WO2003051291A2 - Substituted 5-hydroxy-indole compounds for the treatment of glaucoma - Google Patents

Abstract

The present invention provides novel compounds with 5-HT2 agonist activity, compositions containing the compounds and methods of their use to lower IOP and/or provide neuroprotection.

Description

SUBSTITUTED 5-HYDROXY-INDOLE COMPOUNDS FOR THE TREATMENT OF GLAUCOMA

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to treatment for lowering intraocular pressure and to

compounds for use in such treatments. More particularly, the present invention relates to

the use of compounds with serotonergic 5-HT₂ agonist activity to lower intraocular

pressure (IOP), treat glaucoma, and to provide neuroprotection.

2. Description of the Related Art

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 pressures. 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.

Serotonin (5-hydroxy tryptamine; 5-HT) is an endogenous biogenic amine with a

well defined neurotransmitter function in many tissues of the body including the eye [Zifa

and Fillion 1992; Hoyer et al. 1994; Tobin et al. 1988].

5-HT is known to interact with at least seven major 5-HT receptors (5-HT, - 5-

HT₇), 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. 1994; Martin et al. 1998]. Receptor subtypes within

the 5-HT, family are negatively coupled to adenylyl cyclase (AC) and cause inhibition of

cAMP production, while 5-HT₄, 5-HT₆, and 5-HT- receptors are positively coupled to AC

and thus stimulate cAMP production when activated by 5-HT [Martin et al. 1998]. The

receptors in the 5-HT₂ family are positively coupled to phospholipase C (PLC) and thus

generate inositol phosphates and mobilize intracellular calcium when activated to mediate

the effects of 5-HT. The 5-HT₃ receptor is unique in that it couples to an ion channel

which gates sodium, potassium, and calcium [Hoyer et al. 1994]. The human and animal 5-HT₇ receptor has only recently been cloned, expressed,

and shown to be present in various brain areas and peripheral tissues [Eglen et al. 1997].

Recent studies have shown there to be four splice variants of the 5-HT₇ receptor

[Heidmann et al. 1997]. It has been proposed that the 5-HT₇ receptor may be involved in

the pathophysiology of sleep disorders, depression, and other psychiatric disorders [Eglen

et al. 1997]. In the periphery, stimulation of 5-HT₇ receptors results in relaxation of blood

vessels and hence vasodilation [Eglen et al. 1997].

Known compounds exhibiting 5-HT₂ agonist activity have typically been designed

to treat numerous central nervous system (CNS)-related conditions, particularly the

treatment of obesity and depression, by activation of 5-HT_2C receptors. Thus, one desired

property of known 5-HT₂ agonist compounds is that they easily penetrate the blood brain

barrier. Compounds that readily penetrate the blood-brain-barrier by passive diffusion are

generally lipophilic molecules, which do not contain polar functional groups that might

impede this diffusion.

To treat ocular diseases, it is desirable to administer compositions orally or

topically that will remain in the ocular tissues and not cross the blood brain barrier to enter

the CNS. What are needed are 5-HT₂ agonist compounds that are useful in the treatment

of ocular diseases characterized by an elevated intraocular pressure, the treatment of

glaucoma, and also provide neuroprotection to the retina. Such compounds would not

have a high propensity to cross the blood brain barrier. SUMMARY OF THE INVENTION

The present invention overcomes these and other drawbacks of the prior art by

providing compounds having 5-HT₂ agonist activity that do not cross the blood brain

barrier. More specifically, the present invention provides compounds having the following

general formula:

Formula I:

wherein R¹ and R² are C,.₆alkyl or R¹ and R² can together complete a four to seven-

membered heterocyclic ring which may contain a second heteroatom selected from O, S,

NH, NC,-₄alkyl; R³ is hydrogen, C alkyl; R⁴, R⁵, and R⁷ are independently selected from

hydrogen, C,.₄alkyl, halogen, nitrile, C,.₆alkylthiol, trifluoromethyl; R⁶ is hydrogen, or

C(=O)C,.₈alkyl, which may be branched or unbranched. The compound, bufotenine,

discussed hereinbelow, is not within the scope of the compounds of the invention. In

preferred embodiments, R¹ and R² are methyl, R³ and R⁶ are hydrogen and R⁴, R⁵ and R⁷

are hydrogen or halogen. In more preferred embodiments, R⁶ is a branched C(=O)C,_.

₈alkyl. Most preferably, R⁶ is hydrogen or valproic acid.

In another aspect, the present invention provides compositions containing the

compounds described above in a pharmaceutically acceptable excipient. The compositions of the invention may also include bufotenine in a pharmaceutically acceptable excipient.

The compositions are most preferably in the form of topical ophthalmic formulations for

delivery to the eye. The compounds of the invention 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 to form the compositions of the invention.

The compositions of the invention are preferably formulated as topical ophthalmic

suspensions or solutions, with a pH of about 5 to 8. The compounds of the invention as

described above will normally be contained in these formulations in an amount .01% 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 according to the routine discretion of a skilled clinician.

The present invention further provides a method of lowering intraocular pressure in

a mammal by administering to a patient in need thereof a therapeutically effective amount

of a composition comprising a compound having the structure as described above. The

methods of the invention may include the use of compositions containing bufotenine. In

preferred embodiments, the composition can be administered systemically or locally to the

eye (e.g., topically, intracamerally, or via an implant).

DETAILED DESCRIPTION PREFERRED EMBODIMENTS

Unexpectedly, it has been found that serotonergic compounds which possess

agonist activity at 5-HT₂ receptors effectively lower and control elevated IOP and glaucoma. In addition, the compounds provide neuroprotective activity and are useful for

treating persons suffering from ocular diseases associated with neuronal cell death.

It has been found that serotonergic compounds which possess agonist activity at 5-HT₂

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-HT₂ receptors are known and have shown a

variety of utilities, primarily for disorders or conditions associated with the central nervous

system (CNS). U.S. Patent 5,494,928 discloses certain 2-(indol-l-yl)-ethylamine

derivatives that are 5-HT_2C agonists for the treatment of obsessive compulsive disorder and

other CNS derived personality disorders. U.S. Patent 5,571 ,833 discloses tryptamine

derivatives that are 5-HT₂ agonists for the treatment of portal hypertension and migraine.

U.S. Patent 5,874,477 discloses a method for treating malaria using 5-HT_2AΩC agonists.

U.S. Patent 5,902,815 discloses the use of 5-HT_2A agonists to prevent adverse effects of

NMDA receptor hypo-function. WO 98/31354A2 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 [Fiorella et al 1995].

A specific disclosure in co-pending application PCT/US99/19888 relates to certain

substituted α-methyltryptamines which are effective agents for lowering intraocular

pressure in mammals. However, when a phenolic moiety is included in this substitution,

e.g. a hydroxyl group at indole ring position five, such compounds can be particularly

sensitive to oxidation reactions well known to occur with phenolic compounds in general, including hydroxytryptamines [Hela et al. 1999; Wrona et al. 1998; Wrona et al. 1987;

Wrona et al. 1988], which are of particular relevance to the present application. Protection

of such hydroxy substituted tryptamines from oxidation can be accomplished by

derivatization of the aryl hydroxy group to provide a suitable ester, carbamate, or

carbonate. Though the ester, carbamate, or carbonate derivatives do not themselves

possess a high affinity for the above mentioned receptors, they do have utility in the

treatment of glaucoma since suitably protected phenols can be cleaved in vivo either by

chemical hydrolysis or through the action of tissue esterases, thereby delivering the desired

therapeutic agent, that is, the desired hydroxytryptamine compound in the present case.

The concept of utilizing such derivatized phenolic compounds as chemical delivery agents

is well known in the art [Lee et al. 1992; Bodor et al. 1984].

It has been found that 5-methoxy-N,N-dimethyl-tryptamine - (5-MeO-DMT) has a

high affinity for and potent efficacy at both the 5-HT₂ and 5-HT,_A receptors coupled with

an IOP lowering effect (WO 00/16761). Unfortunately, this compound is also known to

exhibit hallucinogenic activity [A. T. Shulgin et al. 1978]. Serotonin is a very polar

molecule, which does not readily cross the blood-brain barrier due, at least in part, to its

low lipid solubility. Similarly, N.N-dimethyl-serotonin [N,N-dimethyl-5-HT or

bufotenine] [DC₇₄ 0.15] would be expected to have a low propensity to penetrate the

blood-brain barrier relative to 5-MeO-DMT [DC₇₄ 3.3]. In fact, it has been demonstrated

that O-acetyl bufotenine does readily cross the blood-brain barrier and is rapidly

hydrolyzed to bufotenine in the brain, thus, providing a method of delivery of bufotenine

to the brain (Gessner et al. 1968; Gessner et al. 1975). Bufotenine has been reported to ellicit hallucinations in man. This observation is

based on a single small study (Fabing et al. 1956) (four males), which has been broadly

refuted based on other interpretations of the original observations (Fischer 1968) and

subsequent studies. It has been reported that up to 20 mg of bufotenine i.v., did not

produce hallucinations in humans (Turner 1959).

Though bufotenine has a low propensity to cross the blood-brain barrier, if it does

gain entry to the brain, e.g. via a prodrug modification, such as O-acetyl bufotenine, it

would be anticipated based on its pharmacological profile, to have a propensity to ellicit

marked central nervous system effects similar to 5-MeO-DMT (McBride 2000; Gessner et

al. 1962).

Bufotenine has not been reported to have IOP lowering activity, or any other

activity in the eyes. The present inventors have discovered that bufotenine effectively

lowers IOP in a lasered monkey model of ocular hypertension. Furthermore, bufotenine

has good affinity and acceptable agonist activity at both the 5-HT_2A and 5-HT,_A receptors.

The observed reduction in IOP following topical ocular administration of bufotenine, a

molecule known to have a very low level of transport to the brain, illustrates that ready

access to the CNS is not a requirement for achieving a significant reduction of IOP in the

monkey with a 5-HT₂ receptor agonist. This is a distinct advantage with regard to a

potential absence of significant CNS related side effects in man. The present inventors have discovered that compounds having the general formula

(Formula I) below are useful in treating patients with glaucoma, for lowering intraocular

pressure (IOP), and or to provide neuroprotective activity for retinal ganglion cells.

Formula I

In preferred compounds described by Formula I, R¹ and R² are C,_.6alkyl or R¹ and

R² can together complete a four to seven-membered heterocyclic ring which may contain a

second heteroatom selected from O, S, NH, NC_Malkyl; R³ is hydrogen, C alkyl; R⁴, R⁵,

and R⁷ are independently selected from hydrogen, C_Malkyl, halogen, nitrile, C,_.6alkylthiol,

trifluoromethyl; R⁶ is hydrogen or C(=O)C,.₈alkyl, which may be branched or unbranched,

provided that the compound is not bufotenine. The most preferred compounds are those

where R¹ and R² are methyl; R³, R⁴, R⁶ are hydrogen, R⁵, R⁷ are hydrogen, halogen, or

methyl. In one particularly preferred embodiment, R⁶ is a branched C(=O)C,.₈ alkyl. One

preferred branched C(=O)C,.₈alkyl is valproic acid. Valproic acid is a clinically proven

anti-epileptic and neuroprotective agent. The presence of valproic acid at the 5-hydroxyl

terminus of the compounds of the invention would enable the compounds to cross the

cornea after topical instillation. The compound would either be hydrolyzed or remain

intact to lower IOP and reach the back of the eye to protect the retina. 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 Ci-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.

The compounds of the invention can be made using known synthetic techniques.

For example, preparations of fluoro derivatives, particularly where R⁵ or R⁷ are fluoro,

follow the reported synthesis for related alkoxy compounds (Blair et al. 2000; Laban et al.

2001).

The compounds of the invention can be administered systemically or locally 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. Additionally, 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 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 of the invention 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 .01% 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 according to

the routine discretion of a skilled clinician. The compounds can also be used in combination with other IOP lowering agents,

such as, but not limited to, β-blockers, prostaglandins, carbonic anhydrase inhibitors, α-₂

agonists and miotics. The compounds can also be used in combination with other agents

useful for treating glaucoma, such as, but not limited to, calcium channel blockers and

NMDA antagonists. These agents may be administered topically, but usually systemically.

The following examples are included to demonstrate preferred embodiments of the

invention. It should be appreciated by those of skill in the art that the techniques disclosed

in the examples which follow represent techniques discovered by the inventor to function

well in the practice of the invention, and thus can be considered to constitute preferred

modes for its practice. However, those of skill in the art should, in light of the present

disclosure, appreciate that many changes can be made in the specific embodiments which

are disclosed and still obtain a like or similar result without departing from the spirit and

scope of the invention.

Example 1

Bufotenine was purchased as the oxylate salt from BioSynth International and

transformed by the inventors to the fumarate salt. This salt conversion was critical in

order to achieve a meaningful evaluation of the compound during in vivo tests in the

monkey. It has been observed that a compound, which is not well tolerated by rabbits

during a general ocular safety evaluation will also generally not be well tolerated by

monkeys when administered topically to the eye, thereby not providing a reliable

evaluation of the activity of the test compound in this model. Oxalic acid or oxalate salts are typically not well tolerated by rabbits when evaluated in such studies, and hence it is

not acceptable to potentially compromise the monkeys by exposure to oxalate salts.

To further assess the CNS activity of bufotenine, the inventors evaluated its

response in a mouse head-twitch assay. A positive response in this assay is well

documented to be initiated by activation of central 5-HT_2A receptors. Following

subcutaneous dosing (1-10 mg/kg), bufotenine did not initiate any observable head-twitch

responses in the test group of mice. However, when DOI, a selective 5-HT₂ agonist which

is known to readily enter the brain, was dosed in a similar manner a significant positive

response was observed within the test group of mice. The interpolated effective dose of

DOI that produced a mean of five twitches (ED₅) was determined to be 0.1 mg/kg. These

observations further support the lack of entry of bufotenine into the brain.

All of the compositions and/or methods disclosed and claimed herein can be made

and executed without undue experimentation in light of the present disclosure. While the

compositions and methods of this invention have been described in terms of preferred

embodiments, it will be apparent to those of skill in the art that variations may be applied

to the compositions and/or methods and in the steps or in the sequence of steps of the

method described herein without departing from the concept, spirit and scope of the

invention. More specifically, it will be apparent that certain agents which are both

chemically and structurally related may be substituted for the agents described herein to

achieve similar results. All such substitutions and modifications apparent to those skilled

in the art are deemed to be within the spirit, scope and concept of the invention as defined

by the appended claims. References

The following references, to the extent that they provide exemplary procedural or

other details supplementary to those set forth herein, are specifically incorporated herein

by reference.

United States Patents

5,494,928

5,571,833

5,874,477

5,902,815

Foreign Patents and Published Applications

PCT/US99/19888

WO 98/31354 A2

Books

A. T. Shulgin et al, in R. C. Stillman et al, The Psychopharmacology of

Hallucinogens, p 74 (1978).

Other Publications

Blair et α/., J. Med. Chem. 43:4701 (2000).

Bodor et al Pharm. Res., 168 (1984).

Eglen et al, Trend Pharmacol. Scl, 18:104-107, 1997.

Fabing etal, Science, 123:886 (1956). Fiorella et al Psychopharmacology, Vol. 121:357, 1995

Fischer, Nature, 220:441 (1968).

Gessner et al., Amer. J. Physiol. 203:167 (1962).

Gessner et al, Life Sci. 7:267 (1968).

Gessner et al, Pharmacologist, 17:259 (1975).

Heidmann et al, J. Neurochem., 68:1372-1381, 1997.

Hela etα/., J. Phys. Chem. 103, 8606 (1999).

Hoyer et al, Pharmacol. Rev., 46:157-203, 1994.

Laban et al, Bioorg. Med. Chem. Lett. 11 :793 (2001).

Lee et al, Drugs Pharm. Sci. 53 , 221 ( 1992).

Martin et al, Trends Pharmacol. Sci., 19:2-4, 1998.

McBride, J. Psychoactive Drugs, 32:321 (2000).

Tobin et al, J. Neurosci., 8:3713-3721, 1988.

Turner, Arch. Neurol. Psychiatry, 81 :121 (1959).

Wrona et al, Chem. Res. Toxicol 11 , 639 (1998).

Wrona et α/., J Org. Chem. 52, 2817 (1987).

Wrona et al, J. Pharm. Sci. 77, 911 (1988).

Zifa and Fillion, Pharmacol. Rev., 44:401-458, 1992.

Claims

We Claim:

1. A compound having the structure as follows:

wherein R¹ and R² are C,-₆alkyl or R¹ and R² can together complete a four to seven- membered heterocyclic ring which may contain a second heteroatom selected from O, S, NH, NC alkyl; R³ is hydrogen, C_Malkyl; R⁴, R⁵, and R⁷ are independently selected from hydrogen, C,.₄alkyl, halogen, nitrile, C,.₆alkylthiol, trifluoromethyl; R⁶ is hydrogen, or C(=O)C,.₈alkyl, which may be branched or unbranched, provided that the compound is not bufotenine.

2. The compound of claim 1, wherein R¹ and R² are methyl, R³ and R⁶ are hydrogen and R⁴, R⁵ and R⁷ are hydrogen or halogen.

3. The compound of claim 1 , wherein R⁶ is valproic acid.

4. A composition comprising at least one compound having the structure as follows and a pharmaceutically acceptable excipient:

wherein R¹ and R² are C,.₆alkyl or R¹ and R² can together complete a four to seven- membered heterocyclic ring which may contain a second heteroatom selected from O, S, NH, NC alkyl; R³ is hydrogen, C alkyl; R⁴, R⁵, and R⁷ are independently selected from hydrogen, C alkyl, halogen, nitrile, C,.₆alkylthiol, trifluoromethyl; R⁶ is hydrogen, or C(=O)C,.₈alkyl, which may be branched or unbranched.

5. The compound of claim 4, wherein R¹ and R² are methyl, R³ and R⁶ are hydrogen and R⁴, R⁵ and R⁷ are hydrogen or halogen.

6. The composition of claim 4, further comprising ophthalmologically acceptable preservatives.

7. The composition of claim 4, further comprising ophthalmologically acceptable surfactants.

8. The composition of claim 4, further comprising an agent to increase viscosity.

9. The composition of claim 9, wherein the agent is selected from the group consisting of hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, and polyvinylpyrrolidone.

10. The composition of claim 4, further comprising ophthalmologically acceptable preservatives, ophthalmologically acceptable surfactants and at least one agent to increase viscosity.

11. The composition of claim 4, further defined as a topical ophthalmic suspension or solution having a pH of about 5 to about 8.

12. The composition of claim 12, wherein the concentration of the compound is from .01% to 5% by weight.

13. The composition of claim 13, wherein the composition of the compound is from .25% to 2% by weight.

14. The composition of claim 4, further comprising at least one agent selected from the group consisting of β-blockers, prostaglandins, carbonic anhydrase inhibitors, α-₂ agonists and miotics.

15. The composition of claim 4, further comprising at least one agent selected from the group consisting of calcium channel blockers and NMDA antagonists.

16. A method of lowering intraocular pressure in a mammal, said method comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising a compound having the structure as follows:

wherein R¹ and R² are C,.₆alkyl or R¹ and R² can together complete a four to seven- membered heterocyclic ring which may contain a second heteroatom selected from O, S, NH, NC_Malkyl; R³ is hydrogen, C,.₄alkyl; R⁴, R⁵, and R⁷ are independently selected from hydrogen, C,-₄alkyl, halogen, nitrile, C,.₆alkylthiol, trifluoromethyl; R⁶ is hydrogen, or C(=O)C,_.galkyl, which may be branched or unbranched.

17. The method of claim 16, wherein R¹ and R² are methyl, R³ and R⁶ are hydrogen and R⁴, R⁵ and R⁷ are hydrogen or halogen.

18. The method of claim 17, wherein the composition is in the form of a topical ophthalmic suspension or solution.

19. The method of claim 17, wherein the composition is administered topically to the eye.