| STRUCTURE | Indan-1-Ph-3-(NPr-Me) |
| PATENT ASSIGNEE'S COUNTRY | USA |
| UPDATE | 01.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | October 13, 1998 |
| PATENT TITLE |
Compounds for treating cocaine abuse |
| PATENT ABSTRACT |
Disclosed are novel compounds which are dopamine reuptake blockers for treating cocaine abuse. The compounds are represented by the following structural formula: ##STR1## R2 is n-propyl, iso-propyl, n-butyl, sec-butyl, or tert-butyl. Phenyl Ring B is unsubstituted or substituted with one, two or three substituents. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | August 15, 1997 |
| PATENT REFERENCES CITED |
S. Rosonzweig-lipson et al., "Stereoselective Behavorial Effects of Lu 19-005 in Monkeys: Relation to Binding at Cocaine Recognition Sites," Psychopharmacology, 107: 186-194 (1992). K. P. Bogeso, et al., 3-Phenyl-1-Indanamines Potential Antidepressant Activity and Potent inhibition of Dopamine, Norepinephrine and Serotonin Uptake, J. Med. Chem., 28:1817-1828 (1985). S. Izenwasser, et al., "Differential Relationships Among Dopamine Transporter Affiniities and Stimulant Potencies of Various Uptake inhibitors," European Journal of Pharmacology, 263:277-283 (1994). N. Tomita, "Structure-Actuvuty Relationaships of dopamine-a nd Norepinephrine-Uptake Inhibitors," Chem. Pharm. Bull. 38(6):1563-1569 (1990). M. Froimowitz, et al., "Slow Onset, Long Lasting Dopamine Reuptake Blockers as Potential Medications for the Treatment of Cocaine Abuse," 1996 Annual Meeting, Washington, D.C., Nov. 16-21, 1996, Abstract, Mail Date: Aug. 18, 1996. M. Froimowitz, et a;., "Effects of a Slow-Onset, Long-Acting Dopamine Reuptake Blocker on Cocaine Self-Administration and on Nucleus Accumbers Dopamine," Society for Neuroscience Abstracts, vol. 23, Part 1, 27.sup.th Annual Meeting, New Orleans, LA, Oct. 25-30, 1997, Mail Date: Aug. 25, 1997. Agenda for oral presentation at the National Instistute in Drug Abuse National Instistutes of Health Meeting entitled, "Cocaine Medications-Better Treatment Through chemistry," Scientific Meeting at the National Instistute on Drug Abuse, Apr. 29-30, 1996. Elliot L. Gardner, et al., Poster presented at meetings of the College on Problems of Drug Dependence, Nashville, Tennessee, Jun. 1997. |
| PATENT GOVERNMENT INTERESTS |
GOVERNMENT FUNDING This invention was made with Government support under Contract No. NO1DA-4-8313 awarded by the National Institute on Drug Abuse. The Government has certain rights in the invention. |
| PATENT CLAIMS |
What is claimed is: 1. A compound represented by the following structural formula: ##STR7## wherein R2 is n-propyl, iso-propyl, n-butyl, sec-butyl, or tert-butyl; and Ring B is unsubstituted or substituted with one, two or three substituents. 2. The compound of claim 1 wherein the compound has the trans sterochemistry. 3. The compound of claim 2 wherein the compound is represented by the following structural formula: ##STR8## wherein: R2 is n-propyl, iso-propyl, n-butyl, sec-butyl, or tert-butyl; and R5 and R6 are independently selected from the group consisting of --H, halogen, an alkyl group, a substituted alkyl group, hydroxy, (lower alkyl)--O--, (substituted lower alkyl)--O--, --CN, --NO.sub.2, amine, (lower alkyl) amine, (substituted lower alkyl) amine, (di-lower alkyl) amine and (substituted di-lower alkyl) amine. 4. The compound of claim 3 wherein R2 is n-propyl. 5. The compound of claim 4 wherein R5 and R6 are each --Cl. 6. The compound of claim 2 wherein R2 is n-butyl, sec-butyl or t-butyl. 7. The compound of claim 6 wherein R5 and R6 are each --Cl. 8. A compound represented by the following structural formula: ##STR9## -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
RELATED APPLICATIONS This application claims priority to U.S. Ser. No. 60/024,099, filed Aug. 16, 1996, the teachings of which are incorporated herein by reference. BACKGROUND OF THE INVENTION Drugs which block the reuptake of dopamine have many uses, including the treatment of individuals who abuse cocaine. It is believed that the abuse potential of cocaine is a result of its short onset of action (on the order of seconds) and its short duration of action (on the order of minutes). A slow onset, long duration dopamine reuptake blocker would have greatly reduced abuse potential and could be used as a treatment for chronic cocaine use. Many dopamine reuptake blockers are non-selective, and, for example, can inhibit the reuptake of other neurotransmittors such as serotonin and/or norepinephrine. Dopamine reuptake blockers which inhibit the reuptake of other neurotransmittors or bind other receptor sites have pharmacological profiles which differ from the pharmacological profile of cocaine. Preferred dopamine reuptake inhibitors for use in treating cocaine abuse have pharmacological profiles resembling the pharmacological profile of cocaine. Dopamine reuptake inhibitors which block the reuptake of other neurotransmittors also have the potential to cause undesirable side-effects. Consequently, there is a need to identify slow-onset long-duration dopamine reuptake blockers which do not block the reuptake of other neurotransimittors. SUMMARY OF THE INVENTION The present invention is directed to novel N,N-dialkyl 3-phenyl-1-indamines, which are slow-onset, long-lasting dopamine reuptake blockers. The use of N,N-dialkyl 3-phenyl-1-indamines for treating individuals who abuse cocaine, individuals with Parkinson's disease and individuals with attention deficit hyperactivity disorder are disclosed in co-pending U.S. Application, entitled SLOW-ONSET, LONG-LASTING DOPAMINE REUPTAKE BLOCKERS U.S. application Ser. No. 08/911,778, filed on Aug. 15, 1997, the entire teachings of which are incorporated herein by reference. One embodiment of the present invention is a novel compound represented by Structural Formula (I): ##STR2## Ring B is unsubstituted or substituted with one, two or three substituents other than hydrogen. Suitable substituents include halogen, an alkyl group, a substituted alkyl group, hydroxy, (lower alkyl)--O--, (substituted lower alkyl)--O--, --CN, --NO.sub.2, amine, (lower alkyl) amine, (substituted lower alkyl) amine, (di-lower alkyl) amine and (substituted di-lower alkyl) amine. R2 is n-propyl, iso-propyl, n-butyl, sec-butyl, or tert-butyl, preferably n-propyl. The compound represented by Structural Formula (I) preferably has the trans stereochemistry. Another embodiment of the present invention is a compound represented by Structural Formula (I), wherein R2 is ethyl, and Phenyl Ring B is substituted in the meta and para positions relative to carbon atom bonded to the indane group with --Cl (Compound 3). Another embodiment is a compound represented by Structural Formula (I), wherein R2 is an aralkyl group (--(CH.sub.2).sub.n -aryl or --(CH.sub.2).sub.n -(substituted aryl)). Phenyl Ring B is as described for Structural Formula (I) and n is an integer from one to about three. The compound preferably has the trans stereochemistry. The N-methyl-N-(n-propyl) 3-phenyl-1-indamines of the present invention, e.g., Compound 2, are superior, when used to treat cocaine abuse, to the corresponding N,N-dimethyl 3-phenyl-1-indamine, Compound 1, because Compound 1 selectively inhibits serotonin and norepinephrine reuptake (Example 5). In contrast, Compound 2 shows reduced inhibition of serotonin and norepinephrine reuptake and more closely resembles the pharmacological profile of cocaine (Example 5). Thus, N-methyl-N-(n-propyl) 3-phenyl-1-indamines such as Compound 2, are expected to be more efficacious and cause fewer side effects than the corresponding N,N-dimethyl compounds when substituted for cocaine during the treatment of individuals ______________________________________ ##STR3## ______________________________________ 1 R1 = methyl R2 = methyl 2 R1 = methyl R2 = n-propyl 3 R1 = methyl R2 = ethyl 4 R1 = H R2 = ethyl 5 R1 = H R2 = methyl 6 R1 = H R2 = t-butyl 7 R1 = methyl R2 = t-butyl ______________________________________ for cocaine abuse. It has also been found that the N-ethyl-N-butyl 3-phenyl-1-indamines (e.g., Compound 7) lock the effects of cocaine in laboratory mice while reducing locomotor activity (Examples 2 and 3). Thus, N-ethyl-N-butyl 3-phenyl-1-indamines such as Compound 7 can be used to treat individuals who abuse cocaine without causing the stimulatory effects of cocaine. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 is a graph showing the number of ambulation counts resulting from the stimulation of locomotor activity in mice over time by the administration of 1) vehicle; 2) 1 mg/kg of Compound 1; 3) 3 mg/kg of Compound 1; 4) 10 mg/kg of Compound 1; and 5) 30 mg/kg of Compound 1. FIG. 2 is a graph showing the average number of ambulation counts/10 minutes over 30 minutes resulting from the stimulation of locomotor activity in mice versus the dosage of Compound 1 administered to the mice. FIG. 3 is a graph showing the number of ambulation counts resulting from the stimulation of locomotor activity in mice over time by the administration of 1) vehicle; 2) 1 mg/kg of Compound 2; 3) 3 mg/kg of Compound 2; 4) 10 mg/kg of Compound 2; and 5) 30 mg/kg of Compound 2. FIG. 4 is a graph showing the average number of ambulation counts/10 minutes over 30 minutes resulting from the stimulation of locomotor activity in mice versus the dosage of Compound 2 administered to the mice. FIG. 5 is a graph showing the number of ambulation counts resulting from the stimulation of locomotor activity in mice over time by the administration of 1) vehicle; 2) 1 mg/kg of Compound 3; 3) 3 mg/kg of Compound 3; 4) 10 mg/kg of Compound 3; and 5) 30 mg/kg of Compound 3. FIG. 6 is a graph showing the average number of ambulation counts/10 minutes over 30 minutes resulting from the stimulation of locomotor activity in mice by Compound 3 versus the dosage of Compound 3 administered to the mice. FIG. 7 is a graph showing the number of ambulation counts resulting from the stimulation of locomotor activity in mice over time by the administration of 1) vehicle; 2) 1 mg/kg of Compound 4; 3) 3 mg/kg of Compound 4; 4) 10 mg/kg of Compound 4; and 5) 30 mg/kg of Compound 4. FIG. 8 is a graph showing the average number of ambulation counts/10 minutes over 30 minutes resulting from the stimulation of locomotor activity in mice 4 versus the dosage of Compound 4 administered to the mice. FIG. 9 is a graph showing the number of ambulation counts resulting from the stimulation of locomotor activity in mice over time by the administration of 1) vehicle; 2) cocaine; 3) cocaine and 1 mg/kg of Compound 2; 4) cocaine 3 mg/kg of Compound 2; 5) cocaine and 10 mg/kg of Compound 2; and 6) cocaine and 30 mg/kg of Compound 2. FIG. 10 is a graph showing the average number of ambulation counts/10 minutes over 30 minutes over thirty minutes resulting from the stimulation of locomotor activity in mice induced by the administration of 1) vehicle; 2) cocaine; 3) cocaine and 1 mg/kg of Compound 2; 4) cocaine 3 and mg/kg of Compound 2; 5) cocaine and 10 mg/kg of Compound 2; and 6) cocaine and 30 mg/kg of Compound 2. FIG. 11 is a graph showing the number of ambulation counts resulting from the stimulation of locomotor activity in mice over time by the administration of 1) vehicle; 2) 3 mg/kg of Compound 6; 3) 10 mg/kg of Compound 6; 4) 30 mg/kg of Compound 6 and 5) 100 mg/kg of Compound 6. FIG. 12 is a graph showing the average number of ambulation counts/10 minutes over 30 minutes resulting from the stimulation of locomotor activity in mice versus the dosage of Compound 6 administered to the mice. FIG. 13 is a graph showing the number of ambulation counts resulting from the stimulation of locomotor activity in mice over time by the administration of 1) vehicle; 2) 1 mg/kg of Compound 7; 3) 3 mg/kg of Compound 7; 4) 10 mg/kg of Compound 7; 5) 30 mg/kg of Compound 7 and 100 mg/kg of Compound 7. FIG. 14 is a graph showing the average number of ambulation counts/10 minutes over 30 minutes resulting from the stimulation of locomotor activity in mice versus the dosage of Compound 7 administered to the mice. FIG. 15 is a graph showing the number of ambulation counts resulting from the stimulation of locomotor activity in mice over time by the administration of 1) vehicle; 2) cocaine; 3) cocaine and 3 mg/kg of Compound 6; 4) cocaine 10 mg/kg of Compound 6; 5) cocaine and 30 mg/kg of Compound 6; and 6) cocaine and 100 mg/kg of Compound 6. FIG. 16 is a graph showing the average number of ambulation counts/10 minutes over 30 minutes over thirty minutes resulting from the stimulation of locomotor activity in mice induced by the administration of 1) vehicle; 2) cocaine; 3) cocaine and 3 mg/kg of Compound 6; 4) cocaine and 10 mg/kg of Compound 6; 5) cocaine and 30 mg/kg of Compound 6; and 6) cocaine and 100 mg/kg of Compound 6. FIG. 17 is a graph showing the number of ambulation counts resulting from the stimulation of locomotor activity in mice over time by the administration of 1) vehicle; 2) cocaine; 3) cocaine and 3 mg/kg of Compound 7; 4) cocaine 10 mg/kg of Compound 7; 5) cocaine and 30 mg/kg of Compound 7; and 6) cocaine and 100 mg/kg of Compound 7. FIG. 18 is a graph showing the average number of ambulation counts/10 minutes over 30 minutes over thirty minutes resulting from the stimulation of locomotor activity in mice induced by the administration of 1) vehicle; 2) cocaine; 3) cocaine and 3 mg/kg of Compound 7; 4) cocaine and 10 mg/kg of Compound 7; 5) cocaine and 30 mg/kg of Compound 7; and 6) cocaine and 100 mg/kg of Compound 7. FIG. 19 is a graph showing the effect on mice of 1) 5 mg/kg, 2) 10 mg/kg, 3) 20 mg/kg and 4) 40 mg/kg of cocaine compared with saline on horizontal activity counts/10 minute over an eight hour session. FIG. 20 is a graph showing the effect on mice of 1) 1 mg/kg, 2) 3 mg/kg, 3) 10 mg/kg and 4) 30 mg/kg of Compound 2 compared with saline on horizontal activity counts/10 minute over an eight hour session. DETAILED DESCRIPTION OF THE INVENTION In a preferred embodiment, the compound of the present invention is represented by Structural Formula (II): ##STR4## R2 is as described for Structural Formula (I). R5 and R6 are each --H or a substituent, as described for Ring B in Structural Formula (I). More preferably, R2 is n-propyl or tert-butyl. Even more preferably, R5 and R6 are each --Cl. In another preferred embodiment, the compound of the present invention is represented by Structural Formula (II), wherein R2 is a benzyl or substituted benzyl group. R5 and R6 are each --H or a substituent, as described for Ring B in Structural Formula (I). More preferably, R2 is a benzyl group. Even more preferably, R5 and R6 are each --Cl. An "aryl group" includes carbocyclic aromatic structures. An "aryl group" can be monocyclic (e.g., phenyl) or polycyclic. A polycyclic aromatic group includes moieties having one or more fused carbocyclic aromatic structures, e.g. naphthyl or anthracyl. Suitable heteroaryl groups include monocyclic or polycyclic aromatic groups containing one or more heteroatoms such as oxygen, nitrogen or sulfur. Suitable monocyclic heterocyclic groups include imidazolyl, thienyl, pyridyl, furanyl, oxazoyl, pyrollyl, pyrimidinyl, furanyl, pyrazolyl, pyrrolyl, thiazolyl and the like. A polycyclic heteroaryl group includes fused structures such as quinonyl, isoquinonyl, indoyl benzimidazoyl, benzothiazolyl, benzothiophenyl, benzofuranyl and benzopyranyl. A "lower alkyl group" includes C1 to about C10 straight or branched chain hydrocarbons. The hydrocarbon can be saturated or can have one or more units of unsaturation. Preferred lower alkyl groups are straight chain C1-C3 hydrocarbons. Alternatively, lower alkyl groups preferably include C1 to C4 straight chain and branched hydrocarbons. Suitable substituents for an aryl, heteroaryl, benzyl or lower alkyl group include substituents which do not signifiantly decrease the affinity of the N,N-dialkyl 3-phenyl-1-indamine for the dopamine transporter or the bioavailability of the N,N-dialkyl 3-phenyl-1-indamine. Suitable examples include halogens, lower alkyl, hydroxy, (lower alkyl)--O--, (substituted lower alkyl)--O--, --CN, --NO.sub.2, --NH.sub.2, (lower alkyl)NH--, (substituted alkyl)NH--, dialkylamine and (substituted dialkyl)amine. In the method of treatment disclosed herein the trans stereoisomer of the compound represented by Structural Formula (I) is preferentially administered. Examples of cis and trans stereoisomers are shown below. ##STR5## The compound can be administered as a racemic mixture of enantiomers, as an optically pure enantiomer or as a mixture enriched in one enantiomer. A "therapeutically effective" amount of a compound is the amount of compound which decreases or alleviates the severity of the symptoms associated with a disease, e.g., Parkinson's disease, attention deficit disorder or cocaine abuse, in an individual being treated with the compound. In the case of treatment of cocaine abuse, a "therapeutically effective" amount of a compound can be the amount of compound which decreases the craving for cocaine of an individual who abuses cocaine. Typically, a "therapeutically effective amount" of the compound ranges from about 1 mg/day to about 1000 mg/day. The compounds of the present invention can be administered by a variety of known methods, including orally, rectally, or by parenteral routes (e.g., intramuscular, intravenous, subcutaneous, nasal or topical). The form in which the compounds are administered will be determined by the route of administration. Such forms include, but are not limited to capsular and tablet formulations (for oral and rectal administration), liquid formulations (for oral, intravenous, intramuscular or subcutaneous administration) and slow releasing microcarriers (for rectal, intramuscular or intravenous administration). The formulations can also contain a physiologically acceptable vehicle and optional adjuvants, flavorings, colorants and preservatives. Suitable physiologically acceptable vehicles may include saline, sterile water, distilled water, Ringer's solution, and isotonic sodium chloride solutions. The specific dosage level of active ingredient will depend upon a number of factors, including, for example, biological activity of the particular preparation, age, body weight, sex and general health of the individual being treated. The pharmaceutical compositions used in the methods of treatment disclosed herein can contain one N,N-dialkyl 3--phenyl-1-indamine. Alternatively, the pharmaceutical composition can contain more than one N,N-dialkyl 3-phenyl-1-indamine, e.g. the individual is being administered a mixture of N,N-dialkyl 3-phenyl-1-indamines. When a mixture is being administered, virtually any ratio of N,N-dialkyl 3-phenyl-1-indamines can be used that is non-toxic and therapeutically effective. The compounds of the present invention used in the treatment of an individual with Parkinson's disease or attention deficit disorder can be co-administered with other pharmaceutically active agents used in the treatment of Parkinson's disease or attention deficit disorder. The compounds of the present invention used in the treatment of an individual who abuses cocaine can be combined with other therapies used to treat individuals who abuse cocaine. Such therapies can include the co-administration of other pharmaceutically active agents used to treat cocaine abuse or psychological therapies. When the compounds of the present invention are used in combination with other pharmaceutically active agents, the specific combination will vary, depending on a number of factors, including, for example, activity of the agents, their side-effects, and the weight, age, sex and general health of the individual being treated. The preparation of compounds of the present invention is shown in the Scheme and described more fully in Example 1. It is noted that compounds represented by Structural Formula (I) in which Ring A is an aryl group other than phenyl can be prepared by using the corresponding aryl aldehyde as a starting material in place of benzaldehyde. For example, compounds represented by Structural Formula (I) in which Ring A is a 1-naphthyl or 1-thiophene group can be prepared by using 1-CHO-napthalene or 1-CHO-thiophene as a starting material in place of benzaldehyde. ##STR6## |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
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