Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-15
2003-12-16
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S392000, C514S913000
Reexamination Certificate
active
06664286
ABSTRACT:
The present invention is directed to the use of compounds with serotonergic 5HT
2
agonist activity (Compound) to treat glaucoma, which includes lowering intraocular pressure.
BACKGROUND OF THE INVENTION
Serotonin (5-hydroxytryptamine; 5HT) 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 (1992); Hoyer et al.,
Pharmacol. Rev.,
46, 157 (1994); Tobin et al.,
J. Neurosci.,
8, 3713 (1988)].
5HT can interact with at least seven major 5HT receptors (5HT
1
-5HT
7
) 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 et al., supra; Martin et al.,
Trends Pharmacol. Sci.,
19, 2 (1998)]. Receptor subtypes within the 5HT
1
family are negatively coupled to adenylyl cyclase (AC) and cause inhibition of cAMP production, while 5HT
4
, 5HT
6
, and 5HT
7
receptors are positively coupled to AC and thus stimulate cAMP production when activated by 5HT [Martin et al., supra]. The 5HT
3
receptor is unique in that it couples to an ion channel which gates sodium, potassium, and calcium [Hoyer et al., supra].
The receptors in the 5HT
2
family are positively coupled to phospholipase C (PLC) and thus generate inositol phosphates and mobilize intracellular calcium when activated by 5HT. The 5HT
2
receptor classification consists of the 5HT
2A
, 5HT
2B
, and 5HT
2C
receptor subtypes, all of which have highly homologous amino acid sequences. The receptor previously referred to as 5HT
1C
in an earlier nomenclature (prior to about 1990), has been reclassified as the 5HT
2C
receptor because of its greater similarity with other PLC coupled receptors of the 5HT
2
family, based on molecular cloning and its pharmacological characteristics (Hoyer, et al, 1994).
Serotonergic nerves innervate the eye [Tobin et al.,
J. Neurosci.,
8, 3713 (1988)] and 5HT has been found in the aqueous humor of human eyes [Martin et al.,
Ophthalmol.,
95, 1221 (1988)]. In addition, receptor binding sites for. [
3
H]5HT have been demonstrated and pharmacologically characterized in the iris-ciliary body (ICB) of rabbits [Mallorga and Sugrue,
Curr. Eye Res.,
6, 527 (1987) and Chidlow et al., Invest.
Ophthalmol. Vis. Sci.,
36, 2238 (1995)]. These 5HT binding sites have been shown to be functionally coupled to second messenger generation in rabbits [Tobin and Osborne,
J. Neurochem.,
53, 686 (1989) and Tobin et al.,
J. Neurosci, supra
]. In the human ICB these binding sites are characterized as 5HT
1A
and 5HT
2
receptors [Barnet and Osborne,
Exp. Eye Res.,
57, 209 (1993)]. In addition, the presence of mRNAs for 5HT
1A
and 5HT
7
receptors in the rabbit ICB have been reported [Chidlow et al.,
Invest. Ophthalmol. Vis. Sci.,
supra and Osborne and Chidlow,
Ophthalmologica,
210, 308 (1996)]. The precise functions of these receptors in the eye are unknown.
5HT or 5-carboxamidotryptamine (5-CT) topically applied to the rabbit eye raise intraocular pressure (IOP) [Meyer-Bothling et al.,
Invest. Ophthalmol. Vis. Sci.,
34, 3035 (1993)]. By contrast, another group has shown that topically applied 5HT decreased IOP in the rabbit; however, when 5HT was administered to the rabbit intracarnerally it resulted in an increase in IOP and caused breakdown of the blood-aqueous barrier [Krootila et. al.,
J. Ocular Pharmacol.,
3, 279 (1987)]. In addition, the 5HT uptake inhibitor, fluoxetine (Prozac®), also raises IOP in human subjects upon oral administration [Costagliola et al.,
Br. J Ophthalmol.,
80, 678 (1996)] and may cause glaucoma [Ahmad
Ann. Pharmacother.,
25, 436 (1992)]. However, the 5HT receptor subtype(s) involved in the IOP-elevating effects of 5HT, 5-CT and fluoxetine are unknown.
Studies conducted in rabbits with 8-hydroxy DPAT and MKC-242 (5HT
1A
agonists) have shown these compounds lower IOP [Osborne and Chidlow
Ophthalmologica,
210, 308 (1996), and EP 0771563-A2]. In addition, 5-methylurapidil (5HT
1A
agonist) lowered IOP in glaucomatous monkeys [Wang et al.,
Curr. Eye Res.,
16, 679 (1997)]. Both MKC-242 and 5-methylurapidil are relatively potent &agr;
1
receptor antagonists (&agr;
1
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 &agr;
1
antagonist activity and not its 5HT
1A
agonist activity [Wang et al.,
Invest. Ophthal Vis. Sci.,
39(Suppl), 2236 (1998)]. U.S. Pat. No. 5,693,654, discloses 5HT
1
-like (now designated 5HT
1D
) receptor agonists, such as sumatriptan, for lowering IOP. WO92/20338 discloses certain 5HT
1A
antagonists for the treatment of glaucoma.
Methysergide (5HT
2
antagonist, but with other activities) lowered IOP in rabbits [Krootila et al.,
Exp. Eye Res.,
supra]. Ketanserin (5HT
2A/C
antagonist), also with significant &agr;
1
antagonist activity, lowers IOP in rabbits and man [Chan et al.,
J. Ocular Pharmacol.,
1, 137 (1985) and Costagliola et al.,
Exp. Eye Res.,
52, 507 (1991)]. Saprogrelate (5HT
2A
antagonist) lowers IOP in rabbits and in man when dosed topically or orally [Mano et al.,
Invest. Ophthal. Vis. Sci.,
36(Suppl), 3322 (1995) and Takenaka et al.,
Invest Ophthal. Vis. Is Sci.,
36(Suppl), 3390 (1995)]. EP 522226 and U.S. Pat. No. 5,290,781 disclose the use of ketanserin and its derivatives for treating ocular hypertension. U.S. Pat. Nos. 5,290,781 and 5,106,555 disclose the use of certain 5HT
2
antagonists for lowering IOP. U.S. Pat. No. 5,652,272 discloses saprogrelate for reducing IOP. U.S. Pat. No. 5,538,974 discloses ophthalmic compositions of certain 5HT
2
antagonists for lowering IOP. WO/9911619 discloses 5HT
2A
antagonists which may be efficacious in treating glaucoma.
U.S. Pat. No. 5,011,846 discloses certain 5HT
3
receptor antagonists for treating glaucoma.
WO 97/17345 discloses that particular compounds with 5HT
4
serotonergic receptor 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 non-serotonergic receptors which are known to be involved in lowering IOP.
SUMMARY OF THE INVENTION
The present invention is directed to the use of compounds with 5HT
2
receptor agonist activity to treat glaucoma, which includes lowering intraocular pressure. Compositions of the compounds are contemplated for such uses.
DETAILED DESCRIPTION PREFERRED EMBODIMENTS
Unexpectedly, it has been found that serotonergic compounds which possess agonist activity at 5HT
2
receptors effectively lower and control elevated IOP and are useful for treating glaucoma.
Specific compounds which exemplify the present invention include: 1) (R)4-iodo-2,5 dimethoxy-&agr;-methyl-benzeneethanamine [(R)-DOI], the prototypical selective 5HT
2
agonist which is not selective amongst the 5HT
2
receptor subtypes [Baxter et al.,
Trends. Pharmacol. Sci.,
16, 105 (1995)]; 2) &agr;-methyl-serotonin, a potent 5HT
2
agonist with modest receptor subtype selectivity: 5HT
2B
>5HT
2C
>5HT
2A
[Baxter, et al., supra]; 3) 5-methoxy-&agr;-methyltryptamine, with a profile similar to that of &agr;-methyl-serotonin [Nichols et al.,
J. Med. Chem.,
31, 1406 (1998)]. The following references are not limiting, but rather exemplify Compounds useful according to the present invention and are incorporated herein by reference: U.S. Pat. Nos. 5,861,425; 5,64
Dean Thomas R.
Hellberg Mark R.
May Jesse A.
Sharif Najam A.
Alcon Manufacturing Ltd.
Schultz Teresa J.
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