CA2234342A1 - Pancreatitis remedy - Google Patents
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- CA2234342A1 CA2234342A1 CA002234342A CA2234342A CA2234342A1 CA 2234342 A1 CA2234342 A1 CA 2234342A1 CA 002234342 A CA002234342 A CA 002234342A CA 2234342 A CA2234342 A CA 2234342A CA 2234342 A1 CA2234342 A1 CA 2234342A1
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
Abstract
The present invention relates to a prophylactic agent or a therapeutic agent of pancreatitis, containing an adenosine uptake inhibitor or a pharmaceutically acceptable salt thereof.
Description
PANCREATITIS REMEDY
Field of the Invention The present invention relates to a prophylactic agent of pancreatitis or a therapeutic agent thereof.
Background of the Invention Pancreatitis is a disease of which the onset is triggered by activation of pancreatic enzymes in pancreas, so that pancreas is auto-digestedby activated pancreatic enzymes. As therapeutic agents of pancreatitis, use is made of for example gastric acid secretion ~u~lessing agents, proteinase inhibiting agents, analgesics and anti-spasmodics, antibiotics and the like (Practice of Gastro-Intestinal Diagnostics 6, edited by Tadahiko Kozu, chief editor, Bunkodo, Tokyo, 1993).
More specifically, hist~mine. H2 receptor antagonists (blockers) including cimetidine, ranitidine, famotidine and the like are used as gastric acid secretion suppressing agents (Therapeutic Medicine Guide, '96 edition, edited by Medical Practice Editorial Committee, Bunkodo, Tokyo, 1996). Proteinase inhibiting agents include high-molecular urinastatin extracted from human urine and gabexate mesilate and nafamostat mesilate as lower molecular synthetic products [Mebio, 13(6), 74-80 (1996)]. As the analgesics and anti-spasmodics, use is made of non-steroidal, anti-inflar.,matory analgesics (indomethacin) and non-opioid analgesics (pentazocine).
As the antibiotics, use is made of penicillin-series antibiotics with wide spectrum (piperacillin), and cefem-series antibiotics of first and second generations (cefazolin and cefmetazole) (Practice of Gastro-Intestinal Diagnostics 6, edited by Tadahiko Kozu, chief editor, Bunkodo, 1993). However, the phAnr~cological effects of any of these phAr~ceutical agents are not sufficient. m us, more excellent prophylactic or therapeutic agents of pancreatitis have been needed.
Adenosine causes variousphysiological effectthrough receptor (Al, A2A' A2B' A3) which present on plasma membrane. Adenosine uptake inhibitor maintains adenosine concentration around adenosine receptor and increase adenosine effect by inhibiting adenosine uptake into tissue.
Most of quinazoline derivatives represented by the following formula (I) to be used in accordance with the present invention have been known, and it has been known also that such derivatives have an adenosine uptake inhibitory activity and are effective for myocardial protection and prophylaxis or treatment of inflammation such as paw edema (WO94/19342, WO96/06841). Additionally, Chemical Pharmaceutical Bulletin, 38, 1591-1595 (1990) describes a 1,2,3,4-tetrahydro-2,4-dioxoquinazoline derivative with 1-(6,7-dimethoxy-4-quinazolyl)-4-piperidinyl group at position 3 and hydrogen, chloride atom or nitro group at position 6.
It has also been known that an N-aryl piperazine alkaneamide derivative with some relation to the compound represented by the following Formula (II) has various phArmAcological actions. More specifically, Japanese Publ'~he~ Fx~mine~ Patent Application No.232/69 describes that the derivative has coronary vasodilator action, central stim~ nt action, local anesthetic action, or anti-carrageenan action; Japanese Publ;~h~ Unex~mine~ Patent Application No. 4774/83 describes that the derivative has an action of myocardial protection: Japanese Publ,~he~ Unexamined Patent Application No. 290869/88 describes that the derivative has an action of ameliorating sleep quality; and European Journal of ph~rr-~ology~
172, 273-281 (1989) describes that the derivative has an action of inhibiting adenosine uptake. Furthermore, Japanese Publ;~he~
Unexamined Patent Application No. 157472/94 describes that N-piperazine acet~mi~e derivatives of 4,5-~iphenyloxazol~ thiazole and imidazole have an action of inhibiting adenosine uptake and a neuroprotective action. Still additionally, Nucleosides &
Nucleotides, 10, 975-982 (1991) describes that dipyridamole, dilazep, hexoben~ne, lidoflazine and R75231 have an action of inhibiting . .
adenosine uptake.
However, it has not yet been known that the compound represented by Formula (I) or Formula (II) is effective for the prophylaxis or treatment of pancreatitis. No report has been published yet, indicating that a compound with an action of inhibiting adenosine uptake is effective for the prophylaxis or treatment of pancreatitis.
Summary of the Invention The object of the present invention is to provide an excellent prophylactic or therapeutic agent of pancreatitis.
m e present invention relates to a prophylactic or therapeutic agent of pancreatitis, containing an adenosine uptake inhibitor or a phArmAcologically acceptable salt thereof as 1:he effective ingredient.
Detailed Description of the Invention me present inventors have found a novel finding ~hat the adenosine uptake inhibitor or a phArmAcologically acceptable salt thereof is widely effective for the prophylaxis or treatment of pancreatitis. In accordance with the present invention, th- term "adenosine uptake inhibitorn means any of all compounds with an action of inhibiting adenosine uptake as one of the properties, irrespective of the structure or whether or not the agent is novel or known The examples include a quinazoline derivative represented by the following Formula (I);
R
R5 ~1 (I) wherein R~ represents hydrogen, substituted or unsubstituted lower alkyl, alkenyl, or substituted or unsubstituted aralkyl; R2, R3, R4 and R5 independently represent hydrogen, halogen, amino, mono- or di(lower alkyl)amino, lower alkanoylamino, nitro, cyano, substituted or unsubstituted lower alkyl, hydlo~y, lower alkoxy, lower alkylthio, carboxy, lower alkoxycarbonyl, lower alkanoyl, aralkyloxy, or lower alkanoyloxy; R6, R', R3 and R9 independently represent hydrogen, lower alkyl, hydloxy, substituted or unsubstituted lower alkoxy or aralkyloxy, or any adjoining two of them are combined to form methylenedioxy, or ethylenedioxy; Rl~ represents hydrogen, substituted or unsubstituted lower alkyl, halogen, or NRl2Rl3(wherein Rl2 and Rl3 independently represent hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; or Rl2 and Rl3 are combined together with N to form a substituted or unsubstituted heterocyclic group); Rllrepresents hydrogen, lower alkyl, or halogen;
and n represents 0, 1, or 2(WO94/19342 or WO96/06841): or a pharmacologically acceptable salt thereof, and a compound represented by the Formula (II);
Rl5 lRl6 rl~
A~-N-C~ C H ~ N~ ~ N ~ C H2 ~ Q
Rl4 (II) wherein Rl~represents hydrogen, or lower alkyl; Rlsrepresents hydrogen, carbamoyl, mono- or di(lower alkyl) aminocarbonyl, lower alko~y~ou~onyl, or carboxy; Rl6 represents hydrogen, or lower alkyl;
Ar represents substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group; m represents 1, or 2; p represents an integer of O to 5; Q represents substituents selected from the group consisting of (a) to (m) represented by the following formulas;
(a) --O--Arl (b) --O--CH-Arl ( c ) --C=C-Arl ( d ) Ar2 Ar O O
--C--CH-Arl ( e ) --C--Arl ( f ) lr2 - C -N - Arl (g ) - C-N - Arl ( h ) H Ar2 - C H-Arl (i) - N - Arl (i ) Ar2 H
- N - Arl (I{) - N - Arl (1) Ar2 CO-Ar2 Arl --<y~Ar2 wherein Y represents S, O, or NH; Arl and Ar2 independently represent substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group [Japanese Published ~m;ned Patent Application No. 232/69; J~pAnese Publ; ~he~ Un~x~mined Patent Application No.
4774/83; European Journal of Ph~r~-cology, 172, 273-281 (1989); or Japanese Publi~he~ Une~mined Patent Application No.290869/88] or a ph~rT-Geutically acceptable salt thereof, N-piper~7.ine~cetamide derivatives of 4,5-~iphenyloxazol, thiazole and imidazole (Japanese Publi.che~ Un~minedPatent Application No. 157472/94), dipyridamole, diazep, hexobenzine, lidofrazine, and R75231 [Nucleosides &
Nucleotides, 10, 975-982 (1991)]. Preferable examples of the adenosine enhancing agent of the present invention include the compound represented by Formula (I) or Formula (II) or a ph~rT-cologically acceptable salt thereof.
The compounds represented by Form~ (I) are referred to as Compound (I) and the compounds represented by Formula (II) is referred to as Compound (II),hereinafter.
In the definitions of the groups in Formula (I) and Formula (II), the lower alkyl and the lower alkyl moiety of the mono- or di-(lower alkyl)amino, mono- or di-(lower alkyl)aminocarbonyl, lower alkanoylamino, lower alkoxy, lower alkylthio, lower alkoxycarbonyl, lower alkanoyl, and lower alkanoyloxy mean a straight-chain or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, and octyl. The alkenyl means a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, methacryl, crotyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, and 5-hexenyl. The cycloalkyl means a straight-chain or branched cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. me aryl includes phenyl or naphthyl, and the aralkyl and the aralkyl moiety of the aralkyloxy mean an aralkyl group having 7 to 13 carbon atoms, such as benzyl, phenethyl, benzhydryl and naphthylmethyl. me heterocyclic group includes pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperazinyl, pyridyl, pyrazolyl, quinolyl, and quinazolyl. me halogen incl~ fluorine, chlorine, bromine and iodine atoms.
me substituted lower alkyl and the substituted lower alkoxy each has 1 to 3 independently selected substituents. Examples of the substituents are halogen, nitro, cyano, hy~lloxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkanoyl, cycloalkyl, amino, mono- or di(lower alkyl)amino, and phth~ n;de. me substituted aryl and substituted aralkyl each has 1 to 3 independently selected substituents on the benzene ring thereof. Examples of the substituents are halogen, lower alkyl, nitro, cyano, amino, mono- or di(lower alkyl)amino, hy~lLoxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkanoyl, methylene dioxy, and trifluoromethyl.
me substituted heterocyclic group has 1 to 3 independently selected substituents. Example of the substituents are halogen, lower alkyl, amino, mono- or di(lower alkyl)amino, hy~oxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkanoyl, trifluoromethyl, phenyl and aralkyl.
In the definitions of the substituents, the halogen, the lower alkoxy, the lower alkoxycarbonyl, the lower alkanoyl, the cycloalkyl, the mono- or di(lower alkyl)amino, the lower alkyl and the aralkyl have the same ~An;ngs as defined above.
m e phArmAceutically acceptable salts of the adenosine uptake inhibitor to be used in accordance with the present invention includes pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts and amino acid addition salts.
Examples of the phArmAceutically acceptable acid addition salts of the adenosine uptake inhibitor include are inorganic acid addition salts such as hydrochloride salt, sulfate salt, andphosphate salt; and organic acid addition salts such as acetate salt, maleate salt, fumarate salt, tartrate salt, citrate salt and methAnesulfonate salt. Examples of the pharmaceutically acceptable metal salts are alkali metal salts such as sodium salt and potassium salt; alkali earth metal salts such as magnesium salt and calcium salt; aluminium salt;
zinc salt. Examples of the phArmAceutically acceptable ammonium salts are ammonium salt and tetramethylammonium salt. Examples of the phAr~-ceutically acceptable organic amine addition salts are addition salts with morpholine and piperidine. Examples of the phArmAceutically acceptable amino acid addition salts are addition salts with lysine, glycine, and phenylAlAn;ne.
m e adenosine uptake inhibitor to be used in accordance with the present invention can be produced by the methods disclosed in the publications or according to the methods. The int~rme~;Ates and desired compounds in the processes can be isolated and purified by purification methods conventionally used in organic synthetic chemistry, for example, neutralization, filtration, extraction, rinsing, drying, concentration, recrystAlli~Ation, and various kind of chromatoyla~hy.
In the case where a salt of the adenosine uptake inhibitor is desired and it is produced in the form of the desired salt, it can be subjected to purification as such. In the case where the adenosine uptake inhibitor is produced in the free state and its salt desired, the adenosine uptake inhibitor is dissolved or suspended in a suitable organic solvent, followed by addition of an acid or a base to form a salt.
The adenosine uptake inhibitor and phArmAceutically acceptable salts thereof may be in the form of adducts with water or various solvents, which may satisfactorily be used as the therapeutic agent of the present invention.
Some of the adenosine uptake inhibitor to be used in accordance with the present invention have optical isomers, and all potential stereoisomers and mixtures thereof may satisfactorily be used as the therapeutic agent of the present invention.
Specific examples of the adenosine uptake inhibitor to be used in accordance with the present invention are shown in Table 1.
Table 1 Compound No.
~ N~
N ~ N
H3C~[~ N G ~OCH2CH3 N ~ O OCH2CH3 2 H2N~Clo ~N ----~F
2 ~ o ~N--N~
N ~ N
~ ~GN~'OCH2CH20H
N ~ O OCH2CH3 Compound 1 3-[1-(6,7-Diethoxy-2-morpholino-4-quinazolynyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline hydrochloride salt (WO 96/06841) Melting point: 193 - 195 ~C
H-NMR(CDCl3) ~: 8.49(br-s, lH), 8.00(s, lH), 7.50(d, lH, J=8.5Hz), 7.11(d, lH, J=8.5Hz), 7.07(s, lH), 5.45-5.30(m, lH), 4.66-4.61(br.-d, 2H), 4.35-4.32(m, 2H), 4.13-4.08(m, 6H), 3.84(br.-s, 4H), 3.57(s, 3H), 3.40-3.31(br.-t, 2H), 3.01-2.89(m, 2H), 2.43(s, 3H), 1.92-1.88(br.-d, 2H), 1.50(t, 3H, J=7.OHz), 1.48(t, 3H, J=7.OHz).
Compound 2 2-Am~inocarbonyl-N-(4-amino-2,6-dichlorophenyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-1-piperazine acetam-ide (Japanese Publi~he~l Un~x~m;ned Patent Application No. 290869/88) Melting point: 118 - 120 C
Value of elemental analysis: C30H33Cl2F2NsO2 Calculated value (%): C 59.61, H 5.50, N 11.58 Experimental value (%) : C 59.53, H 5.45, N 11.58 IR(KBr) v max (cm~1): 1668, 1601, 1506, 1223, 1157.
H-NMR(CDCl3) ~: 7.19-7.14(m, 4H), 7.00-6.93(m, 4H), 6.67(s, 2H), 4.31(s, 2H), 3.89-3.83(br-t, lH), 3.39-3.07(m, 4H), 2.86-2.82(br-d, lH), 2.50-2.44(m, 2H), 2.35-2.29(br-t, 2H), 2.04-1.95(m, 2H), 1.58-1.47(m, 2H), 1.30-1.22(m, 2H).
Compound 3 2-Aminocarbonyl-N-(2,6-dichloro-4-nitrophenyl)-4-[(4,5-~liphenyl-2-oxazolyl)methyl]-1-piperazine acetamide ~ dihydrochloride salt (Japanese Publ;~he-l Un~ mined Patent Application No. 157472/94) Melting point: 183 - 185 C
Value of elemental analysis: C29H26ClzN60s 2HCl Calculated value (%) : C 51.04, H 4.14, N 12.32 Experimental value (%) : C 51.35, H 4.26, N 12.14 IR(KBr) v max (cm~1) : 1687, 1514, 1446, 1389, 1346.
lH-NMR(CDCl3) ~: 8.26(s, 2H), 7.64-7.55(m, 4H), 7.42-7.32(m, 6H), 3.94-3.67(m, 3H), 3.48-3.33(m, 2H), 3.20-3.05(m, 2H), 2.96-2.76(m, 4H).
Compound 4 3-[1-[6-ethoxy-7-(2-hidloxyethyl)oxy-2-morpholino-4-quinazolynyl]-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline(W097/29749) Melting point : 236-237~
IR(KBr tab.) (cm~l) : 1701, 1655, 1560, 1483, 1439, 1238.
H-NMR(CDCl3) ~: 8.01(d, lH, J=2.0Hz), 7.49(dd, lH, J=8.3, 2.0Hz), 7.11(s, lH), 7.09(d, lH, J=8.3Hz), 6.96(s, lH), 5.28-5.21(m, lH), 4.27-4.20(m,4H),4.12(q, 2H, J=7.0Hz), 4.05-4.02(m, 2H),3.84-3.79(m, 8H),3.58(s,3H), 3.15-2.96(m,4H), 2.42(s, 3H), 1.82-1.78(br.-d, 2H), 1.49(t, 3H, J=7.0Hz).
Then, the ph~r~-~.ological actions of the Compounds (I) and Compound (II) are described in test examples.
Test Example 1 Test of the effects on murine cerulein pancreatitis Experiment was conducted in accordance with the method described in Digestive Diseases and Science, 37, 274-279 (1992).
Female BALB/C mice weighing 17 to 24 g were fasted for 16 hours. Water was provided ad libitum. Acute pancreatitis was induced by the ~ministration of seven intraperitoueally injections of cerulein (50 ~ g/kg) at hourly intervals. Blood was drawn from ab~omin~l vein, 3, 6, and 9 hours after the first injection of cerulein in case of Compound 1, Compound 2 and compound 3, while in case of Compound 4, bloodwas drawntherefrom7hours afterthefirstinjectionof cerulein.
Blood samples were centrifuged at 4 ~ and 3,000 rpm for 10 minutes, and serum was separated. Serum amylase (Amy), lipase (Lip), and glutamic ~yLuvic tr~ns~m;n~e (GPT) activities were measured. For Compound 1, Compound 2 and Compound 3, serum Amy was assayed with AU500/550 specific reagent "Katayama" Amy test(Katayama Chemical Industry Co., Ltd.); for Compound 4, serum Amy was assayed with "Rikitech P-AMY EPS" of BM pancreas-related reagent series (Boehringer M~nnheim K. K.). Serum GPT was assayed with "Katayama "
GPT test (Katayama Chemical Industry, Co., Ltd.). Serum Lip was assayed with an auto-analyzer reagent "Kyowan Detçrminçr Lipase (Kyowa Medex, Co., Ltd.). Compound 1, Compound 2, and Compound 3 were suspended in 0.5 % methyl cellulose, and one orally ~ministered hour before the first injection of cerulein, the resulting suspension was orally given at a dose of 10 ml/kg. The solvent (0.5 % methyl cellulose) was simil~rly given to a control group. Compound 4 was dissolved in distilled water, which was adjusted to pH 2 with O.lN
HCl, and then the resulting solution was adjusted to pH 4.5 with O.lN
sodium hy~Loxide. Compound 4 was orally ~mini~stered one hour before the first injection of cerulein. m e solvent (distilled water for injections, after adjustment to pH 4.5 with O.lN HCl) was simil~rly given to a control group.
Results are expressed as means + SEM where a~lv~liate.
Difference betweennormal group and control group were evaluatedusing the Wilcoxon's rank su~m test. And for differences between control group and test compound-treated group, the Steel's test was used for Compound 1 and the Wilcoxon's rank sum test was used for Compounds 2, Compound 3 and Compound 4.
m e effects of Compound 1, Compound 2 and Compound 3 on serum Amy, serum Lip and serum GPT are shown in Tables 2, 3 and 4: and the effect of Compound 4 are shown in Table 5.
Table 2 Test groups Dose of test Serum amylase (IU/L) compoundTime after the first injection (mg/kg) of cerulein _________________________________ Normal 3758 + 117 4067 + 79 3883 + 191 Control5125 + 203 ~ 7817 + 501 ~ 15917 + 567 Compound 1 104283 + 245 4967 + 167#~ 14817 + 1459 Compound 1 304133 + 264 i 5200 + 274 ~ 5658 + 682 ~#
Normal 4192 + 152 3650 + 298 3508 + 123 Control 4108 + 326 5908 + 348 ~ 15150 + 951 Compound 2 3004967 + 291 4417 + 305 ~ 9517 + 23 Compound 3 304050 + 309 3733 + 149 #~ 3958 + 146 ** ; p < 0.01 (compared with the normal group) # ; p < 0.05 (compared with the control group) ## : p < 0.01 (compared with the control group) Table 3 Test Dose of test Serum lipase (IU/L) groupscompoundTime after the first injection (mg/kg) of cerulein _________________________________.
Normal 17 + 1 24 + 2 24 + 2 Control 93 + 13 ~ 190 + 38 ~-503 + 39 Compound 1 10 55 + 3 ~# 91 + 22 t466 + 74 Compound 1 30 58 + 5 ~ 81 + 8 #95 + 15 Normal 88 + 2 85 + 3 89 + 4 Control 158 + 12 ~ 261 + 22 ~730 + 64 Compound 2 300 238 + 9 #~ 217 + 51726 + 23 Compound 3 30 243 + 40 # 135 + 6 #~200 + 13 * ; p < 0.05 (compared with the normal group) ** : p < 0.01 (compared with the normal group) # ; p < 0.05 (compared with the control group) ## ; p < 0.01 (compared with the control group) Table 4 Dose of test Serum GPT (IU/L) Test groups compound Time after the first injection (mg/kg) _____ 3______ of_cerule_n Normal 33 + 3 41 + 5 50 + 5 Control 44 + 2 ~ 80 + 3 ~106 + 6 Compound 1 10 37 + 3 Y 50 + 3 #76 + 5 t Compound 1 30 32 + 3 ~ 51 + 6 # 52 + 5 Normal 21 + 1 22 + 1 27 + 1 Control 40 + 4 ~ 88 + 7 ~141 + 6 Compound 2 300 55 + 2 ## 59 + 6 #129 + 23 Compound 3 30 64 + 11 ~ 40 + 1 ~#59 + 7 ##
* ; p < 0.05 (c~mpAred with the normal group) ** ; p < 0.01 (compared with the normal group) # ; p < 0.05 (compared with the control group) ## ; p < 0.01 (compared with the control group) Table 5 Dose of Serum Serum Lipase Serum GPT
Test groups test compound Amirase (IU/L) (IU/l) (mg/kg) (IU/L) 7 hours after the first injection of cerulein Reference 99920+457 22+1 23+2 Control 23230+2576* 466+102* 108+7*
Compound 4 1014690+922~ 195+23~ 67+2#
* ; p < 0.05 (compared with reference group) # ; p < 0.05 (compared with control group) m e above results indicate that Compound (I) and Compound (II) or ph~r~~cologically acceptable salts thereof have an inhibitory action on the enzymes as the markers of pancreatitis and these are therefore useful as the therapeutic agent of pancreatitis.
Test Example 2 Test of the effects on murine pancreatitis induced by choline -deficient and ethionine - supplemented (CDE) diet Experiment was conducted in accordance with the method describedinInternational Journalof Pancreatology, 11, 59-65(1992).
Female CDF 1 mice weighing 15 to 21 g were fasted for 24 hours. Water provided ad libitum. Acute paucreatitis was induced in mice by means of a choline - deficient diet that was supplemented with 0.5% of DL-ethionine for 72 hours. Seventy-two hours later, the CDE diet was changed to nor~-l diet, and the mortality was observed up to 144 hours later. m e survivalratewasevaluated as an indicatorof theseverity of pancreatitis.
Compound 1 suspended in 0.5 ~ methyl cellulose was orally given at a dose of 1, 3 and 10 mg/kg to the mice 0, 24, 48, 72, 96 and 120 hours after the onset of CDE diet. To a control group, the solvent (0.5 ~ methyl cellulose) was sim;lArly given. Alternatively, dosing was initiated in a group with induced pancreatitis (therapeutic administration). Compound 1 was orally given at a dose of 10 mg/kg to this group, 32, 56, 80, 104 and 128 hours after the onset of CDE
diet.
The following groups were set;
1. normal group (n = 20) 2. control group (n = 30) 3. group at a dose of 1 mg/kg of Compound 1 (n = 30) 4. group at a dose of 3 mg/kg of Compound 1 (n = 30 ) 5. group at a prophylactic dose of 10 mg/kg of Compound 1 (n = 30) 6. group at a therapeutic dose of 10 mg/kg of Compound 1 (n = 30).
The survival rate was expressed in percentage (as the percentage of the survived Anir -l~ in number to the whole in logarithm) ; and difference was evaluated using the Fisher's exact method. Significant difference was defined at a risk factor of less than 5 %.
The effect of the test compound on the survival rate are shown in Fig 1 and Fig 2.
Test Example 3 Inhibitory Effect of [3H]-Adenosine Uptake A blood sample was obtained from a healthy male adult under 40 years of age by branchial venipuncture using a syringe contAining sodium citrate and subjected to centrifugation to obtain washed erythrocytes. To 100 ~ l of an erythrocyte suspension (2.5X109cells /ml), 10 ~ l of a 21% dimethylsulfoxide (DMSO) solution of a test compound was added. After allowing the suspension to stand at room temperature for 1 hour, 100 ~ l of a [3H]-adenosine solution was added thereto. Ten seconds later, 200 ~ l of a dilazep solution (1 mg/ml) was added to stop the adenosine uptake. m en, dibutyl phthalate was added dropwise to the reaction mixture, followed by centrifugation.
m esupernatantwas~ vedandtheerythrocytefractionwasseparated.
me erythrocytes were dissolved in Triton X-100, and uptake amount of ~H was measured with a liquid scintillation counter. m e concentration of the test compound which inhibits the [~H]-adenosine uptake by 50~ (IC50) was calculated.
Consequently, any of the compound group described in this speclfication had IC50 values of 10-6 M or less.
Test Example 4 Acute Toxicity Test Test compounds were orally or intraperitone~lly ~m;n;ctered to groups of dd-strain male mice weighing 20 + 1 g, each group consisting of three mice. Seven days after the A~m;n;~tration, the mortality was observed to obtain a m;n;m~lm lethal dose (MLD) of the compound.
Consequently, the MLD value of Compound 1 was greater than 1000 mg/kg for oral dosing; and greater than 100 mg/kg for intraperitoneal dosing. Additionally, the MLD value of Compound 2 was greater than 300 mg/kg for oral dosing; and greater than 100 mg/kg for intraperitoneal dosing.
me adenosineuptake inhibitor andph~rm~ceutically acceptable salts thereof to be used in accordance with the present invention can be ~m;n;~tered as they are, or in the forms of various ph~rmAceutical compositions. The pharmaceutical compositions in accordance withthe present invention can be prepared by uniformly mixing an effective amount of adenosine uptake inhibitor or ~hArmAceutically acceptable salts thereof, as an active ingredient, with a pharmacologically acceptable carrier. It is desired that such phAr~celltical compositions are prepared in a unit dose form suitable for oral or parenteral (subcutaneous, intra-rectum, intravenous or intra-muscular) A~m; n; ~tration.
For preparing a pharmaceutical composition for oral administration, any useful pharmaceutically acceptable carrier can be used. For example, liquid preparations for oral administration such as suspensions and syrups can be prepared by using water, sugars such as sucrose, sorbitol, and fructose; glycols such as polyethylene glycol and propylene glycol; oils such as sesame oil, olive oil, and soybean oil; preservatives such as p-hydLoxybenzoates; flavors such as strawberry flavor and peppermint, and the like. Powders, pills, capsules and tablets can bë prepared using excipients such as lactose, glucose, sucrose, and mannitol; disintegrating agents such as starch and sodium alginate; lubricants such as magnesium stearate and talc;
binders such as polyvinyl alcohol, hydloxy~lo~yl cellulose and gelatin; surfactants such as fatty acid esters; and plasticizers such as glycerin, and the like. Tablets and capsules are the most useful oral unit dose forms because of the readiness of A~m;n;~tration, For preparing tables and capsules, solid phAr~ceutical carriers are used.
Injectable preparations can be prepared using a carrier such as distilled water , a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution. The preparations can be prepared in the form of solution, suspension or dispersion according to a conventional method by using a suitable solub;l;~;ng ~llX;liAry or suspending agent.
The adenosine uptake inhibitor and ph~rmAceutically acceptable salts thereof to be used in accordance with the present invention can be ~m;ni~tered orally or parenterally in the said dosage form. The effective dose and the ~mini~tration schedule vary depending upon the mode of ~min;~tration, the age, body weight, and conditions of a patient, etc. However, it is generally appropriate to ~m;n;~ter the adenosine uptake inhibitor and a ph~rmAceutically acceptable salt thereof in a dose of 1 to 900 mg/60 kg/day, preferably 1 to 200 mg/60 kg/day.
Brief Description of the Drawings Fig.l is a graph showing the effects of the test compound on the murine pancreatitis induced by CDE diet.
-{~ normal group :control group - - :group at a dose of 1 mg/kg of Compound 1 :group at a dose of 3 mg/kg of Compound 1 -~C~-:group at a dose of 10 mg/kg of Compound 1 Fig.2 is a graph showing the effects of the test compound on murine pancreatitis induced by CDE diet.
normal group :control group :group at a prophylactic dose of 10 mg/kg of Compound 1 -~C~-:group at a therapeutic dose of 10 mg/kg of Compound 1 Description of the Preferred Embodiments m e embodiments of the present invention will now be described in Examples.
Example 1 Tablet Tablets having the following composition were prepared in a conventional m~nnçr.
Compound 1 (40 g) was mixed with 286.8 g of lactose and 60 g of potato starch, followed by addition of 120 g of a 10% aqueous solution of hydloxy~ ylcellulose. m e resultant mixture was kne~e~, granulated, and then dried by a conventional method. The granules were refined to give granules used to make tablets. After mixing the granules with 1.2 g of magnesium stearate, the mixture was formed into tablets each cont~i ni ng 20 mg of the active ingredient by using a tablet maker (Model RT-15, Kikusui) having pestles of 8 mm diameter.
Composition of One Tablet Compound 1 20 mg Lactose 143.4mg Potato Starch 30 mg Hydloxy~Lo~ylcellulose 6 mg Magnesium Stearate0.6mg 200 mg Example 2 Capsules Capsules having the following composition were prepared in a conventional manner.
Compound 2 (200 g) was mixed with 995 g of Avicel and 5 g of magnesium stearate. The mixture was put in hard capsules No. 4 each having a capacity of 120 g by using a capsule filler (Model LZ-64, Zanasi) to give capsules each cont~ining 20 mg of the active ingredient.
Composition of One Capsule Compound 2 20 mg Avicel 99.5mg Magnesium Stearate 0.5mg 120 mg Example 3 Injections Injections having the following composition were prepared in a conventional manner.
Compound 3 (1 g) was dissolved in 100 g of purified soybean oil, followed by addition of 12 g of purified egg yolk lecithin and 25 g of glycerin for injection. m e resultant mixture was made up to 1,000 ml with distilled water for injection, thoroughly mixed, and emulsified by a conventional method. m e resultant dispersion was subjected to aseptic filtration by using 0.2 ~m disposable membrane filters, and then aseptically put into glass vials in 2 ml portions to give injections contA;n;ng 2 mg of the active ingredient per vial.
Composition of One Injection Vial Compound 3 2 mg Purified Soybean Oil 200 mg Purified Egg Yolk Lecithin24 mg Glycerine for Injection50 mg Dist;lle~ Water for Injection 1.72 ml 2.00 ml Example 4 Anal suppository For~llAtions for rectal dosing having the following composition were prepared in a conventional ~-nn~.r.
678.8 g of Witepzol0 H15 (manufactured by Dynamite Nobel, Co.) and 290.9 g of Witepzol0 E75 (manufactured by Dynamite Nobel, Co.) were melt at 40 to 50 C. Into the resulting molten matter were homogeneously mixed and dispersed 2.5 g of Compound 1, 13.6 g of potassium primary phosphate and 14.2 g of sodium secondary phosphate indiv~ lly. The resultant dispersion was put in a plastic suppository mold, and then followed by gradual cooling to form into formulations cont~;n;ng 2.5 mg of the active ingredient per formulation.
Composition of One Formulation Compound 1 2.5 mg Whitepzol H15 678.8 mg Whitepzol E75 290.9 mg potassium dihydrogen phosphate 13.6 mg disodium phosphate 14.2 mg 1000 mg The present invention provides a prophylactic agent or a therapeutic agent of pancreatitis, cont~n;ng an adenosine uptake inhibitor or ph~rm~ceutically acceptable salts thereof as the effective ingredient.
Field of the Invention The present invention relates to a prophylactic agent of pancreatitis or a therapeutic agent thereof.
Background of the Invention Pancreatitis is a disease of which the onset is triggered by activation of pancreatic enzymes in pancreas, so that pancreas is auto-digestedby activated pancreatic enzymes. As therapeutic agents of pancreatitis, use is made of for example gastric acid secretion ~u~lessing agents, proteinase inhibiting agents, analgesics and anti-spasmodics, antibiotics and the like (Practice of Gastro-Intestinal Diagnostics 6, edited by Tadahiko Kozu, chief editor, Bunkodo, Tokyo, 1993).
More specifically, hist~mine. H2 receptor antagonists (blockers) including cimetidine, ranitidine, famotidine and the like are used as gastric acid secretion suppressing agents (Therapeutic Medicine Guide, '96 edition, edited by Medical Practice Editorial Committee, Bunkodo, Tokyo, 1996). Proteinase inhibiting agents include high-molecular urinastatin extracted from human urine and gabexate mesilate and nafamostat mesilate as lower molecular synthetic products [Mebio, 13(6), 74-80 (1996)]. As the analgesics and anti-spasmodics, use is made of non-steroidal, anti-inflar.,matory analgesics (indomethacin) and non-opioid analgesics (pentazocine).
As the antibiotics, use is made of penicillin-series antibiotics with wide spectrum (piperacillin), and cefem-series antibiotics of first and second generations (cefazolin and cefmetazole) (Practice of Gastro-Intestinal Diagnostics 6, edited by Tadahiko Kozu, chief editor, Bunkodo, 1993). However, the phAnr~cological effects of any of these phAr~ceutical agents are not sufficient. m us, more excellent prophylactic or therapeutic agents of pancreatitis have been needed.
Adenosine causes variousphysiological effectthrough receptor (Al, A2A' A2B' A3) which present on plasma membrane. Adenosine uptake inhibitor maintains adenosine concentration around adenosine receptor and increase adenosine effect by inhibiting adenosine uptake into tissue.
Most of quinazoline derivatives represented by the following formula (I) to be used in accordance with the present invention have been known, and it has been known also that such derivatives have an adenosine uptake inhibitory activity and are effective for myocardial protection and prophylaxis or treatment of inflammation such as paw edema (WO94/19342, WO96/06841). Additionally, Chemical Pharmaceutical Bulletin, 38, 1591-1595 (1990) describes a 1,2,3,4-tetrahydro-2,4-dioxoquinazoline derivative with 1-(6,7-dimethoxy-4-quinazolyl)-4-piperidinyl group at position 3 and hydrogen, chloride atom or nitro group at position 6.
It has also been known that an N-aryl piperazine alkaneamide derivative with some relation to the compound represented by the following Formula (II) has various phArmAcological actions. More specifically, Japanese Publ'~he~ Fx~mine~ Patent Application No.232/69 describes that the derivative has coronary vasodilator action, central stim~ nt action, local anesthetic action, or anti-carrageenan action; Japanese Publ;~h~ Unex~mine~ Patent Application No. 4774/83 describes that the derivative has an action of myocardial protection: Japanese Publ,~he~ Unexamined Patent Application No. 290869/88 describes that the derivative has an action of ameliorating sleep quality; and European Journal of ph~rr-~ology~
172, 273-281 (1989) describes that the derivative has an action of inhibiting adenosine uptake. Furthermore, Japanese Publ;~he~
Unexamined Patent Application No. 157472/94 describes that N-piperazine acet~mi~e derivatives of 4,5-~iphenyloxazol~ thiazole and imidazole have an action of inhibiting adenosine uptake and a neuroprotective action. Still additionally, Nucleosides &
Nucleotides, 10, 975-982 (1991) describes that dipyridamole, dilazep, hexoben~ne, lidoflazine and R75231 have an action of inhibiting . .
adenosine uptake.
However, it has not yet been known that the compound represented by Formula (I) or Formula (II) is effective for the prophylaxis or treatment of pancreatitis. No report has been published yet, indicating that a compound with an action of inhibiting adenosine uptake is effective for the prophylaxis or treatment of pancreatitis.
Summary of the Invention The object of the present invention is to provide an excellent prophylactic or therapeutic agent of pancreatitis.
m e present invention relates to a prophylactic or therapeutic agent of pancreatitis, containing an adenosine uptake inhibitor or a phArmAcologically acceptable salt thereof as 1:he effective ingredient.
Detailed Description of the Invention me present inventors have found a novel finding ~hat the adenosine uptake inhibitor or a phArmAcologically acceptable salt thereof is widely effective for the prophylaxis or treatment of pancreatitis. In accordance with the present invention, th- term "adenosine uptake inhibitorn means any of all compounds with an action of inhibiting adenosine uptake as one of the properties, irrespective of the structure or whether or not the agent is novel or known The examples include a quinazoline derivative represented by the following Formula (I);
R
R5 ~1 (I) wherein R~ represents hydrogen, substituted or unsubstituted lower alkyl, alkenyl, or substituted or unsubstituted aralkyl; R2, R3, R4 and R5 independently represent hydrogen, halogen, amino, mono- or di(lower alkyl)amino, lower alkanoylamino, nitro, cyano, substituted or unsubstituted lower alkyl, hydlo~y, lower alkoxy, lower alkylthio, carboxy, lower alkoxycarbonyl, lower alkanoyl, aralkyloxy, or lower alkanoyloxy; R6, R', R3 and R9 independently represent hydrogen, lower alkyl, hydloxy, substituted or unsubstituted lower alkoxy or aralkyloxy, or any adjoining two of them are combined to form methylenedioxy, or ethylenedioxy; Rl~ represents hydrogen, substituted or unsubstituted lower alkyl, halogen, or NRl2Rl3(wherein Rl2 and Rl3 independently represent hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; or Rl2 and Rl3 are combined together with N to form a substituted or unsubstituted heterocyclic group); Rllrepresents hydrogen, lower alkyl, or halogen;
and n represents 0, 1, or 2(WO94/19342 or WO96/06841): or a pharmacologically acceptable salt thereof, and a compound represented by the Formula (II);
Rl5 lRl6 rl~
A~-N-C~ C H ~ N~ ~ N ~ C H2 ~ Q
Rl4 (II) wherein Rl~represents hydrogen, or lower alkyl; Rlsrepresents hydrogen, carbamoyl, mono- or di(lower alkyl) aminocarbonyl, lower alko~y~ou~onyl, or carboxy; Rl6 represents hydrogen, or lower alkyl;
Ar represents substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group; m represents 1, or 2; p represents an integer of O to 5; Q represents substituents selected from the group consisting of (a) to (m) represented by the following formulas;
(a) --O--Arl (b) --O--CH-Arl ( c ) --C=C-Arl ( d ) Ar2 Ar O O
--C--CH-Arl ( e ) --C--Arl ( f ) lr2 - C -N - Arl (g ) - C-N - Arl ( h ) H Ar2 - C H-Arl (i) - N - Arl (i ) Ar2 H
- N - Arl (I{) - N - Arl (1) Ar2 CO-Ar2 Arl --<y~Ar2 wherein Y represents S, O, or NH; Arl and Ar2 independently represent substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group [Japanese Published ~m;ned Patent Application No. 232/69; J~pAnese Publ; ~he~ Un~x~mined Patent Application No.
4774/83; European Journal of Ph~r~-cology, 172, 273-281 (1989); or Japanese Publi~he~ Une~mined Patent Application No.290869/88] or a ph~rT-Geutically acceptable salt thereof, N-piper~7.ine~cetamide derivatives of 4,5-~iphenyloxazol, thiazole and imidazole (Japanese Publi.che~ Un~minedPatent Application No. 157472/94), dipyridamole, diazep, hexobenzine, lidofrazine, and R75231 [Nucleosides &
Nucleotides, 10, 975-982 (1991)]. Preferable examples of the adenosine enhancing agent of the present invention include the compound represented by Formula (I) or Formula (II) or a ph~rT-cologically acceptable salt thereof.
The compounds represented by Form~ (I) are referred to as Compound (I) and the compounds represented by Formula (II) is referred to as Compound (II),hereinafter.
In the definitions of the groups in Formula (I) and Formula (II), the lower alkyl and the lower alkyl moiety of the mono- or di-(lower alkyl)amino, mono- or di-(lower alkyl)aminocarbonyl, lower alkanoylamino, lower alkoxy, lower alkylthio, lower alkoxycarbonyl, lower alkanoyl, and lower alkanoyloxy mean a straight-chain or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, and octyl. The alkenyl means a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, methacryl, crotyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, and 5-hexenyl. The cycloalkyl means a straight-chain or branched cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. me aryl includes phenyl or naphthyl, and the aralkyl and the aralkyl moiety of the aralkyloxy mean an aralkyl group having 7 to 13 carbon atoms, such as benzyl, phenethyl, benzhydryl and naphthylmethyl. me heterocyclic group includes pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperazinyl, pyridyl, pyrazolyl, quinolyl, and quinazolyl. me halogen incl~ fluorine, chlorine, bromine and iodine atoms.
me substituted lower alkyl and the substituted lower alkoxy each has 1 to 3 independently selected substituents. Examples of the substituents are halogen, nitro, cyano, hy~lloxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkanoyl, cycloalkyl, amino, mono- or di(lower alkyl)amino, and phth~ n;de. me substituted aryl and substituted aralkyl each has 1 to 3 independently selected substituents on the benzene ring thereof. Examples of the substituents are halogen, lower alkyl, nitro, cyano, amino, mono- or di(lower alkyl)amino, hy~lLoxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkanoyl, methylene dioxy, and trifluoromethyl.
me substituted heterocyclic group has 1 to 3 independently selected substituents. Example of the substituents are halogen, lower alkyl, amino, mono- or di(lower alkyl)amino, hy~oxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkanoyl, trifluoromethyl, phenyl and aralkyl.
In the definitions of the substituents, the halogen, the lower alkoxy, the lower alkoxycarbonyl, the lower alkanoyl, the cycloalkyl, the mono- or di(lower alkyl)amino, the lower alkyl and the aralkyl have the same ~An;ngs as defined above.
m e phArmAceutically acceptable salts of the adenosine uptake inhibitor to be used in accordance with the present invention includes pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts and amino acid addition salts.
Examples of the phArmAceutically acceptable acid addition salts of the adenosine uptake inhibitor include are inorganic acid addition salts such as hydrochloride salt, sulfate salt, andphosphate salt; and organic acid addition salts such as acetate salt, maleate salt, fumarate salt, tartrate salt, citrate salt and methAnesulfonate salt. Examples of the pharmaceutically acceptable metal salts are alkali metal salts such as sodium salt and potassium salt; alkali earth metal salts such as magnesium salt and calcium salt; aluminium salt;
zinc salt. Examples of the phArmAceutically acceptable ammonium salts are ammonium salt and tetramethylammonium salt. Examples of the phAr~-ceutically acceptable organic amine addition salts are addition salts with morpholine and piperidine. Examples of the phArmAceutically acceptable amino acid addition salts are addition salts with lysine, glycine, and phenylAlAn;ne.
m e adenosine uptake inhibitor to be used in accordance with the present invention can be produced by the methods disclosed in the publications or according to the methods. The int~rme~;Ates and desired compounds in the processes can be isolated and purified by purification methods conventionally used in organic synthetic chemistry, for example, neutralization, filtration, extraction, rinsing, drying, concentration, recrystAlli~Ation, and various kind of chromatoyla~hy.
In the case where a salt of the adenosine uptake inhibitor is desired and it is produced in the form of the desired salt, it can be subjected to purification as such. In the case where the adenosine uptake inhibitor is produced in the free state and its salt desired, the adenosine uptake inhibitor is dissolved or suspended in a suitable organic solvent, followed by addition of an acid or a base to form a salt.
The adenosine uptake inhibitor and phArmAceutically acceptable salts thereof may be in the form of adducts with water or various solvents, which may satisfactorily be used as the therapeutic agent of the present invention.
Some of the adenosine uptake inhibitor to be used in accordance with the present invention have optical isomers, and all potential stereoisomers and mixtures thereof may satisfactorily be used as the therapeutic agent of the present invention.
Specific examples of the adenosine uptake inhibitor to be used in accordance with the present invention are shown in Table 1.
Table 1 Compound No.
~ N~
N ~ N
H3C~[~ N G ~OCH2CH3 N ~ O OCH2CH3 2 H2N~Clo ~N ----~F
2 ~ o ~N--N~
N ~ N
~ ~GN~'OCH2CH20H
N ~ O OCH2CH3 Compound 1 3-[1-(6,7-Diethoxy-2-morpholino-4-quinazolynyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline hydrochloride salt (WO 96/06841) Melting point: 193 - 195 ~C
H-NMR(CDCl3) ~: 8.49(br-s, lH), 8.00(s, lH), 7.50(d, lH, J=8.5Hz), 7.11(d, lH, J=8.5Hz), 7.07(s, lH), 5.45-5.30(m, lH), 4.66-4.61(br.-d, 2H), 4.35-4.32(m, 2H), 4.13-4.08(m, 6H), 3.84(br.-s, 4H), 3.57(s, 3H), 3.40-3.31(br.-t, 2H), 3.01-2.89(m, 2H), 2.43(s, 3H), 1.92-1.88(br.-d, 2H), 1.50(t, 3H, J=7.OHz), 1.48(t, 3H, J=7.OHz).
Compound 2 2-Am~inocarbonyl-N-(4-amino-2,6-dichlorophenyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-1-piperazine acetam-ide (Japanese Publi~he~l Un~x~m;ned Patent Application No. 290869/88) Melting point: 118 - 120 C
Value of elemental analysis: C30H33Cl2F2NsO2 Calculated value (%): C 59.61, H 5.50, N 11.58 Experimental value (%) : C 59.53, H 5.45, N 11.58 IR(KBr) v max (cm~1): 1668, 1601, 1506, 1223, 1157.
H-NMR(CDCl3) ~: 7.19-7.14(m, 4H), 7.00-6.93(m, 4H), 6.67(s, 2H), 4.31(s, 2H), 3.89-3.83(br-t, lH), 3.39-3.07(m, 4H), 2.86-2.82(br-d, lH), 2.50-2.44(m, 2H), 2.35-2.29(br-t, 2H), 2.04-1.95(m, 2H), 1.58-1.47(m, 2H), 1.30-1.22(m, 2H).
Compound 3 2-Aminocarbonyl-N-(2,6-dichloro-4-nitrophenyl)-4-[(4,5-~liphenyl-2-oxazolyl)methyl]-1-piperazine acetamide ~ dihydrochloride salt (Japanese Publ;~he-l Un~ mined Patent Application No. 157472/94) Melting point: 183 - 185 C
Value of elemental analysis: C29H26ClzN60s 2HCl Calculated value (%) : C 51.04, H 4.14, N 12.32 Experimental value (%) : C 51.35, H 4.26, N 12.14 IR(KBr) v max (cm~1) : 1687, 1514, 1446, 1389, 1346.
lH-NMR(CDCl3) ~: 8.26(s, 2H), 7.64-7.55(m, 4H), 7.42-7.32(m, 6H), 3.94-3.67(m, 3H), 3.48-3.33(m, 2H), 3.20-3.05(m, 2H), 2.96-2.76(m, 4H).
Compound 4 3-[1-[6-ethoxy-7-(2-hidloxyethyl)oxy-2-morpholino-4-quinazolynyl]-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline(W097/29749) Melting point : 236-237~
IR(KBr tab.) (cm~l) : 1701, 1655, 1560, 1483, 1439, 1238.
H-NMR(CDCl3) ~: 8.01(d, lH, J=2.0Hz), 7.49(dd, lH, J=8.3, 2.0Hz), 7.11(s, lH), 7.09(d, lH, J=8.3Hz), 6.96(s, lH), 5.28-5.21(m, lH), 4.27-4.20(m,4H),4.12(q, 2H, J=7.0Hz), 4.05-4.02(m, 2H),3.84-3.79(m, 8H),3.58(s,3H), 3.15-2.96(m,4H), 2.42(s, 3H), 1.82-1.78(br.-d, 2H), 1.49(t, 3H, J=7.0Hz).
Then, the ph~r~-~.ological actions of the Compounds (I) and Compound (II) are described in test examples.
Test Example 1 Test of the effects on murine cerulein pancreatitis Experiment was conducted in accordance with the method described in Digestive Diseases and Science, 37, 274-279 (1992).
Female BALB/C mice weighing 17 to 24 g were fasted for 16 hours. Water was provided ad libitum. Acute pancreatitis was induced by the ~ministration of seven intraperitoueally injections of cerulein (50 ~ g/kg) at hourly intervals. Blood was drawn from ab~omin~l vein, 3, 6, and 9 hours after the first injection of cerulein in case of Compound 1, Compound 2 and compound 3, while in case of Compound 4, bloodwas drawntherefrom7hours afterthefirstinjectionof cerulein.
Blood samples were centrifuged at 4 ~ and 3,000 rpm for 10 minutes, and serum was separated. Serum amylase (Amy), lipase (Lip), and glutamic ~yLuvic tr~ns~m;n~e (GPT) activities were measured. For Compound 1, Compound 2 and Compound 3, serum Amy was assayed with AU500/550 specific reagent "Katayama" Amy test(Katayama Chemical Industry Co., Ltd.); for Compound 4, serum Amy was assayed with "Rikitech P-AMY EPS" of BM pancreas-related reagent series (Boehringer M~nnheim K. K.). Serum GPT was assayed with "Katayama "
GPT test (Katayama Chemical Industry, Co., Ltd.). Serum Lip was assayed with an auto-analyzer reagent "Kyowan Detçrminçr Lipase (Kyowa Medex, Co., Ltd.). Compound 1, Compound 2, and Compound 3 were suspended in 0.5 % methyl cellulose, and one orally ~ministered hour before the first injection of cerulein, the resulting suspension was orally given at a dose of 10 ml/kg. The solvent (0.5 % methyl cellulose) was simil~rly given to a control group. Compound 4 was dissolved in distilled water, which was adjusted to pH 2 with O.lN
HCl, and then the resulting solution was adjusted to pH 4.5 with O.lN
sodium hy~Loxide. Compound 4 was orally ~mini~stered one hour before the first injection of cerulein. m e solvent (distilled water for injections, after adjustment to pH 4.5 with O.lN HCl) was simil~rly given to a control group.
Results are expressed as means + SEM where a~lv~liate.
Difference betweennormal group and control group were evaluatedusing the Wilcoxon's rank su~m test. And for differences between control group and test compound-treated group, the Steel's test was used for Compound 1 and the Wilcoxon's rank sum test was used for Compounds 2, Compound 3 and Compound 4.
m e effects of Compound 1, Compound 2 and Compound 3 on serum Amy, serum Lip and serum GPT are shown in Tables 2, 3 and 4: and the effect of Compound 4 are shown in Table 5.
Table 2 Test groups Dose of test Serum amylase (IU/L) compoundTime after the first injection (mg/kg) of cerulein _________________________________ Normal 3758 + 117 4067 + 79 3883 + 191 Control5125 + 203 ~ 7817 + 501 ~ 15917 + 567 Compound 1 104283 + 245 4967 + 167#~ 14817 + 1459 Compound 1 304133 + 264 i 5200 + 274 ~ 5658 + 682 ~#
Normal 4192 + 152 3650 + 298 3508 + 123 Control 4108 + 326 5908 + 348 ~ 15150 + 951 Compound 2 3004967 + 291 4417 + 305 ~ 9517 + 23 Compound 3 304050 + 309 3733 + 149 #~ 3958 + 146 ** ; p < 0.01 (compared with the normal group) # ; p < 0.05 (compared with the control group) ## : p < 0.01 (compared with the control group) Table 3 Test Dose of test Serum lipase (IU/L) groupscompoundTime after the first injection (mg/kg) of cerulein _________________________________.
Normal 17 + 1 24 + 2 24 + 2 Control 93 + 13 ~ 190 + 38 ~-503 + 39 Compound 1 10 55 + 3 ~# 91 + 22 t466 + 74 Compound 1 30 58 + 5 ~ 81 + 8 #95 + 15 Normal 88 + 2 85 + 3 89 + 4 Control 158 + 12 ~ 261 + 22 ~730 + 64 Compound 2 300 238 + 9 #~ 217 + 51726 + 23 Compound 3 30 243 + 40 # 135 + 6 #~200 + 13 * ; p < 0.05 (compared with the normal group) ** : p < 0.01 (compared with the normal group) # ; p < 0.05 (compared with the control group) ## ; p < 0.01 (compared with the control group) Table 4 Dose of test Serum GPT (IU/L) Test groups compound Time after the first injection (mg/kg) _____ 3______ of_cerule_n Normal 33 + 3 41 + 5 50 + 5 Control 44 + 2 ~ 80 + 3 ~106 + 6 Compound 1 10 37 + 3 Y 50 + 3 #76 + 5 t Compound 1 30 32 + 3 ~ 51 + 6 # 52 + 5 Normal 21 + 1 22 + 1 27 + 1 Control 40 + 4 ~ 88 + 7 ~141 + 6 Compound 2 300 55 + 2 ## 59 + 6 #129 + 23 Compound 3 30 64 + 11 ~ 40 + 1 ~#59 + 7 ##
* ; p < 0.05 (c~mpAred with the normal group) ** ; p < 0.01 (compared with the normal group) # ; p < 0.05 (compared with the control group) ## ; p < 0.01 (compared with the control group) Table 5 Dose of Serum Serum Lipase Serum GPT
Test groups test compound Amirase (IU/L) (IU/l) (mg/kg) (IU/L) 7 hours after the first injection of cerulein Reference 99920+457 22+1 23+2 Control 23230+2576* 466+102* 108+7*
Compound 4 1014690+922~ 195+23~ 67+2#
* ; p < 0.05 (compared with reference group) # ; p < 0.05 (compared with control group) m e above results indicate that Compound (I) and Compound (II) or ph~r~~cologically acceptable salts thereof have an inhibitory action on the enzymes as the markers of pancreatitis and these are therefore useful as the therapeutic agent of pancreatitis.
Test Example 2 Test of the effects on murine pancreatitis induced by choline -deficient and ethionine - supplemented (CDE) diet Experiment was conducted in accordance with the method describedinInternational Journalof Pancreatology, 11, 59-65(1992).
Female CDF 1 mice weighing 15 to 21 g were fasted for 24 hours. Water provided ad libitum. Acute paucreatitis was induced in mice by means of a choline - deficient diet that was supplemented with 0.5% of DL-ethionine for 72 hours. Seventy-two hours later, the CDE diet was changed to nor~-l diet, and the mortality was observed up to 144 hours later. m e survivalratewasevaluated as an indicatorof theseverity of pancreatitis.
Compound 1 suspended in 0.5 ~ methyl cellulose was orally given at a dose of 1, 3 and 10 mg/kg to the mice 0, 24, 48, 72, 96 and 120 hours after the onset of CDE diet. To a control group, the solvent (0.5 ~ methyl cellulose) was sim;lArly given. Alternatively, dosing was initiated in a group with induced pancreatitis (therapeutic administration). Compound 1 was orally given at a dose of 10 mg/kg to this group, 32, 56, 80, 104 and 128 hours after the onset of CDE
diet.
The following groups were set;
1. normal group (n = 20) 2. control group (n = 30) 3. group at a dose of 1 mg/kg of Compound 1 (n = 30) 4. group at a dose of 3 mg/kg of Compound 1 (n = 30 ) 5. group at a prophylactic dose of 10 mg/kg of Compound 1 (n = 30) 6. group at a therapeutic dose of 10 mg/kg of Compound 1 (n = 30).
The survival rate was expressed in percentage (as the percentage of the survived Anir -l~ in number to the whole in logarithm) ; and difference was evaluated using the Fisher's exact method. Significant difference was defined at a risk factor of less than 5 %.
The effect of the test compound on the survival rate are shown in Fig 1 and Fig 2.
Test Example 3 Inhibitory Effect of [3H]-Adenosine Uptake A blood sample was obtained from a healthy male adult under 40 years of age by branchial venipuncture using a syringe contAining sodium citrate and subjected to centrifugation to obtain washed erythrocytes. To 100 ~ l of an erythrocyte suspension (2.5X109cells /ml), 10 ~ l of a 21% dimethylsulfoxide (DMSO) solution of a test compound was added. After allowing the suspension to stand at room temperature for 1 hour, 100 ~ l of a [3H]-adenosine solution was added thereto. Ten seconds later, 200 ~ l of a dilazep solution (1 mg/ml) was added to stop the adenosine uptake. m en, dibutyl phthalate was added dropwise to the reaction mixture, followed by centrifugation.
m esupernatantwas~ vedandtheerythrocytefractionwasseparated.
me erythrocytes were dissolved in Triton X-100, and uptake amount of ~H was measured with a liquid scintillation counter. m e concentration of the test compound which inhibits the [~H]-adenosine uptake by 50~ (IC50) was calculated.
Consequently, any of the compound group described in this speclfication had IC50 values of 10-6 M or less.
Test Example 4 Acute Toxicity Test Test compounds were orally or intraperitone~lly ~m;n;ctered to groups of dd-strain male mice weighing 20 + 1 g, each group consisting of three mice. Seven days after the A~m;n;~tration, the mortality was observed to obtain a m;n;m~lm lethal dose (MLD) of the compound.
Consequently, the MLD value of Compound 1 was greater than 1000 mg/kg for oral dosing; and greater than 100 mg/kg for intraperitoneal dosing. Additionally, the MLD value of Compound 2 was greater than 300 mg/kg for oral dosing; and greater than 100 mg/kg for intraperitoneal dosing.
me adenosineuptake inhibitor andph~rm~ceutically acceptable salts thereof to be used in accordance with the present invention can be ~m;n;~tered as they are, or in the forms of various ph~rmAceutical compositions. The pharmaceutical compositions in accordance withthe present invention can be prepared by uniformly mixing an effective amount of adenosine uptake inhibitor or ~hArmAceutically acceptable salts thereof, as an active ingredient, with a pharmacologically acceptable carrier. It is desired that such phAr~celltical compositions are prepared in a unit dose form suitable for oral or parenteral (subcutaneous, intra-rectum, intravenous or intra-muscular) A~m; n; ~tration.
For preparing a pharmaceutical composition for oral administration, any useful pharmaceutically acceptable carrier can be used. For example, liquid preparations for oral administration such as suspensions and syrups can be prepared by using water, sugars such as sucrose, sorbitol, and fructose; glycols such as polyethylene glycol and propylene glycol; oils such as sesame oil, olive oil, and soybean oil; preservatives such as p-hydLoxybenzoates; flavors such as strawberry flavor and peppermint, and the like. Powders, pills, capsules and tablets can bë prepared using excipients such as lactose, glucose, sucrose, and mannitol; disintegrating agents such as starch and sodium alginate; lubricants such as magnesium stearate and talc;
binders such as polyvinyl alcohol, hydloxy~lo~yl cellulose and gelatin; surfactants such as fatty acid esters; and plasticizers such as glycerin, and the like. Tablets and capsules are the most useful oral unit dose forms because of the readiness of A~m;n;~tration, For preparing tables and capsules, solid phAr~ceutical carriers are used.
Injectable preparations can be prepared using a carrier such as distilled water , a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution. The preparations can be prepared in the form of solution, suspension or dispersion according to a conventional method by using a suitable solub;l;~;ng ~llX;liAry or suspending agent.
The adenosine uptake inhibitor and ph~rmAceutically acceptable salts thereof to be used in accordance with the present invention can be ~m;ni~tered orally or parenterally in the said dosage form. The effective dose and the ~mini~tration schedule vary depending upon the mode of ~min;~tration, the age, body weight, and conditions of a patient, etc. However, it is generally appropriate to ~m;n;~ter the adenosine uptake inhibitor and a ph~rmAceutically acceptable salt thereof in a dose of 1 to 900 mg/60 kg/day, preferably 1 to 200 mg/60 kg/day.
Brief Description of the Drawings Fig.l is a graph showing the effects of the test compound on the murine pancreatitis induced by CDE diet.
-{~ normal group :control group - - :group at a dose of 1 mg/kg of Compound 1 :group at a dose of 3 mg/kg of Compound 1 -~C~-:group at a dose of 10 mg/kg of Compound 1 Fig.2 is a graph showing the effects of the test compound on murine pancreatitis induced by CDE diet.
normal group :control group :group at a prophylactic dose of 10 mg/kg of Compound 1 -~C~-:group at a therapeutic dose of 10 mg/kg of Compound 1 Description of the Preferred Embodiments m e embodiments of the present invention will now be described in Examples.
Example 1 Tablet Tablets having the following composition were prepared in a conventional m~nnçr.
Compound 1 (40 g) was mixed with 286.8 g of lactose and 60 g of potato starch, followed by addition of 120 g of a 10% aqueous solution of hydloxy~ ylcellulose. m e resultant mixture was kne~e~, granulated, and then dried by a conventional method. The granules were refined to give granules used to make tablets. After mixing the granules with 1.2 g of magnesium stearate, the mixture was formed into tablets each cont~i ni ng 20 mg of the active ingredient by using a tablet maker (Model RT-15, Kikusui) having pestles of 8 mm diameter.
Composition of One Tablet Compound 1 20 mg Lactose 143.4mg Potato Starch 30 mg Hydloxy~Lo~ylcellulose 6 mg Magnesium Stearate0.6mg 200 mg Example 2 Capsules Capsules having the following composition were prepared in a conventional manner.
Compound 2 (200 g) was mixed with 995 g of Avicel and 5 g of magnesium stearate. The mixture was put in hard capsules No. 4 each having a capacity of 120 g by using a capsule filler (Model LZ-64, Zanasi) to give capsules each cont~ining 20 mg of the active ingredient.
Composition of One Capsule Compound 2 20 mg Avicel 99.5mg Magnesium Stearate 0.5mg 120 mg Example 3 Injections Injections having the following composition were prepared in a conventional manner.
Compound 3 (1 g) was dissolved in 100 g of purified soybean oil, followed by addition of 12 g of purified egg yolk lecithin and 25 g of glycerin for injection. m e resultant mixture was made up to 1,000 ml with distilled water for injection, thoroughly mixed, and emulsified by a conventional method. m e resultant dispersion was subjected to aseptic filtration by using 0.2 ~m disposable membrane filters, and then aseptically put into glass vials in 2 ml portions to give injections contA;n;ng 2 mg of the active ingredient per vial.
Composition of One Injection Vial Compound 3 2 mg Purified Soybean Oil 200 mg Purified Egg Yolk Lecithin24 mg Glycerine for Injection50 mg Dist;lle~ Water for Injection 1.72 ml 2.00 ml Example 4 Anal suppository For~llAtions for rectal dosing having the following composition were prepared in a conventional ~-nn~.r.
678.8 g of Witepzol0 H15 (manufactured by Dynamite Nobel, Co.) and 290.9 g of Witepzol0 E75 (manufactured by Dynamite Nobel, Co.) were melt at 40 to 50 C. Into the resulting molten matter were homogeneously mixed and dispersed 2.5 g of Compound 1, 13.6 g of potassium primary phosphate and 14.2 g of sodium secondary phosphate indiv~ lly. The resultant dispersion was put in a plastic suppository mold, and then followed by gradual cooling to form into formulations cont~;n;ng 2.5 mg of the active ingredient per formulation.
Composition of One Formulation Compound 1 2.5 mg Whitepzol H15 678.8 mg Whitepzol E75 290.9 mg potassium dihydrogen phosphate 13.6 mg disodium phosphate 14.2 mg 1000 mg The present invention provides a prophylactic agent or a therapeutic agent of pancreatitis, cont~n;ng an adenosine uptake inhibitor or ph~rm~ceutically acceptable salts thereof as the effective ingredient.
Claims (3)
1. A prophylactic or therapeutic agent of pancreatitis, containing an adenosine uptake inhibitor or a pharmaceutically acceptable salt thereof as the active ingredient.
2. A prophylactic or therapeutic agent of pancreatitis according to claim 1, wherein the adenosine uptake inhibitor is a quinazoline derivative represented by the following Formula (I);
wherein R1 represents hydrogen, substituted or unsubstituted lower alkyl, alkenyl, or substituted or unsubstituted aralkyl; R2, R3, R4 and R5 independently represent hydrogen, halogen, amino, mono- or di(lower alkyl)amino, lower alkanoylamino, nitro, cyano, substituted or unsubstituted lower alkyl, hydroxy, lower alkoxy, lower alkylthio, carboxy, lower alkoxycarbonyl, lower alkanoyl, aralkyloxy, or lower alkanoyloxy; R6, R7, R8 and R9 independently represent hydrogen, lower alkyl, hydroxy, substituted or unsubstituted lower alkoxy or aralkyloxy, or any adjoining two of them are combined to form methylenedioxy, or ethylenedioxy; R10 represents hydrogen, substituted or unsubstituted lower alkyl, halogen, or NR12R13(wherein R12 and R13 independently represent hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; or R12 and R13 are combined together with N to form a substituted or unsubstituted heterocyclic group); R11 represents hydrogen, lower alkyl, or halogen;
and n represents 0, 1, or 2; or a pharmaceutically acceptable salt thereof.
wherein R1 represents hydrogen, substituted or unsubstituted lower alkyl, alkenyl, or substituted or unsubstituted aralkyl; R2, R3, R4 and R5 independently represent hydrogen, halogen, amino, mono- or di(lower alkyl)amino, lower alkanoylamino, nitro, cyano, substituted or unsubstituted lower alkyl, hydroxy, lower alkoxy, lower alkylthio, carboxy, lower alkoxycarbonyl, lower alkanoyl, aralkyloxy, or lower alkanoyloxy; R6, R7, R8 and R9 independently represent hydrogen, lower alkyl, hydroxy, substituted or unsubstituted lower alkoxy or aralkyloxy, or any adjoining two of them are combined to form methylenedioxy, or ethylenedioxy; R10 represents hydrogen, substituted or unsubstituted lower alkyl, halogen, or NR12R13(wherein R12 and R13 independently represent hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; or R12 and R13 are combined together with N to form a substituted or unsubstituted heterocyclic group); R11 represents hydrogen, lower alkyl, or halogen;
and n represents 0, 1, or 2; or a pharmaceutically acceptable salt thereof.
3. An adenosine uptake inhibitor is a compound represented by the following Formula (II);
wherein R14 represents hydrogen, or lower alkyl; R15 represents hydrogen, carbamoyl, mono- or di(lower alkyl) aminocarbonyl, lower alkoxycarbonyl, or carboxy; R16 represents hydrogen, or lower alkyl;
Ar represents substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group; m represents 1, or 2; p represents an integer of 0 to 5; Q represents substituents selected from the group consisting of (a) to (m) represented by the following formulas;
-AR1 ( a ) wherein Y represents S, O, or NH: Ar1 and Ar2 independently represent substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group; or a pharmacologically acceptable salt thereof.
wherein R14 represents hydrogen, or lower alkyl; R15 represents hydrogen, carbamoyl, mono- or di(lower alkyl) aminocarbonyl, lower alkoxycarbonyl, or carboxy; R16 represents hydrogen, or lower alkyl;
Ar represents substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group; m represents 1, or 2; p represents an integer of 0 to 5; Q represents substituents selected from the group consisting of (a) to (m) represented by the following formulas;
-AR1 ( a ) wherein Y represents S, O, or NH: Ar1 and Ar2 independently represent substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group; or a pharmacologically acceptable salt thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9196097 | 1997-04-10 | ||
| JP91960/97 | 1997-04-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2234342A1 true CA2234342A1 (en) | 1998-10-10 |
Family
ID=14041138
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002234342A Abandoned CA2234342A1 (en) | 1997-04-10 | 1998-04-08 | Pancreatitis remedy |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US5866574A (en) |
| EP (1) | EP0870502A3 (en) |
| CA (1) | CA2234342A1 (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6943168B2 (en) * | 1998-06-30 | 2005-09-13 | Neuromed Technologies Inc. | Calcium channel inhibitors comprising benzhydril spaced from piperazine |
| US20040266784A1 (en) * | 1998-06-30 | 2004-12-30 | Snutch Terrance P. | Calcium channel inhibitors comprising benzhydril spaced from piperazine |
| US20040259866A1 (en) * | 1998-06-30 | 2004-12-23 | Snutch Terrance P. | Calcium channel blockers comprising two benzhydril moieties |
| US20060084660A1 (en) * | 1998-06-30 | 2006-04-20 | Neuromed Technologies Inc. | Calcium channel blockers comprising two benzhydril moieties |
| US7186726B2 (en) | 1998-06-30 | 2007-03-06 | Neuromed Pharmaceuticals Ltd. | Preferentially substituted calcium channel blockers |
| US6951862B2 (en) * | 1998-06-30 | 2005-10-04 | Neuromed Technologies, Inc. | Calcium channel blockers comprising two benzhydril moieties |
| WO2002044160A1 (en) * | 2000-11-30 | 2002-06-06 | Senju Pharmaceutical Co., Ltd. | Pancreatitis remedies and medicines for prevention and therapy of reflux esophagitis |
| CA2347879A1 (en) | 2001-05-11 | 2002-11-11 | Vanderbilt University | Substituted dicinnamoylquinides and their use in augmentation of adenosine function |
| JP2009528365A (en) * | 2006-02-28 | 2009-08-06 | アムゲン インコーポレイティッド | Cinnoline and quinazoline derivatives as phosphodiesterase 10 inhibitors |
| US8362021B2 (en) * | 2006-05-11 | 2013-01-29 | Zalicus Pharmaceuticals Ltd. | Method for increasing the bioavailability of benzhydryl piperazine containing compounds |
| MX2013010306A (en) | 2011-03-08 | 2013-12-09 | Zalicus Pharmaceuticals Ltd | Solid dispersion formulations and methods of use thereof. |
| US8409560B2 (en) | 2011-03-08 | 2013-04-02 | Zalicus Pharmaceuticals Ltd. | Solid dispersion formulations and methods of use thereof |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL137318C (en) * | 1964-06-09 | |||
| US4766125A (en) * | 1981-06-23 | 1988-08-23 | Janssen Pharmaceutica N.V. | N-aryl-piperazinealkanamides useful for protecting hearts from myocardial injury caused by ischaemia, anoxia or hypoxia |
| NZ223847A (en) * | 1987-04-01 | 1989-12-21 | Janssen Pharmaceutica Nv | Substituted piperazine derivatives and pharmaceutical compositions |
| EP0497258B1 (en) * | 1991-01-29 | 2002-01-02 | Fujisawa Pharmaceutical Co., Ltd. | Use of adenosine antagonists in the prevention and treatment of pancreatitis and ulcer |
| DE69322707T2 (en) * | 1992-07-31 | 1999-08-19 | Bristol Myers Squibb Co | Diphenyl oxazole, thiazole and imidazole derivatives as inhibitors of adenosine reuptake |
| IL108523A0 (en) * | 1993-02-03 | 1994-05-30 | Gensia Inc | Pharmaceutical compositions containing adenosine kinase inhibitors for preventing or treating conditions involving inflammatory responses and pain |
| EP0638567A4 (en) * | 1993-02-18 | 1995-05-10 | Kyowa Hakko Kogyo Kk | Adenosine incorporation inhibitor. |
| JPH09165385A (en) * | 1994-08-26 | 1997-06-24 | Kyowa Hakko Kogyo Co Ltd | Quinazoline derivative |
| JPH08151377A (en) * | 1994-11-25 | 1996-06-11 | Kyowa Hakko Kogyo Co Ltd | Quinazoline derivative |
-
1998
- 1998-04-08 CA CA002234342A patent/CA2234342A1/en not_active Abandoned
- 1998-04-08 EP EP98302748A patent/EP0870502A3/en not_active Withdrawn
- 1998-04-08 US US09/056,710 patent/US5866574A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US5866574A (en) | 1999-02-02 |
| EP0870502A3 (en) | 2001-04-04 |
| EP0870502A2 (en) | 1998-10-14 |
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Legal Events
| Date | Code | Title | Description |
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| FZDE | Discontinued |