Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-10
2003-12-09
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06660870
ABSTRACT:
The present invention is directed to novel substituted 2-acylaminobenzimidazoles and the use of novel and known 2-acylaminobenzimidazoles for lowering and controlling normal or elevated intraocular pressure (IOP) and treating glaucoma.
BACKGROUND OF THE INVENTION
The disease state referred to as glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve. The several morphologically or functionally distinct types of glaucoma are typically characterized by elevated IOP, which is considered to be causally related to the pathological course of the disease. Ocular hypertension is a condition wherein intraocular pressure is elevated, but no apparent loss of visual function has occurred; such patients are considered to be a high risk for the eventual development of the visual loss associated with glaucoma. Some patients with glaucomatous field loss have relatively low intraocular pressure. These so called normotension or low tension glaucoma patients can also benefit from agents that lower and control IOP. If glaucoma or ocular hypertension is detected early and treated promptly with medications that effectively reduce elevated intraocular pressure, loss of visual function or its progressive deterioration can generally be ameliorated. Drug therapies that have proven to be effective for the reduction of intraocular pressure include both agents that decrease aqueous humor production and agents that increase the outflow facility. Such therapies are in general administered by one of two possible routes, topically (direct application to the eye) or orally.
There are some individuals who do not respond well when treated with certain existing glaucoma therapies. There is, therefore, a need for other topical therapeutic agents that control IOP.
It has been found that serotonergic compounds which possess agonist activity at 5-HT
2
receptors effectively lower and control normal and elevated IOP and are useful for treating glaucoma, see commonly owned co-pending application, PCT/US99/19888. Compounds that act as agonists at 5-HT
2
receptors are well known and have shown a variety of utilities, primarily for disorders or conditions associated with the central nervous system (CNS). U.S. Pat. No. 5,494,928 discloses certain 2-(indol-1-yl)-ethylamine derivatives that are 5-HT
2C
agonists for the treatment of obsessive compulsive disorder and other CNS derived personality disorders. U.S. Pat. No. 5,571,833 discloses tryptamine derivatives that are 5-HT
2
agonists for the treatment of portal hypertension and migraine. U.S. Pat. No. 5,874,477 discloses a method for treating malaria using 5-HT
2A/2C
agonists. U.S. Pat. No. 5,902,815 discloses the use of 5-HT
2A
agonists to prevent adverse effects of NMDA receptor hypo-function. WO98/31354A2 discloses 5-HT
2B
agonists for the treatment of depression and other CNS conditions. Agonist response at the 5-HT
2A
receptor is reported to be the primary activity responsible for hallucinogenic activity, with some lesser involvement of the 5-HT
2C
receptor possible [Psychopharmacology, Vol. 121:357, 1995].
Certain 2-acylamino benzimidazole analogs have been reported [
Chemistry of Heterocyclic Compounds
33, 293 (1997),
Eur. J. Med. Chem
. 33, 685 (1998)]. No utility has been associated with these compounds.
SUMMARY OF THE INVENTION
The present invention is directed to derivatives of 2-acylaminobenzimidazole which can be used to lower and control IOP associated with normal-tension glaucoma, ocular hypertension, and glaucoma in warm blooded animals, including man (Compounds). The compounds are formulated in pharmaceutical compositions suitable for topical delivery to the eye.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Compounds that are useful for lowering and controlling normal or elevated intraocular pressure (IOP) and treating glaucoma according to the present invention are represented by the following Formula I.
Wherein:
X=H, F, Cl, Br, OR
1
, CN, C(═O)R
1
, C(═O)NR
1
R
2
, C
1-6
alkyl, OC(═O)R
1
, OC(═O)NR
1
R
2
, or CF
3
;
R, R
1
, R
2
=H or C
1-6
alkyl;
Y=CH
2
NRR
2
or CHR
1
NRR
2
,
Z=CH or N
R
3
=H, F, Cl, Br, OR
1
, CN, C
1-6
alkyl or CF
3
; and
R
4
=H, C
1-3
alkyl, F, Cl, Br, I or CF
3
.
The preferred compounds are those in which: X=H, F, Cl, Br, OR
1
, or C
1-3
alkyl, and R
1
=H, Z=CH.
The most preferred compounds are those wherein: X=H, F, Cl, Br, OR
1
, C
1-3
alkyl, or CF
3
; R and R
2
=CH
2
CH
3
; and R
4
=CH
3
, Z=CH.
Novel compounds are represented by the following Formula I.
Wherein:
X=H, F, Cl, Br, OR
1
, CN, C(═O)R
1
, C(═O)NR
1
R
2
, C
1-6
alkyl, OC(═O)R
1
, OC(═O)NR
1
R
2
, or CF
3
;
R, R
1
, R
2
=H or C
1-6
alkyl;
Y=CH
2
NRR
2
or CHR
1
NRR
2
or with the proviso that when X=H, Y does not equal CH
2
N(CH
2
CH
3
)
2
;
Z=CH or N
R
3
=H, F, Cl, Br, OR
1
, CN, C
1-6
alkyl or CF
3
; and
R
4
=H, C
1-3
alkyl, F, Cl, Br, I or CF
3
.
It is recognized that compounds of Formula I can contain one or more chiral centers. This invention contemplates all enantiomers, diastereomers, and mixtures thereof.
In the above definitions, the total number of carbon atoms in a substituent group is indicated by the C
i-j
prefix where the numbers i and j define the number of carbon atoms; this definition includes straight chain. branched chain, and cyclic alkyl or (cyclic alkyl)alkyl groups.
It is important to recognize that a substituent may be present either singly or multiply when incorporated into the indicated structural unit. For example, the substituent halogen, which means fluorine, chlorine, bromine, or iodine, would indicate that the unit to which it is attached may be substituted with one or more halogen atoms, which may be the same or different.
SYNTHESIS
The desired substituted 2-acylaminobenzimidazoles can be prepared by the method below outlined:
The appropriately substituted 2-nitrofluorobenzene 1 is reacted with the aminoalkylamine derivative 2. Reduction of the resulting nitroaniline 3 by catalytic hydrogenation (Pd/C, H
2
) or by reaction with dithionite yields the diamine 4. Cyclization with cyanogen bromide leads to the desired 2-aminobenzimidazole 5. Acylation of the 2-aminobenzimidazole derivative 5 with an acid chloride in the presence of a base such as triethylamine provides the desired 2-acylaminobenzimidazole 6. The modification of the described synthetic method by the use of certain protecting groups as appropriate can be readily accomplished by one skilled in the art.
The Compounds of this invention, can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant). The Compounds are preferably 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 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, such as, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival 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, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the Compound i
Abdelmoula Namil
Hellberg Mark R.
Ruskinko Andrew
Alcon Inc.
Morris Patricia L.
Schultz Teresa J.
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