Derivatives of tryptamine and analogous compounds, and pharmaceutical formulations containing them
This invention relates to the administration of novel substituted tryptamines and related derivatives for the treatment of several types of medical conditions, such as prostate conditions, impotence, cardiovascula disorders, central nervous system and psychiatric disorders (such as sleep disorders, epilepsy and other convulsive disorders, anxiety, neurodegenerative diseases), chronobiological-based disorders (such as jet lag, delayed sleep syndrome, shift-work-associated sleep disorder or seasonal affective disorder), endocrine indications, neoplastic conditions, conditions associated with senescence, ophthalmological diseases, cluster headaches and migraines, and weight gain disorders.
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This application is a continuation-in-part of U.S. Ser. No. 10/381,976, which is a national stage filing of PCT/IL01/00989, filed Sep. 25, 2001.
FIELD OF THE INVENTIONThe present invention relates to new compounds which are derivatives of tryptamine and their analogs, pharmaceutical formulations containing them, and use of the compounds in the manufacture of medicaments for treating various diseases.
BACKGROUND OF THE INVENTIONMelatonin is the principal hormone secreted by the pineal gland in all vertebrates. In all mammals studied to date, including humans, a nocturnal rise in the production of melatonin by the pineal gland is evident; melatonin production by the body is acutely suppressed by light. Melatonin is involved in the coordination of photoperiod dependent and physiological processes. The ability of the animals or humans to respond to the melatonin signal may depend upon melatonin receptors. Melatonin acts on the CNS to affect neural mechanisms through receptors located in the brain. Additionally, a number of studies indicate the existence of direct effects of melatonin in peripheral organs via peripheral melatonin receptors. Melatonin receptors are present in the heart, lungs, prostate gland, gonads, white blood cells, retina, pituitary, thyroid, kidney, gut and blood vessels. Retention patterns of radioactive-melatonin injected to rats demonstrate melatonin accumulation in the brain, pituitary, lung, heart, gonads and accessory sex organs (Withyachumnarnkul et al., Life Sci 12:1757-65, 1986).
The synthesis and secretion of melatonin exhibit a circadian rhythm that changes with the seasons and with age, e.g., pubescence and senescence. There is very strong evidence that melatonin is important for the regulation of a variety of neural and endocrine functions, especially those that exhibit circadian and circannual rhythmicity.
Melatonin has been implicated in many human disorders. Some are known to be linked to chronobiological abnormalities. Melatonin has been administered to re-synchronize circadian rhythms that are out of phase with the local photoperiodical cycle. For example, sleep/wake disorders with rapid crossing of time zones (jet lag), or in delayed sleep phase syndrome (DSPS) patients, changes in work shifts, or those experienced by blind people can be treated with melatonin or melatonin analogs (see U.S. Pat. Nos. 4,600,723 and 4,666,086 of Short et al. and U.S. Pat. No. 5,242,941 of Lewy et al.).
However, it appears that melatonin also has direct sedative/hypnotic properties in normal human subjects (e.g., Waldhauser et al., Psychopharmacology, 100: 222-226, 1990; Vollrath et al., Bioscience 29:327-329, 1981: Dollins et al., Proc. Natl. Acad. Sci, 99:1824-1828, 1994, U.S. Pat. No. 5,403,851 of D'Orlando et al). Three melatonin receptor subtypes have been identified so far mt-1, MT-2 and Me11c (Barrett et al., Biol. Signals Recept., 1999, 8: 6-14). MT-2 is localized mainly in the central nervous system and mt-1, localized in the CNS as well as in peripheral organs such as kidney and the urogenital tract (Dubocovich et al., IUPHAR media, London, UK, 187-93, 1998). The presently known subtypes are not sufficient to evaluate the large variety of melatonin effects and additional receptor subtypes await discovery.
Melatonin has been demonstrated in a number of rodent experimental paradigms to have both anxiolytic (Golus and King, Pharmacol. Biochem. Behav., 41:405-408, 1992, Naranjo-Rodriguez et al., Soc. Neurosci. Abst. 18:1167, 1992; Golombek et al., Eur. J. Pharmacol, 237:231-236, 1993) and antiseizure activity (Brallowsky, Electroencephalo. clin. Neurophysiol. 41:314-319, 1976: Farielloet al., Neurology 27:567-570, 1977, Rudeen et al., Epilepsia 21:149-154, 1980; Sugden, J. Pharmacol Exp. Ther. 227:587-591, 1983; Golombek et al., Eur. J. Pharmacol 210:253-258, 1992). Recently, melatonin was found to improve the quality fo life in epileptic children on valproate monotherapy (Gupta, M. et al., Epilepsy Behav. 5(3):316-321 (June, 2004)).
Melatonin is effective in the treatment of cluster headache and migraine (Claustrat et al., Headache, 29:241-4, 1989). Melatonin may play a role in other psychiatric conditions, particularly depression, but also mania and schizophrenia (see Dobocovich “Antidepressant Agents”, U.S. Pat. No. 5,093,352; Miles and Philbrick, Biol. Psychiatry 23:405-425, 1988: Sandyk and Kay, Schizophr. Bull. 16:653-662, 1990). In some instance, psychiatric disorders may have underlying chronobiological etiologies (e.g. seasonal effective disorder) and are definite candidates for melatonin therapy.
Melatonin is involved in the regulation of circadian and circannual changes in body temperature. Administration of exogenous melatonin to humans lowers core body temperature (Strassman et al., J. Appl. Physiol, 71:2178-2182, 1991; Cagnacci et al., J. Clin. Endocrinol. Merab. 75:447-452, 1992). Melatonin may also possess analgesic properties (Sugden, J. Pharmacol. Exp. Ther. 227:587-591, 1983). Therefore, melatonin-like compounds may be useful as an alternative to non-steroidal anti-inflammatory, anti-pyretic drugs, such as aspirin, acetaminophen and ibuprofen.
Melatonin is an effective free radical scavenger and antioxidant. the efficacy of melatonin in inhibiting oxidative damage has been shown in a variety of neurological disease models where free radicals have been implicated as being in part causative of the condition. Thus, melatonin has been shown prophylactically to reduce amyloid beta protein toxicity of Alzheimer's disease, to reduce oxidative damage in several models of Parkinson's disease (dopamine auto-oxidation, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine), to protect against glutamate excitotoxicity, to reduce ischemia-reprefusion injury, to lower neural damage due to gamma-aminolevulinic acid (porphyria), hyperbaric hyperoxia and a variety of neural toxins. Since endogenous melatonin levels fall markedly in advanced age (Sack et al., J. Pineal Res. 4:379-388, 1986; Waldhauser et al., J. Clin. Endocrinol. Metab., 66:648-652, 1988; Van Coavorden et al., Am. J. Physiol. 260:E651-661, 1991), the implication of these findings is that the loss of this antioxidant may contribute to the incidence or severity of some age-associated neurodegenerative diseases (Reiter, R. J., Prog. Neurobiol. 56(3):359-384 (October, 1998). Therefore, neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) may be treated with melatoninergic compounds (Wu, Y. H., et al. J. Clin. Endocrinol. Metab. 88(12):5898-5906 (December 1988); Maurizi, Med. Hypotheses 31:233-242, 1990; Sandyk, Int. J. Neurosci. 50:37-53, 1990; Skene et al., Brain Rev. 528:170-174, (1990); Peoggeler, J. S. et al., J. Pineal Res. 33(3):186-187 (2002); Sandyk, R. and G. I. Awerbuch, Int. J. Neurosci. 72(1-2):95-106 (1993)). A significant age-related declline of the circadian amplitude of the melatonin rhythm is found in demented patients and the meltonin nocturnal peak is significantly correlated with the severity of the cognitive impairment, suggesting that derivatives interacting with the melatoninergic system could be effective in treating cognitive impairment (Magri, F. et al., J. Pineal res. 36(4):256-261 (2004)). Melatonin has been found to be useful for the care of patients with Alzheimer's type of dementia; it ameliorated sundowning and slowed evolution of cognitive impairment in Alzheimer's patients (Asayama, K. et al., J. Nippon Med. Sch. 70(4):334-341 (2003); Cardinali, D. P. et al., Neuro Endocrinol. Lett. 23 (supp 1):20-23 (2002)).
Numerous reports have documented the neuroprotective actions of melatonin in experimental models of ischemia/reperfusion injury (Stroke). As well as the beneficial pharmacologic actions of melatonin, several studies show that a relative deficiency of endogneous melatonin exaggerates neural damage due to stroke; this suggests that even physiologic concentrations of melatonin normally serve to protect the brain against damage (Reiter, R. J. et al, Ann NY Acad. Sci. 993:35-53(2003)).
Sleep disorders in the elderly have been shown to respond to melatonin treatment (Garfinkel et al., Lancet, 346:541-543, 1995, U.S. Pat. No. 5,498,423 of Zisapel). Soporific effects of melatonin (0.3-240 mg) have been reported in humans following intravenous, intranasal and oral administration. Apart from its soporific effects, exogenous melatonin may affect sleep via its phase-resetting action on the biological clock. Melatonin administration advanced sleep in delayed sleep syndrome patients, and synchronized sleep to the day-night cycles in blind subjects. The efficacy of melatonin (0.3-5 mg/os) for treatment of insomnia has been demonstrated in studies performed mainly with elderly patients, patients treated with atenolol and chronic heart patients, most of which patients have low or distorted melatonin rhythms. In some of these studies, formulations which release melatonin throughout the night were used, in order to circumvent fast clearance of the hormone and to mimic its endogenous profile (Nutrition, 1998, 14: 1-2; The Aging Male, 1998, 1: 1-8). Melatonin, 3 mg, given to patients with sleep disorders and dementia for 21 days, significantly augmented sleep quality and decreased the number of wakening episodes, while agitated behavior at night (sundowning) decreased significantly (Biol. Signals Recept. 1999, 8(1-2): 126-31).
We have recently found that melatonin treatment may be beneficial not only for improving sleep quality, but may also lead to an improvement in the general state of diabetic patients, as indicated by the decrease in HbA1c levels after long-term treatment.
Daily melatonin supplementation to male Sprague-Dawley rats, starting at middle age (10 months) and continuing into old age (22 months) via the drinking water at a dosage of 4 μg/ml, restored the age-related elevated levels of relative (% of body weight) retroperitoneal and epididymal fat, as well as plasma insulin and leptin levels to youthful (4 month) levels (Rasmussen et al., Endocrinology, 1999, 140(2): 1009-12).
Even osteoporosis may have a melatoninergic component (Sandyk et al., Int. J. Neurosci. 62:215-225, 1992). In fact, melatonin has been suggested to be an anti-aging, anti-stress hormone (Armstrong and Redman, Med. Hypotheses 34:300-309, 1991; Reiter, Bioassays, 14:169-175, 1992). This may be due to its action as a free radical scavenger (Pooggeler et al., J. Pineal Res. 14:151-168, 1993) or its interaction with the immune system (Maestroni and Conti, J. Neuroimmun. 28:167-176 1990; Fraschini et al., Acta. Oncol. 29:775-776 1990, Guerrero and Reiter, Endocr. Res. 18:91-113, 1992). Melatonin may protect from ischemic stroke (Cho et al., Brain Research 755:335-338, 1997), decrease cell-death in Alzheimer's disease (Pappola et al., J Neurosci 17:1683-90, 1997) and lower the risk of SIDS in young infants with low endogenous melatonin levels (Israel Patents Nos. 115861/2 and U.S. Pat. No. 5,500,225 of Laudon et al).
Related to the above are the findings that melatonin has oncostatic properties in a variety of cancers, the most studied being its effect on estrogen receptor positive breast cancers (Blasak and Hill, J. Neural. Transm. Suppl. 21:433-449, 1986; Gonzalez et al. Melanoma. Res. 1:237-243, 1991; Lissoni et al. Eur. J. Cancer 29A:185-189, 1993; Shellard et al. Br. J. Cancer 60:288-290, 1989; Philo and Berkowitz, J. Urol. 139:1099-1102, 1988; see U.S. Pat. No. 5,196,435 of Clemens et al. and U.S. Pat. No. 5,272,141 of Fraschini et al.). It is also possible that melatonin has antiproliferatlve effects on noncancerous cells as well and may be of use to treat benign tumors and proliferative diseases such as BPH (U.S. Pat. No. 5,750,557 and European Patent No. EP 0565296B of Zisapel) and psoriasis.
In animal models of tumorigenesis, the most common conclusion is that either experimental manipulations that activate the pineal gland or the administration of melatonin, reduces the incidence and development of chemically induced mammary tumors, whereas pinealectomy usually stimulates brest cancer growth (Blask, D. E., “The Pineal: an Oncostatic Gland?” in The Pineal Gland pp 253-284 (R. J. Reiter, ed.) (1984); Blask, D. E. and S. M. hill, “Melatonin and Cancer: Basic and Clinical Aspects” in Melatonin Clinical Perspectives pp 128-173 (A. Miles, D. R. S. Philbrick and C. Thompson, eds.) (1988);Sanchez-Barcel, E., et al., “effects of Melatonin on Experimental Mammary Cancer Development,” in Pineal update: From Molecular Mechaisms to CLinical Implications pp 361-368 (S. M. webb, M. Puig-Domingo, M. Moller and P. Pevet, eds. PJD Publications Ltd., NY). Epidemiiological studies have shown a low incidence of breast tumors in blind women as well as an inverse relationship between breast cancer incidence and the degree of visual impariment. since light inhibits melatonin secretion, the increase in melatonin circulating levels might be interpreted as a proof of the protective role of this hormone on mammary carcinogenesis (Coleman, M. P. and R. J. Reiter, Eur. J. Cancer 28 (2-3):501-503). A moderate increase in breast cancer risk also has been described among women who worked extended periods of rotating night shifts (light exposure during the night suprresses melatonin production) (Schernhammer, E. S. et al., J. Natl. Cancer Inst. 93(20):1563-1568).
The anticancer therapeutic activity of melatonin was demonstrated in glioblastoma patients treated with melatonin and was suggested for the treatment of brain tumor (Lissoni, P. et al., Oncology 53(1):43-46 (1996); Mandera M., Wiad Lek. 56(11-12) 569-573 (2003)).
A major portion of research on melatonin has been devoted to studying is effects on reproduction, particularly in seasonally breeding species (such as hamsters and sheep), in which melatonin is known to regulate fertility and puberty, hibernation, and coat color. These effects have obvious significance for animal husbandry use. Reproductive endocrine uses in humans for melatonin include: contraceptive and fertility agents, treatment for precocious puberty, treatment for premenstrual syndrome and hyperprolactinemia (Pevre et al., J. Clin. Endocrinol. Metab. 47:1383-1386, 1978; Purry et al., Am. J. Psychiatry 144:762-766, 1987: Waldhauser et al., Clin. Endocrinol. Metab. 73:793-796, 1991; Bispink et al., Pineal Res. 8:97-106, 1990; Cagnacci et al., J. Clin. Endocrinol. Metab. 73:210-220, 1991; Voordouw et al., J. Clin. Endocrinol. Metab. 74:107-108, 1992; see U.S. Pat. Nos. 4,855,305 and 4,945,103 of Cohen et al., and U.S. Pat. No. 5,272,141 of Fraschini et al.). It is likely that melatonin compounds may also be useful in other endocrine conditions, particularly those involving growth hormone (Cramer et al., Arzeneim-Forsch, 26:1076-1078,1976; Wright et al., Clin. Endocrinol. 24:375-382, 1986; Paccotti et al., Chronobiologica 15:279-288, 1988; Valcavi et al., Clin. Endocrinol. 39:139-199, 1993). Melatonin may serve to reduce prostate enlargement (see above-cited US and EP patents of Zisapel) Orally administered melatonin to castrated juvenile rats inhibited the androgen-dependent growth of the ventral prostate and the seminal vesicles. (Gilad et al., J. of Urol. 159:1069-73, 1998). Recently, we have demonstrated high affinity melatonin receptors in the human benign prostate epithelial cells, which may affect cell growth and viability (Endocrinology, 137:1412-17, 1996).
In addition to the pineal gland, the eye also synthesizes melatonin. Recently melatonin has been implicated in the control of intraocular pressure and may be of use in glaucoma (Samples et al., Curr, Eye, Res. 7:649-653, 1988; Rhode et al., Ophthalmic. Res. 25:10-15, 1993).
The kidney also expresses melatonin receptors and melatonin has been shown to affect vasopressin and urine excretion (Song et al., FASEB J 11:93-100, 1997, Yasin et al., Brain Res. Bull 39:1-5, 1997).
It is clear that there exists a broad range of therapeutic uses for melatonin. Accordingly it is of continuing interest to identify novel compounds that interact with melatoninergic system as potential therapeutic agents. These compounds may offer longer duration, selective localization and greater efficacy to those of melatonin.
Novel compounds related to melatonin, but with pharmacological or pharmacokinetic profiles different from melatonin, are likely to be important new pharmaceuticals, For examples, see U.S. Pat. No. 5,403,851, which discloses the use of substituted tryptamines, phenylalkylamines and related compounds, in order to treat a number of pharmaceutical indications including sleep disorders, endocrine indications, immune-system disorders etc. PCT Patent Application No. WO 87/00432 describes compositions, for treating or preventing psoriasis, which contain melatonin or related compounds. European Patent Application No. 0330625A2 discloses the production of melatonin and analogs thereof, for various therapeutic purposes, including the administration of melatonin in combination with an azidothymidine for the treatment of AIDS. Melatonin analogs based on the bioisosteric properties naphthalenic ring and the indole ring has been disclosed in J. Med. Chem. 1992. 35:1484-1485, EP 662471 A2 950712 of Depreux et al., WO 9529173 A1 951102 of Ladlow et al., U.S. Pat. No. 5,151,446 of Horn et al., U.S. Pat. No. 5,194,614 of Adrieux et al. and U.S. Pat. No. 5,276,051 of Lesieur et al. 1
Inhibition by melatonin of dopamine release from specific brain areas has been demonstrated in vitro in rats (Zisapel et al., Brain Res 246(1):161-3 (1982)); sheep and hamsters (Malpaux et al. Reprod Nutr Dev 39(3):355-66 (1999)). In addition, melatonin was able to reduce excitability of nigrostriatal neurons (Escames et al Neuroreport 7(2):597-600 (1996)) and increase the affinity of D2 dopamine receptors in the rat striatum (Hamdi Life Sci 1998;63:2115-20). It may therefore treat disorders associated with increased dopamine release or dopamine supersensitivity, e.g. for tardive—dyskinesia, or cocaine addiction.
Melatonin antagonist are also of potential therapeutic use. A reduction in nigrostriatal dopaminergic activity as that caused by melatonin could lead to worsening of parkinsonian side effects and akathisia, as is indeed supported by findings in animal models of Parkinson disease (Willis and Armstrong Brain Res Brain Res Rev 1998;27(3):177-242). Melatonin antagonists may thus be helpful to prevent the effects of endogenous melatonin in Parkinson's disease. Melatonin antagonists may also be helpful in preventing fatigue and sleepiness of shift workers caused by the increase in endogenous melatonin at night; in blind persons that are not synchronized with the environmental light dark cycle, in delayed sleep phase syndrome patients who secrete melatonin during daytime and in jet lag.
There is evidence suggesting both melatonin agonists and antagonists would be of potential therapeutic use for a variety of maladies and conditions. The present invention addresses the need for more therapeutically selective compounds than melatonin.
The compounds N-(2,4-dinitrophenyl)-5-methoxytryptamine (“ML-23”) and N-(2,4-dinitrophenyl)-2-iodo-5-methoxytryptamine, are known to have antagonistic effects on melatonin (Zisapel et al 1989, U.S. Pat. No. 4,880,826, Laudon et al, J Endocrinol. 1988;116:43-53, Oaknin-Bendahan et al, Neuroreport 1995 27;6:785-8, Nordio et al Proc Soc Exp Biol Med 1989;191:321-5, Zisapel et al, Eur J Pharmacol 1987:136, 259-60). To the best of the present inventors' knowledge, it has never been previously suggested that other N-(2,4-dinitrophenyl)-5-methoxytryptamines, or their ether or thioether analogs, might have potential use for interacting with the melatoninergic system.
The entire contents of the above-cited patents, patent applications and literature articles are deemed to be incorporated herein by reference.
SUMMARY OF THE INVENTION In one aspect, the present provides compounds having the formula (I):
and their acid addition salts where the compounds are basic, wherein:
-
- each of R1, R2 and R3 is independently selected from among hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, NR′R″, N(R′)C(:O)R°, nitro, aryl, aryl-C1-4 alkyl, or aryl-C1-4 alkoxy, R° is C1-4 alkyl or aryl, and each of R′ and R″ is independently H or C1-4 alkyl, or R′=R″=ClCH2CH2, or NR′R″ constitutes a saturated heterocyclic ring containing 3-8 ring members; m is 0-4; t is 0-3; X is NH, N—C1-4 alkyl, O or S; provided that X is not NH when simultaneously (R1)m is 5-methoxy, R2 is H or I and t=0.
In the above definition, “aryl” is the monovalent residue of an unsubstituted or substituted aromatic nucleus, preferably a benzene ring, but it may also be e.g., another monovalent carbocyclic aryl residue such as naphthyl, or the monovalent residue of a heterocyclic aromatic ring such as furan, thiophene, pyrrole, pyridine, benzopyran or benzothiophene. When aryl is substituted, the substituent may be, e.g., one or more of hydroxy, C1-4-alkoxy, halogen, cyano, nitro, carboxylic acid, ester or amide, sulfonic acid, ester or amide, sulfone, sulfoxide or halogenated C1-4-alkyl such as chloro- or dichloro-methyl or CF3, amino, mono(C1-4-alkyl)amino, di(C1-4-alkyl)amino, or C1-4-alkyl.
In another aspect, the invention provides a pharmaceutical formulation which comprises at least one pharmaceutically acceptable diluent, preservative, solubilizer, emulsifier, adjuvant, and/or carrier, and at least one member of the group consisting of the compounds of the invention as defined above and pharmaceutically acceptable salts thereof.
In yet another aspect, the invention provides use of at least one member of the group consisting of the compounds of the invention as defined above and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for interacting with the melatoninergic system, e.g. a medicament for use in animal breeding, or for the prevention or treatment of prostate conditions, impotence, cardiovascular disorders, central nervous system and psychiatric disorders, chronobiological-based disorders endocrine indications, neoplastic conditions, immune system, conditions associated with senescence, ophthalmological diseases, cluster headache and migraine.
In still another aspect, the invention provides a method for treating a medical condition in a mammal (human or non-human) which is susceptible to alleviation by treatment with a medicament which interacts with the melatoninergic system, which comprises treating such condition with an effective amount of at least one member of the group consisting of the compounds defined in claim 1 and pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTIONWithout prejudice to the generality of the definition of the compounds of the present invention, presently preferred sub-groups of compounds having the above formula are the following:
-
- those wherein m=0, t=1, R3 is N(R′)C(:O)R° in the 3-position of the unfused benzene ring and X is NH, NH—C1-4 alkyl or O;
- those wherein m=1, t=1, R1 is methyl or methoxy in the 5-position of the indole ring, R3 is N(R′)C(:O)R° in the 3-position of the unfused benzene ring and X is NH, NH—C1-4 alkyl or O;
- those wherein m=0, t=1, R3 is NH2 in the 3-position of the unfused benzene ring and X is NH, NH—C1-4 alkyl or O;
- those wherein m=1, t=1, R1 is methyl or methoxy in the 5-position of the indole ring, R3 is NH2 in the 3-position of the unfused benzene ring and X is NH, NH—C1-4 alkyl or O;
- those wherein m=0 or 1, t=0, and when m=1, R1 is methyl in the 5-position of the indole ring.
The pharmaceutical formulation according to the invention is preferably characterized by at least one of the following features:
- (i) it is adapted for oral, rectal, parenteral, transbuccal, intrapulmonary (e.g. by inhalation) or transdermal administration;
- (ii) it is in unit dosage form, each unit dosage comprising an amount of said at least one member which lies within the range of 0.0025-1000 mg;
- (iii) it is a controlled release formulation, wherein said at least one member is released at a predetermined controlled rate.
In the pharmaceutical formulations of the present invention, the pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and carriers are those conventionally used in pharmaceutical and veterinary formulations. The present pharmaceutical formulations may be adapted for administration to humans and/or animals.
For oral administration, the pharmaceutical formulations may be utilized as e.g. tablets, capsules, emulsions, solutions, syrups or suspensions. For parenteral administration, the formulations may be utilized as ampoules, or otherwise as suspensions, solutions or emulsions in aqueous or oily vehicles. The need for suspending, stabilizing and/or dispersing agents will of course take account of the fact of the solubility or otherwise of the active compounds, in the vehicles which are used in particular embodiments. The formulations may additionally contain e.g. physiologically compatible preservatives and antioxidants.
The pharmaceutical formulations may also be utilized as suppositories with conventional suppository bases such as cocoa butter or other glycerides. Alternatively, the formulations may be made available in a depot form which will release the active composition slowly in the body, over a preselected time period.
The compounds of the invention may further be administered by using transbuccal, intrapulmonary or transdermal delivery systems.
By way of further elaboration or explanation of conditions which are amenable to treatment by administration of the present compounds, such conditions include benign and tumor prostate growth, and impotence; cardiovascular disorders including hypertension, unwanted blood coagulation ischemic strokes and brain damage associated with strokes; central nervous system and psychiatric disorders, e.g., sleep disorders, epilepsy and other convulsive disorders, anxiety, psychiatric diseases, such as depression, mania or schizophrenia, neuropathy, neurodegenerative diseases e.g. Alzheimer's, Parkinson's and Huntigton's diseases, MS, amyloid lateral sclerosis (ALS), conditions associated with dementia or cognitive impairment, fever and analgesia; chronobiological-based disorders, e.g., jet lag, circadian sleep disorders such as delayed sleep syndrome, sleep disorders associated with shift-work, and seasonal-related disorders e.g. seasonal affective disorder (SAD); endocrine indications, e.g., undesired fertility or infertility, precocious puberty, premenstrual syndrome, hyperprolactinemia, or growth hormone deficiency; neoplastic diseases including e.g. cancer and other proliferative diseases; immune system disorders including AIDS; conditions associated with senescence; ophthalmological diseases; cluster headache, migraine; Tardive dyskinesia, unstabilized diabetes; and weight gain disorders (leptin, obesity). the compounds further can be useful for administration to non-human mammals as an aid to breeding, e.g., regulation of fertility, puberty, or pelage color.
It is still further contemplated that the present compounds (and particularly those where in formula (I) having antioxidant and radical scavenging activity and the invention thus includes skin-protective and cosmetic compositions for topical application, such as (merely by way of illustrative examples) ointments, creams, salves and lotions, which comprise at least one compound according to the present invention, together with at least one diluent, carrier and adjuvant
The invention will be illustrated by the following Examples.
EXAMPLE 1 N-(2,4-dinitrophenyl)tryptamine (ML-25)
1 mMole of tryptamine was dissolved in 100 ml of water and the pH was adjusted to pH 8.3 with 2.5 moles of sodium bicarbonate (NaHCO3), A 1.5% solution of 2,4-dinitrofluorobenzene in 200 liters ethanol was added and the mixture was stirred during 2 hours at room temperature. The desired product precipitates out, it is washed and dried. The product is obtained in 90% yield, and TLC (chloroform, silica-gel plates, reveals one yellow spot (Rf=0.84) which is well resolved from the starting materials under the same conditions.
EXAMPLE 2 N-(2,4-dinitrophenyl)-5-methyltryptamine (ML-28)
1 mMole of 5-metyltryptamine was dissolved in 100 ml of water and the pH was adjusted to pH 8.3 with 2.5 moles of sodium bicarbonate (NaHCO3), A 1.5% solution of 2,4-dinitrofluorobenzene in 200 ml ethanol was added and the mixture was stirred during 2 hours at room temperature. The desired product precipitates out, it is washed and dried. The product is obtained in 85% yield, and TLC (chloroform, silica-gel plates, reveals one yellow spot (Rf=0.8) which is well resolved from the starting materials under the same conditions.
EXAMPLE 3 2,4-dinitro-5-tryptylaminoacetanilide (ML-26)
1 mMole of tryptamine was dissolved in 100 ml of water and the pH was adjusted to pH 8.3 with 2.5 moles of sodium bicarbonate (NaHCO3), A 1.5% solution of 2,4-dinitro-5-fluoroacetanilide in 200 ml ethanol was added and the mixture was stirred during 2 hours at room temperature. The desired product precipitates out, it is washed and dried. The product is obtained in 80% yield, and TLC (chloroform, silica-gel plates, reveals one yellow spot (Rf=0.76) which is well resolved from the starting materials under the same conditions.
EXAMPLE 4 2,4-dinitro-5-(5′-methyltryptyl)aminoacetanilide (ML-29)
1 mMole of 5-methyltryptamine was dissolved in 100 ml of water and the pH was adjusted to pH 8.3 with 2.5 moles of sodium bicarbonate (NaHCO3), A 1.5% solution of 2,4-dinitro-5-fluoroacetanilide in 200 ml ethanol was added and the mixture was stirred during 2 hours at room temperature. The desired product precipitates out, it is washed and dried. The product is obtained in 95% yield, and TLC (chloroform, silica-gel plates, reveals one yellow spot (Rf=0.7) which is well resolved from the starting materials under the same conditions.
EXAMPLE 5 2,4-dinitro-5-(5′-methoxytryptyl)aminoacetanilide (ML-30)
1 mMole of 5-methoxytryptamine was dissolved in 100 ml of water and the pH was adjusted to pH 8.3 with 2.5 moles of sodium bicarbonate (NaHCO3), A 1.5% solution of 2,4-dinitro-5-fluoroacetanilide in 200 ml ethanol was added and the mixture was stirred during 2 hours at room temperature. The desired product precipitates out, it is washed and dried. The product is obtained in 85% yield, and TLC (chloroform, silica-gel plates, reveals one yellow spot (Rf=0.57) which is well resolved from the starting materials under the same conditions.
EXAMPLE 6 N-(2,4-dinitro-5-aminophenyl)tryptamine (ML-27)
1 mMole of tryptamine was dissolved in 100 ml of water and the pH was adjusted to pH 8.3 with 2.5 moles of sodium bicarbonate (NaHCO3), A 1.5% solution of 2,4-dinitro-5-fluoroaniline in 200 ml ethanol was added and the mixture was stirred during 2 hours at room temperature. The desired product precipitates out, it is washed and dried. The product is obtained in 90% yield, and TLC (chloroform, silica-gel plates, reveals one yellow spot (Rf=0.57) which is well resolved from the starting materials under the same conditions
EXAMPLE 7 N-(2,4-dinitro-5-aminophenyl)-5′-methyltryptamine (ML-31)
1 Mole of 5-methyltryptamine was dissolved in 100 ml of water and the pH was adjusted to pH 8.3 with 2.5 moles of sodium bicarbonate (NaHCO3), A 1.5% solution of 2,4-dinitro-5-fluoroaniline in 200 ml ethanol was added and the mixture was stirred during 2 hours at room temperature. The desired product precipitates out, it is washed and dried. The product is obtained in 90% yield, and TLC (chloroform, silica-gel plates, reveals one yellow spot (Rf=0.59) which is well resolved from the starting materials under the same conditions.
EXAMPLE 8 N-(2,4-dinitro-5-aminophenyl)-5′-methoxytryptamine (ML-32)
1 mmole of 5-methoxytryptamine was dissolved in 100 ml of water and the pH was adjusted to pH 8.3 with 2.5 moles of sodium bicarbonate (NaHCO3), A 1.5% solution of 2,4-dinitro-5-fluoroaniline in 200 ml ethanol was added and the mixture was stirred during 2 hours at room temperature. The desired product precipitates out, it is washed and dried. The product is obtained in 95% yield, and TLC (chloroform, silica-gel plates, reveals one yellow spot (Rf=0.57) which is well resolved from the starting materials under the same conditions.
EXAMPLE 9 0-2,4-dinitrophenyl-5′-methoxytryptophol (ML-33)
To a solution of 5-methoxytryptophol 1 (700 mg, 3.7 mmol) in 3 ml of dichloromethane (DCM) was added dropwise a solution of 2,4-dinitro-5-fluoro benzene (205 mg, 4.0 mmol) in DCM, and the mixture was stirred under argon. Triethylamine (410 mg, 4.1 mmol) was added slowly and the mixture was stirred overnight, after which the solvent was evaporated. and TLC (chloroform, silica-gel plates, reveals one yellow spot (Rf=0.80) which is well resolved from the starting materials under the same conditions. The crude product was dissolved in chloroform (200 ml) and washed with 0.1 N HCl (2×200 ml), with 1 N NaOH (2×200 ml) and 1 with water (200 ml). The organic layer was dried with MgSO4 and concentrated in vacuo. Flash chromatography on silica gel, with chloroform as eluent, resulted in pure 5-methoxytryptophyl 2,4-dinitrophenyl ether (890 mg, 2.5 mmol, 67% yield) as a bright yellow powder.
Biological Testing of Compounds of the Invention
Experiment 1
Table 1: Effects of ML Compounds of the Invention on Glutamate-Induced Oxidative Toxicity in Hippocampal Cell Line (HT22)
The changes in the mithochondrial membrane potential was assessed using the fluorescent probe 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanine iodide (JC-1) according to Nuydens et al, 1999, L of Neuroscience;92, 153-9. Immortalized mouse hipocampal cells (HT-22) were maintained in Dulbecco's modified minimal essential medium (DMEM) supplemented with 10% fetal bovine serum and passaged by trypsinization. Cells (3000 per 96 palte well) were cultured for 24 h with DMEM containing 5 mM glutamate and were treated with 10−7 M of the ML compounds. Cells were then loaded with JC-1 by changing the culture medium to Phosphate buffered saline (PBS) containing 1 g/L glucose and 10 μM JC-1 for 10 min. at 370 and were washed once. Flouresence was then measured in a plate reader at excitation/emission wavelengths of 480/530 nm and 530/590 nm. The ratio of the fluoresence intensities in the two wavelengths 530/590:480/530 is an indication of the mitochondrial membrane potential. Decrease in this ratio indicates depolarization of the mitochondrial membrane due to damage induced by anoxic or other phathological situations leading to apoptosis of cells. The results (table 1) demonstrate the decreased fluorescence ratio by glutamate indicating damage to mitochondrial membrane potential in the hippocampal cells. Melatonin, ML-23 and four compounds of the invention (ML-25, ML-27, ML-26, ML-30) significantly protected against glutamate-mediated damage to the mitochondria so that the fluorescence ratio remained high compared to cells treated with glutamate. Among these, three (ML-23, ML-25, ML-26) did not decrease membrane potential of the control cells whereas others (ML-27 and ML-30) decreased it. Other compounds in the group presented in Table 1 (ML-29, ML-32, ML-31) decreased mitochondrial membrane potential in control cells without providing protection against glutamate and one (ML-28) elevated the potential in control cells but did not protect against glutamate induced damage.
This experiment indicates a direct inhibitory action of compounds of the invention on mitochondrial membrane potential, which resemble the effect of melatonin.
Experiment 2
125I-Melatonin Binding in Membranes of Rat Brain
Two whole rat brains were homogenized with Teflon-glass homogenizer in 10 vol/g tissue of ice cold Tris-HCl buffer (50 mmol/L Tris, 5 mmol/L CaCl2, pH=7.4) and spun at 10,000 g for 10 min. the supernatant were spun at 100,000 g for two hours to yield a crude synaptosomal pellet (P2). Aliquots of suspended P2 (20 ul) were incubated at 37° C. with 125I-melatonin (250 pM) for 60 min. in Tris-Hcl buffer in the absence or presence of 1 nM-100 μM test-substances (ML compounds and melatonin). The binding reaction was terminated by the addition of 4 ml ice cold Tris buffer. Membranes were then collected by vacuum filtration using GF/C glass fiber filters and washed with 3×4 ml ice-cold buffer. The filters containing the bound 125I-melatonin were assayed for the amount of radioactivity in a γ counter. The results (table 2) demonstrate the competition of ML compounds on specific 125I-melatonin binding to membrane fraction of rat brain. ML-29, ML-30 and ML-31 (10−6M) inhibited (≧20%) the specific 125I-melatonin binding. ML-27, ML-28 and ML-23 reduced the specific I-melatonin binding to a lesser extent (˜13%). Melatonin (10−6M) also decreased the specific I-melatonin binding to a similar extent (20%).
Experiment 3
The Effects of ML-25 and ML-23 on MPTP-Induced Parkinson's Disease in the Common Marmoset
The MPTP (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned primate is considered the “gold-standard” in terms of animal models of Parkinson's disease. MPTP has been shown to cause parkinsonism in man and monkey. This animal model has proved to be invaluable in defining the mechanisms underlying parkinsonism, as well as being predictive of potential therapies for alleviating parkinsonian symptoms (Nash, J. E., et al., Exp Neurol. 165(1):136-42 (September 2000) Antiparkinsonian Actions of Ifenprodil in the MPTP-lesioned Marmoset Model of Parkinson's Disease.)
MPTP-Treated Marmosets:
Five adult marmosets (328-424 g) obtained from Monash University Animal Services, Churchill, Victoria, Australia, were used in each of the trials. They were housed individually in wire mesh cages (0.6 m(w)×0.6 m(d)×2 m(h)) in pairs of adjacent cages and situated in a room such that visual contact by each pair with the other pairs was possible.
MPTP (Sigma-Aldrich Chemicals) was injected daily for 5 consecutive days (2 mg/kg s.c beneath the skin on the back to achieve a final dose of between 8-10 mg/kg), according to the method employed by Smith at al., Clin. Neuropharmacol. 23 (2), 133-142 (2000).
Drug administration: Study No 1: ML-23 (3 mg per kg body weight) or vehicle (10% DMSO in 1% soybean oil); Study No 2: ML-25 (3 mg per kg body weight), or vehicle (10% DMSO in 1% soybean oil) were administered via gavage onto the back of the tongue twice daily. The administration started 1 day after MPTP treatment was completed and continued for 55 days. All animals were force-fed until day 42 post-MPTP. Two marmosets in each group participated in a cross-over study for a period of 14 days, commencing from day 56.
The assignment of animals to drug groups was performed double blind by 2 persons outside the lab and the studies and assessments were conducted in a blinded fashion.
Behavioural Measures:
Vertical and Horizontal Movement:
For assessment of vertical and horizontal movement a wire cage similar in size to the home cage was constructed and fitted with laminated safety glass in the top and side panel. Video cameras were fitted approximately lm from the top and side glass surfaces and leads connecting the side video camera to VCR and leads connecting each camera to a computer were installed to permit recording and evaluation in an adjacent room.
Computer software was constructed to permit the recording of the number of beams broken from cameras overlooking the activity cage. The cameras employed were security cameras with motion detectors dividing the activity field into equal parts and signaling the number of passages from 1 segment of the field into another and the number of movements during the designated test period were recorded on a computer in an adjacent room.
Each animal was placed in the apparatus and then left to habituate for 3 to 5 minutes after the experimenter left the room. The clock was then started and the animal was observed for a 30 minute period. Activity measurements were made on days 2, 4 and 8 prior to MPTP administration and days 4, 9, 10, 39, 45, 47, 52, 54, 61, 66, 68 after ending MPTP administration.
Head Checking:
Head position was estimated for a period of 2 minutes and the position recorded at 2 second intervals giving a total number of 60 position readings during each session. The head position was recorded using the beat of a metronome to signal the moment of evaluation. If a clear view of the head was obscured during this test then position recording was omitted until the head position became unobscured. The number of changes in head position during each 120 sec. session were calculated from these records. This parameter was measured during test sessions held on days 4, 9, 39, 45, 52, 59 and 66 after MPTP administration was completed.
Clinical Assessment Scale:
Clinical assessment was undertaken in line with the parameters described previously by Treseder et al. 2000. Various measures of motor function, behavioral status and physiological state were assigned values on the basis of normality (0) and severe Parkinsonism (25) (possible total minimal and maximum scores). Animals were each assessed during the 30 minute session in the experimental chamber. This parameter was measured on days 4, 9, 39, 45, 52, 59, 61, 66 and 68 after MPTP administration was completed.
General Behavioral Assessment Scale:
Each animal was rated on several behavioral parameters at 3 minute intervals during the course of several 30 minutes sessions in the experimental chamber (giving 10 ratings per session). The behaviors generally ranged from normal behavior (climbing (+2), jumping(+2), bark chewing and stripping (+2), grooming/scratching (+2), playing (+2), hiding (+2), checking (+2) and looking (+1), to intermediate behavior (i.e. could be regarded as slightly parkinsonian or normal) and was rated as stationary (0), or parkinsonian features (including freezing (−2), tremor (−2), and obstinate progression/escape (−2)). This point system was based on the principle that each rating represents degrees of severity for each behavior exhibited and are expressed in the parenthesis next to each behavior with normal behaviors given a plus rating, intermediate behavior given a rating of zero and parkinsonian features rated with a minus score. The location in the cage and body position were also recorded. General behavior rating scales were done on days 47, 52, 54, 59, 61, 66 and 68 following MPTP administration.
Assessment of Positive Feature of MPTP Induced PD:
During the post-MPTP period several changes in behavior were noted during the daily exposure to the animals during routine care. Many exhibited a bizarre syndrome characterized in the less excessive form as pronounced agitation and frantic activity with flailing of the arms and legs (1). The occurrence of this stage was often detected by ruffled bedding in the home cage. The more excessive form was characterized by positioning their bodies into a corner of the cage and pushing relentlessly, as if trying to escape (2). This included prolonged periods of scratching frantically and biting at the cage and flailing the upper arms along the glass relentlessly as if trying to escape. This would persist for 1 to 5 minutes without stopping. In the most severe stage, some animals showed relentless forward progression resulting in severe skin abrasion of the head and broken or dislocated fingers (3). For the purpose of scoring these behaviors on a daily basis the basic components of increasing intensity were scored as indicated with the number in brackets. In addition, agitation(1) and tremor(2) were often observed during routine handling and these then were also assigned the values indicated to permit quantification. These features were recorded on a daily basis when observed during routine handling and care. These behaviors are a common component of DA degeneration and PD in the marmoset.
Results:
The results of the two experiments are summarized in the following table:
Values are given as a ratio between the change in the experimental drug group and the change in the placebo group in the same study.
Horizontal and vertical movements improved significantly after administration of ML-25 and ML-23 for 7-8 weeks (two and four fold increase in number of counts after a 30 minute trial for ML-23 and ML-25, respectively, over the amount under placebo).
ML-25 treatment significantly increased the amount of head checking during each 2 minute test. In the short term, those treated with ML-25 and ML-23 were 5 or 2 times better than those treated with vehicle, repectively, while in the long term those treated with ML-25 or ML-23 were 4 or 2 times better than after vehicle treatment, respectively.
In the short and longer term, all animals in the ML-25 and ML-23 groups were rated as exhibiting several magnitudes less parkinsonian features than those treated with vehicle, according to the clinical rating and general behavior scores. The animals in the ML-23 group were rated as normal in the clinical rating score after long term treatment.
After the cross-over, the monkeys newly treated with ML-25 and ML-23 exhibited significantly fewer Parkinsonian features than before the cross-over, and the occurrence of Parkinsonian features did not change when administration of ML-25 or ML-23 was stopped.
Similarly, the occurrence of features associated with parkinsonism, including the obstinate progression syndrome, tremor and agitation, occurred about four times more frequently in the vehicle treated animals than those treated with ML-23 for the entire 8 week period of observation. A less pronounced, but significant effect was seen in ML-25 treated animals. The occurrence of self-induced injury is a common encountered event when experimental PD is induced in marmosets. This occurred in 2 of the 3 animals treated with vehicle, but was not observed in any of the 3 marmosets maintained on ML-23.
After the cross-over, the ML-25- and ML-23-treated monkeys exhibited significantly fewer features associated with parkinsonism, and the occurrence of such features did not change when ML-25 or ML-23 administration was stopped.
Taken together, these results demonstrate that ML-23 and ML-25 can reverse the bradykinesia, rigidity and positive features associated with Parkinson's Disease in primates. ML-23 and ML-25 anti-symptomatic effect was sustained after the withdrawal of the drugs, lasting for at least two weeks. These results also show that these drugs also have antipsychotic features. They are also superior to DOPA treatment bacause they do not induce dyskinesia, tolerance or any other side effects associated with the treatment of DOPA in primates (humans included).
While the present invention has been particularly described with reference to certain embodiments, it will be apparent to those skilled in the art that many modifications and variations may be made. The invention is accordingly not to be construed as limited in any way by such embodiments, rather its concept is to be understood according to the spirit and scope of the claims.
Claims
1. A method for treating a mammal suffering from a medical condition susceptible to alleviation by treatment with a medicament which interacts with the melatoninergic system which comprises administering to the mammal an effective amount of a pharmaceutical formulation comprising at least one member of the group consisting of the compounds of formula I or a pharmaceutically acceptable acid addition salt thereof wherein each of R1, R2 and R3 is independently selected from among hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, NR′R″, N(R′)C(:O)R°, nitro, aryl, aryl-C1-4 alkyl, or aryl-C1-4 alkoxy, R° is C1-4 alkyl or aryl, and each of R′ and R″ is independently H or C1-4 alkyl, or R′=R″=ClCH2CH2, or NR′R″ constitutes a saturated heterocyclic ring containing 3-8 ring members; m is 0-4; t is 0-3; and X is NH, N—C1-4 alkyl, O or S; provided that X is not NH when simultaneously (R1)m is 5-methoxy, R2 is H or I and t=0, and that X is not S when simultaneously R2 is H and m=t=0.
2. The method of claim 1, wherein the medical condition comprises a prostate condition, impotence, cardiovascular disorder, central nervous system or psychiatric disorder, chronobiological-based disorder, endocrine indication, neoplastic condition, immune system disorder, condition associated with senescence, ophthamological disease, cluster headache and migraine, Tardive dyskinesia, diabetes or a weight gain disorder.
3. The method of claim 2, wherein said prostate condition comprises benign or cancerous prostate growth.
4. The method of claim 2, wherein said cardiovascular disorder comprises hypertension, undesired blood coagulation, ischemic stroke or brain damage from stroke.
5. The method of claim 2, wherein said central nervous system or psychiatric disorder comprises a sleep disorder, epilepsy or other convulsive disorder, anxiety, depression, mania, neuropathy, a neurodegenerative disease, MS, ALS, condition associated with dementia or cognitive impairment, fever or analgesia.
6. The method of claim 2, wherein said chronobiological-based disorder comprises jet lag, a circadian sleep disorder or seasonal-related disorder.
7. The method of claim 6, wherein said carcadian sleep disorder comprises delayed sleep syndrome or shift-work sleep disorder.
8. The method of claim 6, wherein said seasonal-related disorder is seasonal affective disorder.
9. The method of claim 2, wherein said endocrine indication comprises infertility, precocious puberty, premenstrual sysndrome, hyperprolactinemia, or growth hormone deficiency.
10. The method of claim 2, wherein said compound is administered as a contraceptive agent.
11. The method of claim 2, wherein said immune system disorder is AIDS.
12. The method of claim 2, wherein said weight gain disorder comprises leptin or obesity.
13. The method of claim 2, wherein said pharmaceutical formulation is characterized by at least one of the following features:
- (i) it is adapted for oral, rectal, parenteral, transbuccal, intrapulmonary or transdermal administration;
- (ii) it is in unit dosage form, each unit dosage comprising an amount of said at least one member which lies within the range of 0.0025-1000 mg;
- (iii) it is a controlled release formulation, wherein said at least one member is released at a predetermined controlled rate.
14. A method of treating a non-human mammal so as to regulate said mammal's fertility, puberty or pelage color which comprises administering to the mammal an effective amount of a pharmaceutical formulation comprising at least one member of the group consisting of the compounds of formula I or a pharmaceutically acceptable acid addition salt thereof, wherein each of R1, R2 and R3 is independently selected from among hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, NR′R″, N(R′)C(:O)R°, nitro, aryl, aryl-C1-4 alkyl, or aryl-C1-4 alkoxy, R° is C1-4 alkyl or aryl, and each of R′ and R″ is independently H or C1-4 alkyl, or R′=R″=ClCH2CH2, or NR′R″ constitutes a saturated heterocyclic ring containing 3-8 ring members; m is 0-4; t is 0-3; and X is NH, N—C1-4 alkyl, O or S; provided that X is not NH when simultaneously (R1)m is 5-methoxy, R2 is H or I and t=0, and that X is not S when simultaneously R2 is H and m=t=0.
15. A method for preventing a medical condition in a mammal which is susceptible to alleviation by treatment with a medicament which interacts with the mammal's melatoninergic system which comprises administering to the mammal an effective amount of a pharmaceutical formulation comprising at least one member of the group consisting of the compounds of formula I or an acid addition salt thereof, wherein each of R1, R2 and R3 is independently selected from among hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, NR′R″, N(R′)C(:O)R°, nitro, aryl, aryl-C1-4 alkyl, or aryl-C1-4 alkoxy, R° is C1-4 alkyl or aryl, and each of R′ and R″ is independently H or C1-4 alkyl, or R′=R″=ClCH2CH2, or NR′R″ constitutes a saturated heterocyclic ring containing 3-8 ring members; m is 0-4; t is 0-3; and X is NH, N—C1-4 alkyl, O or S; provided that X is not NH when simultaneously (R1)m is 5-methoxy, R2 is H or I and t=0, and that X is not S when simultaneously R2 is H and m=t=0.
16. The method of claim 15, wherein said condition comprises a prostate condition, impotence, cardiovascular disorder, central nervous system or psychiatric disorder, chronobiological-based disorder, endocrine indication, neoplastic condition, immune system disorder, condition associated with senescence, ophthamological disease, cluster headache and migraine, Tardive dyskinesia, diabetes or a weight gain disorder.
Type: Application
Filed: Aug 20, 2004
Publication Date: Jan 27, 2005
Applicant: Neurim Pharmaceuticals (1991) Ltd. (Tel Aviv)
Inventors: Nava Zisapel (Tel Aviv), Moshe Laudon (Kfar Saba)
Application Number: 10/921,823
