Anti-spasticity of an eicosanoid analog

Details Anti-spasticity of an eicosanoid analog Anti-spasticity of an eicosanoid analog

2003-01-17

2004-10-05

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Fatty compounds having an acid moiety which contains the...

C554S054000, C554S061000, C558S414000, C514S509000, C514S521000, C514S627000

Reexamination Certificate

active

06800770

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention generally relates to the treatment of motor disorders. In particular, the invention provides an eicosanoid analog which is effective in ameliorating motor disorders such as spasticity caused by multiple sclerosis (MS).
2. Background of the Invention
Numerous pathological diseases and conditions exist which can severely impair the motor function of afflicted persons. Examples include central nervous system (CNS) disorders such as multiple sclerosis (MS), Huntington's Chorea, amyotrophic lateral sclerosis, and Parkinson's Disease, and acute brain and/or spinal cord injury due to stroke, head or spinal cord trauma, and cerebral palsy. For persons suffering from such diseases or conditions, the consequent inability to control or direct motor function (e.g. spasticity) often severely attenuates the individual's self-care ability and has a huge negative impact on mobility and quality of life. In many cases, other symptoms such as pain and bladder instability also occur.
Cannabinoids are known to display anti-spastic activity by acting at cannabinoid receptors such as the CB
1
receptor. However, potential problems and disadvantages associated with utilizing compounds which act as therapeutic agents in this manner are unwanted psychoactive effects, such as euphoria, paranoia, sedation, and psychosis. Further, some cannabinoids such as arvanil and methanandamide display anti-spasticity effects but have the drawbacks that they bind to CB
1
and so may induce such side effects, and may also induce irritancy due to stimulation of the vanilloid receptor.
There is thus an ongoing need to develop new, effective therapeutic agents and methods of treatment for motor disorders which are free from these undesirable side effects.
SUMMARY OF THE INVENTION
The present invention provides a novel compound for the treatment of motor disorders such as spasticity associated with multiple sclerosis, and methods for the treatment of patients with such motor disorders. The compound, O-2093, and related derivatives, display excellent anti-spasticity activity. However, O-2093 does not interact significantly with cannabinoid or vanilloid receptors, and thus does not elicit the undesirable side effects associated with activation of those receptors.
The invention thus provides a novel compound having the structural formula
in which the value of n ranges from 0 to about 5, the value of p ranges from 0 to about 5, and n and p may be the same or different; X
1
=H, alkyl, Cl, Br, I, F, OH, OCH
3
, or O-alkyl; X
2
=H, alkyl, Cl, Br, I, F, OH, OCH
3
, or O-alkyl; Y
1
=H, alkyl, Cl, Br, I, F, OH, OCH
3
, or O-alkyl; Y
2
=H, alkyl, Cl, Br, I, F, OH, OCH
3
, or O-alkyl; and X
1
, X
2
, Y
1
and Y
2
can be the same or different in any combination; and
wherein the value of m ranges from 1 to about 7; R
1
=R
2
and may be H or alkyl; and R
3
=OH, Cl, Br, I, CN, ONO, ONO
2
, NO
2
, H, or CH
3
.
In preferred embodiments of the invention, the compound is one in which:
1) X
1
and X
2
are Cl; Y
1
and Y
2
are OH; n and p are 1; R
1
and R
2
are H; m=3; CH
3
; or
2) X
1
is H and X
2
is Cl; Y
1
and Y
2
are Cl; n and p are 1; R
1
and R
2
are H; m=3; and R
3
=Ch
3
; or
3) X
1
is H and X
2
is Cl; Y
1
and Y
2
are Cl; n is 1 and p is 0; R
1
and R
2
are H; m=3; and R
3
=CH
3
.
The invention further provides a method of treating motor disorders in a patient in need thereof. The method includes the step of administering to the patient a sufficient amount of a pure or salt form of a compound having the structural formula
in which the value of n ranges from 0 to about 5, the value of p ranges from 0 to about 5, and n and p may be the same or different; X
1
=H, alkyl, Cl, Br, I, F, OH, OCH
3
, or O-alkyl; X
2
=H, alkyl, Cl, Br, I, F, OH, OCH
3
, or O-alkyl; Y
1
=H, alkyl, Cl, Br, I, F, OH, OCH
3
, or O-alkyl; Y
2
=H, alkyl, Cl, Br, I, F, OH, OCH
3
, or O-alkyl; and X
1
, X
2
, Y
1
and Y
2
can be the same or different in any combination; and
wherein the value of m ranges from 1 to about 7; R
1
=R
2
and may be H or alkyl; and R
3
=OH, Cl, Br, I, CN, ONO, ONO
2
, NO
2
, H, or CH
3
.
In preferred embodiments of the invention, the compound in one in which:
1) X
1
and X
2
are Cl; Y
1
and Y
2
are OH; n and p are 1; R
1
and R
2
are H; m=3; and R
3
=CH
3
; or
2) X
1
is H and X
2
is Cl; Y
1
and Y
2
are Cl; n and p are 1; R
1
and R
2
are H; m=3; and R
3
=CH
3
; or
3) X
1
is H and X
2
is Cl; Y
1
and Y
2
are Cl; n is 1 and p is 0; R
1
and R
2
are H; m=3; and R
3
=CH
3
.
Administration of the compound may be carried out by any of several suitable known means, including but not limited to intraperitoneal, subcutaneous, oral, intramuscular, and intravenous.
The motor disorder that is treated by the methods of the invention may result from any of several disorders including multiple sclerosis, spinal cord injury, Huntington's disease and Parkinson's disease. The motor disorder may be, for example, spasticity, gait abnormality, or ataxia.
The invention further provides a method for the treatment of spasticity in a patient in need thereof. The method includes the step of administering to the patient a sufficient amount of a compound having the structural formula
in which the value of n ranges from 0 to about 5, the value of p ranges from 0 to about 5, and n and p may be the same or different; X
1
=H, alkyl, Cl, Br, I, F, OH, OCH
3
, or O-alkyl; X
2
=H, alkyl, Cl, Br, I, F, OH, OCH
3
, or O-alkyl; Y
1
=H, alkyl, Cl, Br, I, F, OH, OCH
3
, or O-alkyl; Y
2
=H, alkyl, Cl, Br, I, F, OH, OCH
3
, or O-alkyl; and X
1
, X
2
, Y
1
and Y
2
can be the same or different in any combination; and
wherein the value of m ranges from 1 to about 7; R
1
=R
2
and may be H or alkyl; and R
3
=OH, Cl, Br, I, CN, ONO, ONO
2
, NO
2
, H, or CH
3
.
In preferred embodiments of the invention, the compound in one in which:
1) X
1
and X
2
are Cl; Y
1
and Y
2
are OH; n and p are 1; R
1
and R
2
are H; m=3; and R
3
=CH
3
; or
2) X
1
is H and X
2
is Cl; Y
1
and Y
2
are Cl; n and p are 1; R
1
and R
2
are H; m=3; and R
3
=CH
3
; or
3) X
1
is H and X
2
is Cl; Y
1
and Y
2
are Cl; n is 1 and p is 0; R
1
and R
2
are H; m=3: and R
3
=CH
3
.
In the method, the step of administering may be carried out by any of several suitable means such as intraperitoneal, subcutaneous, oral, intramuscular, and intravenous.
The invention further provides a composition comprising,
in which the value of n ranges from 0 to about 5, the value of p ranges from 0 to about 5, and n and p may be the same or different; X
1
=H, alkyl, Cl, Br, I, F, OH, OCH
3
, or O-alkyl; X
2
=H, alkyl, Cl, Br, I, F, OH, OCH
3
, or O-alkyl; Y
1
=H, alkyl, Cl, Br, I, F, OH, OCH
3
, or O-alkyl; Y
2
=H, alkyl, Cl, Br, I, F, OH, OCH
3
, or O-alkyl; and X
1
, X
2
, Y
1
and Y
2
can be the same or different in any combination; and
wherein the value of m ranges from 1 to about 7; R
1
=R
2
and may be H or alkyl; and R
3
=OH, Cl, Br, I, CN, ONO, ONO
2
, NO
2
, H, or CH
3
;
and a carrier in which the compound is dissolved or dispersed. The compound may be present in the carrier in salt form.


REFERENCES:
Marzo et al, Journal of Pharmacology and Experimental Therapeutics, vol. 300, Issue 3, Mar. 2002, pp. 984-991.

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