


Benzalkonium chloride 0.01%


Sodium hydroxide / HydrochloricFor adjusting pH to 7.3 - 7.4
acid


Purified water q.s. to 100%


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WO 99/59499 PCT/US99/10179
EXAMPLE 9
Ingredients Amount (wt %)


SHT~ Compound 0.01 - 2%


Guar gum 0.4- 6.0%


Dibasic sodium phosphate (anhydrous)0.2%


Sodium chloride 0.5%


Disodium EDTA (Edetate disodium)0.01


Polysorbate 80 0.05%


Benzalkonium chloride 0.01


Sodium hydroxide / HydrochloricFor adjusting pH to 7.3 - 7.4
acid


Purified water q.s. to 100%


EXAMPLE 10
Ingredients Amount (wt %)


SHT~ Compound 0.01 - 2%


Tyloxapol 0.2 - 4.0%


Dibasic sodium phosphate (anhydrous)0.2%


Sodium chloride 0.5%


Disodium EDTA (Edetate disodium)0.01


Polysorbate 80 0.05%


Benzalkonium chloride 0.01


Sodium hydroxide / HydrochloricFor adjusting pH to 7.3 - 7.4
acid


Purified water ~ q.s. to 100%


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WO 99/59499 PCT/US99/10179
EXAMPLE 11
Ingredients Amount (wt %)


SHT~ Compound 0.01 - 2%


White petrolatum and mineral Ointment consistency
oil and
lanolin


Dibasic sodium phosphate (anhydrous)0.2%


Sodium chloride 0.5%


Disodium EDTA (Edetate disodium)0.01


Polysorbate 80 0.05%


Benzalkonium chloride 0.01


Sodium hydroxide / HydrochloricFor adjusting pH to 7.3 - 7.4
acid


EXAMPLE 12
io
Formulation for Oral Administration
Tablet: 0.2 - 5 mg. of SHT~ Compound with inactive ingredients such as
cornstarch, lactose,
colloidal silicon dioxide, microcrystalline cellulose, and magnesium sterate
can be formulated
according to procedures known to those skilled in the art of tablet
formulation.
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