CA2244085C - Therapeutic anti-asthma agents containing selenium compounds - Google Patents
Therapeutic anti-asthma agents containing selenium compounds Download PDFInfo
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- CA2244085C CA2244085C CA002244085A CA2244085A CA2244085C CA 2244085 C CA2244085 C CA 2244085C CA 002244085 A CA002244085 A CA 002244085A CA 2244085 A CA2244085 A CA 2244085A CA 2244085 C CA2244085 C CA 2244085C
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- 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
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P11/08—Bronchodilators
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Abstract
The present invention provides a safe therapeutic agent for asthma which suppresses both immediate and late asthmatic responses in bronchial asthma. The therapeutic agent of the invention comprises, as an active component, a compound represented by the following formula (1) or (1'): (see formula 1) (see formula 1') or a pharmaceutically acceptable salt of the compound. The agent of the invention shows highly effects on both immediate and late asthmatic responses, and particularly on late asthmatic responses. The agent can be safely administered to humans as it has low toxicity.
Description
THERAPEUTIC ANTI-ASTHMA AGENTS CONTAINING SELENIUM
COMPOUNDS
BA_!C .RO TNP OF '-,~'HE Z~LtT~ION
gjeld Qf the Tnv _nt? cn:
The present invention relates to therapeutic agents for asthma that effectively suppress asthmatic responses, especially late asthmatic r3sponses, in bronchial asthma.
I?PSSr:n$.inS,Qf the Relat~d~ ;t~=
=. In general, bronchi,al asthma has been recognized as a disease which is characterized by contraction of smooth muscles in the airway due to type I anaphylaxis. However, recent advances in the research in this field have revealed a part of the pathogenesis of asthma, which is characterized by reversal airflow limitation, airway inflammation, mucus hypersecretion and remodeling of the airday structure due to c!zroni,c inf lammation . Phamaacologic therapy should be established beyond understanding of such pathogenesis.
At present available medications for asthma are relievers to reverse airtlow limitation like as a beta-aqonist and controllers to pzevent 3ymptoms by means of suppressing airway inflamtaation such as a corticosteroid inhalant. A beta-agonist acts quickly to relieve bronchoconstriction and its acompanying symptoms like cough, chest :ightness and wheezing. An inhaled corticosteroid used daily on a long term basis to achieve and maintain control of cersistent asthma.
However, beta-agonists have_a few adverse effects such as cardiovascular stimulation, skeletal muscle tremor, hypokalemia and irritability. on the other hand, an inhaled corticosteroid potentiates orophar-Ingeal candidiasis, dysphonia and occasional coughing from upper-airway irritation in spite that the risk for systemic effects of an inhalant is less than systemic corticosteroids. Long zerm use of oral or parenteral corticosteroids can cause serious adverse effects like as osteoporosis, arterial :iypertension, diabetes, hypothalamic-pituitary-adrenal axis suppression, cataracts, obesity, skin thinning leading to cuzaneous striae and easy bruiaability, and ,muscle weakness. Contr:,3l-ar agents are administered for a long period, and therefors t:e svstemic side effects of those agents should be avoided or minimized.
=rom the concept :h3t zontroller agents should have minimal adverse effects exceoz =or :najor bronchodilative or anti-inflammatory effects, ant:;.-allergic agents such as histamine receptor antagonists, i-su)co=riene receptor antagonists, thromboxane synthetase yzh~.bitors/re.ceptor antagonists were developed. :iowever, ,=hare itre insuf f i cient data about their clinical advantages in z_he long-term management of asthma, and then the development of more potent aintri-inflanuaatory agents and further clinical evaluation is expected.
It is suggested thaz late-onset asthmatic response after the immunochallenge is associated with airway inflammation.
Two kinds of asthmatic resovnses are observed immediate after the antigen-cha],lenge and several hours following that. The early reaction is refered as immediate asthmatic response(IAR) and following phenomenon as ].ate asth=aatic response(I.AR). IAR
has been recognized by airflow limitation which results from acute bronchoconstriction due to allergen exposure, while LAR
COMPOUNDS
BA_!C .RO TNP OF '-,~'HE Z~LtT~ION
gjeld Qf the Tnv _nt? cn:
The present invention relates to therapeutic agents for asthma that effectively suppress asthmatic responses, especially late asthmatic r3sponses, in bronchial asthma.
I?PSSr:n$.inS,Qf the Relat~d~ ;t~=
=. In general, bronchi,al asthma has been recognized as a disease which is characterized by contraction of smooth muscles in the airway due to type I anaphylaxis. However, recent advances in the research in this field have revealed a part of the pathogenesis of asthma, which is characterized by reversal airflow limitation, airway inflammation, mucus hypersecretion and remodeling of the airday structure due to c!zroni,c inf lammation . Phamaacologic therapy should be established beyond understanding of such pathogenesis.
At present available medications for asthma are relievers to reverse airtlow limitation like as a beta-aqonist and controllers to pzevent 3ymptoms by means of suppressing airway inflamtaation such as a corticosteroid inhalant. A beta-agonist acts quickly to relieve bronchoconstriction and its acompanying symptoms like cough, chest :ightness and wheezing. An inhaled corticosteroid used daily on a long term basis to achieve and maintain control of cersistent asthma.
However, beta-agonists have_a few adverse effects such as cardiovascular stimulation, skeletal muscle tremor, hypokalemia and irritability. on the other hand, an inhaled corticosteroid potentiates orophar-Ingeal candidiasis, dysphonia and occasional coughing from upper-airway irritation in spite that the risk for systemic effects of an inhalant is less than systemic corticosteroids. Long zerm use of oral or parenteral corticosteroids can cause serious adverse effects like as osteoporosis, arterial :iypertension, diabetes, hypothalamic-pituitary-adrenal axis suppression, cataracts, obesity, skin thinning leading to cuzaneous striae and easy bruiaability, and ,muscle weakness. Contr:,3l-ar agents are administered for a long period, and therefors t:e svstemic side effects of those agents should be avoided or minimized.
=rom the concept :h3t zontroller agents should have minimal adverse effects exceoz =or :najor bronchodilative or anti-inflammatory effects, ant:;.-allergic agents such as histamine receptor antagonists, i-su)co=riene receptor antagonists, thromboxane synthetase yzh~.bitors/re.ceptor antagonists were developed. :iowever, ,=hare itre insuf f i cient data about their clinical advantages in z_he long-term management of asthma, and then the development of more potent aintri-inflanuaatory agents and further clinical evaluation is expected.
It is suggested thaz late-onset asthmatic response after the immunochallenge is associated with airway inflammation.
Two kinds of asthmatic resovnses are observed immediate after the antigen-cha],lenge and several hours following that. The early reaction is refered as immediate asthmatic response(IAR) and following phenomenon as ].ate asth=aatic response(I.AR). IAR
has been recognized by airflow limitation which results from acute bronchoconstriction due to allergen exposure, while LAR
is due to airway infla.mmation in the airway. The airway inflammation, characterized usually by extensive infiltration of cosinophils, mast cells and mononuclear cells, causes edematous swelling of the airway wall with or without smooth muscle'contraction. Those pathologic changes would be related not only to LAR but also to airway hyperreactivity and aggravating asthma (Metzger, W.J., iiunninghake, G.W. and Richardson, H.B.: Late Asthinatic Responses; Inquiry into ,Mechanism and Significance, Clin. Rev. Allergy 3:145,1985).
The mechanism of this pathological feature has not been elucidated fully.
Accordingly, it is des.i.red to develop an agent for treating bronchial asthma wizich exhibits the excellent efficacv similar to that of adrenal cortex hormones, which simultaneously Suppresses both immediate asthmatic rasponses and late asthmats.c resnonses, and which is safe.
it is known that 2-phenvl-1,2-benzoisoselenazole-3(2H)-one (non-nroprietarj name: ebselen), a typical compound used in the present inventIon, :zas strong lipoxygenase inhibitory activitv (Peter Kuhl ?rostaglandins, 31(1986), 1029-1048). However, it has never teen reporteci as to whether ebselen i.s effective in the Lreatament of asthma.
Under the above circumstances, the present i4nventors carried out extensive studies, and found that the compounds represented bv the zormula (1) or (?=) described below are highly effective in suppressing asthmatic responses, especially late asthmatic resnonses, in bronchial asthma.
SUM=Y OF 'MtL' INVRNTTC)N
The mechanism of this pathological feature has not been elucidated fully.
Accordingly, it is des.i.red to develop an agent for treating bronchial asthma wizich exhibits the excellent efficacv similar to that of adrenal cortex hormones, which simultaneously Suppresses both immediate asthmatic rasponses and late asthmats.c resnonses, and which is safe.
it is known that 2-phenvl-1,2-benzoisoselenazole-3(2H)-one (non-nroprietarj name: ebselen), a typical compound used in the present inventIon, :zas strong lipoxygenase inhibitory activitv (Peter Kuhl ?rostaglandins, 31(1986), 1029-1048). However, it has never teen reporteci as to whether ebselen i.s effective in the Lreatament of asthma.
Under the above circumstances, the present i4nventors carried out extensive studies, and found that the compounds represented bv the zormula (1) or (?=) described below are highly effective in suppressing asthmatic responses, especially late asthmatic resnonses, in bronchial asthma.
SUM=Y OF 'MtL' INVRNTTC)N
SEE CERTiF9CATE
CORRECTiE3i;i- ARTiCLE 0 ~. VOIR CERTiFiCA'1' Accordingly, the present invention provides a therapeutic agent for treating asthma compriaincl, as an active component, a compound represented by the following formula (1) or (1') or a pharmaceutically acceptable salt of the compound:
q Rs H-(CK&'R3 (1) R:
Y Rt I
R N-(CH2)n-R9 C 1' ) gs 39- 2 wherein each of RL and R2 independently represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a nitro group, Cl-C6 alkyl group or Cl-C6 alkoxyl group, or R1 and R`
may be linked to each other to form a methylenedioxy group; R3 represents an aryl group, an aromatic heterocyclic group, a 5-to 7- membered cycloalkyl group, or a 5- to 7- membered cycloalkenyl group, wherein the aryl group, aromatic heterocyclic group, cycloalkyl group, and the cycloalkenyl group may have a substituent; R represents a hydrogen atom, a hydroxyl group, an -S-g]utathione group, an =-S-ar-amino acid group, or an aralkyl group which may have a substituent at its aryl moiety; RS
represents a hydrogen atom or a C1-C6 alkyl qroup; or R4 and RS
may be linked to each other to fo rnt a single bond; Y represents an oxygen atom or a sulfur atom, n represents an integer of 0 to ir.clusive, and the selenium atom may be oxidized.
CORRECTiE3i;i- ARTiCLE 0 ~. VOIR CERTiFiCA'1' Accordingly, the present invention provides a therapeutic agent for treating asthma compriaincl, as an active component, a compound represented by the following formula (1) or (1') or a pharmaceutically acceptable salt of the compound:
q Rs H-(CK&'R3 (1) R:
Y Rt I
R N-(CH2)n-R9 C 1' ) gs 39- 2 wherein each of RL and R2 independently represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a nitro group, Cl-C6 alkyl group or Cl-C6 alkoxyl group, or R1 and R`
may be linked to each other to form a methylenedioxy group; R3 represents an aryl group, an aromatic heterocyclic group, a 5-to 7- membered cycloalkyl group, or a 5- to 7- membered cycloalkenyl group, wherein the aryl group, aromatic heterocyclic group, cycloalkyl group, and the cycloalkenyl group may have a substituent; R represents a hydrogen atom, a hydroxyl group, an -S-g]utathione group, an =-S-ar-amino acid group, or an aralkyl group which may have a substituent at its aryl moiety; RS
represents a hydrogen atom or a C1-C6 alkyl qroup; or R4 and RS
may be linked to each other to fo rnt a single bond; Y represents an oxygen atom or a sulfur atom, n represents an integer of 0 to ir.clusive, and the selenium atom may be oxidized.
BRIEF DESCRIPTION OF A DRAWING
Fig. 1 shows effects of suppressing effect of ebselen on asthmatic responses of evselen on guinea pigs having antigen-induced asthma.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
In the present invention, agents for treating asthma include drugs which are used for the treatment of asthma . r .
4(a) with the expectation of improving asthmatic conditions and preventive treatment.
Compounds used as an active component of the agents for treating asthma are represented by the aforementioned formul"a (1) or (1') (hereinafter referred to as compound (1) or (1')). Examples of the Cl -C6 alkyl group represented by R1 include methyl group,-ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, ,and pentyl group. Examples of the Cl-C6 alkoxyl group include methoxyl group, ethoxvi gro=up, and propoxyl grouD.
Examples of the aryi-group :representQd by R3 include phenyl group; examples of the cyclua].kyl group include cyclopentyl group, cyclohexyl group, anci cycloheptyl group; examples of the .cvcloa2kenyl group include :L-cvclopentenyl group, 1-cyclohexenyl group,=and 1-cycloheptenyi yroup; and examples of the aromatic heterocyclic group include 5- or 6- membered aromatic heterocyclic groups such as _oyridvl group, pyrimidyl group, imidazolyl group, oxazolyl cjrcup, isoxazolyl group, thxazolyl group, and furyl group. These groups mav'have substituents.
Examo7.es of the substiLuent:s include C2-C6 alkyl group, CI-C6 alkoxyl group, halogen crout), carboxvl group, and hydroxyl group.
The number of substitusnzs is preferably 1 to 3. Of R4 groups, the -S-glutathione groua inc.icazes a group formed by removing a hydrogen atom f=cm the thiol moiety of glutathione; and the -3-7-anino acid group indicates a group formed bv removing a hvcirogen atom from thethio2 moiety of thio3.-containi.ng ?-amino ac :d. Examples of the aralkyl group include benzyl group. R4 and RS preferably form a si.ngle bond. Particularly preferably, the compound of the present invention is 2-pheny7.-l,2-benzoisoselenazole-3(2H)-one represented by the fol?owirg formula:
These compounds =epresented by the following foriuulas which are considered =_- he active metabolites ofthe above compound are also pr2ier_aci.
a :z ~
a o Se-0(i (-S-G denotes a -S-gZutathine group) o 'N a o :
Se Se o y fl o o = ' .
Moreover, in the present invention, pharraaceutically acceptable salts derived from these compounds may also be used.
The above-described compounds (1) or (1') are already known. =They can be prepared, for example, in accordance with a method described in Japanese Patent Application Laid-open (kokai) Nos. 59-42373, 57-67568, 59-39894, 60-226868, 61-50963, or in Biochemical Pharmacology val. 3, No. 20, 3235-3239 and 3241-3245 (1984).
Compounds (1) or (1') and pharmaceutically acceptable salts thereof exhibited excellent effects of-suppressing irnmediate and late ast'r.natic responses in bronchial asthma, particularly late asthmatic rasnonses, as shown in the tost example described below. Also, as a result of a toxicity test using mice and rats to ifinich the compounds were administered orallv or intraneritoneally, it was found that f safe as evidenced bv the LD50 (mg/kg) :ahe compounds are ver-values shown in Table 1. Moreover, even after the compounds were administered at h:.gi=n doses, -no side effects that might cause serious -oroblems were observed..
Table I
-------i.dministration ------z,D5~- (mg /kg) ----r~.nimal route ---------------------------------------------------Mouse P.O. > 68I0 3.p. 740 Rat p.o. > 6810 i.v. 580 ---------------------------------------------------The agents for treating asthma according to the present invention may be formulated into various forms of drugs for oral and parenteral use such as tablets, capsules, powders, fine'granules, liquids, .3uspensions, emulsions, dry syrups, inhalants, injections, and suapositories. Such drugs are prepared using a routi^.e met.hod by adding, to compound (1) or (1') or to a pharmacsuzic.3lly acceptable salt thereof, lubricants, disintegrants, b.inders, and vehicles.
, The dose of compound (1), (2') or of a pharmaceutically acceptable salt thereol.: rarilas depending on the admi.nistration route, concii*_::on of the patient, body. weight of the patient, etc. :n the case of oral administration to adults, it is usuallv 100-2,000 mg/day, and preferably 200-1,000 mg/day.
As-described above, the agents of the present invention suppress both immediate and late asthmatic responses in bronchS.al asthma. ?arz~.cularly, the agents exhibit remarkable effects on lata asthmatic responses. Moreover, agents of the invention have low toxicity and thus are quite safe to hunaans.
ExamDles:
The present invenzion will next be described by way of examples, which should not be construed as limiting the invention.
Test Example:
Effects of ebselen were investigated us3.ng gu3nea pigs CA 02244085 2009-04-21 ....
having antigen-induced asthma by checking pulmonar-I
functions under consciousness and spontaneous respiration.
<Methods>
(1) Animals Each of female Hartley guinea pigs (SLC) (4 weeks old, body weight: approximately 250-300 g) was pretreated with cyclophosmide (2 mg/kg). After 2 days, ovalbumin (OA, 1 rDg) and aluminum gel (ig) were injected intraperitoneally.
Three weeks thereafter, OA (0.1 mg) and aluminum gel (1 g) were again injected intraperitonea3.ly. The thus-treated guinea pigs were used as sensitized animals. At the time of testing, guinea pigs had c;rown to 11 weeks old and had body weights of 450-580 g.
(2) Apparatus and tools;
= Pressure-type bodv prE:ssismograph = Pulmotacograph (TP-601G, Nippon xodensha) = Differential transauce:r (T-601, Nippon Kodensha) - Gas flow resistor _sbe: (Lilly type,'Nipnon Kodensha) Oscill.oscooe (DS-3121, Iwasaki Tsushi.nki) = Comvuter (Kacintosn Ce_ntris 660AV, Apple) Software (created for analyzing respiration based on LabView for Macintosh 3.01) = Nebulizer (NE-UIo, ':'ateishi Denki) (3) Methods for administering agents and for exposing to antigens:
- Groups of guinea pigs pretreated with dexamethasone:
Dexamethasone (1, mg/kg) was dissolved in 100% DMSO (1 ml), and the solution was infected intraperitoneally for 4 consecutive days. The last intraperitoneal injection was performed 24 hours prior to the exposure to antigens.
= Groups of guinea pigs pretreated with ebselen:
Evselen (5 mg/kg) ;was dissolved in 100%.DMSO (1 ml), and the solution was injected intraperitoneally 30 minutes before exposure to anzigens.
= Control grougs:
100% DMSO (Z ml) -gas injected intraperitoneally 30 :ninutes before exposura Lo antigens.
= Method for exposinq to antigens:
OA (40 mg) was dissolveci in physiologic saline (4 mg/ml ), and the solutj-r,n was i.nhaled for 2 minutes using an ultrasonic nebulizer.
(4) Method for c::eckincT pulmonary functions:
In accordance with a method of Agrawal (Agrawal, R.P.;
Specific Airway Conducz=ncs in Guinea Pigs: "Normal Values and Histamine Induced :ali", Respiratory Physiology 43: 23, 1981), each guinea pig aas fixed on a pressure-type body pressismograph, and %variat=on of specific airway conductance (sGaw) was measured. Air flow through the nose and changes of internal pressure of the box were monitored.
Reapective wave forms were digital-sampled at 1024 Hz, and dots from the end expirium to the start of inspiriu:u were reverted to a regression line. Using the inclination (tan) of the regression line, sGaw was obtained. sGaw data was measured before exposure to antigens. After physiologic saline was inhaled for 2 minutes, sGaw was measured agai.n to confirm that the data had no change. The value at this time was taken as 100%, and %variation of sGaw after exposure to antigens was obtained.
The results are shown in Fig. 1. In groups of guinea pigs pretreated with ebselen, both immediate and late asthmatic responses were more effectively suppressed than those in guinea pigs of control group.
When ebselen pretreatment groups are compared with dexamethasone pretreatment groups, the levels of suppression of immediate asthmatic responses were a7.most equal.
However, late asthmatic responses were significantly suppressed in ebselen pretre,3tment groups, almost perfectly suppressi.ng late asthmatic r-esponses which were observed at .between 180 and 420 minutas .in the control group.
In this connection, the dexamethasone dose of-1 mg/kg-~or 4 days to a guinea pig is estimated to be a dose of 240 (60 mg x 4 days) mg of dexamezhasone to a human (body weight:
60 kg). This amount of dexarnethasone is equal to 2400 mg of, prednisolone (0.5 mg of dexariethasone is ecuivalent to 5 mg of prednisolone).
This amount oi preciniso].one (2400 mg) is equivalent to the amount consumea in a pul:;e therapy in which 1 g/day of prednisolone is consecuti-reis= administered for 3 days.
As is understood from t2':e above, ebselen gives more excellent effects than do therapies adopted in current clinical, situations.
Example 1:
Fig. 1 shows effects of suppressing effect of ebselen on asthmatic responses of evselen on guinea pigs having antigen-induced asthma.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
In the present invention, agents for treating asthma include drugs which are used for the treatment of asthma . r .
4(a) with the expectation of improving asthmatic conditions and preventive treatment.
Compounds used as an active component of the agents for treating asthma are represented by the aforementioned formul"a (1) or (1') (hereinafter referred to as compound (1) or (1')). Examples of the Cl -C6 alkyl group represented by R1 include methyl group,-ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, ,and pentyl group. Examples of the Cl-C6 alkoxyl group include methoxyl group, ethoxvi gro=up, and propoxyl grouD.
Examples of the aryi-group :representQd by R3 include phenyl group; examples of the cyclua].kyl group include cyclopentyl group, cyclohexyl group, anci cycloheptyl group; examples of the .cvcloa2kenyl group include :L-cvclopentenyl group, 1-cyclohexenyl group,=and 1-cycloheptenyi yroup; and examples of the aromatic heterocyclic group include 5- or 6- membered aromatic heterocyclic groups such as _oyridvl group, pyrimidyl group, imidazolyl group, oxazolyl cjrcup, isoxazolyl group, thxazolyl group, and furyl group. These groups mav'have substituents.
Examo7.es of the substiLuent:s include C2-C6 alkyl group, CI-C6 alkoxyl group, halogen crout), carboxvl group, and hydroxyl group.
The number of substitusnzs is preferably 1 to 3. Of R4 groups, the -S-glutathione groua inc.icazes a group formed by removing a hydrogen atom f=cm the thiol moiety of glutathione; and the -3-7-anino acid group indicates a group formed bv removing a hvcirogen atom from thethio2 moiety of thio3.-containi.ng ?-amino ac :d. Examples of the aralkyl group include benzyl group. R4 and RS preferably form a si.ngle bond. Particularly preferably, the compound of the present invention is 2-pheny7.-l,2-benzoisoselenazole-3(2H)-one represented by the fol?owirg formula:
These compounds =epresented by the following foriuulas which are considered =_- he active metabolites ofthe above compound are also pr2ier_aci.
a :z ~
a o Se-0(i (-S-G denotes a -S-gZutathine group) o 'N a o :
Se Se o y fl o o = ' .
Moreover, in the present invention, pharraaceutically acceptable salts derived from these compounds may also be used.
The above-described compounds (1) or (1') are already known. =They can be prepared, for example, in accordance with a method described in Japanese Patent Application Laid-open (kokai) Nos. 59-42373, 57-67568, 59-39894, 60-226868, 61-50963, or in Biochemical Pharmacology val. 3, No. 20, 3235-3239 and 3241-3245 (1984).
Compounds (1) or (1') and pharmaceutically acceptable salts thereof exhibited excellent effects of-suppressing irnmediate and late ast'r.natic responses in bronchial asthma, particularly late asthmatic rasnonses, as shown in the tost example described below. Also, as a result of a toxicity test using mice and rats to ifinich the compounds were administered orallv or intraneritoneally, it was found that f safe as evidenced bv the LD50 (mg/kg) :ahe compounds are ver-values shown in Table 1. Moreover, even after the compounds were administered at h:.gi=n doses, -no side effects that might cause serious -oroblems were observed..
Table I
-------i.dministration ------z,D5~- (mg /kg) ----r~.nimal route ---------------------------------------------------Mouse P.O. > 68I0 3.p. 740 Rat p.o. > 6810 i.v. 580 ---------------------------------------------------The agents for treating asthma according to the present invention may be formulated into various forms of drugs for oral and parenteral use such as tablets, capsules, powders, fine'granules, liquids, .3uspensions, emulsions, dry syrups, inhalants, injections, and suapositories. Such drugs are prepared using a routi^.e met.hod by adding, to compound (1) or (1') or to a pharmacsuzic.3lly acceptable salt thereof, lubricants, disintegrants, b.inders, and vehicles.
, The dose of compound (1), (2') or of a pharmaceutically acceptable salt thereol.: rarilas depending on the admi.nistration route, concii*_::on of the patient, body. weight of the patient, etc. :n the case of oral administration to adults, it is usuallv 100-2,000 mg/day, and preferably 200-1,000 mg/day.
As-described above, the agents of the present invention suppress both immediate and late asthmatic responses in bronchS.al asthma. ?arz~.cularly, the agents exhibit remarkable effects on lata asthmatic responses. Moreover, agents of the invention have low toxicity and thus are quite safe to hunaans.
ExamDles:
The present invenzion will next be described by way of examples, which should not be construed as limiting the invention.
Test Example:
Effects of ebselen were investigated us3.ng gu3nea pigs CA 02244085 2009-04-21 ....
having antigen-induced asthma by checking pulmonar-I
functions under consciousness and spontaneous respiration.
<Methods>
(1) Animals Each of female Hartley guinea pigs (SLC) (4 weeks old, body weight: approximately 250-300 g) was pretreated with cyclophosmide (2 mg/kg). After 2 days, ovalbumin (OA, 1 rDg) and aluminum gel (ig) were injected intraperitoneally.
Three weeks thereafter, OA (0.1 mg) and aluminum gel (1 g) were again injected intraperitonea3.ly. The thus-treated guinea pigs were used as sensitized animals. At the time of testing, guinea pigs had c;rown to 11 weeks old and had body weights of 450-580 g.
(2) Apparatus and tools;
= Pressure-type bodv prE:ssismograph = Pulmotacograph (TP-601G, Nippon xodensha) = Differential transauce:r (T-601, Nippon Kodensha) - Gas flow resistor _sbe: (Lilly type,'Nipnon Kodensha) Oscill.oscooe (DS-3121, Iwasaki Tsushi.nki) = Comvuter (Kacintosn Ce_ntris 660AV, Apple) Software (created for analyzing respiration based on LabView for Macintosh 3.01) = Nebulizer (NE-UIo, ':'ateishi Denki) (3) Methods for administering agents and for exposing to antigens:
- Groups of guinea pigs pretreated with dexamethasone:
Dexamethasone (1, mg/kg) was dissolved in 100% DMSO (1 ml), and the solution was infected intraperitoneally for 4 consecutive days. The last intraperitoneal injection was performed 24 hours prior to the exposure to antigens.
= Groups of guinea pigs pretreated with ebselen:
Evselen (5 mg/kg) ;was dissolved in 100%.DMSO (1 ml), and the solution was injected intraperitoneally 30 minutes before exposure to anzigens.
= Control grougs:
100% DMSO (Z ml) -gas injected intraperitoneally 30 :ninutes before exposura Lo antigens.
= Method for exposinq to antigens:
OA (40 mg) was dissolveci in physiologic saline (4 mg/ml ), and the solutj-r,n was i.nhaled for 2 minutes using an ultrasonic nebulizer.
(4) Method for c::eckincT pulmonary functions:
In accordance with a method of Agrawal (Agrawal, R.P.;
Specific Airway Conducz=ncs in Guinea Pigs: "Normal Values and Histamine Induced :ali", Respiratory Physiology 43: 23, 1981), each guinea pig aas fixed on a pressure-type body pressismograph, and %variat=on of specific airway conductance (sGaw) was measured. Air flow through the nose and changes of internal pressure of the box were monitored.
Reapective wave forms were digital-sampled at 1024 Hz, and dots from the end expirium to the start of inspiriu:u were reverted to a regression line. Using the inclination (tan) of the regression line, sGaw was obtained. sGaw data was measured before exposure to antigens. After physiologic saline was inhaled for 2 minutes, sGaw was measured agai.n to confirm that the data had no change. The value at this time was taken as 100%, and %variation of sGaw after exposure to antigens was obtained.
The results are shown in Fig. 1. In groups of guinea pigs pretreated with ebselen, both immediate and late asthmatic responses were more effectively suppressed than those in guinea pigs of control group.
When ebselen pretreatment groups are compared with dexamethasone pretreatment groups, the levels of suppression of immediate asthmatic responses were a7.most equal.
However, late asthmatic responses were significantly suppressed in ebselen pretre,3tment groups, almost perfectly suppressi.ng late asthmatic r-esponses which were observed at .between 180 and 420 minutas .in the control group.
In this connection, the dexamethasone dose of-1 mg/kg-~or 4 days to a guinea pig is estimated to be a dose of 240 (60 mg x 4 days) mg of dexamezhasone to a human (body weight:
60 kg). This amount of dexarnethasone is equal to 2400 mg of, prednisolone (0.5 mg of dexariethasone is ecuivalent to 5 mg of prednisolone).
This amount oi preciniso].one (2400 mg) is equivalent to the amount consumea in a pul:;e therapy in which 1 g/day of prednisolone is consecuti-reis= administered for 3 days.
As is understood from t2':e above, ebselen gives more excellent effects than do therapies adopted in current clinical, situations.
Example 1:
Tablets Tablets having the following composition were prepared using a known method.
Ebselen 50 mg Carboxymethylcellulose 25 mg Starch 5 mg Crystalline cellulose 40 mg Magnesium stearate 2 mg ---------------------------=------------Total 122 mg The present invention provides a safe therapeutic agent for asthma which suppresses both immediate and late asthmatic responses in bronchial asthma. The therapeutic agent of the invention compr.ises, as an active component, a compound represented by the :Eollowi.ng formula (i) or (1 =):
iY(CH2)a-R3 . (1) R2 Se-R4 Y R~
t R K(CH2)a-R3 C 1 ' ) PT Sa- Z
or a pharmaceutically accectaible salt of the compound. The agent of the invention shows highly effects on both immediate and late asthmatic responses, and particularly on late asthmatic responses. The agent can be safely administered to humans as it has low toxici.ty.
Ebselen 50 mg Carboxymethylcellulose 25 mg Starch 5 mg Crystalline cellulose 40 mg Magnesium stearate 2 mg ---------------------------=------------Total 122 mg The present invention provides a safe therapeutic agent for asthma which suppresses both immediate and late asthmatic responses in bronchial asthma. The therapeutic agent of the invention compr.ises, as an active component, a compound represented by the :Eollowi.ng formula (i) or (1 =):
iY(CH2)a-R3 . (1) R2 Se-R4 Y R~
t R K(CH2)a-R3 C 1 ' ) PT Sa- Z
or a pharmaceutically accectaible salt of the compound. The agent of the invention shows highly effects on both immediate and late asthmatic responses, and particularly on late asthmatic responses. The agent can be safely administered to humans as it has low toxici.ty.
Claims (6)
1. A pharmaceutical composition for treating asthma which comprises, as active component, 2-phenyl-1,2-benzoisoselenazole-3(2H)-one or a pharmaceutically acceptable salt thereof, and a non-medicinal component selected from the group consisting of lubricants, disintegrants, binders, vehicles and combinations thereof.
2. A pharmaceutical composition for treating asthma as defined in Claim 1, which is directed to the treatment of bronchial asthma.
3. A pharmaceutical composition for treating asthma as defined in Claim 1, which suppresses late asthmatic responses in bronchial asthma.
4. Use of 2-phenyl-1,2-benzoisoselenazole-3(2H)-one or a pharmaceutically acceptable salt thereof for the treatment of asthma.
5. Use according to claim 4, for the treatment of bronchial asthma.
6. Use according to claim 4, for the suppression of last asthmatic responses in bronchial asthma.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8/11848 | 1996-01-26 | ||
| JP1184896 | 1996-01-26 | ||
| PCT/DE1997/000135 WO1997026968A2 (en) | 1996-01-26 | 1997-01-27 | Therapeutic anti-asthma agents containing selenium compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2244085A1 CA2244085A1 (en) | 1997-07-31 |
| CA2244085C true CA2244085C (en) | 2008-10-14 |
Family
ID=11789151
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002244085A Expired - Fee Related CA2244085C (en) | 1996-01-26 | 1997-01-27 | Therapeutic anti-asthma agents containing selenium compounds |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0876144B1 (en) |
| CN (1) | CN1116876C (en) |
| AT (1) | ATE207746T1 (en) |
| AU (1) | AU728713B2 (en) |
| BR (1) | BR9707303A (en) |
| CA (1) | CA2244085C (en) |
| CZ (1) | CZ292670B6 (en) |
| DE (2) | DE59705183D1 (en) |
| DK (1) | DK0876144T3 (en) |
| EA (1) | EA001066B1 (en) |
| ES (1) | ES2165034T3 (en) |
| HK (1) | HK1019862A1 (en) |
| HU (1) | HUP9901639A3 (en) |
| IL (1) | IL124006A (en) |
| NO (1) | NO983217L (en) |
| NZ (1) | NZ330198A (en) |
| PL (1) | PL187620B1 (en) |
| PT (1) | PT876144E (en) |
| TR (1) | TR199801398T2 (en) |
| WO (1) | WO1997026968A2 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000016935A (en) * | 1998-07-01 | 2000-01-18 | Dai Ichi Seiyaku Co Ltd | Cyclooxygenase inhibitor |
| CA2368484A1 (en) | 1999-03-31 | 2000-10-05 | Daiichi Pharmaceutical Co., Ltd. | Substrates for thioredoxin reductase |
| SG174389A1 (en) | 2009-03-17 | 2011-10-28 | Daiichi Sankyo Co Ltd | Amide derivative |
| US10058542B1 (en) | 2014-09-12 | 2018-08-28 | Thioredoxin Systems Ab | Composition comprising selenazol or thiazolone derivatives and silver and method of treatment therewith |
| CN105622478B (en) * | 2014-10-27 | 2017-08-25 | 中国科学院大连化学物理研究所 | The ketone derivatives of 3,3 2 alkylthio group, 2 phenylseleno, 2 propylene 1 and synthesis |
| CN109627198B (en) * | 2019-02-01 | 2020-11-10 | 河南科技大学 | 2-acetonyl selenium-based benzamide compound and preparation method and application thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4778814A (en) * | 1987-03-18 | 1988-10-18 | Ciba-Geigy Corporation | Method of treating ocular allergy by topical application of a 2-substituted-1,2-benzisoselenazol-3(2H)-one |
| DZ1460A1 (en) * | 1989-11-22 | 2004-09-13 | Sod Conseils Rech Applic | New selenophen derivatives and their preparation process. |
| IT1250751B (en) * | 1991-08-02 | 1995-04-21 | Boehringer Mannheim Italia | (3H, 7H) SELENAZOLO (3,4-A | PYRIDIN WITH ANTIASMATIC AND ANTIINFLAMMATORY ACTIVITIES OF THE AERIAL ROUTES |
| JP2553434B2 (en) * | 1992-04-28 | 1996-11-13 | 第一製薬株式会社 | Granular formulation |
| JPH07233056A (en) * | 1993-09-03 | 1995-09-05 | Dai Ichi Seiyaku Co Ltd | Lipoxygenase inhibitor |
| DE19506669A1 (en) * | 1995-02-25 | 1996-08-29 | Nattermann A & Cie | Lipoxygenase inhibitor for treating asthma, tumours, shock etc. |
-
1997
- 1997-01-27 CZ CZ19982356A patent/CZ292670B6/en not_active IP Right Cessation
- 1997-01-27 TR TR1998/01398T patent/TR199801398T2/en unknown
- 1997-01-27 DE DE59705183T patent/DE59705183D1/en not_active Expired - Lifetime
- 1997-01-27 PL PL97328198A patent/PL187620B1/en not_active IP Right Cessation
- 1997-01-27 WO PCT/DE1997/000135 patent/WO1997026968A2/en active IP Right Grant
- 1997-01-27 DE DE19780042T patent/DE19780042D2/en not_active Ceased
- 1997-01-27 HU HU9901639A patent/HUP9901639A3/en unknown
- 1997-01-27 CN CN97191886A patent/CN1116876C/en not_active Expired - Fee Related
- 1997-01-27 CA CA002244085A patent/CA2244085C/en not_active Expired - Fee Related
- 1997-01-27 EA EA199800658A patent/EA001066B1/en not_active IP Right Cessation
- 1997-01-27 PT PT97914084T patent/PT876144E/en unknown
- 1997-01-27 BR BR9707303-2A patent/BR9707303A/en not_active Application Discontinuation
- 1997-01-27 AT AT97914084T patent/ATE207746T1/en not_active IP Right Cessation
- 1997-01-27 EP EP97914084A patent/EP0876144B1/en not_active Expired - Lifetime
- 1997-01-27 AU AU21497/97A patent/AU728713B2/en not_active Ceased
- 1997-01-27 DK DK97914084T patent/DK0876144T3/en active
- 1997-01-27 NZ NZ330198A patent/NZ330198A/en unknown
- 1997-01-27 IL IL12400697A patent/IL124006A/en not_active IP Right Cessation
- 1997-01-27 ES ES97914084T patent/ES2165034T3/en not_active Expired - Lifetime
-
1998
- 1998-07-13 NO NO983217A patent/NO983217L/en not_active Application Discontinuation
-
1999
- 1999-11-03 HK HK99104998A patent/HK1019862A1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NO983217L (en) | 1998-09-25 |
| PL187620B1 (en) | 2004-08-31 |
| PL328198A1 (en) | 1999-01-18 |
| NO983217D0 (en) | 1998-07-13 |
| DK0876144T3 (en) | 2002-02-25 |
| CA2244085A1 (en) | 1997-07-31 |
| BR9707303A (en) | 2000-05-02 |
| ES2165034T3 (en) | 2002-03-01 |
| PT876144E (en) | 2002-04-29 |
| CZ292670B6 (en) | 2003-11-12 |
| EP0876144B1 (en) | 2001-10-31 |
| EA001066B1 (en) | 2000-10-30 |
| ATE207746T1 (en) | 2001-11-15 |
| CN1219127A (en) | 1999-06-09 |
| IL124006A (en) | 2004-07-25 |
| CZ235698A3 (en) | 1999-04-14 |
| AU2149797A (en) | 1997-08-20 |
| DE59705183D1 (en) | 2001-12-06 |
| EA199800658A1 (en) | 1999-02-25 |
| WO1997026968A2 (en) | 1997-07-31 |
| AU728713B2 (en) | 2001-01-18 |
| WO1997026968A3 (en) | 1997-09-25 |
| NZ330198A (en) | 2000-06-23 |
| HUP9901639A1 (en) | 1999-09-28 |
| EP0876144A2 (en) | 1998-11-11 |
| HUP9901639A3 (en) | 2000-10-30 |
| TR199801398T2 (en) | 1998-10-21 |
| DE19780042D2 (en) | 1999-01-28 |
| HK1019862A1 (en) | 2000-03-03 |
| CN1116876C (en) | 2003-08-06 |
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