Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

• Bipolar mood disorder commonly begins with depression and is characterized by at least one elated period sometime during the course of the illness.
• bipolar I disorder full blown manic and major depressive episodes alternate.
• bipolar II disorder depressive episodes alternate with hypomanias (i.e., mild, nonpsychotic periods of excitement) of relatively short duration.
• insomnia and poor appetite do occur during the depressive phase of bipolar illness, such atypical depressive signs as hypersomnia and overeating are more characteristic and may recur on a seasonal basis (e.g., in the autumn or winter) .
• HCA heterocyclic antidepressants
• MAOI monoamine oxidase inhibitors
• lithium salts Merck, p. 1603
• HCA and MAOI drugs are indicated for the depressive phase of the bipolar disorder, lithium is known to attenuate the bipolar mood swings.
• rodent models relevant to the manic phase like amphetamine, amphetamine with chlordiazepoxide, morphine or desmethylimipramme induced hyperactivity or to the depression phase like immobilizations, are usually used (D.L. Murphy, Anim. Mod. Psych. Neur., 1977, pp. 211-225).
• a variety of substituted 1-am ⁇ nomdans have been proposed to have some activity m the central nervous system (CNS) .
• This group of compounds has a wide range of activities, for example, U.S. Patent No. 4,096,173 discloses 1-am ⁇ nomdans with ring chloro substituents as having anti-allergic, anti- spasmodic and local anesthetic activities, whereas U.S Patent No. 3,886,168 discloses the antl-inflammatory and vasodilatory activity of certain 1-ammomdans .
• U.S. Patent No. 3,637,740 discloses dl - l -N, N- dimethylammo- 4 -met oxy-7-chloromdane as an antidepressant and/or an antianxiety agent. However, no clear evidence is provided of either activity.
• the subject mvention describes a method of treating mania the bipolar mood disorder in a subject comprising administering to the subject a therapeutically effective amount of derivatives of 1-ammomdan, their racemic mixtures, enantiomers, and salts thereof, of the general formula :
• n is 0 or 1; each of R 1 and R 2 are hydrogen, C 1 -C 4 alkyl , halogen; R 3 is hydrogen, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy;
• R 4 is hydrogen, Ci-C 4 alkyl
• R 6 is hydrogen, substituted or unsubstituted alkyl, C 6 - C 12 aryl, C 7 -C 12 aralkyl or A-N-R 9 R 10 , provided that R 6 is not methyl when R 1 , R 2 , R 3 and R 4 are hydrogen atoms, wherein A is substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 7 -C 12 aralkyl, and each of R 9 and R 10 are independently hydrogen, C 1 -C 12 alkyl, C 6 -C 12 aryl, C 7 -C 12 aralkyl, COOtBu, or danyl ; and racemic mixtures, enantiomers, and salts thereof. Description of the Figures
• FIG. 1 shows four specific compounds discussed m the experiments: (R) -N-acetyl ammomdan (1), (S)-N-mdanyl glycinamide HC1 (2), (rac) -N- (2-ammoacetyl) -1 -ammomdan HC1 (3), (S) -N-formyl ammomdan (4).
• FIG. 2A-5B hereinafter describe the means ⁇ SE for activity counts measured for each group for 30 minutes, at 10 minute time intervals.
• the asterisk "*" denotes a significant difference from the control.
• Drug administration is mterpe ⁇ toneal (IP) .
• FIG. 2A shows the locomotor activity level for rats which have been administered (R) -N-acetyl ammomdan (1) as compared to the control .
• FIG. 2B shows the vertical activity level for rats which have been administered (R) -N-acetyl ammomdan (1) as compared to the control.
• FIG. 3A shows the locomotor activity level for rats which have been administered (S) -N-mdanyl glycinamide HC1 (2) as compared to the control .
• FIG. 3B shows the vertical activity level for rats which have been administered (S) -N-mdanyl glycinamide HC1 (2) as compared to the control .
• FIG. 4A shows the locomotor activity level for rats which have been administered (rac) -N- (2-ammoacetyl) -1-ammomdan (3) as compared to the control.
• FIG. 4B shows the vertical activity level for rats which have been administered (rac) -N- (2 -ammoacetyl) -1-ammomdan (3) as compared to the control.
• FIG. 5A shows the locomotor activity level for rats which have been administered (S) -N-formyl ammomdan (4) as compared to the control .
• FIG. 5B shows the vertical activity level for rats which have been administered (S) -N-formyl ammomdan (4) as compared to the control .
• This invention provides a method for the treatment of mania bipolar mood disorder using derivatives of 1-ammomdan or their racemic mixtures, enantiomers, and salts thereof.
• the present invention discloses a method of treating mania m bipolar mood disorder m a subject comprising administering to the subject a therapeutically effective amount of a compound of the formula:
• n is 0 or 1; each of R 1 and R 2 are hydrogen, C 1 -C 4 alkyl, halogen; R 3 is hydrogen, C x -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy; R 4 is hydrogen, C x -C 4 alkyl; R 6 is hydrogen, substituted or unsubstituted C ⁇ - C 12 alkyl, C 6 -C 12 aryl, C 7 -C 12 aralkyl or A-N-R 9 R 10 , provided that R 6 is not methyl when R 1 , R 2 , R 3 and R 4 are hydrogen atoms, wherein A is substituted or unsubstituted alkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 7 -C 12 aralkyl, and each of R 9 and R 10 are independently hydrogen, C 1 -C 12 alkyl, C 6 -C 2 aryl, C 7
• the compound is selected from the group consisting of (R) -N-acetyl ammomdan, (rac) -N-2-ammoacetyl -1-am ⁇ no ⁇ ndan HC1 and (S) -
• the subject is a human sub ect .
• the salt is selected from the group consisting of a hydrochloride salt, a mesylate salt, an ethylsulfonate salt, and a sulfate salt.
• the salt is a hydrochloride salt.
• the administration is selected from the group consisting of oral, mtrape ⁇ toneal , parenteral, topical, transdermal, rectal, nasal, and buccal administration.
• the therapeutically effective amount is an amount from 30 mg/kg to 150 mg/kg .
• the therapeutically effective amount is an amount from 30 mg/kg to 100 mg/kg. In a preferred embodiment of the invention, the therapeutically effective amount is an amount from 30 mg/kg to 75 mg/kg.
• Cohen et al disclose the preparation of the (R) -l- am omdan starting material, and certain novel representatives of ammomdan (U.S. Patents 5,877,221; 5,880,159; 5,877,218).
• the R- and S- enantiomers of each compound may be obtained by optical resolution of the corresponding racemic mixtures. Such a resolution can be accomplished by any conventional resolution method also disclosed in Cohen et al .
• IP mtrape ⁇ toneally
• Amphetamine (0.5 mg/kg, sub-cutaneous (s.c.), diluted in de- ionized water) was injected into all rats (both groups of each experiment) immediately prior to behavioral testing.
• compounds (R) -N-acetyl aminoindan (1); (S) -N-indanyl glycinamide HC1 (2); (rac)-N-(2- aminoacetyl) -1-aminoindan HC1 (3); and (S) -N-formyl aminoindan (4) were injected twice intraperitoneally (IP) at a dose of 75 mg/kg, 19 h and 3 h prior to behavioral testing in experiments. All compounds were suspended in a 5% methyl cellulose solution. The vehicle solution was administered to the control animals.
• Tables 1 and 2 The results of the experiment employing (R) -N-acetyl aminoindan (1) are shown in Tables 1 and 2, as well as FIG. 2A and 2B.
• Table 1 compares the activity counts for rats which have been administered intraperitoneal (R) -N-acetyl aminoindan (1) to control rats for three 10 minute intervals.
• FIG. 2A shows the locomotor activity level for rats which have been administered intraperitoneally (R) -N- acetyl-aminoindan (1) as compared to the control.
• FIG. 2B shows the vertical activity level for rats which have been administered intraperitoneally (R) -N-acetyl -aminoindan (1) as compared to the control .
• FIG. 3A shows the results of the experiment employing (S) -N-mdanyl glycinamide HCl (2) as compared to the control.
• Table 2 compares the activity counts for rats which have been administered (S) -N-indanyl glycinamide HCl (2) to control rats for three 10 minute intervals.
• FIG. 3A shows the locomotor activity level for rats which have been administered (S) -N-mdanyl glycinamide HCl (2) as compared to the control.
• FIG. 3B shows the vertical activity level for rats which have been administered (S) -N-mdanyl glycinamide HCl (2) as compared to the control.
• FIG. 4A shows the results of the experiment employing (rac)-N-(2- am oacetyl) -1-ammomdan HCl (3) to control rats for three 10 mmute intervals.
• FIG. 4A shows the locomotor activity level for rats which have been administered (rac) -N- (2-ammoacetyl) -1- ammomdan HCl (3) as compared to the control.
• FIG. 4B shows the vertical activity level for rats which have been administered (rac) -N- (2-ammoacetyl) -1-ammomdan HCl (3) as compared to the control .
• Table 4 compares the activity counts for rats which have been administered (S) -N-formyl aminoindan (4) to control rats for three 10 minute intervals.
• FIG. 5A shows the locomotor activity level for rats which have been administered (S) -N-formyl aminoindan (4) as compared to the control.
• FIG. 5B shows the vertical activity level for rats which have been administered (S) -N-formyl aminoindan (4) as compared to the control .

Landscapes

• Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• Psychiatry (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Priority Applications (7)

Applications Claiming Priority (2)

Publications (1)

Family

ID=22582876

Family Applications (1)

Country Status (9)

Cited By (1)

Families Citing this family (2)

Citations (3)

Family Cites Families (25)

• 2000
  • 2000-10-27 JP JP2001532759A patent/JP2003512426A/ja active Pending
  • 2000-10-27 DE DE60029131T patent/DE60029131T2/de not_active Expired - Lifetime
  • 2000-10-27 IL IL14930800A patent/IL149308A0/xx active IP Right Grant
  • 2000-10-27 EP EP00976661A patent/EP1242066B1/en not_active Expired - Lifetime
  • 2000-10-27 CA CA002387394A patent/CA2387394C/en not_active Expired - Fee Related
  • 2000-10-27 AT AT00976661T patent/ATE331508T1/de not_active IP Right Cessation
  • 2000-10-27 US US09/699,127 patent/US6492426B1/en not_active Expired - Fee Related
  • 2000-10-27 AU AU14402/01A patent/AU775885B2/en not_active Ceased
  • 2000-10-27 WO PCT/US2000/029618 patent/WO2001030339A1/en not_active Ceased
• 2002
  • 2002-04-23 IL IL149308A patent/IL149308A/en not_active IP Right Cessation

Patent Citations (3)

Also Published As

Similar Documents

Legal Events