NEW APPLICATION OF METAL COMPLEX

Abstract

A drug composition having the structure of formula I for the treatment of pain is provided. The drug can be given to an animal via oral, transdermal, rectal, intravenous, subcutaneous, sublingual or intraperitoneal administration, etc., thereby exerting an analgesic effect. The active components of the drug are convenient to prepare and easy to identify, and are structurally different from those of all other existing analgesic drugs, thus forming a novel class of effective analgesic compounds.

Claims

1. A method of treating pain comprising administering a pharmaceutical composition comprising a compound of formula I: ##STR00016## wherein M′=VO(IV), Co.sup.2+, Zn.sup.2+, MoO.sub.2(IV) or Pt.sup.2+; X.sub.1═O or S; X.sub.2═O or S; Y═O or NR.sub.4, and R.sub.1, R.sub.2, R.sub.3 or R.sub.4 is H, hydroxyl, mercapto, C.sub.1-C.sub.14 alkyl, hydroxy C.sub.1-C.sub.14 alkyl, C.sub.1-C.sub.14 alkoxy, mercapto C.sub.1-C.sub.14 alkyl, C.sub.1-C.sub.14 alkylthio, aryl or aryl C.sub.1-C.sub.14 alkyl.

2. A method of treating pain comprising administering a pharmaceutical composition comprising a compound of formula III: ##STR00017## wherein Y═O, R.sub.1, R.sub.2 and R.sub.3 are each hydroxy, mercapto, hydroxy C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkyl, mercapto C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkylthio, phenyl or phenyl C.sub.1-C.sub.4 alkyl; or Y═NR.sub.4, R.sub.3═H, R.sub.1, R.sub.2 and R.sub.4 are each hydroxy, mercapto, hydroxy C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkyl, mercapto C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkylthio, phenyl or phenyl C.sub.1-C.sub.4 alkyl.

3. A method of treating pain comprising administering a pharmaceutical composition comprising a compound of formula IV: ##STR00018## wherein, R.sub.1═H, and R.sub.232 Me; or R.sub.1═H, and R.sub.2═—CH.sub.2CH.sub.3; or R.sub.1═—CH.sub.2OH, and R.sub.2═H.

4. The method of claim 1, wherein the compound of the formula I is selected from the following compounds: bis(maltolato)platinum ##STR00019## bis(maltolato)zinc ##STR00020## bis(maltolato)dioxomolybdenum ##STR00021## bis(kojato)dioxomolybdenum (VI) ##STR00022## bis(maltolato)oxovanadium ##STR00023## bis(ethylmaltolato)oxovanadium ##STR00024## bis(kojato)oxovanadium ##STR00025## bis(3-hydroxy-1-methyl-4-pyridinonato)oxovanadium(IV) ##STR00026## bis(3-hydroxy-2-methyl-4-pyridinonato)cobalt(II) ##STR00027##

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0041] FIG. 1 is a graph showing the pain-inhibiting effects of bis(maltolato)oxovanadium (S1), bis(ethylmaltolato)oxovanadium (S2) and bis(kojato)oxovanadium (S3), wherein the horizontal coordinate represents time and the vertical coordinate represents pain threshold; the analgesic drug used in the positive control group is aspirin.

DETAILED DESCRIPTION

[0042] Drug Analgesic Activity Experiments

[0043] The analgesic assays of three vanadium compounds (bis(maltolato)oxovanadium, bis(ethylmaltolato)oxovanadium, and bis(kojato)oxovanadium) in mice are presented below. Some of the results are shown in FIG. 1, where S1 is bis(maltolato)oxovanadium, S2 is bis(ethylmaltolato)oxovanadium, S3 is bis(kojato)oxovanadium, and thepositive group (i.e., a positive control group) is aspirin group.

[0044] 10 μl of complete Freund's adjuvant (CFA) was injected subcutaneously into the plantar surface of the left hindpaws of mice (♂ Kunming mice, 22-40 g) to produce inflammation. Von Frey tests were performed at 24 hours after injection or later to determine pain thresholds, i.e., under the guidance of a Dixon's Up-Down method, mice were induced with Von Frey fibers to have mechanical withdrawal of their hindpaws data were collected, and their 50% paw withdrawal thresholds (referred to as paw withdrawal threshold or PWT), namely the pain thresholds, were calculated. Afterwards, the mice were divided into a physiological saline group, a positive control group and a drug group, and injected intraperitoneally with 0.4 ml of physiological saline, 0.4 ml of aspirin (acetylsalicylic acid, or ASA) Tris-buffer solution at a concentration of 20 mg/ml and a mixed solution of a tested compound and 0.4 ml of cellulose solution (1%), respectively. Then, changes in the pain threshold were monitored with the Von Frey tests.

[0045] Experiment 1: Analgesic Activity Test of bis(maltolato)oxovanadium(IV) (VO(ma).sub.2)

[0046] The source of bis(maltolato)oxovanadium(IV) (VO(ma).sub.2): synthesized using a literature method or purchased from Shanghai Dibai Chemical Technology Co. Ltd.

[0047] After intraperitoneal administration at a dose of 9 mg/kg (approximately 0.03 mmol/kg), all seven mice showed a response to the compound with a general increase in pain threshold.

[0048] Experiment 2: Analgesic Activity Test of bis(ethylmaltolato)oxovanadium(IV) (VO(ema).sub.2)

[0049] The source of bis(ethylmaltolato)oxovanadium(IV) (VO(ema).sub.2): synthesized using a literature method or purchased from Hubei Hongxin Ruiyu Fine Chemical Co. Ltd.

[0050] After intraperitoneal administration at a dose of 10 mg/kg (approximately 0.03 mmol/kg), all seven mice showed a response to the compound with a general increase in pain threshold.

[0051] Experiment 3: Analgesic Activity Test of bis(kojato)oxovanadium(IV) (VO(ka).sub.2)

[0052] The source of bis(kojato)oxovanadium(IV) (VO(ka).sub.2): synthesized using a literature method.

[0053] After intraperitoneal administration at a dose of 11 mg/kg (approximately 0.03 mmol/kg), all seven mice showed a response to the compound with a general increase in pain threshold.

[0054] The mice showed a significant decrease in the paw withdrawal threshold (FIG. 1) at 24 hours after the injection of CFA, which was manifested as mechanical hyperalgesia, indicating the development of inflammatory pain. At this time, the drugs, i.e., bis(maltolato)oxovanadium (S1 in FIG. 1), bis(ethylmaltolato)oxovanadium (S2 in FIG. 1), or bis(kojato)oxovanadium (S3 in FIG. 1), were injected, and a significant increase in the paw withdrawal threshold was found in mice with inflammatory pain. At 30 min after administration, S1, S2 or S3 increased the paw withdrawal threshold in mice with inflammatory pain from (0.072±0.0076) to (0.74±0.17) (P<0.01, n=7), (0.45±0.15) (P<0.01, n=7) and (0.52±0.23) (P<0.01, n=7), respectively, demonstrating a similar or stronger analgesic effect than that of aspirin.