US20030134866A1 - Antipsychotic pharmaceutical composition - Google Patents

Abstract

A pharmaceutical composition useful in treating psychosis contains a therapeutically effective amount of 2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one as an active ingredient.

Description

FIELD OF THE INVENTION
• The invention of the present application is related to a method of using 2-[piperidinyl]methyl-2,3 -dihydroimidazo [1,2-c]quinazolin-5(6H)-one in treating psychosis in a patient. [0001]
BACKGROUND OF THE INVENTION
• U.S. Pat. No. 5,158,953 discloses synthesis of a novel series of 2-substituted methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones (-thiones) compounds, and they are found useful as an active ingredient for the prophylaxis and treatment of hypertension. [0002]
• U.S. Pat. No. 5,340,814 and U.S. Pat. No. 5,512,677 disclose a novel series of 3-substituted methyl-2,3-dihydroimidazo[1,2-c]quinazoline-5(6H)-ones (-thiones) compounds. These compounds are found useful as an active ingredient for the treatment of hypertension and dysuria. [0003]
• U.S. Pat. No. 5,932,584 discloses novel optically active 3-substituted methyl-5-methylthio-2,3-dihydroimidazo [1,2-c]quinazoline (I) and 3-substituted methyl-2,3-dihydroimidazo [1,2-c]quinazolin-5(6H)-one (II). These compounds are found useful as an active ingredient for the treatment of hypertension and dysuria. [0004]
• Heretofore, the series of 2-substituted or 3- substituted methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones (-thiones) compounds have not been found other pharmaceutical activity in addition to as an active ingredient for the treatment of hypertension and dysuria. [0005]
SUMMARY OF THE INVENTION
• A primary objective of the present invention is to provide a new use of 2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one in treating psychosis in a patient. [0006]
• An antipsychotic pharmaceutical composition provided according to the present invention comprises an antipsychosis therapeutically effective amount of 2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one having the following formula or a pharmaceutically acceptable salt thereof, as an active ingredient, in combination with a pharmaceutically acceptable carrier or diluent for the active ingredient: [0007]

  
• wherein R[0008] ¹ is C1-C6 alkylene, carbonyl, C1-C6 alkylene carbonyl or carbonyloxy; and R² is hydrogen, C1-C6 alkyl, C1-C6 alkoxy or halogen.
• Preferably, R[0009] ¹ is methylene or carbonyl, and more preferably is carbonyl.
• Preferably, R[0010] ² is hydrogen or halogen, more preferably is halogen, and most preferably is fluorine.
• Preferably, the antipsychotic pharmaceutical composition of the present invention is administered orally.[0011]
DETAILED DESCRIPTION OF THE INVENTION
• 2-[Piperidinyl]methyl-2,3-dihydroimidazo [1,2-c]quinazolin-5(6H)-ones were synthesized according to the method disclosed in U.S. Pat. No. 5,1858,953, the details of which are incorporated herein by reference. Dopamine D[0012] _2L receptor binding assay and serotonin 5-HT₂ receptor binding assay were conducted to evaluate these compounds as potential antipsychotic D_2L/5-HT₂ antagonists. It is believed that a significantly greater affinity for the 5-HT₂ receptor than for the D_2L receptor has the best possibility of exhibiting an atypical profile.
• Two compounds having D[0013] _2L/5-HT₂ affinity ratios less than 1 were evaluated as to their potential antipsychotic activities by testing their effects on apomorphine-induced climbing behavior in mice. Inhibition of climbing would suggest that a compound was a D_2L antagonist, a characteristic of all clinically effective antipsychotics.
• Dopamine D[0014] _2L Receptor Binding Assay
• This assay measures binding of [[0015] ³H]Spiperone to human dopamine D_2L receptors. CHO cells stably transfected with a plasmid encoding the human dopamine D_2L receptor were used to prepare membranes in modified Tris-HCl pH 7.4 buffer. A 20 μg aliquot of membrane, in the presence or absence of a test compound, was incubated with 0.16 nM [³H]Spiperone for 120 minutes at 25° C. Non-specific binding was estimated in the presence of 10 μM hapoperidol. Membranes were filtered and washed three times and the filters were counted to determine [³H]Spiperone specifically bound. [References: Grandy D K, Marchionni M A, Makam H, Stofko R E, Alfano M, Frothingham L, Fischer J B, Burker-Howie K J, Bunzow J R, Server A C. Proc. Natl. Acad. Sci. (USA) 86: 9762-9766, 1989; Bunzow J R, Van Tol H H, Grandy D K, Albert P, Salon J, Christie M, Machida C A, Neve K A, Civelli O. Nature 336: 783-787, 1988; Hayes G, Biden T J, Selbie L A, Shine J. Mol. Endocrin. 6: 920-926, 1992]
• Serotonin 5-HT[0016] ₂ Receptor Binding Assay
• This assay measures binding of [[0017] ³H]Ketanserin to serotonin 5-HT₂ receptors. Whole brain (except cerebellum) membranes of male Wistar derived rats weighing 175±25 g were prepared in Tris-HCl pH 7.7 buffer. A 10 mg aliquot of membrane was incubated with 0.5 nM [³H]Ketanserin for 40 minutes at 25° C. Non-specific binding was estimated in the presence of 1 μM Ketanserin. Membranes were filtered and washed three times and the filters were counted to determine [³H]Ketanserin specifically bound. [Reference: Leysen J E, Niemegeers C J, Van Nauten J M, Laduron D M. Mol. Pharmacol. 21: 301-314, 1982]

  TABLE 1
  Effect of 2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-
  5(6H)-one compounds on radioligand binding assay

  Inhibition %

  	Samples*	Concentration	D2L	5-HT2

  	PDC-121	30 nM	18	21
  	PDC-122	30 nM	13	2
  	PDC-123	30 nM	11	4
  	PDC-124	30 nM	14	62
  	PDC-125	30 nM	23	0
  	PDC-126	30 nM	29	11
  	PDC-127	30 nM	11	20
  	PDC-130	30 nM	16	88
  	PDC-131	30 nM	10	47
  	PDC-132	30 nM	15	5

• 2-[4-benzyl-1-piperazinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one [0018]
• PDC-122 (Example 5 in U.S. Pat. No. 5,158,953) [0019]
• 3-{2,3 -dihydroimidazo[1,2-c]quinazolin-5(6H)-one-2-yl}methyl-azaspiro-[5,5]undecane [0020]
• PDC-123 (Example 6 in U.S. Pat. No. 5,158,953) [0021]
• 2-[4-piperonyl-1-piperazinyl]methyl-2,3-dihydroimidazo[1,2-c]-quinazolin-5(6H)-one [0022]
• PDC-124 (Example 9 in U.S. Pat. No. 5,158,953) [0023]
• 2-[4-Benzyl-1-piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one [0024]
• PDC-126 (Example 12 in U.S. Pat. No. 5,158,953) [0025]
• 2-[1-benzylpiperidin-4-yl]aminomethyl-2,3-dihydroimidazo[1,2-c]-quinazolin-5(6H)-one [0026]
• PDC-127 (Example 11 in U.S. Pat. No. 5,158,953) [0027]
• 2-[4-(4-fluorobenzyl)-1-piperazinyl]methyl-2,3-dihydroimidazo[1,2-c]-quinazolin-5(6H)-one [0028]
• PDC-130 (Example 15 in U.S. Pat. No. 5,158,953) [0029]
• 2-[1-(4-p-fluorobenzoyl)piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]-quinazolin-5(6H)-one [0030]
• PDC-131 (Example 14 in U.S. Pat. No. 5,158,953) [0031]
• 2-[1-(4-chlorobenzhydryl)piperazinyl]methyl-2,3-dihydroimidazo[1,2-c]-quinazolin-5(6H)-one [0032]
• PDC-132 (Example 16 in U.S. Pat. No. 5,158,953) [0033]
• 2- [1-(4-methoxyphenyl)piperazinyl]methyl-2,3-dihydroimidazo[1,2-c]-quinazolin-5(6H)-one [0034]
• Effects on Apomorphine-induced Climbing Behavior [0035]
• Test substance was administered PO (30 mg/kg, initial dose) to a group of 3 ICR derived male or female mice preselected non-climbing animals weighing 22±2 gms placed in specially constructed cages. Climbing behavior was scored 0-2 for each animal from 30 to 60-minutes post-dosing: all four paws on floor=0, both forefeet holding the wall=1, all four paws on wall=2. Consequently, maximum possible group score was 2×3 mice=6. A score of 3 or more (≧3) during this 30 minute observation period denotes dopamine-agonist activity. Mice in which no significant dopamine agonist activity occurred were then used to determine antagonistic activity. Sixty minutes after administration of test substance PO (30 mg/kg), apomorphine (1 mg/kg, SC) was administered and the climbing behavior was observed and scored during the 30 minutes. In groups of three vehicles treated animals, this dose of apomorphine consistently induced climbing behavior with scores of 5-6 recorded. [Reference: Psychopharmacology 50: 1-6, 1976] Percentage inhibition of test substance on apomorphine-induced climbing behavior is calculated as follows: [0036] $\mathrm{Inhibitation}\%=\frac{\begin{array}{c}[\left(\mathrm{Scores}\mathrm{of}\mathrm{apomorphine}\mathrm{group}\right)-\\ \left(\mathrm{Scores}\mathrm{of}\mathrm{test}\mathrm{substance}\mathrm{group}\right)]\end{array}}{\left(\mathrm{Scores}\mathrm{of}\mathrm{apomorphine}\mathrm{group}\right)}\times 100\%$

  

  TABLE 2
  Effect on apomorphine-induced climbing behavior

  			Agonist act-
  Sample*	Route	dose	ivity (score)	Inhibition %

  Vehicle (2% Tween	PO	20 ml/kg	0	0
  80)
  PDC-124	PO	30 mg/kg	0	50
  PDC-130	PO	30 mg/kg	0	100
  PDC-130	PO	10 mg/kg	0	100
  PDC-130	PO	3 mg/kg	0	60
  PDC-130	PO	1 mg/kg	0	0

• Although the present invention has been described with reference to specific details of certain embodiments thereof, it is not intended that such details should be regarded as limitations upon the scope of the invention except as and to the extent that they are included in the accompanying claims. Many modifications and variations are possible in light of the above disclosure. [0037]

Claims (8)

What is claimed is:

1. An antipsychotic pharmaceutical composition comprising an antipsychosis therapeutically effective amount of

2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one having the following formula or a pharmaceutically acceptable salt thereof, as an active ingredient, in combination with a pharmaceutically acceptable carrier or diluent for the active ingredient:

wherein R¹ is C1-C6 alkylene, carbonyl, C1-C6 alkylene carbonyl or carbonyloxy; and R² is hydrogen, C1-C6 alkyl, C1-C6 alkoxy or halogen.

2. The antipsychotic pharmaceutical composition according to claim 1, wherein R¹ is methylene or carbonyl.

3. The antipsychotic pharmaceutical composition, wherein R¹ is carbonyl.

4. The antipsychotic pharmaceutical composition according to claim 1, wherein R² is hydrogen or halogen.

5. The antipsychotic pharmaceutical composition according to claim 2, wherein R² is hydrogen or halogen.

6. The antipsychotic pharmaceutical composition according to claim 3, wherein R² is halogen.

7. The antipsychotic pharmaceutical composition according to claim 6, wherein R² is fluorine.

8. The antipsychotic pharmaceutical composition according to claim 6, which is orally administered.