Patent Application
20100292257
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 providing an analgesic effect, anti-allergic effect and a histamine H1 receptor antagonism effect in a patient.
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.
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.
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.
U.S. Pat. No. 6,946,470B2 discloses a new use of 2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one in treating psychosis in a patient.
Heretofore, the 2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one compounds have not been found other pharmaceutical activity in addition to as an active ingredient for the treatment of hypertension, dysuria, and psychosis in patient.
An 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 providing an analgesic effect in a patient.
Another 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 passive cutaneous anaphylaxis in a patient.
Still another 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 eliciting a histamine H1 receptor antagonism effect in a patient to treat a disease or disorder.
Accordingly, the present invention provides a method of providing an analgesic effect to a patient in need thereof comprising administering to the patient an analgesia therapeutically effective amount of 2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one having the following formula (I) or a pharmaceutically acceptable salt thereof:
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.
The present invention also provides a method of treating a passive cutaneous anaphylaxis in a patient comprising administering to the patient a therapeutically effective amount of 2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one having the formula (I) recited above or a pharmaceutically acceptable salt thereof.
The present invention also provides a method of eliciting a histamine H1 receptor antagonism effect in a patient to treat a disease or disorder such as allergic rhinitis or asthma, which comprises administering to the patient a therapeutically effective amount of 2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one having the formula (I) recited above or a pharmaceutically acceptable salt thereof as a histamine H1 receptor antagonist.
Preferably, R1 is methylene or carbonyl, and more preferably is carbonyl.
Preferably, R2 is hydrogen or halogen, more preferably is halogen, and most preferably is fluorine.
Preferably, said 2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one is 2-[1-(4-p-fluorobenzoyl)piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]-quinazolin-5(6H)-one.
Preferably, said 2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one or a pharmaceutically acceptable salt thereof is orally administered.
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. 5,858,953, the details of which are incorporated herein by reference. Phenylquinone (PQ)-induced writhing assay and acetic acid-induced writhing assay were conducted to evaluate these compounds as a potential analgesic drug.
Passive cutaneous anaphylaxis assay was conducted to evaluate these compounds as a potential anti-allergic drug.
Histamine H1 antagonism assay was conducted to evaluate these compounds as a potential histamine H1 antagonist.
The invention is further described by means of example, but not in any limitative sense.
Percentages and other amounts referred to in this specification are by weight unless indicated otherwise. Percentages are selected from any ranges used to total 100%.
Vehicle (2% Tween 80, 10 ml/kg), PDC-130 or aspirin was orally administered to a group of eight CD-1 (Crl.) derived male mice weighing 24±2 g. One hour later, phenylquinone (2 mg/kg) was given by intraperitoneal injection. Writhes of animals was observed and recorded during a period of time from the 5th to 10th minutes after PQ administration, [Reference: Siegmund, E, Cadmus, R. and Lu, G. A method for evaluating both non-narcotic and narcotic analgesics. Proc. Soc. Exp. Biol. Med. 952: 729-731, 1957.]
As shown in Table 1 the extremely significant reduction in the number of writhes in PDC-130 treated animals as compared with the vehicle control group indicates a possible analgesic activity.
Vehicle (2% Tween 80, 10 ml/kg), PDC-130 or aspirin (100 mg/kg) was administered orally to groups of eight CD-1 (Crl.) derived male mice, weighing 24±2 g, 1 hour before intraperitoneal injection of acetic acid (0.5%, 20 ml/kg). The number of writhes of animals was observed and recorded during a period of time from the 5th to the 10th minutes period after acetic acid administration. [Reference: Inoue. K., Motonaga, A. and Nishimura, T. Mechanism of antiinflammatory action of etodolac. Arzneim-Forsch./Drug Res. 41: 235-239, 1991.]
As shown in Table 2 the extremely significant reduction in the number of writhes in PDC-130 treated animals as compared with the vehicle control group indicates a possible analgesic activity.
A group of five Wistar derived male rats weighing 80±20 g was passively sensitized 16 hours earlier by intradermal injection of reaginic antiovalbumin serum (0.5 ml) on two spots of the dorsal surface. Vehicle (2% Tween 80), PDC-130 or cyproheptadine was orally administered. Within one hour after administration of the above substances, the animals were challenged intravenously with a mixture of ovalbumin (1 mg) and Evans Blue dye (5 mg) and sacrificed 30 minutes later. The two wheal diameters were measured for each animal and scored as follows:
Maximum possible score for each animal total 5×2=10. [Reference: Goose, J. and Blair, A. M. J. N. Passive cutaneous anaphylaxis in the rat, induced with two homologous reagin-like antibodies and its specific inhibition with disodium chromoglycate. Immunology 16: 749-760, 1969.]
(Total score of vehicle group−Total score of tested group)/(Total score of vehicle group)×100%
It can be seen from Table 3 that the good inhibition percentages of the resulting passive cutaneous anaphylaxis blue colored wheal in the PDC-130 groups indicate a possible anti-allergic activity.
Vehicle (2% Tween 80), PDC-130 or cyproheptadine was orally administered to a group of five Wistar derived male rats weighing 80±20 g. After one hour, animals were injected with Evans Blue dye (5 mg/0.5 ml/rat) intravenously and immediately challenged with two intradermal injection of histamine (each 30 μg/0.05 ml). The animals were sacrificed 30 minutes later. The two wheal diameters were then measured for each animal and scored as follows:
Maximum possible score for each animal total 5×2=10.
It can be seen from Table 4 that the good inhibition percentages of the histamine-induced blue colored wheal in the PDC-130 groups indicates a possible histamine H1 receptor antagonism.
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.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0718678.6 | Sep 2007 | GB | national |
This application is a divisional application of pending U.S. patent application Ser. No. 11/907,853, filed Oct. 18, 2007 (of which the entire disclosure of the pending, prior application is hereby incorporated by reference).
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11907853 | Oct 2007 | US |
| Child | 12843364 | US |
