CA2176124A1 - 4-(1h-2-methylimidazo 4,5-c pyridinylmethyl)phenyl sulphonamide carboxylic acid derivatives as antagonists - Google Patents
4-(1h-2-methylimidazo 4,5-c pyridinylmethyl)phenyl sulphonamide carboxylic acid derivatives as antagonistsInfo
- Publication number
- CA2176124A1 CA2176124A1 CA002176124A CA2176124A CA2176124A1 CA 2176124 A1 CA2176124 A1 CA 2176124A1 CA 002176124 A CA002176124 A CA 002176124A CA 2176124 A CA2176124 A CA 2176124A CA 2176124 A1 CA2176124 A1 CA 2176124A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- methylimidazo
- pyridinylmethyl
- phenylsulphonyl
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
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- 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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- A61P27/02—Ophthalmic agents
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Abstract
Compounds of formula (II), wherein R1 represents hydrogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -COC1-C6 alkyl, -CO2C1-C6 alkyl, -(COC1-C6 alkyl)phenyl, -(CO2C1-C6 alkyl)phenyl, -(C1-C6 alkyl)OC1-C6 alkyl, -(C1-C6 alkyl)SC1-C6 alkyl, -(C1-C6 alkyl)CO2C1-C6 alkyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl or a group -D wherein D represents a group (A) wherein n is an integer from 0 to 3, and each of R3 and R4 is independently hydrogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, halogen, -CN, -CO2H, -CO2C1-C6 alkyl, -CONH2, -CONHC1-C6 alkyl, -CONH(C1-C6 alkyl) 2, -CHO, -CH2OH, -CF3, -OC1-C6 alkyl, -SC1-C6 alkyl, -SOC1-C6 alkyl, -SO2C1-C6 alkyl, -NH2 or -NHCOMe; R2 represents hydrogen, halogen, -C1-C6 alkyl optionally substituted by one or more halogen atoms, -C2-C6 alkenyl, -C2-C6 alkynyl, -(C1-C6 alkyl)CO2C1-C6 alkyl, -(C1-C6 alkyl)SC1-C6 alkyl, -(C1-C6 alkyl)OC1-C6 alkyl, -(C1-C6 alkyl)N(C1-C6 alkyl)2, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, -(C1-C6 alkyl)C3-C8 cycloalkyl, -(C1-C6 alkyl)C4-C8 cycloalkenyl, -(C1-C6 alkyl)OC3-C8 cycloalkyl,-(C1-C6 alkyl)OC4-C8 cycloalkenyl, -(C1-C6 alkyl)SC3-C8 cycloalkyl, -(C1-C6 alkyl)SC4-C8 cycloalkenyl, a side chain of a naturally occurring amino acid, a group -D as defined above or a -(C1-C6 alkyl)OD group wherein D is as defined above; or a pharmaceutically or veterinarily acceptable salt thereof, are PAF inhibitors.
Description
w 09~l3064 ;~ ' 2 i 76 1 24 PCT/G394/02460 4-(lH-2-METHYLIMIDAZ0 4,5-C PYRIDINYLMETHYL)P~ENYL SULPHONAMIDE CARB~XYLIC
ACID DERIVATIVES AS ANTAGONISTS
This invention relates to the use of certain 4-(1 H-2-Methylimidazo[4,5-c]pyridi nylmethyl) phenylsulphonamide derivatives, previously proposed as intermediates in the synthesis of antagonists of platelet activating factor ("PAF"), as active PAF
antagonists in their own right, for the preparation of pharmaceutical and veterinary compositions for the management of diseases ~n conditions mediated by PAf.
~k~roun~ to the Invention International Patent ~r)plic~tion WO 92/03423 (British Bio-technology Limited) discloses benzimidazole derivatives of formula (I) below, having PAF antagonist activity:
N (I) R4 ~ S ~ IR5 B
R /~\ ~ R7 wherein:
A1 is =N-, =CH- or =CR1-;
A2 is -N=, -CH= or -CR2=;
provided that, when one of A1 and A2 is a nitrogen atom, the other of A1 and A2 is other than a nitrogen atom;
SUBsT~TuTE SHEET ~RULE 26 WO95tl306~ t i ~17~ ~ i 24 PCT/GB91/02460 R represents hydrogen, -C1-C6 alkyl, -C2-C6 alkenyl, halogen or -OC~-C6 alkyl;
each of R1 and R2 independently represents hydrogen, - C~-C6 alkyl, -C2-C6 alkenyl, halogen, -CN, -CO2H, - CO2C~-C6 alkyl, -CONH2, -CHO, -CH20H, -CF3, -OC1-C6 alkyl, -SC1-C6 alkyl, -SOC1-C6 alkyl, -SO2C1-C6 alkyl, -NH2, -NHCOMe or -NO2 or R1 and R2 together with the carbon atoms to which they are attached form a fused phenyl ring;
R3 represents hydrogen, -C~-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OC~-C6 alkyl, -SC~-C6 alkyl, -(C~-C6 alkyl)OC~-C6 alkyl, -(C~-C6 alkyl)SC1-C6 alkyl, -CF3, -(C~-C6 alkyl)phenyl, -C3-C8 cycloalkyl, -C4.C8 cycloalkenyl, -(C1-C6 alkyl)C3 C8 cycloalkyl, -(C~-C6 alkyl)C4 C8 cycloalkenyl or thiophenyl;
R4 represents hydroyen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -CO2C1-C6 alkyl, -SC1-C6 alkyl, -(C1-C6 alkyl)SC1-C6 alkyl, -(C~-C6 alkyl)OC~-C6 alkyl,-(Cl-C6 alkyl)phenyl or thiophenyl;
R5 represents hydrogen, -C~-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -COC~-C6 alkyl, -CO2C~-C6 alkyl, -(COC~ C6 alkyl)phenyl, -(CO2C~ C6 alkyl)phenyl, -(C1-C6 alkyl)OC~-C6 alkyl, -(C~-C6 alkyl)SC~-C6 alkyl, -(C~-C6 alkyl)CO2C~-C6 alkyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl or a group -D wherein D
represents a group:
~--(CH2)n ~ R9 wherein n is an integer fronl 0 to 3, and each of R8 and R9 is independently hydrogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, halogen, -CN, -CO2H, -CO2C1-C6 alkyl, -CONH2, - CONHCl-C6 alkyl, -CONH(C1-C6 alkyl)2, -CHO, -CH20H, -CF3, - OC~-C6 alkyl, -SC~-C6 alkyl, -SOC1-C6 alkyl, -SO2C1-C6 alkyl, -NH2 or -NHCOMe;
SUBSTITUTE SHEET (RULE 26) WO 95/1306~ J ~ PCTIGB94/02460 ~ 3 2176124 each of R6 and R7 independently represents hydrogen, halogen, -C~ C6 alkyl optionally substituted by one or more halogen atoms, -C2-C6 alkenyl, -C2-C6 alkynyl, -(C1-C6 alkyl)CO2C~ C6 alkyl, -(C~-C6 alkyl)SC~-C6 alkyl, -(C~-C6 alkyl)OC1-C6 alkyl, -(C1-C6 alkyl)N(C1-C6 alkyl)2, -C3 C8 cycloalkyl, -C4 C8 cycloalkenyl, -(C1-C6 alkyl)C3 C8 cycloalkyl, -(C1-C6 alkyl)C4 C8 cycloalkenyl, -(C1-C6 alkyl)OC3 C8 cycloalkyl, -(C,-C6 alkyl)OC4 C8 cycloalkenyl, -(C~-C6 alkyl)SC3 C8 cycloalkyl, -(C~ C6 alkyl)SC4 C8 cycloalkenyl, a side chain of a naturally occurring amino acid, a group -D as defined above or a -(C~-C6 alkyl)OD group wherein D is as defined above;
or R6 together with R~ and the atoms to which they are attached form a 5 to 8 membered nitrogen-containing heterocyclic ring;
or R6 and R7 together with the carbon atom to which they are attached form a C3-C8 cycloalkyl ring;
B represents a) a -ZR10 group wherein Z is -C(=O)-, -C(=O)O-, -C(=S)- or -C(=S)O- and Rl is -C1-C~8 alkyl optionally substituted by one or more halogen atoms, -C2-C18 alkenyl, -C2-C18 alkynyl, -(C,-C6 alkyl)OC~-C6 alkyl, -(C1-C6 alkyl)SC1-C6 alkyl, -(C1-C6 alkyl)O(C1-C6 alkyl)OC1-C6 alkyl, -C3-C8 cycloalkyl, -C4 C8 cycloalkenyl, pyridyl, a group -D as defined above or a -(C~-C6 alkyl)OD group wherein D is as defined above;
b) a -CONR11R12 group wherein each of R11 and R12 is independently hydrogen, -C~-C1~ alkyl optionally substituted by one or more halogen atoms, -C2-C18 alkenyl, -C2-C18 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, pyridyl, a group -D as defined above or R11 and R12 together with the nitrogen atom to which they are attached form a 5 to 8 membered nitrogen-containing h~e~yclic rlng;
In the compounds of formula (I) of WO 92/03423, the carboxylic acid group -CO2H is not amongst the possibilities specified for substituent B. However, it is stated therein SUBSTITUTE SHEET ~RULE 26) ~ .
ACID DERIVATIVES AS ANTAGONISTS
This invention relates to the use of certain 4-(1 H-2-Methylimidazo[4,5-c]pyridi nylmethyl) phenylsulphonamide derivatives, previously proposed as intermediates in the synthesis of antagonists of platelet activating factor ("PAF"), as active PAF
antagonists in their own right, for the preparation of pharmaceutical and veterinary compositions for the management of diseases ~n conditions mediated by PAf.
~k~roun~ to the Invention International Patent ~r)plic~tion WO 92/03423 (British Bio-technology Limited) discloses benzimidazole derivatives of formula (I) below, having PAF antagonist activity:
N (I) R4 ~ S ~ IR5 B
R /~\ ~ R7 wherein:
A1 is =N-, =CH- or =CR1-;
A2 is -N=, -CH= or -CR2=;
provided that, when one of A1 and A2 is a nitrogen atom, the other of A1 and A2 is other than a nitrogen atom;
SUBsT~TuTE SHEET ~RULE 26 WO95tl306~ t i ~17~ ~ i 24 PCT/GB91/02460 R represents hydrogen, -C1-C6 alkyl, -C2-C6 alkenyl, halogen or -OC~-C6 alkyl;
each of R1 and R2 independently represents hydrogen, - C~-C6 alkyl, -C2-C6 alkenyl, halogen, -CN, -CO2H, - CO2C~-C6 alkyl, -CONH2, -CHO, -CH20H, -CF3, -OC1-C6 alkyl, -SC1-C6 alkyl, -SOC1-C6 alkyl, -SO2C1-C6 alkyl, -NH2, -NHCOMe or -NO2 or R1 and R2 together with the carbon atoms to which they are attached form a fused phenyl ring;
R3 represents hydrogen, -C~-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OC~-C6 alkyl, -SC~-C6 alkyl, -(C~-C6 alkyl)OC~-C6 alkyl, -(C~-C6 alkyl)SC1-C6 alkyl, -CF3, -(C~-C6 alkyl)phenyl, -C3-C8 cycloalkyl, -C4.C8 cycloalkenyl, -(C1-C6 alkyl)C3 C8 cycloalkyl, -(C~-C6 alkyl)C4 C8 cycloalkenyl or thiophenyl;
R4 represents hydroyen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -CO2C1-C6 alkyl, -SC1-C6 alkyl, -(C1-C6 alkyl)SC1-C6 alkyl, -(C~-C6 alkyl)OC~-C6 alkyl,-(Cl-C6 alkyl)phenyl or thiophenyl;
R5 represents hydrogen, -C~-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -COC~-C6 alkyl, -CO2C~-C6 alkyl, -(COC~ C6 alkyl)phenyl, -(CO2C~ C6 alkyl)phenyl, -(C1-C6 alkyl)OC~-C6 alkyl, -(C~-C6 alkyl)SC~-C6 alkyl, -(C~-C6 alkyl)CO2C~-C6 alkyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl or a group -D wherein D
represents a group:
~--(CH2)n ~ R9 wherein n is an integer fronl 0 to 3, and each of R8 and R9 is independently hydrogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, halogen, -CN, -CO2H, -CO2C1-C6 alkyl, -CONH2, - CONHCl-C6 alkyl, -CONH(C1-C6 alkyl)2, -CHO, -CH20H, -CF3, - OC~-C6 alkyl, -SC~-C6 alkyl, -SOC1-C6 alkyl, -SO2C1-C6 alkyl, -NH2 or -NHCOMe;
SUBSTITUTE SHEET (RULE 26) WO 95/1306~ J ~ PCTIGB94/02460 ~ 3 2176124 each of R6 and R7 independently represents hydrogen, halogen, -C~ C6 alkyl optionally substituted by one or more halogen atoms, -C2-C6 alkenyl, -C2-C6 alkynyl, -(C1-C6 alkyl)CO2C~ C6 alkyl, -(C~-C6 alkyl)SC~-C6 alkyl, -(C~-C6 alkyl)OC1-C6 alkyl, -(C1-C6 alkyl)N(C1-C6 alkyl)2, -C3 C8 cycloalkyl, -C4 C8 cycloalkenyl, -(C1-C6 alkyl)C3 C8 cycloalkyl, -(C1-C6 alkyl)C4 C8 cycloalkenyl, -(C1-C6 alkyl)OC3 C8 cycloalkyl, -(C,-C6 alkyl)OC4 C8 cycloalkenyl, -(C~-C6 alkyl)SC3 C8 cycloalkyl, -(C~ C6 alkyl)SC4 C8 cycloalkenyl, a side chain of a naturally occurring amino acid, a group -D as defined above or a -(C~-C6 alkyl)OD group wherein D is as defined above;
or R6 together with R~ and the atoms to which they are attached form a 5 to 8 membered nitrogen-containing heterocyclic ring;
or R6 and R7 together with the carbon atom to which they are attached form a C3-C8 cycloalkyl ring;
B represents a) a -ZR10 group wherein Z is -C(=O)-, -C(=O)O-, -C(=S)- or -C(=S)O- and Rl is -C1-C~8 alkyl optionally substituted by one or more halogen atoms, -C2-C18 alkenyl, -C2-C18 alkynyl, -(C,-C6 alkyl)OC~-C6 alkyl, -(C1-C6 alkyl)SC1-C6 alkyl, -(C1-C6 alkyl)O(C1-C6 alkyl)OC1-C6 alkyl, -C3-C8 cycloalkyl, -C4 C8 cycloalkenyl, pyridyl, a group -D as defined above or a -(C~-C6 alkyl)OD group wherein D is as defined above;
b) a -CONR11R12 group wherein each of R11 and R12 is independently hydrogen, -C~-C1~ alkyl optionally substituted by one or more halogen atoms, -C2-C18 alkenyl, -C2-C18 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, pyridyl, a group -D as defined above or R11 and R12 together with the nitrogen atom to which they are attached form a 5 to 8 membered nitrogen-containing h~e~yclic rlng;
In the compounds of formula (I) of WO 92/03423, the carboxylic acid group -CO2H is not amongst the possibilities specified for substituent B. However, it is stated therein SUBSTITUTE SHEET ~RULE 26) ~ .
2 ~ 76 i 24 PCTIGB91/02460 ~
5 ~ 4 that compounds of formula (I) wherein B is a group -CONR1~R12 where R11 and R12 are as defined in formula (I) may be prepared by treatment of a compound of formula (I) wherein B is a -CO2R1 group wherein R10 is a benzyl group with hydrogen in the presence of a noble metal catalyst (eg 10% palladium on charcoal) to give ~
carboxylic acid which is then treated with an amine of formula HNR11R12 in the presence of a coupling reagent (eg 1,3-dicyclohexylcarbodiimide). It is also stated therein that certain compounds of formula (I) wherein B is a -CO2R1 group wherein R10 is as defined in formula (I) may be prepared by base catalysed hydrolysis to ~ive compound of ~eneral formula (I) wherein 8 is a -CO~H grouD which is subsequently esterified with an alcohol of general formula HOR10 in the presence of a coupling reagent (eg 1,3-dicyclohexylcarbodiimide).
Example 77 of WO 92/03423 discloses the carboxylic acid N-methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridylmethyl)phenylsulphonyl-L-leucine, used as an intermediate in the prepara~ion of its octadecyl ester.
Thus, WO 92/03423 discloses the use of compounds of formula (I) wherein B is a carboxylic acid group -CO21~ as intermediates for the synthesis of PAF antagonists of formula (I) wherein B is an esterified or amidated carboxylic acid group. However, there is no suggestion that the carboxylic acids per se have utility as PAF
antagonists.
Rrief Description of the Invention The present invention is based on the discovery that carboxylic acids known fromWO 92/03423 to be useful as intermediates for the preparation of PAF antagonistsdisclosed therein, have PAF antagonist activity in their own right. The invention therefore relates to the use of such carboxylic acids in human and vetQrinary medicine and to pharmaceutical and veterinary compositions comprising them. In connsction with the invention, it is of interest that during investigation of the metabolism of N-methy~-N-4-tt~-2-",~:ll,yli",ida~o~4,~
pyridylmethyl)phenylsulphonyl-L-leucine ethyl ester, ie the compound of Example 53B of WO 92/03423, following administration of that compound to human beings, it was found that N-methyl-N-4-(1 H-2-methylimidazo[4,5-SUBSTITUTE SHEET (RULE 26J
WO 95/1306~ PCT/GB94/02460 c]pyridylmethyl)phenylsulphonyl-L-leucine is a primary metabolite (unpublished data).
Description of the Invention The present invention provides a compound of formula (Il):
N~ \>--CH3 ~S~ ~OH
wherein R1 represents hydrogen, -C~-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -COC1 C6 alkyl, -CO2C1-C6 alkyl, -(COC1 C6 alkyl)phenyl, - (CO2C1 C6 alkyl)phenyl, -(C1-C6 alkyl)OC1-C6 alkyl, -(C,-C6 alkyl)SC1-C6 alkyl, -(C1 C6 alkyl)CO2C1-C6 alkyl, -C3-C8 cycloalkyl, -C4-C8 cycioalkenyl or a group -D
wherein D represents a group:
/=\~ R3 (C~2)n~
wherein n is an integer from 0 to 3, and each of R3 and R4 is independently hydrogen, -C~-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, halogen, -CN, -CO2H, -CO2C~-C6 alkyl, -CONH2, -CONHC1-C6 alkyl, -CONH(C1-C6 alkyl)2, -CHO, -CH20H, -CF3, -OC1-C6 alkyl, - SC~-C6 alkyl, -SOC,-C6 alkyl, -SO2C1-C6 alkyl, -NH2 or -NHCOMe;
R2 represents hydrogen, halogen, -C1 C6 alkyl optionally substituted by one or Sl3Ç~STITUTE SHEET (RULE 261 WO 95113061 , ,~ 1 ~ 6 1 2 4 Pcr/G~94lo~J6~ ~
more halogen atoms, -C2-C6 alkenyl, -C2-C6 alkynyl, -(C1-C6 alkyl)CO2C1 C6 alkyl, -(C1-C6 alkyl)SC1-C~ alkyl, -(C1-C6 alkyl)OC1-C6 alkyl, -(C1-C6 alkyl)N(C1-C6 alkyl)2, -C3 Cs cycloalkyl, -C4 Cs cycloalkenyl, -(C1-C6 alkyl)C3 C8 cycloalkyl, - (C1-C6 alkyl)C4 Cs cycloalkenyl, -(C1-C6 alkyl)OC3 C8 cycloalkyl, -(C1-C6 alkyl)OC4 Cs cycloalkenyl, -(G1-C6 alkyl)SC3 C8 cycloalkyl, -~C1 C6 alkyl)SC4 C~ cycloalkenyl, a side chain of a naturally occurring amino acid, a group -D as defined above or a -(C1-C6 alkyl)OD group wherein D is as defined above;
or a pharmaceutically or veterinarily acceptable salt thereof, for use in human or vererinary medicine.
Herealter, the term "compound of formula (Il)" will be used to refer to a compound as defined in the preceeding paragraph, and is to be understood as referring to thepharmaceutically or veterirlarily acce~la~le salts thereof. Furthermore, the term "pharmaceutical" is to be understood as including both human and veterinary applications.
.
PAF is released directly from cell membranes and mediates a range of potent and specific effects on target cells resulting in a variety of physiological responses which include hypotension, thrornbocytopenia, bronchoconstriction, circulatory shock, and increased vascular permeability (oedema/erythema). It is known that these physiological effects occur in many inflammatory and allergic diseases and PAF has been found to be involved in a number of such disorders including asthma, endotoxin shock, adult respiratory distress syndrome, glomerulonephritis, immuneregulation, transplant rejection, gastric ulceration, psoriasis, cerebral, myocardial and renal ischemia. Thus compounds of formula (Il) for use in accordance with the invention, by virtue of their ability to antagonise the actions of PAF, may be useful to reduce inflammation and pain, to correct espira~ory, cardiovascular, and intravascular alterations or disorders, and to reguiate the activation or coagura~ion of platelets, to correct hypotension during shock, the pathogenesis of immune complex deposition and smooth muscle contractions. In particular, they they have applications in the treatment of inflammatory disorders; such as rheumatoid arthritis, osteoarthritis ~iiUP~STlTUTE SHEE~ (RULE 26~
WO 9~113064 ,` ~ ;r 2 1 76 1 24 PCT/GB94/02460 and eye inflammation, cardiovascular disorder, thrombocytopenia, asthma, endotoxin shock, adult respiratory distress syndrome, glomerulonephritis, immuneregulation, gastric ulceration, transplant rejection, psoriasis, allergic dermatitis, urticaria, multiple sclerosis, cerebral, myocardial and renal ischemia and any other condition in which PAF is implicated.
The invention includes the use of a compound of formula (Il) in the preparation of a pharmaceutical composition adapted for oral, topical, rectal or parenteral administration or for inhalation for the management of diseases or conditions mediated by PAF, for example those referred to above. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Such compositions will include, as is conventional, pharmaceutically acceptable carriers for the active compound, and may contain other conventional pharmaceutical excipients.
Another aspect of the invention is a pharmaceutical composition in dosage unit form, for the management of diseases or conditions mediated by PAF, comprising a compound of formula (Il) and one or more pharmaceutically acceptable carriers.
Pharmaceutical dosage units are of course known in the art in general, but are primarily characterised in that the active compound is substantially free of impurities, and present in the dosage unit in a predetermined unit dose amount. In the present case, dosage units include tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups elixirs, phials containing sterile injectabie suspensions or solutions of the active ingredient, nebulisers containing solid micronised, or atomisable solutions or suspensions of the active ingredient, Each dosage unit may comprise from about 0.1 mg to about 19 of active ingredient, for example from 1 Omg to 500 mg, more particularly from 100 to 300mg.
In ~eneralr the ~uantity of a~tive in~redient present in ea~h rlO~A9e unit.~luill b~
chosen to deliver to the patient from about 0.1 mg to abou 0.5 mg to about 7 9 per patient per day. For example, for treatment of inflammation, the administration of from about 1.0 mg to about 3.5 9 per patient per day may be appropriate. The dosage employed for topical administration will, of course, depend on the size of the SUBS~ITU~E SHEET tRUaE 26) WO 95/13064 . '; ~ ~ ~ t ~ 3 2 ~ I'CT/G~9J/02460 area being treated. For the eyes each dose will be typically in the range from 10 to 100 mg of the drug.
Another aspect of the invention is a method for the management of diseases or conditions mediated by PAF, comprising administering to the patient an effectiveamount of a compound of formula (Il) or a pharmaceutically salt thereof.
As used herein, the term "pharmaceutically acceptable salt" means acid or base addition salts whose anion is generally considered safe for human or animal consumption. Suitable bass addition salts include the sodium, potassium, magnesium, lithium, and calcium salts Suitable acid addition salts include the hydrochloride, sulphate, phosphate, acetate, propionate, lactate, maleate, succinate and t~ le salts.
As used herein the term "halogen" or its abbreviation "halo" means fluoro, chloro, bromo or iodo.
As used herein the term "C~-C6 alkyl" refers to straight chain or branched chainhydrocarbon groups having from one to six carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.
As used herein the term "C2-C6 alkenyl" refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one double bond, of either E or Z stereochemistry where arplicAhl-. This term would include for example, vinyl, 1-propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl.
As used herein the term "C2-C6 alkynyl" refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. ~his term woul~ ~nciude for exar~ t~ny~ propynr~, ~- art~
butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
SUBSTITUTE SHEET (RULE 26) WO95/13064 ~ 2 1 ¦6 ¦ 24 PCT/GB9~/02460 ,, As used herein, the term "~ 4 perfluoroalkyl" refers to straight chain or branched chain groups having from one to four carbon atoms and substituted by more than one fluorine atom. This term would include for example, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoro-n-propyl, sexafluoro-i-propyl,septafluoro-n-propyl, septafluoro-i-propyl, 4,4,4-trifluoro-n-butyl, nonafluoro-n-butyl, nonafluoro-sec-butyl and nonafiuoro-i-butyl.
As used herein the term "OC~-C6 alkyl" refers to straight chain or branched chain alkoxy groups having from one to six carbon atoms. Illustrative of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, ~ert-butoxy, pentoxy, neopentoxy and hexoxy.
As used herein the term "SC~-C6 alkyl" refers to straight chain or branched chain alkylthio groups having ~rom one to six carbon atoms. Illustrative of such alkyl groups are methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, neopentylthio and hexylthio.
As used herein, the term "C3-C8 cycloalkyl" refers to an alicyclic group having from 3 to 8 carbon atoms. Illustrative of such cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As used herein, the term "C4-C8 cycloalkenyl" refers to an alicyclic group having from 4 to 8 carbon atoms and having in addition one or more double bonds. Illustrative of such cycloalkenyl groups are cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
As used herein, the term "side chain of a naturally occurring amino acid" includes the side chains of alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glycine, histidine, 5-hydroxylysine, 4-hydroxyproline, isoleucine, leucine, Iysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, a-aminoadipic acid, a-amino-n-butyric acid, 3,4-dihydroxyphenylalanine, homoserine, a-methylserine, ornithine, pipecolic acid, and thyroxine. The amino acid side chains may be protected; for example the carboxyl groups of aspartic acid, glutamic acid SUB~TITUTE SHEET tRULE 26) WO 95/1306~ i ~ 2 t ~ ~ ~ 2~ PCTIGB9~/02460 ~
~ I 10 and a-aminoadipic acid may be esterified (for example as a C1-C6 alkyl ester), the amino groups of Iysine, ornithine, ~-hydroxyiysine, 4-hydroxyproline may be converted to amides (for example as a COC,-C6 alkyl amide) or carbamates (for example as a C(=O)OC1-C6 alkyl or C(=O)OCH2Ph carbamate), the hydroxyl groups of 5-hydroxylysine, 4-hydroxyproline, serine, threonine, tyrosine, 3,4-dihydroxyphenylalanine, homoserine, a-methylserine and thyroxine may be converted to ethers (for example a C1-C6 alkyl or a (C1-C6 alkyl)phenyl ether) or esters (for example a C(=O)C1-C6 alkyl ester) and the thiol group of cysteine may be converted to thioethers (for example a C1-C6 alkyl thioether) or thioesters (forexample a C(=O)C1-C6 alkyl thioester). The stereochemistry at the carbon atom towhich the amino acid side chain is attached may be either D or L.
In compounds of formula (Il), the presence of several asymmetric carbon atoms gives rise to diastereoisomers, each of which consists of two enantiomers, with the appropriate R or S stereochemistry at each chiral centre. The invention is understood to include the use of all such diastereoisomers, their optically active enantiomers and mixtures thereof.
Although this application relates only to compounds of formula (Il) in which thesubstituents R1, and R2 are the only variables it is understood that the introduction of further substituents on the 2-methylimidazo[4,5-c]pyridinyl group, the benzylic carbon atom and/or the 1 ,4-disubstituted phenyl ring will lead to compounds that retain PAF
antagonist activity.
Preferred compounds for use according to the invention include those in which, independently or in any compatible combination:
R1 represents a hydrogen atom, a -C~-C6 alkyl ffor example methyl, ethyl or propyl) group, a -C2~C6 alkenyl (for example allyl) group or a group -D;
R2 represents a hydrogen atom, a -C1-C6 alkyl (for example ethyl, n-butyl, t-butyl or neopentyl) group, a-C2-C6 alkenyl (for example allyl) group, a -(C1-C6 alkyl)C3-C8 cycloalkyl (for example cyclopropylmethyl, cyclopentylmethyl or S~IBSTITUTE SHEET (RULE 26) ~ WO 9~/1306~ 1 1 2 1 7 ~ PCT/GB9~/02460 cyclohexylmethyl) group, a side chain of a naturally occurring amino acid (for example the side chain of leucine, isoleucine, phenylalanine, valine, tryptophan, methionine or tyrosine) or a group D;
in the group D, R3 represents a hydrogen atom, a -C1-C6 alkyl (for example methyl) group, a halogen (for example fluorine, chlorine or bromine) atom, a -CF3 group or a -OC1-C6 alkyl (for example methoxy) group;
in the group D, R4 represents a hydrogen atom or a -OC~-C6 alkyl (for example methoxy) group;
Examples of compounds of formula (Il) for use in accordance with the present invention are:
N-4-(1 H-2-Methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl -L-leucine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c~pyridinylmethyl)phenylsulphonyl-D-leucine;
N-Ethyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine;
N-Allyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine;
N-Propyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine;
N-Benzyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinyimethyl)phenylsulphonyl-L-leucine;
N-4-Methoxybenzyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmeth yl) -phenylsulphonyl-L-leucine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-- L-isoleucine;
N-Methyi-N-4-(t H-2-methyiimidazor4,5-cJpyridiny~methyl~phenylsulphonyr-L-phenylalanine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-valine;
SUBSTITUTE SHEET (RULE 26 12 PCI/G~19J/0246û
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-tryptophan, N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-methionine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-O-methyl-L-tyrosine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)pheny Isulphonyl-L-norleucine;
N-Methyl-N-4-( 1 H-2-methylimidazo[4,5-c]pyridi nylmethyl)phenylsulphonyl-L-phenylglycine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-t-butylg Iyci ne;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c~pyridinylmethyl)phenylsulphonyl -D,L-ethylglycine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl -D,L-allylglycins;
N-Methyl-N-4-(1 H-2-methylimidazo[4,~-c]pyridinylmethyl)phenylsulphonyl -L-t-butylalanine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-cyclopropylalanine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsu Iphonyl-L-cyclopentylalanine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-cyclohexylalanine;
and their pharmaceutically acceptable salts.
compound of formula (Il) which is at present particularly preferred for use in accordance with the present invention is N-methyl-N-4-(1 H-2-methylimidazo[4,5-c]-pyri~y~nethyl~ph~ny~s~lph~ny~L~e~ci~e aF~d its, pharmaceL~tically ~ce,~
Compounds of the invention may be prepared in accordance with the disclosures ofWO 92/03423 by hydrolysis of corresponding esters (prepared as disclosed in WO
92/03423, or by catalytic hydrogenation of the corresponding benzyl esters, or by ~UP;.'~TI~I.JTE SHE~T (r~ E 26) WO 9511306~ "' 2 1 7~i 1 2 4PCT/GB94/02460 other methods known in the art.
It has been found that the compounds of general formula (Il) exhibit in vitro and In vlvo antagonistic activities with respect to PAF. Compounds of general formula (Il) inhibit PAF-induced functions in both the cellular and tissue levels by changing the PAF binding to its specific receptor site. The ability of compounds of general formula (Il) to inhibit the binding of PAF to its specific receptor binding site on human platelet plasma membranes was measured according to Pharmacological Example 1. The ability of compounds of general formula (Il) to reverse the hypotension caused by an infusion of PAF in rats was measured according to Pharmacology Example 2.
The following abbreviations have been used in the Examples:-DCM - Dichloromethane DIPE- Diisopropyle~her DMF- N,N-Dimethylformamide HPLC - High performance liquid chromatography NBS - N-Bromosuccinimide TDA-1 - Tris(2-(2-methoxyethoxy)ethyl)amine THF - Tetrahydrofuran TLC - Thin layer chromatography Column chromatography was performed with "flash" grade silica gel. Unless otherwise stated anhydrous magnesium sulphate or anhydrous sodium sulphate was used for drying organic solutions. Unless otherwise stated 1 H NMR and 13C NMR
spectra were recorded on a Bruker AC-2~0 spectrometer at 250 MHz and 62.9 MHz respectiveiy using CDCI3 as a solvent and internal re~erence and are reported asppm from TMS.
SVBSTITUTE SHEET (RULE 26 -WO 95/1306~ 6~i 2 4 PCT/GB94/02460 Fxample 1 N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c~pyridinylmethyl)phenylsulphonyl-L-leucine hydrochloride Cl H ' N~ ~>--CH3 ~ C~
(a) 4-Bromomethylphenylsulphonylchloride To a solution of p-toluenesulphonyl chloride (50 g, 0.26 mol) in benzene (150 ml) and NBS (46.7 9, 0.26 mol) heated at reflux was added 2,2'-azobis(2-methylpropionitrile) (100 mg). The mixture was heated at reflux for 12 h and allowed to cool to room temperature. The white precipitate of succinimide that formed was separated and discarded. The filtrate was taken up in DCM (200 ml) and washed with water (3 x 100 ml) followed by brine (100 ml) and dried. Filtration, concentration and subsequent crystallisation (from DIPE) gave in two crops 4-bromomethylphenylsulphonylchloride (46.3 9, 66%) as a white crystalline solid.
m.p. 75-76C
~H 8.02 (2H, d, J 8.5 Hz), 7.64 (2H, d, J 8.5 Hz), 4.52 (2H, s).
(b) N-4-Bromomethylphenylsulphonyl-L-leucine ethyl ester L-leucine ethyl ester hydrochioride (75.0 9. 0.403 mol) was suspended in THF (300 ml) at 0C, and triethylamine (67 ml, 0.484 mol) added slowly. After stirring for 15 mins a solution of 4-bromomethylphenylsulphonyl chloride (108.4 9, 0.403 mol) inTHF (100 ml) was added via cannular. The reaction mixture was allowed to stir overnight at ambient temperature. The solvent was removed under low pressure andthe organics were extracted into ethyl acetate (200 ml) and washed with water (100 ml) and brine (100 ml). The organic portion was dried, filtered and the solvent evaporated under low pressure. The product was recrystallised from DIPE (500 ml) ~IF5STITUTE SHEFT (RULE 26~
WO 95/1306~ h~ PCT/GB91/02460 ~ i i ~ 15 21 76 ~ 24 to give N-4-bromomethylphenylsulphonyl-L-leucine ethyl ester (134.0 9, 85%) as awhite crystalline solid.
~H7.84(2H,d,J8.3Hz),7.52(2H,d,J8.3Hz),5.06(1H,d,J10.1 Hz),4.61 (2H,s),
5 ~ 4 that compounds of formula (I) wherein B is a group -CONR1~R12 where R11 and R12 are as defined in formula (I) may be prepared by treatment of a compound of formula (I) wherein B is a -CO2R1 group wherein R10 is a benzyl group with hydrogen in the presence of a noble metal catalyst (eg 10% palladium on charcoal) to give ~
carboxylic acid which is then treated with an amine of formula HNR11R12 in the presence of a coupling reagent (eg 1,3-dicyclohexylcarbodiimide). It is also stated therein that certain compounds of formula (I) wherein B is a -CO2R1 group wherein R10 is as defined in formula (I) may be prepared by base catalysed hydrolysis to ~ive compound of ~eneral formula (I) wherein 8 is a -CO~H grouD which is subsequently esterified with an alcohol of general formula HOR10 in the presence of a coupling reagent (eg 1,3-dicyclohexylcarbodiimide).
Example 77 of WO 92/03423 discloses the carboxylic acid N-methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridylmethyl)phenylsulphonyl-L-leucine, used as an intermediate in the prepara~ion of its octadecyl ester.
Thus, WO 92/03423 discloses the use of compounds of formula (I) wherein B is a carboxylic acid group -CO21~ as intermediates for the synthesis of PAF antagonists of formula (I) wherein B is an esterified or amidated carboxylic acid group. However, there is no suggestion that the carboxylic acids per se have utility as PAF
antagonists.
Rrief Description of the Invention The present invention is based on the discovery that carboxylic acids known fromWO 92/03423 to be useful as intermediates for the preparation of PAF antagonistsdisclosed therein, have PAF antagonist activity in their own right. The invention therefore relates to the use of such carboxylic acids in human and vetQrinary medicine and to pharmaceutical and veterinary compositions comprising them. In connsction with the invention, it is of interest that during investigation of the metabolism of N-methy~-N-4-tt~-2-",~:ll,yli",ida~o~4,~
pyridylmethyl)phenylsulphonyl-L-leucine ethyl ester, ie the compound of Example 53B of WO 92/03423, following administration of that compound to human beings, it was found that N-methyl-N-4-(1 H-2-methylimidazo[4,5-SUBSTITUTE SHEET (RULE 26J
WO 95/1306~ PCT/GB94/02460 c]pyridylmethyl)phenylsulphonyl-L-leucine is a primary metabolite (unpublished data).
Description of the Invention The present invention provides a compound of formula (Il):
N~ \>--CH3 ~S~ ~OH
wherein R1 represents hydrogen, -C~-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -COC1 C6 alkyl, -CO2C1-C6 alkyl, -(COC1 C6 alkyl)phenyl, - (CO2C1 C6 alkyl)phenyl, -(C1-C6 alkyl)OC1-C6 alkyl, -(C,-C6 alkyl)SC1-C6 alkyl, -(C1 C6 alkyl)CO2C1-C6 alkyl, -C3-C8 cycloalkyl, -C4-C8 cycioalkenyl or a group -D
wherein D represents a group:
/=\~ R3 (C~2)n~
wherein n is an integer from 0 to 3, and each of R3 and R4 is independently hydrogen, -C~-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, halogen, -CN, -CO2H, -CO2C~-C6 alkyl, -CONH2, -CONHC1-C6 alkyl, -CONH(C1-C6 alkyl)2, -CHO, -CH20H, -CF3, -OC1-C6 alkyl, - SC~-C6 alkyl, -SOC,-C6 alkyl, -SO2C1-C6 alkyl, -NH2 or -NHCOMe;
R2 represents hydrogen, halogen, -C1 C6 alkyl optionally substituted by one or Sl3Ç~STITUTE SHEET (RULE 261 WO 95113061 , ,~ 1 ~ 6 1 2 4 Pcr/G~94lo~J6~ ~
more halogen atoms, -C2-C6 alkenyl, -C2-C6 alkynyl, -(C1-C6 alkyl)CO2C1 C6 alkyl, -(C1-C6 alkyl)SC1-C~ alkyl, -(C1-C6 alkyl)OC1-C6 alkyl, -(C1-C6 alkyl)N(C1-C6 alkyl)2, -C3 Cs cycloalkyl, -C4 Cs cycloalkenyl, -(C1-C6 alkyl)C3 C8 cycloalkyl, - (C1-C6 alkyl)C4 Cs cycloalkenyl, -(C1-C6 alkyl)OC3 C8 cycloalkyl, -(C1-C6 alkyl)OC4 Cs cycloalkenyl, -(G1-C6 alkyl)SC3 C8 cycloalkyl, -~C1 C6 alkyl)SC4 C~ cycloalkenyl, a side chain of a naturally occurring amino acid, a group -D as defined above or a -(C1-C6 alkyl)OD group wherein D is as defined above;
or a pharmaceutically or veterinarily acceptable salt thereof, for use in human or vererinary medicine.
Herealter, the term "compound of formula (Il)" will be used to refer to a compound as defined in the preceeding paragraph, and is to be understood as referring to thepharmaceutically or veterirlarily acce~la~le salts thereof. Furthermore, the term "pharmaceutical" is to be understood as including both human and veterinary applications.
.
PAF is released directly from cell membranes and mediates a range of potent and specific effects on target cells resulting in a variety of physiological responses which include hypotension, thrornbocytopenia, bronchoconstriction, circulatory shock, and increased vascular permeability (oedema/erythema). It is known that these physiological effects occur in many inflammatory and allergic diseases and PAF has been found to be involved in a number of such disorders including asthma, endotoxin shock, adult respiratory distress syndrome, glomerulonephritis, immuneregulation, transplant rejection, gastric ulceration, psoriasis, cerebral, myocardial and renal ischemia. Thus compounds of formula (Il) for use in accordance with the invention, by virtue of their ability to antagonise the actions of PAF, may be useful to reduce inflammation and pain, to correct espira~ory, cardiovascular, and intravascular alterations or disorders, and to reguiate the activation or coagura~ion of platelets, to correct hypotension during shock, the pathogenesis of immune complex deposition and smooth muscle contractions. In particular, they they have applications in the treatment of inflammatory disorders; such as rheumatoid arthritis, osteoarthritis ~iiUP~STlTUTE SHEE~ (RULE 26~
WO 9~113064 ,` ~ ;r 2 1 76 1 24 PCT/GB94/02460 and eye inflammation, cardiovascular disorder, thrombocytopenia, asthma, endotoxin shock, adult respiratory distress syndrome, glomerulonephritis, immuneregulation, gastric ulceration, transplant rejection, psoriasis, allergic dermatitis, urticaria, multiple sclerosis, cerebral, myocardial and renal ischemia and any other condition in which PAF is implicated.
The invention includes the use of a compound of formula (Il) in the preparation of a pharmaceutical composition adapted for oral, topical, rectal or parenteral administration or for inhalation for the management of diseases or conditions mediated by PAF, for example those referred to above. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Such compositions will include, as is conventional, pharmaceutically acceptable carriers for the active compound, and may contain other conventional pharmaceutical excipients.
Another aspect of the invention is a pharmaceutical composition in dosage unit form, for the management of diseases or conditions mediated by PAF, comprising a compound of formula (Il) and one or more pharmaceutically acceptable carriers.
Pharmaceutical dosage units are of course known in the art in general, but are primarily characterised in that the active compound is substantially free of impurities, and present in the dosage unit in a predetermined unit dose amount. In the present case, dosage units include tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups elixirs, phials containing sterile injectabie suspensions or solutions of the active ingredient, nebulisers containing solid micronised, or atomisable solutions or suspensions of the active ingredient, Each dosage unit may comprise from about 0.1 mg to about 19 of active ingredient, for example from 1 Omg to 500 mg, more particularly from 100 to 300mg.
In ~eneralr the ~uantity of a~tive in~redient present in ea~h rlO~A9e unit.~luill b~
chosen to deliver to the patient from about 0.1 mg to abou 0.5 mg to about 7 9 per patient per day. For example, for treatment of inflammation, the administration of from about 1.0 mg to about 3.5 9 per patient per day may be appropriate. The dosage employed for topical administration will, of course, depend on the size of the SUBS~ITU~E SHEET tRUaE 26) WO 95/13064 . '; ~ ~ ~ t ~ 3 2 ~ I'CT/G~9J/02460 area being treated. For the eyes each dose will be typically in the range from 10 to 100 mg of the drug.
Another aspect of the invention is a method for the management of diseases or conditions mediated by PAF, comprising administering to the patient an effectiveamount of a compound of formula (Il) or a pharmaceutically salt thereof.
As used herein, the term "pharmaceutically acceptable salt" means acid or base addition salts whose anion is generally considered safe for human or animal consumption. Suitable bass addition salts include the sodium, potassium, magnesium, lithium, and calcium salts Suitable acid addition salts include the hydrochloride, sulphate, phosphate, acetate, propionate, lactate, maleate, succinate and t~ le salts.
As used herein the term "halogen" or its abbreviation "halo" means fluoro, chloro, bromo or iodo.
As used herein the term "C~-C6 alkyl" refers to straight chain or branched chainhydrocarbon groups having from one to six carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.
As used herein the term "C2-C6 alkenyl" refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one double bond, of either E or Z stereochemistry where arplicAhl-. This term would include for example, vinyl, 1-propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl.
As used herein the term "C2-C6 alkynyl" refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. ~his term woul~ ~nciude for exar~ t~ny~ propynr~, ~- art~
butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
SUBSTITUTE SHEET (RULE 26) WO95/13064 ~ 2 1 ¦6 ¦ 24 PCT/GB9~/02460 ,, As used herein, the term "~ 4 perfluoroalkyl" refers to straight chain or branched chain groups having from one to four carbon atoms and substituted by more than one fluorine atom. This term would include for example, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoro-n-propyl, sexafluoro-i-propyl,septafluoro-n-propyl, septafluoro-i-propyl, 4,4,4-trifluoro-n-butyl, nonafluoro-n-butyl, nonafluoro-sec-butyl and nonafiuoro-i-butyl.
As used herein the term "OC~-C6 alkyl" refers to straight chain or branched chain alkoxy groups having from one to six carbon atoms. Illustrative of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, ~ert-butoxy, pentoxy, neopentoxy and hexoxy.
As used herein the term "SC~-C6 alkyl" refers to straight chain or branched chain alkylthio groups having ~rom one to six carbon atoms. Illustrative of such alkyl groups are methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, neopentylthio and hexylthio.
As used herein, the term "C3-C8 cycloalkyl" refers to an alicyclic group having from 3 to 8 carbon atoms. Illustrative of such cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As used herein, the term "C4-C8 cycloalkenyl" refers to an alicyclic group having from 4 to 8 carbon atoms and having in addition one or more double bonds. Illustrative of such cycloalkenyl groups are cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
As used herein, the term "side chain of a naturally occurring amino acid" includes the side chains of alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glycine, histidine, 5-hydroxylysine, 4-hydroxyproline, isoleucine, leucine, Iysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, a-aminoadipic acid, a-amino-n-butyric acid, 3,4-dihydroxyphenylalanine, homoserine, a-methylserine, ornithine, pipecolic acid, and thyroxine. The amino acid side chains may be protected; for example the carboxyl groups of aspartic acid, glutamic acid SUB~TITUTE SHEET tRULE 26) WO 95/1306~ i ~ 2 t ~ ~ ~ 2~ PCTIGB9~/02460 ~
~ I 10 and a-aminoadipic acid may be esterified (for example as a C1-C6 alkyl ester), the amino groups of Iysine, ornithine, ~-hydroxyiysine, 4-hydroxyproline may be converted to amides (for example as a COC,-C6 alkyl amide) or carbamates (for example as a C(=O)OC1-C6 alkyl or C(=O)OCH2Ph carbamate), the hydroxyl groups of 5-hydroxylysine, 4-hydroxyproline, serine, threonine, tyrosine, 3,4-dihydroxyphenylalanine, homoserine, a-methylserine and thyroxine may be converted to ethers (for example a C1-C6 alkyl or a (C1-C6 alkyl)phenyl ether) or esters (for example a C(=O)C1-C6 alkyl ester) and the thiol group of cysteine may be converted to thioethers (for example a C1-C6 alkyl thioether) or thioesters (forexample a C(=O)C1-C6 alkyl thioester). The stereochemistry at the carbon atom towhich the amino acid side chain is attached may be either D or L.
In compounds of formula (Il), the presence of several asymmetric carbon atoms gives rise to diastereoisomers, each of which consists of two enantiomers, with the appropriate R or S stereochemistry at each chiral centre. The invention is understood to include the use of all such diastereoisomers, their optically active enantiomers and mixtures thereof.
Although this application relates only to compounds of formula (Il) in which thesubstituents R1, and R2 are the only variables it is understood that the introduction of further substituents on the 2-methylimidazo[4,5-c]pyridinyl group, the benzylic carbon atom and/or the 1 ,4-disubstituted phenyl ring will lead to compounds that retain PAF
antagonist activity.
Preferred compounds for use according to the invention include those in which, independently or in any compatible combination:
R1 represents a hydrogen atom, a -C~-C6 alkyl ffor example methyl, ethyl or propyl) group, a -C2~C6 alkenyl (for example allyl) group or a group -D;
R2 represents a hydrogen atom, a -C1-C6 alkyl (for example ethyl, n-butyl, t-butyl or neopentyl) group, a-C2-C6 alkenyl (for example allyl) group, a -(C1-C6 alkyl)C3-C8 cycloalkyl (for example cyclopropylmethyl, cyclopentylmethyl or S~IBSTITUTE SHEET (RULE 26) ~ WO 9~/1306~ 1 1 2 1 7 ~ PCT/GB9~/02460 cyclohexylmethyl) group, a side chain of a naturally occurring amino acid (for example the side chain of leucine, isoleucine, phenylalanine, valine, tryptophan, methionine or tyrosine) or a group D;
in the group D, R3 represents a hydrogen atom, a -C1-C6 alkyl (for example methyl) group, a halogen (for example fluorine, chlorine or bromine) atom, a -CF3 group or a -OC1-C6 alkyl (for example methoxy) group;
in the group D, R4 represents a hydrogen atom or a -OC~-C6 alkyl (for example methoxy) group;
Examples of compounds of formula (Il) for use in accordance with the present invention are:
N-4-(1 H-2-Methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl -L-leucine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c~pyridinylmethyl)phenylsulphonyl-D-leucine;
N-Ethyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine;
N-Allyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine;
N-Propyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine;
N-Benzyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinyimethyl)phenylsulphonyl-L-leucine;
N-4-Methoxybenzyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmeth yl) -phenylsulphonyl-L-leucine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-- L-isoleucine;
N-Methyi-N-4-(t H-2-methyiimidazor4,5-cJpyridiny~methyl~phenylsulphonyr-L-phenylalanine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-valine;
SUBSTITUTE SHEET (RULE 26 12 PCI/G~19J/0246û
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-tryptophan, N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-methionine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-O-methyl-L-tyrosine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)pheny Isulphonyl-L-norleucine;
N-Methyl-N-4-( 1 H-2-methylimidazo[4,5-c]pyridi nylmethyl)phenylsulphonyl-L-phenylglycine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-t-butylg Iyci ne;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c~pyridinylmethyl)phenylsulphonyl -D,L-ethylglycine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl -D,L-allylglycins;
N-Methyl-N-4-(1 H-2-methylimidazo[4,~-c]pyridinylmethyl)phenylsulphonyl -L-t-butylalanine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-cyclopropylalanine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsu Iphonyl-L-cyclopentylalanine;
N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-cyclohexylalanine;
and their pharmaceutically acceptable salts.
compound of formula (Il) which is at present particularly preferred for use in accordance with the present invention is N-methyl-N-4-(1 H-2-methylimidazo[4,5-c]-pyri~y~nethyl~ph~ny~s~lph~ny~L~e~ci~e aF~d its, pharmaceL~tically ~ce,~
Compounds of the invention may be prepared in accordance with the disclosures ofWO 92/03423 by hydrolysis of corresponding esters (prepared as disclosed in WO
92/03423, or by catalytic hydrogenation of the corresponding benzyl esters, or by ~UP;.'~TI~I.JTE SHE~T (r~ E 26) WO 9511306~ "' 2 1 7~i 1 2 4PCT/GB94/02460 other methods known in the art.
It has been found that the compounds of general formula (Il) exhibit in vitro and In vlvo antagonistic activities with respect to PAF. Compounds of general formula (Il) inhibit PAF-induced functions in both the cellular and tissue levels by changing the PAF binding to its specific receptor site. The ability of compounds of general formula (Il) to inhibit the binding of PAF to its specific receptor binding site on human platelet plasma membranes was measured according to Pharmacological Example 1. The ability of compounds of general formula (Il) to reverse the hypotension caused by an infusion of PAF in rats was measured according to Pharmacology Example 2.
The following abbreviations have been used in the Examples:-DCM - Dichloromethane DIPE- Diisopropyle~her DMF- N,N-Dimethylformamide HPLC - High performance liquid chromatography NBS - N-Bromosuccinimide TDA-1 - Tris(2-(2-methoxyethoxy)ethyl)amine THF - Tetrahydrofuran TLC - Thin layer chromatography Column chromatography was performed with "flash" grade silica gel. Unless otherwise stated anhydrous magnesium sulphate or anhydrous sodium sulphate was used for drying organic solutions. Unless otherwise stated 1 H NMR and 13C NMR
spectra were recorded on a Bruker AC-2~0 spectrometer at 250 MHz and 62.9 MHz respectiveiy using CDCI3 as a solvent and internal re~erence and are reported asppm from TMS.
SVBSTITUTE SHEET (RULE 26 -WO 95/1306~ 6~i 2 4 PCT/GB94/02460 Fxample 1 N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c~pyridinylmethyl)phenylsulphonyl-L-leucine hydrochloride Cl H ' N~ ~>--CH3 ~ C~
(a) 4-Bromomethylphenylsulphonylchloride To a solution of p-toluenesulphonyl chloride (50 g, 0.26 mol) in benzene (150 ml) and NBS (46.7 9, 0.26 mol) heated at reflux was added 2,2'-azobis(2-methylpropionitrile) (100 mg). The mixture was heated at reflux for 12 h and allowed to cool to room temperature. The white precipitate of succinimide that formed was separated and discarded. The filtrate was taken up in DCM (200 ml) and washed with water (3 x 100 ml) followed by brine (100 ml) and dried. Filtration, concentration and subsequent crystallisation (from DIPE) gave in two crops 4-bromomethylphenylsulphonylchloride (46.3 9, 66%) as a white crystalline solid.
m.p. 75-76C
~H 8.02 (2H, d, J 8.5 Hz), 7.64 (2H, d, J 8.5 Hz), 4.52 (2H, s).
(b) N-4-Bromomethylphenylsulphonyl-L-leucine ethyl ester L-leucine ethyl ester hydrochioride (75.0 9. 0.403 mol) was suspended in THF (300 ml) at 0C, and triethylamine (67 ml, 0.484 mol) added slowly. After stirring for 15 mins a solution of 4-bromomethylphenylsulphonyl chloride (108.4 9, 0.403 mol) inTHF (100 ml) was added via cannular. The reaction mixture was allowed to stir overnight at ambient temperature. The solvent was removed under low pressure andthe organics were extracted into ethyl acetate (200 ml) and washed with water (100 ml) and brine (100 ml). The organic portion was dried, filtered and the solvent evaporated under low pressure. The product was recrystallised from DIPE (500 ml) ~IF5STITUTE SHEFT (RULE 26~
WO 95/1306~ h~ PCT/GB91/02460 ~ i i ~ 15 21 76 ~ 24 to give N-4-bromomethylphenylsulphonyl-L-leucine ethyl ester (134.0 9, 85%) as awhite crystalline solid.
~H7.84(2H,d,J8.3Hz),7.52(2H,d,J8.3Hz),5.06(1H,d,J10.1 Hz),4.61 (2H,s),
3.97-3.82 (3H, m),1.85-1.79 (1 H, m),1.49 (2H, dd, J 7.3, 7.2 Hz),1.08 (3H, t, J 7.1 Hz), 0.92 (3H, d, J 6.7 Hz), 0.91 (3H, d, J 6.5 Hz).
(c) N-4-Azidomethylphenylsulphonyl-L-leucine ethyl ester A solution of sodium azide (75.0 9, 1.054 mol) in water (150 ml) was added to a solution of the N-4-bromomethylphenylsulphonyl-L-leucine ethyl ester (89.0 9, 0.221 mol) in dichloromethane (150 ml). Benzyltriethylammonium chloride (10 9, 0.044 mol) was added and the heterogenous reaction mixture stirred vigorously for 60 h.
The organic portion was separated, washed thoroughly with water, dried, filtered and concentrated to a golden oil, which crystallised on standing. The resulting white solid was freeze dried overnight to yield N-4-azidomethylphenylsulphonyl-L-leucine ethyl ester (78.2 9, 97%).
m.p. 75-77C
Analysis calculated for C15H22N4O4S
Requires C 50.83 H 6.26 N 15.81 Found C 50.80 H 6.28 N 15.82 i.r. (DCM) 2930, 2100, 1730, 1335, 1150 cm-' [alD25 -16.4- (c 2.0, DCM) ~iH 7.86 (2H, d, J 8.4 Hz), 7.45 (2H, d, J 8.6 Hz), 5.13, (1 H, d, J 10.0 Hz), 4.43 (2H, s), 3.98-3.84 (3H, m),1.83-1.75 (1 H, m),1.49 (2H, dd, J 7.7, 6.7 Hz),1.09 (3H, t, J 7.1 Hz), 0.91 (3H, d, J 6.7 Hz), 0.89 (3H, d, J 6.5 Hz).
(d) N-Methyl-N-4-azidomethylphenylsulphonyl-L-leucine ethyl ester A 60% dispersion of sodium hydride in mineral oil (9.68 9, 0.242 mol) was added in portions to a solution of N-4-azidomethylphenylsulphonyl-L-leucine ethyl ester (78.0 9, 0.220 mol) in THF (200 ml) at 0C. After stirring for 20 mins iodomethane (28 ml, 0.44 mol) was added slowly, and the reaction allowed to warm to ambient SUBSTITUTE SHEET (RULE 26) WO 95/13061 ~ 3 ~ ~ s 1 6 ~ l~7~! 2~ PCT/GB9~/02460 ~
temperature overnight. Saturated ammonium chloride solution (~. 15 ml) was added and the THF removed under reduced pressure. The resulting residue was taken up in dichloromethane, washed with saturated hydrogen carbonate solution then water, dried, filtered and concentrated to give N-methyl-N-4-azidomethylphenylsulphonyl-L-leucine ethyl ester as an orange oil (76.0 9, 94%).
Analysis calculated for C16H24N404S
Requires C 52.16 H 6.57 N 15.21 FoundC 52.20 H 6.54 N 15.12 i.r. (DCM) 2100, 1735, 1340, 1160cm-~
[a]D2 -15.3~ 2.2, DCM) ~H 7.83 (2H, dd, J 8.2,1.6 ~Iz), 7.45 (2H, br d, J 8.3 Hz), 4.71-4.65 (1 H, m), 4.44 (2H, s), 3.96-3.86 (2H, m), 2.86 (3H, s),1.67-1.58 (3H, m),1.09 (3H, t, J 7.1 Hz), 0.99 (3H, d, ~1 5.0 Hz), 0.97 (3H, d, J 6.1 Hz).
(e) N-Methyl-N-4-aminomethylphenylsulphonyl-L-leucine ethyl ester Triphenylphosphine (101.80 9, 0.388 mol) was added to a solution of N-methyl-N-4-azidomethylphenylsulphonyl-L-leucine ethyl ester (71.5 9, 0.194 mol) in a mixture of THF and water (4:1, 200 ml), and the reaction mixture stirred overnight at ambient temperature. The THF was removed under reduced pressure, and the product extracted with ethyl acetate, dried, filtered and concentrated to an orange oil. This was purified by chromatography (silica: gradient elution; 1 :2 ethyl acetate/hexane;
ethyl acetate; 10% methanol in ethyl acetate) to give N-methyl-N-4-aminomethylphenylsulphonyl-L-leucine ethyl ester (38 9, 58%) as a yellow oil.
~H 7.76(2H,dd,~8.5,1.711z),7.45(2H,d,J8.3Hz),4.71-4.65(1H,m),3.95(2H,s), 3.95-3.85 (2H, m), 2.83 (3H, s),1.95 (2H, br s),1.68-1.57 (3H, m),1.06 (3H, t, J 7.1 Hz), 0.97 (3H, d, J 5.4 Hz), 0.95 (3H, d, J 5.9 Hz).
(f) N-Methyl-N-4-(N'-3 nitropyridin-4-yl)aminomethylphenylsulphonyl-L-leucine ethyl ester
(c) N-4-Azidomethylphenylsulphonyl-L-leucine ethyl ester A solution of sodium azide (75.0 9, 1.054 mol) in water (150 ml) was added to a solution of the N-4-bromomethylphenylsulphonyl-L-leucine ethyl ester (89.0 9, 0.221 mol) in dichloromethane (150 ml). Benzyltriethylammonium chloride (10 9, 0.044 mol) was added and the heterogenous reaction mixture stirred vigorously for 60 h.
The organic portion was separated, washed thoroughly with water, dried, filtered and concentrated to a golden oil, which crystallised on standing. The resulting white solid was freeze dried overnight to yield N-4-azidomethylphenylsulphonyl-L-leucine ethyl ester (78.2 9, 97%).
m.p. 75-77C
Analysis calculated for C15H22N4O4S
Requires C 50.83 H 6.26 N 15.81 Found C 50.80 H 6.28 N 15.82 i.r. (DCM) 2930, 2100, 1730, 1335, 1150 cm-' [alD25 -16.4- (c 2.0, DCM) ~iH 7.86 (2H, d, J 8.4 Hz), 7.45 (2H, d, J 8.6 Hz), 5.13, (1 H, d, J 10.0 Hz), 4.43 (2H, s), 3.98-3.84 (3H, m),1.83-1.75 (1 H, m),1.49 (2H, dd, J 7.7, 6.7 Hz),1.09 (3H, t, J 7.1 Hz), 0.91 (3H, d, J 6.7 Hz), 0.89 (3H, d, J 6.5 Hz).
(d) N-Methyl-N-4-azidomethylphenylsulphonyl-L-leucine ethyl ester A 60% dispersion of sodium hydride in mineral oil (9.68 9, 0.242 mol) was added in portions to a solution of N-4-azidomethylphenylsulphonyl-L-leucine ethyl ester (78.0 9, 0.220 mol) in THF (200 ml) at 0C. After stirring for 20 mins iodomethane (28 ml, 0.44 mol) was added slowly, and the reaction allowed to warm to ambient SUBSTITUTE SHEET (RULE 26) WO 95/13061 ~ 3 ~ ~ s 1 6 ~ l~7~! 2~ PCT/GB9~/02460 ~
temperature overnight. Saturated ammonium chloride solution (~. 15 ml) was added and the THF removed under reduced pressure. The resulting residue was taken up in dichloromethane, washed with saturated hydrogen carbonate solution then water, dried, filtered and concentrated to give N-methyl-N-4-azidomethylphenylsulphonyl-L-leucine ethyl ester as an orange oil (76.0 9, 94%).
Analysis calculated for C16H24N404S
Requires C 52.16 H 6.57 N 15.21 FoundC 52.20 H 6.54 N 15.12 i.r. (DCM) 2100, 1735, 1340, 1160cm-~
[a]D2 -15.3~ 2.2, DCM) ~H 7.83 (2H, dd, J 8.2,1.6 ~Iz), 7.45 (2H, br d, J 8.3 Hz), 4.71-4.65 (1 H, m), 4.44 (2H, s), 3.96-3.86 (2H, m), 2.86 (3H, s),1.67-1.58 (3H, m),1.09 (3H, t, J 7.1 Hz), 0.99 (3H, d, ~1 5.0 Hz), 0.97 (3H, d, J 6.1 Hz).
(e) N-Methyl-N-4-aminomethylphenylsulphonyl-L-leucine ethyl ester Triphenylphosphine (101.80 9, 0.388 mol) was added to a solution of N-methyl-N-4-azidomethylphenylsulphonyl-L-leucine ethyl ester (71.5 9, 0.194 mol) in a mixture of THF and water (4:1, 200 ml), and the reaction mixture stirred overnight at ambient temperature. The THF was removed under reduced pressure, and the product extracted with ethyl acetate, dried, filtered and concentrated to an orange oil. This was purified by chromatography (silica: gradient elution; 1 :2 ethyl acetate/hexane;
ethyl acetate; 10% methanol in ethyl acetate) to give N-methyl-N-4-aminomethylphenylsulphonyl-L-leucine ethyl ester (38 9, 58%) as a yellow oil.
~H 7.76(2H,dd,~8.5,1.711z),7.45(2H,d,J8.3Hz),4.71-4.65(1H,m),3.95(2H,s), 3.95-3.85 (2H, m), 2.83 (3H, s),1.95 (2H, br s),1.68-1.57 (3H, m),1.06 (3H, t, J 7.1 Hz), 0.97 (3H, d, J 5.4 Hz), 0.95 (3H, d, J 5.9 Hz).
(f) N-Methyl-N-4-(N'-3 nitropyridin-4-yl)aminomethylphenylsulphonyl-L-leucine ethyl ester
4-Chloro-3-nitropyridine (6.0 9, 38 mmol) was added to a stirred solution of N-methyl-5UBSTlTUrE SHEET (RULE 26~
~ WO 9~/13064 ~ 2 1 7 6 1 2 4 PCT/GBg~/02460 ~ . 17 N-4-aminomethylphenylsulphonyl-L-leucine ethyl ester (13.0 9, 38 mmol) and triethylamine (5.3 ml, 38 mmol) in chloroform (150 ml) at ambient temperature. The reaction mixture was stirred for 60 h, then washed with water, dried, filtered and the solvent removed under reduced pressure to leave a brown oil. This was purified by chromatography over silica (gradient elution; 33% ethy! acetate in hexane; ethylacetate) to give N-methyl-N-4-(N'-3-nitropyridin-4-yl)aminomethyl-phenylsulphonyl-L-leucine ethyl ester (10.9 g, 62%) as a yellow amorphous solid.
m.p. 71-75C
i.r. (DCM) 3390, 1730, 1510, 1330 cm-~
a]D25 -13.8- (~ 2.0, DCM) dH 9.00(1H,s)8.55(1H,t,J5.9Hz),8.04(1H,d,J6.1 Hz),7.60(2H,d,J8.3Hz), 7.32 (2H, d, J 8.3 Hz), 6.50 (1 H, d, ~ 6.2 Hz), 4.57 (2H, d, J 5.9 Hz), 4.50-4.44 (1 H, m), 3.75-3.62 (2H, m), 2.69 (3H, s),1.45 (3H, br d), 0.86 (3H, t, J 7.1 Hz) 0.77 (6H, d, J 5.9 Hz).
(g) N-Methyl-N-4-(N'-3-aminopyridin-4-yl)aminomethylphenylsulphonyl-L-leucine ethyl ester A solution of N-methyl-N-4-(N'-3-nitropyridin-4-yl)aminomethylphenylsulphonyl-L-leucine ethyl ester (10.9 9, 0.023 mol) in ethanol (40 ml) was hydrogenated at 100 p.s.i. overnight in the presence of 10% palladium on charcoal (1.0 9). The catalyst was removed by filtration through GF/F filter paper, and the filtrate evaporated under reduced pressure to give N-methyl-N-4-(N'-3-aminopyridin-4-yl)aminomethylphenylsulphonyl- L-leucine ethyl ester (8.90 9, 87%) as a brown foam.
~iH 7.86 (1 H, s) 7.83 (1 H, d, J 5.5 Hz), 7.73 (2H, d, J 8.3 Hz), 7.41 (2H, d, J 8.3 Hz), 6.29 (1 H, d, J 5.4 Hz), 5.09-4.97 (1 H, m), 4.67-4.61 (1 H, m), 4.44 (2H, d, J 5.6 Hz), 3.90-3.8t (ZH, ml, 2.84 (3H, s), t.62-1.57 (5H, m), 1.04 (3H, t, J 7.1 Hz~, 0.96 (3H, d, J
6.0 Hz), 0.95 (3H, d, J 6.1 Hz).
(h) N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine ethyl ester SUBsTlTu~E SHE~T (~ULE 26) WO 95/1306~ 2 i 7 6 ~ ~4 PCT/GB9~/02460 ~
N-Methyl-N-4-(N-3-aminopyridin-4-yl)aminomethylphenylsulphonyl- L-leucine ethyl ester (8.90 9, 20.~ mmol) was refluxed overnight in acetic anhydride (90 ml). The reaction mixture was allowed to cool, then methanol added cautiously until effervescence ceased. The volatiles were removed under reduced pressure and the residue partitioned between saturated sodium hydrogen carbonate solution and ethyl acetate. The organic portion was washed with saturated sodium hydrogen carbonate (x3), and water, dried, filtered and concentrated to a brown oil. This was passed down a pad of silica (3% methanol in DCM) to remove baseline material, and the product further purified by medium pressure liquid chromatography (silica gel:
3% methanol in DCM plus trace of triethylamine) to give a pale yellow oil (5.12 9, ~5%), which solidified slowly on standing. Recrystallisation from ethyl acetate/DlPE
gave N-methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine ethyl ester as a white crystalline solid.
m.p. 105C
Analysis calculated for C23H30N4O4S
Requires C 60.24 H 6.60 N 12.22 FoundC 60.21 H 6.59 N 12.08 i.r. (KBr) 2960, 1730, 1330, 1150 cm-[a]D2-6.7 (_2.0, CDCI3) ~H9.03(1H,s),8.37(1H,d,J5.5Hz),7.76(2H,d,J8.4Hz),7.18-7.11 (3H,m),5.39 (2H, s), 4.65-4.59 (1H, m), 3.83 (2H, q, J 7.1 Hz), 2.82, (3H, s), 2.59 (3H, s), 1.69-1.55 (3H, m), 1.02.(3H, t, J 7.1 H~), 0.97 (3H, d, J 6.1 Hz), 0.95 (3H, d, J 6.2 Hz).
(i) N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c~pyridylmethyl)phenylsulphonyl-L-leucine hydrochloride A solution of N-methyl-N-4-~1 H-2-methylimidazoL4,5-clpyridylmethyl~-phenylsulphonyl-L-leucine ethyl ester (6.00 9, 13 mmol) in 8M hydrochloric acid (100 ml) was refluxed for 3 hours. The reaction mixture was concentrated to an orangegum which was taken up in ethyl acetate and evaporated to dryness, to give N-methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridylmethyl)phenyl-sulphonyl-L-leucine SUBSTITV~E SHEET tRULE 26) WO 95/1306-1 ,,~ 2 1 7 6 1 2 4 PCT/GB94/02460 (5.30 9, 87%) as a pale yellow solid.
i.r. (KBr) 1725, 1338, 1157 cm-1 ~H(d6DMSO)9.42(1H,s),8.67(1H.d.J6.6Hz).8.28(1H,d,J6.6Hz),7.75(2H,d,J
8.3 Hz), 7.40 (2H, d, J 8.3 Hz), 5,87 (2H, s), 4.39 (lH, dd, J 9.1), 5.5 Hz), 2.75 (3H, S), 2.64 (3H, s), 2.50-1.40 (3H, m), 0.86 (3H, d, J 6.2 Hz), 0.82 (3H, d, J 6.0 Hz).
Fxam~le 2 N-Methyl-N-4-(1 H-2-Methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine The title compound was prepared from N-methyl-N-4-(1 H-2-methylimidazo[4,5-c~pyridinylmethyl)phenylsulphonyl-L-leucine ethyl ester by base hydrolysis according to Example 77 of WO 92/03423.
Fx~n~ple 3 N-4-(1 H-2-Methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine The title compound was prepared from N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine ethyl ester by base hydrolysis in ananalogous manner to that for preparation of the compound of Example 2 above.
Characterising data:
1H-NMR; ~ (d4-MeOH), 8.64 (1 H, s), 8.32 (1 H, d, J=5.7Hz), 7.78 (2H, d, J=8.4Hz), 7.68 (1 H, d, J=5.7Hz), 7.29 (2H, d, J=8.4Hz), 5.65 (2H, s), 3.73 (1 H, t, J=7.6Hz), 2.63 (3H, s),1.70-1.59 (1 H, m),1.42 (2H, m), 0.81 (3H, d, J=6.6Hz), 0.72 (3H, d, J=6.6Hz).
3C-NMR; ~ (d4-MeOH). 175.6, 160.5,150.1,142.3, 141.2, 140.4,132.4, 129.3, 129.0, 128.6, 128.4, 115.3, 55.6, 48.5, 43.1, 25.5, 23.2, 21.6, 21.4,14Ø
F~rn~le 4 SUBS~ITUTE S~!E'T (!'~'!E 26) WO 95/1306`1 ~ PCT/GB9~1/02460 .
N-Allyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine The title compound was prepared from N-allyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine ethyl ester by base hydrolysis in ananalogous manner to that for preparation of the compound of Example 2 above.
Characterising data:
~ H-NMR; ~ (CDCI3), 8.77 (1 H, s), 8.10 (1 H, bs), 8.02 (1 H, s), 7.86 (2H, d, J=8.3Hz), 7.16 (2H, d, J=8.0Hz), 6.20-5.92(1H, m), 5.50 (2H, d, J=5.6Hz), 5.18 (1H, d, J=17.1Hz), 5.11 (1H, d, J=10.2Hz), 4.72-4.66 (1H, m), 4.14-3.95 (1H, m), 3.84-3.74 (1 H, m), 2.55 (3H, s),1.83- 1.69 (3H, m),1.04 (3H, d), 0.93 (3H, d, J=6.6Hz).
3C-NMR; ~ (CDCI3),174.3,155.4,141.6,140.3,139.1,138.8,138.6,136.4,136.3, 128.8,126.3,116.7,10~.7, 59.3, 48.5, 47.3, 39.3, 24.1, 22.8, 20.9,13.9.
Examples 5-24 The compounds of Examples 5-24 are prepared as their hydrochloride acid additionsalts by the method of Example 1 employing the appropriate amino acid derivative in Ijeu of L-leucine ethyl ester hydrochloride in Step (b) and for certain compounds missing out the methylation Step (d) or employing a different alkyl halide in liev of methyl iodide in Step (d).
~ WO 9~/13064 ~ 2 1 7 6 1 2 4 PCT/GBg~/02460 ~ . 17 N-4-aminomethylphenylsulphonyl-L-leucine ethyl ester (13.0 9, 38 mmol) and triethylamine (5.3 ml, 38 mmol) in chloroform (150 ml) at ambient temperature. The reaction mixture was stirred for 60 h, then washed with water, dried, filtered and the solvent removed under reduced pressure to leave a brown oil. This was purified by chromatography over silica (gradient elution; 33% ethy! acetate in hexane; ethylacetate) to give N-methyl-N-4-(N'-3-nitropyridin-4-yl)aminomethyl-phenylsulphonyl-L-leucine ethyl ester (10.9 g, 62%) as a yellow amorphous solid.
m.p. 71-75C
i.r. (DCM) 3390, 1730, 1510, 1330 cm-~
a]D25 -13.8- (~ 2.0, DCM) dH 9.00(1H,s)8.55(1H,t,J5.9Hz),8.04(1H,d,J6.1 Hz),7.60(2H,d,J8.3Hz), 7.32 (2H, d, J 8.3 Hz), 6.50 (1 H, d, ~ 6.2 Hz), 4.57 (2H, d, J 5.9 Hz), 4.50-4.44 (1 H, m), 3.75-3.62 (2H, m), 2.69 (3H, s),1.45 (3H, br d), 0.86 (3H, t, J 7.1 Hz) 0.77 (6H, d, J 5.9 Hz).
(g) N-Methyl-N-4-(N'-3-aminopyridin-4-yl)aminomethylphenylsulphonyl-L-leucine ethyl ester A solution of N-methyl-N-4-(N'-3-nitropyridin-4-yl)aminomethylphenylsulphonyl-L-leucine ethyl ester (10.9 9, 0.023 mol) in ethanol (40 ml) was hydrogenated at 100 p.s.i. overnight in the presence of 10% palladium on charcoal (1.0 9). The catalyst was removed by filtration through GF/F filter paper, and the filtrate evaporated under reduced pressure to give N-methyl-N-4-(N'-3-aminopyridin-4-yl)aminomethylphenylsulphonyl- L-leucine ethyl ester (8.90 9, 87%) as a brown foam.
~iH 7.86 (1 H, s) 7.83 (1 H, d, J 5.5 Hz), 7.73 (2H, d, J 8.3 Hz), 7.41 (2H, d, J 8.3 Hz), 6.29 (1 H, d, J 5.4 Hz), 5.09-4.97 (1 H, m), 4.67-4.61 (1 H, m), 4.44 (2H, d, J 5.6 Hz), 3.90-3.8t (ZH, ml, 2.84 (3H, s), t.62-1.57 (5H, m), 1.04 (3H, t, J 7.1 Hz~, 0.96 (3H, d, J
6.0 Hz), 0.95 (3H, d, J 6.1 Hz).
(h) N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine ethyl ester SUBsTlTu~E SHE~T (~ULE 26) WO 95/1306~ 2 i 7 6 ~ ~4 PCT/GB9~/02460 ~
N-Methyl-N-4-(N-3-aminopyridin-4-yl)aminomethylphenylsulphonyl- L-leucine ethyl ester (8.90 9, 20.~ mmol) was refluxed overnight in acetic anhydride (90 ml). The reaction mixture was allowed to cool, then methanol added cautiously until effervescence ceased. The volatiles were removed under reduced pressure and the residue partitioned between saturated sodium hydrogen carbonate solution and ethyl acetate. The organic portion was washed with saturated sodium hydrogen carbonate (x3), and water, dried, filtered and concentrated to a brown oil. This was passed down a pad of silica (3% methanol in DCM) to remove baseline material, and the product further purified by medium pressure liquid chromatography (silica gel:
3% methanol in DCM plus trace of triethylamine) to give a pale yellow oil (5.12 9, ~5%), which solidified slowly on standing. Recrystallisation from ethyl acetate/DlPE
gave N-methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine ethyl ester as a white crystalline solid.
m.p. 105C
Analysis calculated for C23H30N4O4S
Requires C 60.24 H 6.60 N 12.22 FoundC 60.21 H 6.59 N 12.08 i.r. (KBr) 2960, 1730, 1330, 1150 cm-[a]D2-6.7 (_2.0, CDCI3) ~H9.03(1H,s),8.37(1H,d,J5.5Hz),7.76(2H,d,J8.4Hz),7.18-7.11 (3H,m),5.39 (2H, s), 4.65-4.59 (1H, m), 3.83 (2H, q, J 7.1 Hz), 2.82, (3H, s), 2.59 (3H, s), 1.69-1.55 (3H, m), 1.02.(3H, t, J 7.1 H~), 0.97 (3H, d, J 6.1 Hz), 0.95 (3H, d, J 6.2 Hz).
(i) N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c~pyridylmethyl)phenylsulphonyl-L-leucine hydrochloride A solution of N-methyl-N-4-~1 H-2-methylimidazoL4,5-clpyridylmethyl~-phenylsulphonyl-L-leucine ethyl ester (6.00 9, 13 mmol) in 8M hydrochloric acid (100 ml) was refluxed for 3 hours. The reaction mixture was concentrated to an orangegum which was taken up in ethyl acetate and evaporated to dryness, to give N-methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridylmethyl)phenyl-sulphonyl-L-leucine SUBSTITV~E SHEET tRULE 26) WO 95/1306-1 ,,~ 2 1 7 6 1 2 4 PCT/GB94/02460 (5.30 9, 87%) as a pale yellow solid.
i.r. (KBr) 1725, 1338, 1157 cm-1 ~H(d6DMSO)9.42(1H,s),8.67(1H.d.J6.6Hz).8.28(1H,d,J6.6Hz),7.75(2H,d,J
8.3 Hz), 7.40 (2H, d, J 8.3 Hz), 5,87 (2H, s), 4.39 (lH, dd, J 9.1), 5.5 Hz), 2.75 (3H, S), 2.64 (3H, s), 2.50-1.40 (3H, m), 0.86 (3H, d, J 6.2 Hz), 0.82 (3H, d, J 6.0 Hz).
Fxam~le 2 N-Methyl-N-4-(1 H-2-Methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine The title compound was prepared from N-methyl-N-4-(1 H-2-methylimidazo[4,5-c~pyridinylmethyl)phenylsulphonyl-L-leucine ethyl ester by base hydrolysis according to Example 77 of WO 92/03423.
Fx~n~ple 3 N-4-(1 H-2-Methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine The title compound was prepared from N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine ethyl ester by base hydrolysis in ananalogous manner to that for preparation of the compound of Example 2 above.
Characterising data:
1H-NMR; ~ (d4-MeOH), 8.64 (1 H, s), 8.32 (1 H, d, J=5.7Hz), 7.78 (2H, d, J=8.4Hz), 7.68 (1 H, d, J=5.7Hz), 7.29 (2H, d, J=8.4Hz), 5.65 (2H, s), 3.73 (1 H, t, J=7.6Hz), 2.63 (3H, s),1.70-1.59 (1 H, m),1.42 (2H, m), 0.81 (3H, d, J=6.6Hz), 0.72 (3H, d, J=6.6Hz).
3C-NMR; ~ (d4-MeOH). 175.6, 160.5,150.1,142.3, 141.2, 140.4,132.4, 129.3, 129.0, 128.6, 128.4, 115.3, 55.6, 48.5, 43.1, 25.5, 23.2, 21.6, 21.4,14Ø
F~rn~le 4 SUBS~ITUTE S~!E'T (!'~'!E 26) WO 95/1306`1 ~ PCT/GB9~1/02460 .
N-Allyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine The title compound was prepared from N-allyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine ethyl ester by base hydrolysis in ananalogous manner to that for preparation of the compound of Example 2 above.
Characterising data:
~ H-NMR; ~ (CDCI3), 8.77 (1 H, s), 8.10 (1 H, bs), 8.02 (1 H, s), 7.86 (2H, d, J=8.3Hz), 7.16 (2H, d, J=8.0Hz), 6.20-5.92(1H, m), 5.50 (2H, d, J=5.6Hz), 5.18 (1H, d, J=17.1Hz), 5.11 (1H, d, J=10.2Hz), 4.72-4.66 (1H, m), 4.14-3.95 (1H, m), 3.84-3.74 (1 H, m), 2.55 (3H, s),1.83- 1.69 (3H, m),1.04 (3H, d), 0.93 (3H, d, J=6.6Hz).
3C-NMR; ~ (CDCI3),174.3,155.4,141.6,140.3,139.1,138.8,138.6,136.4,136.3, 128.8,126.3,116.7,10~.7, 59.3, 48.5, 47.3, 39.3, 24.1, 22.8, 20.9,13.9.
Examples 5-24 The compounds of Examples 5-24 are prepared as their hydrochloride acid additionsalts by the method of Example 1 employing the appropriate amino acid derivative in Ijeu of L-leucine ethyl ester hydrochloride in Step (b) and for certain compounds missing out the methylation Step (d) or employing a different alkyl halide in liev of methyl iodide in Step (d).
5. N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-D-leucine
6. N-Ethyl-N-4-(1H-2-methylimidazo[4,5-clpyridinylmethyl)phenylsulphonyl-L-leucine
7. N-Propyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucin~
8. N-Benzyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine SUBSTITUTE SHEET (RUEE 26) WO 95/1306J 2 1 7 6 1 2 4 Pcr/GBgJ/0246~
9. N-4-Methoxybenzyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl) phenylsulphonyl-L-leucine
10. N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-isoleucine
11. N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-phenylalanine
12. N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-valine
13. N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-tryptophanol
14. N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-methionine
15. N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-O-methyl-L-tyrosine
16. N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-norleucine
17. N-Methyl-N-4-(1H-2-methylimidazo[4.5-c]pyridinylmethyl)phenylsulphonyl-L-phenylglycine
18. N-Methyl-N-4-(1H-2-methylimidazo[4,5-clpyridinylmethyl)phenylsulphonyl-L-t-butylglycine
19. N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-D,L-ethylglycine
20. N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-D,L-allylglycine
21. N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-t-5lJBSTITUTE SHEET (RULE 26) WO 9S/13064 ~ 7 6 i ~ PCT/GB9~/02460
22 butylalanine 22 . N-Methyl-N-4-(1 H-2-methylimidazo[4 ,5-c]pyridi nylmethyl)phenylsu Iphonyl-L-cyclopropylalanine
23. N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-cyclopentylalanine
24. N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-cyclohexylalanine The inhibition of [3H]-PAF binding to human platelet plasma membrane bycompounds of general formula I was determined by isotopic labelling and filtration techniques. Platelet concel,l,ales were obtained from a hospital blood bank. These platelet concentrates (500-2500 ml.) were centrifuged at 800 rpm for 10 minutes in a SORVALL RC3B centrifuge to remove the red blood cells present. (The word SORVALL is a trade mark.~ The supernatant was subsequently centrifuged at 3,000 rpm in a SORVALL RC3B centrifuge to pellet the platelets present. The platelet rich pellets were resuspended in a minimum volume of buffer (1~0 mM NaCI, 10 mM Tris,2 mM EDTA, pH 7.5) and layered onto Ficoll-Paque gradients, 9 ml platelet concentrate to 2 ml Ficoll, and centrifuged at 1,900 rpm for 15 minutes in a SORVALL
RT6000 centrifuge. This step removes the residual red blood cells and other nonspecific material such as Iyrr~phocytes from the preparation. The platelets which form a band between the plasma and the Ficoll were removed, resuspended in the above buffer and centrifuged at 3,000 rpm for 10 minutes in a SORVALL RT6000 centrifuge. The pelleted platelets were resuspended in buffer (10 mM Tris, 5mM
MgCI2, 2 mM EDTA, pH 7.0), snap freezed in liquid N2 and allowed to thaw slowly at room temperature in order to Iyse the platelets. The latter step was repeated at least 3 times to ensure proper Iysis. The Iysed platelets were centrifuged at 3,000 rpm for 10 minutes in a SORVALL RT6000 centrifuge and resuspended in buffer. The latter step was repeated twice in order to remove any cytoplasmic proteins which may hydrolyse the platelet activating factor (PAF) receptor. The prepared platelet SUBSTITUTE SHEET (r~ULE 26~
Wo 95/13064 ~ j 2 1 7 6 1 2 4 PCr/GB94/02460 membranes may be stored at -7QC. After thawing the prepared membranes were centrifuged in a SORVALL RT6000 at 3,000 rpm for 10 minutes and resuspended in assay buffer.
The assay was conducted by preparing a series of Tris-buffered solutions of the selected antagonist of predetermined concentrations. Each of these solutions contained [3H]-PAF (0.5 nM; 1-0~3H]octadecyl-2-acetyl-sn-glycero-3-phosphoryl choline with a specific activity of 132 Ci/mmol), unlabelled PAF (1000 nM), a known amount of the test antagonist, and a sufficient amount of Tris-buffer solution (1 OmM
Tris, 5mM MgCI2, pH 7.0, 0.25% BSA) to make the flnal volume 1 ml. Incubation was initiated by the addition of 100 ,ug of the isolated membrane fraction to each of the above solutions at 0C. Two control samples, one (C1) which contained all the ingredients described above except the antagonlst and the other (C2) contains C1plus a 1000-fold excess of unlabelled PAF, were also prepared and incubated simu~taneously with the test samples. After 1 hour incubation, each solution wasfiltered rapidly under vacuo through a WHATMAN GF/C glass fibre filter in order to separate unbound PAF from bound PAF. (The word WHATMAN is a trade mark.) The residue in each case was rapidly washed 4 times with 5 ml cold (4C) Tris-buffer solution. Each washed residue was dried under vacuum on a sampling manifold and placed into vials containing 20 ml of OPTIPHASE MP scintillation fluid and the radioactivity counted in a liquid scintillation counter. (The word OPTIPHASE is a trade mark.) Defining the counts for total binding with antagonist from a test sample as "TBA"; the counts for total binding from the control sample C1 as "TB"; and the counts for nonspecific binding from the control sample C2 as "NSB", the percent inhibition of each test antagonist can b~ determined by the following equation:
%Inhibition = ~(TB^TBA)/SB]x100 where the specific binding SB = TB-NSB
Table 1: Result for inhibition of [3H]-PAF receptor binding xample Inhibition of [3H~-PAF
binding IC50 nM
SUBSTITUTE SHE~T (I~UL~ 26 WO 9~/1306~ 2 1 7~ PCT/GB9-1/02460 PHARMACnl O(~Y FXAMPI F ~
The activity of the compounds of general formula I is also demonstrated in vivo by their ability to reverse the hypotension caused by an infusion of PAF in rats. Male Sprague-Dawley rats (300-350 9) were anaesthetised with a mixture of sodium pentobarbitone, 22.5 mg/kg and thiopental 62.5 mg/kg. Through a midline incision in the neck, the trachea was cannulated and the animals breathed spontaneously. A
carotid artery was cannulated for the measurement of blood pressure and this signal was used to trigger a rate meter to measure heart rate. Both jugular veins were cannulated: one for the infusion of PAF and the other for the bolus administration of test compounds.
PAF, 100 ng/kglmin was infused i.v. until a sustained fall in mean blood pressure of 50 mmHg was achieved. Test co,n~ounds were adminis~ered i.v. as a bolus and resulted in a dose dependent reversal of the PAF induced hypotension. The peak of this reversal was measured and the dose to cause a 50% reversal of the hypotensive PAF response (ED50) calculated by straight line interpolation and the results are presented in Table 2.
Table 2: Result (average of several tests) for inhibition of PAF-induced hypotension in the rat Example ED50 (~g/kg i v ) SUBSTITUTE SHEET (r~aJl E 26
RT6000 centrifuge. This step removes the residual red blood cells and other nonspecific material such as Iyrr~phocytes from the preparation. The platelets which form a band between the plasma and the Ficoll were removed, resuspended in the above buffer and centrifuged at 3,000 rpm for 10 minutes in a SORVALL RT6000 centrifuge. The pelleted platelets were resuspended in buffer (10 mM Tris, 5mM
MgCI2, 2 mM EDTA, pH 7.0), snap freezed in liquid N2 and allowed to thaw slowly at room temperature in order to Iyse the platelets. The latter step was repeated at least 3 times to ensure proper Iysis. The Iysed platelets were centrifuged at 3,000 rpm for 10 minutes in a SORVALL RT6000 centrifuge and resuspended in buffer. The latter step was repeated twice in order to remove any cytoplasmic proteins which may hydrolyse the platelet activating factor (PAF) receptor. The prepared platelet SUBSTITUTE SHEET (r~ULE 26~
Wo 95/13064 ~ j 2 1 7 6 1 2 4 PCr/GB94/02460 membranes may be stored at -7QC. After thawing the prepared membranes were centrifuged in a SORVALL RT6000 at 3,000 rpm for 10 minutes and resuspended in assay buffer.
The assay was conducted by preparing a series of Tris-buffered solutions of the selected antagonist of predetermined concentrations. Each of these solutions contained [3H]-PAF (0.5 nM; 1-0~3H]octadecyl-2-acetyl-sn-glycero-3-phosphoryl choline with a specific activity of 132 Ci/mmol), unlabelled PAF (1000 nM), a known amount of the test antagonist, and a sufficient amount of Tris-buffer solution (1 OmM
Tris, 5mM MgCI2, pH 7.0, 0.25% BSA) to make the flnal volume 1 ml. Incubation was initiated by the addition of 100 ,ug of the isolated membrane fraction to each of the above solutions at 0C. Two control samples, one (C1) which contained all the ingredients described above except the antagonlst and the other (C2) contains C1plus a 1000-fold excess of unlabelled PAF, were also prepared and incubated simu~taneously with the test samples. After 1 hour incubation, each solution wasfiltered rapidly under vacuo through a WHATMAN GF/C glass fibre filter in order to separate unbound PAF from bound PAF. (The word WHATMAN is a trade mark.) The residue in each case was rapidly washed 4 times with 5 ml cold (4C) Tris-buffer solution. Each washed residue was dried under vacuum on a sampling manifold and placed into vials containing 20 ml of OPTIPHASE MP scintillation fluid and the radioactivity counted in a liquid scintillation counter. (The word OPTIPHASE is a trade mark.) Defining the counts for total binding with antagonist from a test sample as "TBA"; the counts for total binding from the control sample C1 as "TB"; and the counts for nonspecific binding from the control sample C2 as "NSB", the percent inhibition of each test antagonist can b~ determined by the following equation:
%Inhibition = ~(TB^TBA)/SB]x100 where the specific binding SB = TB-NSB
Table 1: Result for inhibition of [3H]-PAF receptor binding xample Inhibition of [3H~-PAF
binding IC50 nM
SUBSTITUTE SHE~T (I~UL~ 26 WO 9~/1306~ 2 1 7~ PCT/GB9-1/02460 PHARMACnl O(~Y FXAMPI F ~
The activity of the compounds of general formula I is also demonstrated in vivo by their ability to reverse the hypotension caused by an infusion of PAF in rats. Male Sprague-Dawley rats (300-350 9) were anaesthetised with a mixture of sodium pentobarbitone, 22.5 mg/kg and thiopental 62.5 mg/kg. Through a midline incision in the neck, the trachea was cannulated and the animals breathed spontaneously. A
carotid artery was cannulated for the measurement of blood pressure and this signal was used to trigger a rate meter to measure heart rate. Both jugular veins were cannulated: one for the infusion of PAF and the other for the bolus administration of test compounds.
PAF, 100 ng/kglmin was infused i.v. until a sustained fall in mean blood pressure of 50 mmHg was achieved. Test co,n~ounds were adminis~ered i.v. as a bolus and resulted in a dose dependent reversal of the PAF induced hypotension. The peak of this reversal was measured and the dose to cause a 50% reversal of the hypotensive PAF response (ED50) calculated by straight line interpolation and the results are presented in Table 2.
Table 2: Result (average of several tests) for inhibition of PAF-induced hypotension in the rat Example ED50 (~g/kg i v ) SUBSTITUTE SHEET (r~aJl E 26
Claims (10)
1. A compound of formula (II):
(¦¦) wherein R1 represents hydrogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -COC1-C6 alkyl, -CO2C1-C6 alkyl, -(COC1-C6 alkyl)phenyl, -(CO2C1-C6 alkyl)phenyl, -(C1-C6 alkyl)OC1-C6 alkyl, -(C1-C6 alkyl)SC1-C6 alkyl, -(C1-C6 alkyl)CO2C1-C6 alkyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl or a group -D
wherein D represents a group:
wherein n is an integer from 0 to 3, and each of R3 and R4 is independently hydrogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, halogen, -CN, -CO2H, -CO2C1-C6 alkyl, -CONH2, -CONHC1-C6 alkyl, -CONH(C1-C6 alkyl)2, -CHO, -CH2OH, -CF3, -OC1-C6 alkyl, - SC1-C6 alkyl, -SOC1-C6 alkyl, -SO2C1-C6 alkyl, -NH2 or -NHCOMe;
R2 represents hydrogen, halogen, -C1-C6 alkyl optionally substituted by one or more halogen atoms, -C2-C6 alkenyl, -C2-C6 alkynyl, -(C1-C6 alkyl)CO2C1-C6 alkyl, -(C1-C6 alkyl)SC1-C6 alkyl, -(C1-C6 alkyl)OC1-C6 alkyl, -(C1-C6 alkyl)N(C1-C6 alkyl)2, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, -(C1-C6 alkyl)C3-C8 cycloalkyl, -(C1-C6 alkyl)C4-C8 cycloalkenyl, -(C1-C6 alkyl)OC3-C8 cycloatkyl, -(C1-C6 alkyl)OC4-C8 cycloalkenyl, -(C1-C6 alkyl)SC3-C8 cycloalkyl, -(C1-C6 alkyl)SC4-C8 cycloalkenyl, a side chain of a naturally occurring amino acid, a group -D as defined above or a -(C1-C6 alkyl)OD group wherein D is as defined above;
or a pharmaceutically or veterinarily acceptable salt thereof, for use in human or veterinary medicine.
(¦¦) wherein R1 represents hydrogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -COC1-C6 alkyl, -CO2C1-C6 alkyl, -(COC1-C6 alkyl)phenyl, -(CO2C1-C6 alkyl)phenyl, -(C1-C6 alkyl)OC1-C6 alkyl, -(C1-C6 alkyl)SC1-C6 alkyl, -(C1-C6 alkyl)CO2C1-C6 alkyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl or a group -D
wherein D represents a group:
wherein n is an integer from 0 to 3, and each of R3 and R4 is independently hydrogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, halogen, -CN, -CO2H, -CO2C1-C6 alkyl, -CONH2, -CONHC1-C6 alkyl, -CONH(C1-C6 alkyl)2, -CHO, -CH2OH, -CF3, -OC1-C6 alkyl, - SC1-C6 alkyl, -SOC1-C6 alkyl, -SO2C1-C6 alkyl, -NH2 or -NHCOMe;
R2 represents hydrogen, halogen, -C1-C6 alkyl optionally substituted by one or more halogen atoms, -C2-C6 alkenyl, -C2-C6 alkynyl, -(C1-C6 alkyl)CO2C1-C6 alkyl, -(C1-C6 alkyl)SC1-C6 alkyl, -(C1-C6 alkyl)OC1-C6 alkyl, -(C1-C6 alkyl)N(C1-C6 alkyl)2, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, -(C1-C6 alkyl)C3-C8 cycloalkyl, -(C1-C6 alkyl)C4-C8 cycloalkenyl, -(C1-C6 alkyl)OC3-C8 cycloatkyl, -(C1-C6 alkyl)OC4-C8 cycloalkenyl, -(C1-C6 alkyl)SC3-C8 cycloalkyl, -(C1-C6 alkyl)SC4-C8 cycloalkenyl, a side chain of a naturally occurring amino acid, a group -D as defined above or a -(C1-C6 alkyl)OD group wherein D is as defined above;
or a pharmaceutically or veterinarily acceptable salt thereof, for use in human or veterinary medicine.
2. The use of a compound of formula (II) or salt thereof as defined in claim 1 in the preparation of a pharmaceutical composition adapted for oral, topical, rectal or parenteral administration or for inhalation for the management of diseases or conditions mediated by PAF.
3. A pharmaceutical composition in dosage unit form, for the management of diseases or conditions mediated by PAF, comprising a compound of formula (II) orsalt thereof as defined in claim 1, and one or more pharmaceutically acceptable carriers.
4. A method for the management of diseases or conditions mediated by PAF, comprising administering to the patient an effective amount of a compound of formula (II) or salt thereof as defined in claim 1.
5. A use as claimed in claim 1 or claim 2, a composition as claimed in claim 3, or a method as claimed in claim 4, for the management of inflammatory disorders; such as rheumatoid arthritis, osteoarthritis and eye inflammation, cardiovascular disorder, thrombocytopenia, asthma, endotoxin shock, adult respiratory distress syndrome, glomerulonephritis, immune regulation, gastric ulceration, transplant rejection,psoriasis, allergic dermatitis, urticaria, multiple sclerosis, cerebral, myocardial and renal ischemia.
6. A use as claimed in claim 1 or claim 2, a composition as claimed in claim 3, or a method as claimed in claim 4, wherein the compound of formula (II) used is one in which R1 represents a hydrogen atom, a -C1-C6 alkyl group, a -C2-C6 alkenyl group or a group -D as defined in claim 1.
7. A use as claimed in claim 1 or claim 2, a composition as claimed in claim 3, or a method as claimed in claim 4, wherein the compound of formula (II) used is one in which R2 represents a hydrogen atom, a -C1-C6 alkyl group, a -C2-C6 alkenyl group, a -(C1-C6 alkyl)C3-C8 cycloalkyl group, a side chain of a naturally occurring amino acid or a group D as defined in claim 1.
8. A use as claimed in claim 1 or claim 2, a composition as claimed in claim 3, or a method as claimed in claim 4, wherein the compound of formula (II) used is onecontaining a group D as defined in claim 1 wherein R3 represents a hydrogen atom, a -C1-C6 alkyl group, a halogen atom, a -CF3 group or a -OC1-C6 alkyl group, and R4 represents a hydrogen atom or a -OC1-C6 alkyl group.
9. A use as claimed in claim 1 or claim 2, a composition as claimed in claim 3, or a method as claimed in claim 4, wherein the compound of formula (II) used is N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine, or a pharmaceutically acceptable salt thereof.
10. A use as claimed in claim 1 or claim 2, a composition as claimed in claim 3, or a method as claimed in claim 4, wherein the compound of formula (II) used is selected from:
N-4-(1H-2-Methylimidazol4,6-c]pyridinylmethyl)phenylsulphonyl-L-leucine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-D-leucine, N-Ethyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine,N-Allyl-N-4-(1H-2-methylimidazo[4,4-c]pyridinylmethyl)phenylsulphonyl-L-leucine,N-Propyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine, N-Benzyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine, N-4-Methoxybenzyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl) phenyl-sulphonyl-L-leucine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-isoleucine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-phenylalanine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-valine,N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-tryptophanol, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-methionine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-O-methyl-L-tyrosine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-norleucine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-phenylglycine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-t-butylglycine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-D,L-ethylglycine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-D,L-allylglycine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-t-butylalanine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-cyclopropylalanine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-cyclopentylalanine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-cyclohexylalanine, and their pharmaceutically or veterinarily acceptable salts.
N-4-(1H-2-Methylimidazol4,6-c]pyridinylmethyl)phenylsulphonyl-L-leucine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-D-leucine, N-Ethyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine,N-Allyl-N-4-(1H-2-methylimidazo[4,4-c]pyridinylmethyl)phenylsulphonyl-L-leucine,N-Propyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine, N-Benzyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine, N-4-Methoxybenzyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl) phenyl-sulphonyl-L-leucine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-isoleucine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-phenylalanine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-valine,N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-tryptophanol, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-methionine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-O-methyl-L-tyrosine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-norleucine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-phenylglycine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-t-butylglycine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-D,L-ethylglycine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-D,L-allylglycine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-t-butylalanine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-cyclopropylalanine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-cyclopentylalanine, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-cyclohexylalanine, and their pharmaceutically or veterinarily acceptable salts.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9323162.9 | 1993-11-10 | ||
| GB939323162A GB9323162D0 (en) | 1993-11-10 | 1993-11-10 | 4-(1h-2-methylimidazo(4,5-c)pyridinylmethyl)phenylsulphonamid e derivatives as antagonists of paf |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2176124A1 true CA2176124A1 (en) | 1995-05-18 |
Family
ID=10744942
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002176124A Abandoned CA2176124A1 (en) | 1993-11-10 | 1994-11-09 | 4-(1h-2-methylimidazo 4,5-c pyridinylmethyl)phenyl sulphonamide carboxylic acid derivatives as antagonists |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0727995A1 (en) |
| JP (1) | JPH09505040A (en) |
| AU (1) | AU8112594A (en) |
| CA (1) | CA2176124A1 (en) |
| GB (1) | GB9323162D0 (en) |
| WO (1) | WO1995013064A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9508748D0 (en) * | 1995-04-28 | 1995-06-14 | British Biotech Pharm | Benzimidazole derivatives |
| KR100338861B1 (en) * | 1996-01-23 | 2003-02-20 | 시오노기세이야쿠가부시키가이샤 | Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same |
| US6919375B1 (en) | 1996-01-23 | 2005-07-19 | Shionogi & Co., Ltd. | Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same |
| US6747027B1 (en) | 1996-07-22 | 2004-06-08 | Pharmacia Corporation | Thiol sulfonamide metalloprotease inhibitors |
| PL331369A1 (en) * | 1996-07-22 | 1999-07-05 | Monsanto Co | Thiosulphonic metaloprotease inhibitors |
| US6800646B1 (en) | 1999-02-08 | 2004-10-05 | Pharmacia Corporation | Sulfamato hydroxamic acid metalloprotease inhibitor |
| MXPA04010555A (en) | 2002-04-25 | 2005-02-17 | Pharmacia Corp | Piperidinyl-and piperazinyl-sulfonylmethyl hydroxamic acids and their use as protease inhibitors. |
| WO2010051245A1 (en) | 2008-11-03 | 2010-05-06 | Merck Sharp & Dohme Corp. | Benzimidazole and aza-benzimidazole carboxamides |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT98673B (en) * | 1990-08-15 | 1999-01-29 | British Bio Technology | METHOD FOR PREPARING COMPOUNDS THAT ARE ANTAGONISTS OF THE ACTIVATION FACTOR OF PLATELETS FOR EXAMPLE DERIVATIVES OF BENZIMIDAZOLE AND THEIR INTERMEDIARIES |
-
1993
- 1993-11-10 GB GB939323162A patent/GB9323162D0/en active Pending
-
1994
- 1994-11-09 WO PCT/GB1994/002460 patent/WO1995013064A1/en not_active Ceased
- 1994-11-09 CA CA002176124A patent/CA2176124A1/en not_active Abandoned
- 1994-11-09 AU AU81125/94A patent/AU8112594A/en not_active Abandoned
- 1994-11-09 JP JP7513680A patent/JPH09505040A/en active Pending
- 1994-11-09 EP EP95900227A patent/EP0727995A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| AU8112594A (en) | 1995-05-29 |
| WO1995013064A1 (en) | 1995-05-18 |
| JPH09505040A (en) | 1997-05-20 |
| EP0727995A1 (en) | 1996-08-28 |
| GB9323162D0 (en) | 1994-01-05 |
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