Claims
- 1. A process for preparing a compound as defined by the general formula ##STR101## wherein: A.sup.1 is .dbd.N--, .dbd.CH-- or .dbd.CR.sup.1 --;
- A.sup.2 is --N.dbd., --CH.dbd. or --CR.sup.2 .dbd.;
- provided that, when one of A.sup.1 and A.sup.2 is a nitrogen atom, the other of A.sup.1 and A.sup.2 is other than a nitrogen atom;
- R represents hydrogen, --C.sub.1 -C.sub.6 alkyl, --C.sub.2 -C.sub.6 alkenyl, halogen or --OC.sub.1 -C.sub.6 alkyl;
- each of R.sup.1 and R.sup.2 independently represents hydrogen, --C.sub.1 -C.sub.6 alkyl, --C.sub.2 -C.sub.6 alkenyl, halogen, --CN, --CO.sub.2 H, --CO.sub.2 C.sub.1 -C.sub.6 alkyl, --CONH.sub.2, --CHO, --CH.sub.2 OH, --CF.sub.3, --OC.sub.1 -C.sub.6 alkyl, --SC.sub.1 -C.sub.6 alkyl, --SOC.sub.1 -C.sub.6 alkyl, --SO.sub.2 C.sub.1 -C.sub.6 alkyl, --NH.sub.2, --NHCOMe or --NO.sub.2, or R.sup.1 and R.sup.2 together with the carbon atoms to which they are attached form a fused phenyl ring;
- R.sup.3 represents hydrogen, --C.sub.1 -C.sub.6 alkyl, --C.sub.2 -C.sub.6 alkenyl, --C.sub.2 -C.sub.6 alkynyl, --OC.sub.1 -C.sub.6 alkyl, --SC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub.1 -C.sub.6 alkyl, --CF.sub.3, --(C.sub.1 -C.sub.6 alkyl)phenyl, --C.sub.3 -C.sub.8 cycloalkyl, --C.sub.4 -C.sub.8 cycloalkenyl, --(C.sub.1 -C.sub.6 alkyl)C.sub.3 -C.sub.8 cycloalkyl, --(C.sub.1 -C.sub.6 alkyl)C.sub.4 -C.sub.8 cycloalkenyl or thiophenyl;
- R.sub.4 represents hydrogen, --C.sub.1 -C.sub.6 alkyl, --C.sub.2 -C.sub.6 alkenyl, --C.sub.2 -C.sub.6 alkynyl, --CO.sub.2 C.sub.1 -C.sub.6 alkyl, --SC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)phenyl or thiophenyl;
- R.sup.5 represents hydrogen, --C.sub.1 -C.sub.6 alkyl, --C.sub.2 -C.sub.6 alkenyl, --C.sub.2 -C.sub.6 alkynyl, --COC.sub.1 -C.sub.6 alkyl, --CO.sub.2 C.sub.1 -C.sub.6 alkyl, --(COC.sub.1 -C.sub.6 alkyl)phenyl, --(CO.sub.2 -C.sub.1 -C.sub.6 alkyl)phenyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)CO.sub.2 C.sub.1 -C.sub.6 alkyl, --C.sub.3 -C.sub.8 cycloalkyl, --C.sub.4 -C.sub.8 cycloalkenyl or a group --D wherein D represents a group: ##STR102## wherein n in an integer from 0 to 3, and each of R.sup.8, and R.sup.9 is independently hydrogen, --C.sub.1 -C.sub.6 alkyl, --C.sub.2 -C.sub.6 alkenyl, --C.sub.2 -C.sub.6 alkynyl, halogen, --CN, --CO.sub.2 H, --CO.sub.2 C.sub.1 -C.sub.6 alkyl, --CONH.sub.2, CONHC.sub.1 -C.sub.6 alkyl, --CONH(C.sub.1 -C.sub.6 alkyl).sub.2, --CHO, --CH.sub.2 OH, --CF.sub.3, --OC.sub.1 -C.sub.6 alkyl, --SC.sub.1 -C.sub.6 alkyl, --SOC.sub.1 -C.sub.6 alkyl, or --SO.sub.2 C.sub.1 -C.sub.6 alkyl, --NH.sub.2 or --NHCOMe;
- each of R.sup.6 and R.sup.7 independently represents hydrogen, halogen, --C.sub.1 C.sub.6 alkyl optionally substituted by one or more halogen atoms, --C.sub.2 -C.sub.6 alkenyl, --C.sub.2 -C.sub.6 alkynyl, --(C.sub.1 -C.sub.6 alkyl)CO.sub.2 C.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)N(C.sub.1 -C.sub.6 alkyl).sub.2, --C.sub.3 -C.sub.8 cycloalkyl, --C.sub.4 -C.sub.8 cycloalkenyl, --(C.sub.1 -C.sub.6 alkyl)C.sub.3 -C.sub.8 cycloalkyl, --(C.sub.1 -C.sub.6 alkyl)C.sub.4 -C.sub.8 cycloalkenyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.3 -C.sub.8 cycloalkyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.4 -C.sub.8 cycloalkenyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub.3 -C.sub.8 cycloalkyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub.4 -C.sub.8 cycloalkenyl, a side chain of a naturally occurring amino acid, a group --D as defined above or a --(C.sub.1 -C.sub.6 alkyl)OD group wherein D is as defined above;
- or R.sup.6 together with R.sup.5 with the atoms to which they are attached form a 5 to 8 membered nitrogen-containing heterocyclic ring;
- or R.sup.6 and R.sup.7 together with the carbon atom to which they are attached form a C.sub.3 -C.sub.8 cycloalkyl ring;
- B represents a) --ZR.sup.10 group wherein Z is --C(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.S)-- or --C(.dbd.S)O-- and R.sup.10 is --C.sub.1 -C.sub.18 alkyl optionally substituted by one or more halogen atoms, --C.sub.2 -C.sub.18 alkenyl, --C.sub.2 -C.sub.18 alkynyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)O(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl, --C.sub.3 -C.sub.8 cycloalkyl, --C.sub.4 -C.sub.8 cycloalkenyl, pyridyl, a group --D as defined above or a --(C.sub.1 -C.sub.6 alkyl)OD group wherein D is as defined above;
- b) a --CONR.sup.11 R.sup.12 group wherein each of R.sup.11 and R.sup.12 is independently hydrogen, --C.sub.11-C.sub.18 alkyl optionally substituted by one or more halogen atoms, --C.sub.2 -C.sub.18 alkenyl, --C.sub.2 -C.sub.18 alkynyl, --C.sub.3 -C.sub.8 cycloalkyl, --C.sub.4 -C.sub.8 cycloalkenyl, pyridyl, a group --D as defined above or R.sup.11 and R.sup.12 together with the nitrogen atom to which they are attached form a 5 to 8 membered nitrogen-containing heterocyclic ring;
- or a pharmaceutically or veterinarily acceptable acid addition salt or hydrate thereof for use in human or veterinary medicine, particularly in the management of diseases or conditions mediated by platelet-activating factor,
- the process comprising:
- treating a substituted diamino compound of general formula IV ##STR103## wherein A.sup.1, A.sup.2, R, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and B are as defined in general formula I, with a carboxylic acid of general formula V
- R.sup.3 CO.sub.2 H V
- wherein R.sup.3 is as defined in general formula I.
Priority Claims (3)
| Number |
Date |
Country |
Kind |
| 901787 |
Aug 1990 |
GBX |
|
| 9018040 |
Aug 1990 |
GBX |
|
| 9112214 |
Jun 1993 |
GBX |
|
Parent Case Info
This is a continuation of application Ser. No. 07/745,471, filed on Aug. 15, 1991, now U.S. Pat. No. 5,200,412.
This invention relates primarily to novel compounds which are agonists of platelet activating factor.
Platelet Activating Factor (PAF) is a bioactive phospholipid which has been identified as 1-O-hexadecyl/octadecyl-2-acetyl-sn-glyceryl-3-phosphoryl choline. 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, thrombocytopenia, 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, immune regulation, transplant rejection, gastric ulceration, psoriasis, cerebral, myocardial and renal ischemia. Thus the compounds of the invention, by virtue of their ability to antagonise the actions of PAF, should be of value in the treatment of any of the above conditions and any other conditions in which PAF is implicated (e.g. embryo implantation).
Compounds which have been disclosed as possessing activity as PAF antagonists include compounds which are structurally related to the PAF molecule such as glycerol derivatives (EP-A-0238202), and heterocyclic compounds such as 2,5-diaryl tetrahydrofurans (EP-A-0144804) and imidazopyridine derivatives (EP-A-0266613 and WO-A-8908653).
The present invention provides novel and useful substituted amino acid derivatives and their pharmaceutically acceptable acid addition salts, and pharmaceutical uses thereof as PAF. antagonists.
According to a first aspect of the invention there is provided a compound of general formula I; ##STR2## wherein:
A.sup.1 is .dbd.N--, .dbd.CH-- or .dbd.CR.sup.1 --;
A.sup.2 is --N.dbd., --CH.dbd. or --CR.sup.2 .dbd.;
provided that, when one of A.sup.1 and A.sup.2 is a nitrogen atom, the other of A.sup.1 and A.sup.2 is other than a nitrogen atom;
R represents hydrogen, --C.sub.1 -C.sub.6 alkyl, --C.sub.2 -C.sub.6 alkenyl, halogen or --OC.sub.1 -C.sub.6 alkyl;
each of R.sup.1 and R.sup.2 independently represents hydrogen, --C.sub.1 -C.sub.6 alkyl, --C.sub.2 -C.sub.6 alkenyl, halogen, --CN, --CO.sub.2 H, --CO.sub.2 C.sub.1 -C.sub.6 alkyl, --CONH.sub.2, --CHO, --CH.sub.2 OH, --CF.sub.3, --OC.sub.1 -C.sub.6 alkyl, --SC.sub.1 -C.sub.6 alkyl, --SOC.sub.1 -C.sub.6 alkyl, --SO.sub.2 C.sub.1 -C.sub.6 alkyl, --NH.sub.2, --NHCOMe or --NO.sub.2 or R.sup.1 and R.sup.2 together with the carbon atoms to which they are attached form a fused phenyl ring;
R.sup.3 represents hydrogen, --C.sub.1 -C.sub.6 alkyl, --C.sub.2 -C.sub.6 alkenyl, --C.sub.2 -C.sub.6 alkynyl, --OC.sub.1 -C.sub.6 alkyl, --SC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub.1 -C.sub.6 alkyl, --CF.sub.3, --(C.sub.1 -C.sub.6 alkyl)phenyl, --C.sub.3 -C.sub.8 cycloalkyl, --C.sub.4 -C.sub.8 cycloalkenyl, --(C.sub.1 -C.sub.6 alkyl)C.sub.3 -C.sub.8 cycloalkyl, --(C.sub.1 -C.sub.6 alkyl)C.sub.4 -C.sub.8 cycloalkenyl or thiophenyl;
R.sup.4 represents hydrogen, --C.sub.1 -C.sub.6 alkyl, --C.sub.2 -C.sub.6 alkenyl, --C.sub.2 -C.sub.6 alkynyl, --CO.sub.2 C.sub.1 -C.sub.6 alkyl, --SC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)phenyl or thiophenyl;
R.sup.5 represents hydrogen, --C.sub.1 -C.sub.6 alkyl, --C.sub.2 -C.sub.6 alkenyl, --C.sub.2 -C.sub.6 alkynyl, --COC.sub.1 -C.sub.6 alkyl, --CO.sub.2 C.sub.1 -C.sub.6 alkyl, --(COC.sub.1 -C.sub.6 alkyl)phenyl, --(CO.sub.2 C.sub.1 -C.sub.6 alkyl)phenyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)CO.sub.2 C.sub.1 -C.sub.6 alkyl, --C.sub.3 -C.sub.8 cycloalkyl, --C.sub.4 -C.sub.8 cycloalkenyl or a group --D wherein D represents a group: ##STR3##
wherein n is an integer from 0 to 3, and each of R.sup.8 and R.sup.9 is independently hydrogen, --C.sub.1 -C.sub.6 alkyl, --C.sub.2 -C.sub.6 alkenyl, --C.sub.2 -C.sub.6 alkynyl, halogen, --CN, --CO.sub.2 H, --CO.sub.2 C.sub.1 -C.sub.6 alkyl, --CONH.sub.2, --CONHC.sub.1 -C.sub.6 alkyl, --CONH(C.sub.1 -C.sub.6 alkyl).sub.2, --CHO, --CH.sub.2 OH, --CF.sub.3, --OC.sub.1 -C.sub.6 alkyl, --SC.sub.1 -C.sub.6 alkyl, --SOC.sub.1 -C.sub.6 alkyl, --SO.sub.2 C.sub.1 -C.sub.6 alkyl, --NH.sub.2 or --NHCOME;
each of R.sup.6 and R.sup.7 independently represents hydrogen, halogen, --C.sub.1 -C.sub.6 alkyl optionally substituted by one or more halogen atoms, --C.sub.2 -C.sub.6 alkenyl, --C.sub.2 -C.sub.6 alkynyl, --(C.sub.1 -C.sub.6 alkyl)CO.sub.2 C.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)N(C.sub.1 -C.sub.6 alkyl).sub.2, --C.sub.3 -C.sub.8 cycloalkyl, --C.sub.4 -C.sub.8 cycloalkenyl, --(C.sub.1 -C.sub.6 alkyl)C.sub.3 -C.sub.8 cycloalkyl, --(C.sub.1 -C.sub.6 alkyl)C.sub.4 -C.sub.8 cycloalkenyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.3 -C.sub.8 cycloalkyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.4 -C.sub.8 cycloalkenyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub.3 -C.sub.8 cycloalkyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub. 4 -C.sub.8 cycloalkenyl, a side chain of a naturally occurring amino acid, a group --D as defined above or a --(C.sub.1 -C.sub.6 alkyl)OD group wherein D is as defined above;
or R.sup.6 together with R.sup.5 and the atoms to which they are attached form a 5 to 8 membered nitrogen-containing heterocyclic ring;
or R.sup.6 and R.sup.7 together with the carbon atom to which they are attached form a C.sub.3 -C.sub.8 cycloalkyl ring;
B represents a) a --ZR.sup.10 group wherein Z is --C(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.S)-- or --C(.dbd.S)O-- and R.sup.10 is --C.sub.1 -C.sub.18 alkyl optionally substituted by one or more halogen atoms, --C.sub.2 -C.sub.18 alkenyl, --C.sub.2 -C.sub.18 alkynyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)O(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl, --C.sub.3 -C.sub.8 cycloalkyl, --C.sub.4 -C.sub.8 cycloalkeny pyridyl, a group --D as defined above or a --(C.sub.1 -C.sub.6 alkyl)OD group wherein D is as defined above;
b) a --CONR.sup.11 R.sup.12 group wherein each of R.sup.11 and R.sup.12 is independently hydrogen, --C.sub.1 -C.sub.18 alkyl optionally substituted by one or more halogen atoms, --C.sub.2 -C.sub.18 alkenyl, --C.sub.2 -C.sub.18 alkynyl, --C.sub.3 -C.sub.8 cycloalkyl, --C.sub.4 -C.sub.8 cycloalkenyl, pyridyl, a group --D as defined above or R.sup.11 and R.sup.12 together with the nitrogen atom to which they are attached form a 5 to 8 membered nitrogen-containing heterocyclic ring;
or a pharmaceutically or veterinarily acceptable acid addition salt or hydrate thereof.
Hereafter in this specification the term "compound" includes "salt" or "hydrate" unless the context requires otherwise.
As used herein the term "halogen" or its abbreviation "halo" means fluoro, chloro, bromo or iodo.
As used herein the term "C.sub.1 -C.sub.6 alkyl" refers to straight chain or branched chain hydrocarbon 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 "C.sub.1 -C.sub.18 alkyl" refers to straight chain or branched chain hydrocarbon groups having from one to eighteen carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl. From one to six carbon atoms may be preferred.
As used herein the term "C.sub.2 -C.sub.6 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 applicable. This term would include for example, vinyl, 1-propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl.
As used herein the term "C.sub.2 -C.sub.18 alkenyl" refers to straight chain or branched chain hydrocarbon groups having from two to eighteen carbon atoms and having in addition one or more double bonds, of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1-propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl, geranyl, and farnesyl. From two to six carbon atoms may be preferred.
As used herein the term "C.sub.2 -C.sub.6 alkynyl" refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
As used herein the term "C.sub.2 -C.sub.18 alkynyl" refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 10-undecynyl, 4-ethyl-1-octyn-3-yl, 7-dodecynyl, 9-dodecynyl, 10-dodecynyl, 3-methyl-1-dodecyn-3-yl, 2-tridecynyl, 11-tridecynyl, 3-tetradecynyl, 7-hexadecynyl and 3-octadecynyl. From two to six carbon atoms may be preferred.
As used herein the term "OC.sub.1 -C.sub.6 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, tert-butoxy, pentoxy, neopentoxy and hexoxy.
As used herein the term "SC.sub.1 -C.sub.6 alkyl" refers to straight chain or branched chain alkylthio groups having from 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 "C.sub.3 -C.sub.8 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 "C.sub.4 -C.sub.8 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 "naturally occurring-amino acid" includes alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glycine, histidine, 5-hydroxylysine, 4-hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, .alpha.-aminoadipic acid, .alpha.-amino-n-butyric acid, 3,4-dihydroxyphenylalanine, homoserine, .alpha.-methylserine, ornithine, pipecolic acid, and thyroxine. The amino acids may have their side chains protected for example the carboxyl groups of aspartic acid, glutamic acid and .alpha.-aminoadipic acid may be esterified (for example as a C.sub.1 -C.sub.6 alkyl ester) , the amino groups of lysine, ornithine, 5-hydroxylysine, 4-hydroxyproline may be converted to amides (for example as a COC.sub.1 -C.sub.6 alkyl amide) or carbamates (for example as a C(.dbd.O)OC.sub.1 -C.sub.6 alkyl or C(.dbd.O)OCH.sub.2 Ph carbamate), the hydroxyl groups of 5-hydroxylysine, 4-hydroxyproline, serine, threonine, tyrosine, 3,4-dihydroxyphenylalanine, homoserine, .alpha.-methylserine and thyroxine may be converted to ethers (for example a C.sub.1 -C.sub.6 alkyl or a (C.sub.1 -C.sub.6 alkyl)phenyl ether) or esters (for example a C(.dbd.O)C.sub.1 - C.sub.6 alkyl ester) and the thio group of cystein may be converted to thioethers (for example a C.sub.1 -C.sub.6 alkyl thioether) or thioesters (for example a C(.dbd.O)C.sub.1 -C.sub.6 alkyl thioester).
As used herein, the term "nitrogen-containing heterocyclic ring" refers to an aromatic or alicyclic ring comprising one or more nitrogen atoms and optionally one or more other heteroatoms. Illustrative of such rings are pyrrolidine, piperidine, hexamethyleneimine, heptamethyleneimine, morpholine and piperazine.
In compounds of this invention, 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 all such diastereoisomers, their optically active enantiomers and mixtures thereof.
The term "pharmaceutically or veterinarily acceptable acid addition salt" refers to a salt prepared by contacting a compound of formula (I) with an acid whose anion is generally considered suitable for human or animal consumption.
Examples of pharmaceutically and/or veterinarily acceptable acid addition salts include the hydrochloride, sulphate, phosphate, acetate, propionate, lactate, maleate, succinate and tartrate salts.
Preferred compounds include those in which, independently or in any compatible combination:
A.sup.1 represents .dbd.N--, .dbd.CH-- or .dbd.CR.sup.1 --;
A.sup.2 represents --N.dbd., --CH.dbd. or --CR.sup.2 .dbd.;
R represents a halogen (for example chlorine) atom or a hydrogen atom;
R.sup.1 represents a halogen (for example fluorine) atom or a hydrogen atom;
R.sup.2 represents a halogen (for example fluorine) atom or a hydrogen atom;
R.sup.3 represents a hydrogen atom or a --C.sub.1 -C.sub.6 alkyl (for example methyl, ethyl or n-pentyl) group;
R.sup.4 represents a hydrogen atom;
R.sup.5 represents a hydrogen atom, a --C.sub.1 -C.sub.6 alkyl (for example methyl or propyl) group, a --C.sub.2 -C.sub.6 alkenyl (for example allyl) group, a --COC.sub.1 -C.sub.6 alkyl (for example acetyl) group, a --CO.sub.2 C.sub.1 -C.sub.6 alkyl (for example ethoxycarbonyl) group, or a --(C.sub.1 -C.sub.6 alkyl)CO.sub.2 C.sub.1 -C.sub.6 alkyl (for example methoxycarbonylmethyl, ethoxycarbonylmethyl or t-butoxycarbonylmethyl) group;
R.sup.6 represents a hydrogen atom, a --C.sub.1 -C.sub.6 alkyl (for example methyl, isopropyl, n-butyl, isobutyl or 2-methylpropyl) group, a --C.sub.2 -C.sub.6 alkenyl (for example allyl) group, a --(C.sub.1 -C.sub.6 alkyl)CO.sub.2 C.sub.1 -C.sub.6 alkyl (for example ethyl 3-propionate) group, a --(C.sub.1 -C.sub.6 alkyl)SC.sub.1 -C.sub.6 alkyl (for example methylthioethylene) group, the side chain of a naturally occurring amino acid, a group --D or a --(C.sub.1 -C.sub.6 alkyl)OD group, or R.sup.5 and R.sup.6, and the atoms to which they are attached form a 5 to 8 membered nitrogen-containing heterocyclic (for example pyrrolidine) ring;
R.sup.7 represents a hydrogen atom or a --C.sub.1 -C.sub.6 alkyl (for example methyl) group, or together with R.sup.6 and the carbon atom to which they are attached forms a C.sub.3 -C.sub.8 cycloalkyl (for example cyclohexyl) ring;
when R.sup.6 represents the side-chain of a naturally occurring amino acid the preferred stereochemistry of the carbon atom to which R.sup.6 and R.sup.7 are attached is the same as that of the naturally occurring amino acid;
n represents an integer of 0 or 1;
R.sup.8 represents a hydrogen atom or a --OC.sub.1 -C.sub.6 alkyl (for example methoxy) group;
R.sup.9 represents a hydrogen atom;
Z represents a --C(.dbd.O)-- group or a --C(.dbd.O)O-- group;
R.sup.10 represents a --C.sub.1 -C.sub.18 alkyl (for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or octadecyl) group a --C.sub.2 -C.sub.18 alkenyl (for example allyl) group, a --(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkoxy (for example 2-ethoxyethyl, 1-methyl-2-methoxyethyl) group, a --(C.sub.1 -C.sub.6 alkyl)O(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl (for example 2-(2-ethoxyethoxyethyl) group, a group --D or a --(C.sub.1 -C.sub.6 alkyl)OD (for example 2-benzoxyethyl) group;
R.sup.11 represents a --C.sub.1 -C.sub.6 alkyl (for example methyl) group or a pyridyl (for example 2-pyridyl) group, or together with R.sup.12 and the nitrogen atom to which they are attached forms a 5 to 8 membered nitrogen-containing heterocyclic (for example pyrrolidine or morpholine) ring; and
R.sup.12 represents a hydrogen atom.
Preferred side chains of naturally occurring amino acids include side chains of alanine, valine, isoleucine, leucine, phenylalanine, tyrosine, serine, methionine, and aspartic acid.
Particularly preferred compounds include those in which, independently or in any compatible combination:
A.sup.1 represents --N.dbd.;
A.sup.2 represents .dbd.CH--;
R represents a halogen (for example chlorine) atom or a hydrogen atom;
R.sup.1 represents a hydrogen atom;
R.sup.2 represents a hydrogen atom;
R.sup.3 represents a --C.sub.1 -C.sub.6 alkyl (for example methyl, ethyl or n-pentyl) group;
R.sup.4 represents a hydrogen atom;
R.sup.5 represents a hydrogen atom or a --C.sub.1 -C.sub.6 alkyl (for example methyl or propyl) group, a --C.sub.2 -C.sub.6 alkenyl (for example allyl) group, a --CO.sub.2 C.sub.1 -C.sub.6 alkyl (for example ethoxycarbonyl) group or a --(C.sub.1 -C.sub.6 alkyl)CO.sub.2 C.sub.1 -C.sub.6 alkyl (for example methoxycarbonylmethyl, ethoxycarbonylmethyl or t-butoxycarbonylmethyl) group;
R.sup.6 represents a --C.sub.1 -C.sub.6 alkyl (for example methyl, isopropyl, n-butyl, isobutyl or 2-methylpropyl) group, a --C.sub.2 -C.sub.6 alkenyl, (for example allyl) group, a --(C.sub.1 -C.sub.6 alkyl)CO.sub.2 C.sub.1 -C.sub.6 alkyl (for example ethyl 3-propionate) group, --(C.sub.1 -C.sub.6 alkyl)SC.sub.1 -C.sub.6 alkyl (for example methylthioethylene) group or the side chain of a naturally occurring amino acid;
R.sup.7 represents a hydrogen atom;
when R.sup.6 represents the side chain of a naturally occurring amino acid the preferred stereochemistry of the carbon atom to which R.sup.6 and R.sup.7 are attached is the same as that of the naturally occurring amino acid;
n represents an integer of 1;
R.sup.8 represents a hydrogen atom;
R.sup.9 represents a hydrogen atom;
B represents a --ZR.sup.10 group;
Z represents a --C(.dbd.O)O-- group;
R.sup.10 represents a --C.sub.1 -C.sub.18 alkyl (for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or octadecyl) group, a --C.sub.2 -C.sub.18 alkenyl (for example allyl) group, a --(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl (for example 2-ethoxyethyl, 1-methyl-2-methoxyethyl) group, --(C.sub.1 -C.sub.6 alkyl)O(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl (for example 2-(2-ethoxyethoxyethyl) group, a group --D or a --(C.sub.1 -C.sub.6 alkyl)OD (for example 2-benzoxyethyl) group.
Particularly preferred side chains of naturally occurring amino acids include side chains of isoleucine, leucine and methionine.
Exemplary compounds include:
Compounds of general formula I may be prepared by any suitable method known in the art and/or by the following process, which itself forms part of the invention.
According to a second aspect of the invention, there is provided a process for preparing a compound of general formula I as defined above, the process comprising:
(a) treating an imidazole derivative represented by general formula II ##STR4## wherein A.sup.1, A.sup.2, R.sup.1, R.sup.2 and R.sup.3 are as defined in general formula I, with a suitable base (e.g. sodium hydride, potassium hydride, sodium bis(trimethylsilyl)amide, or potassium hydroxide), followed by a compound of general formula III ##STR5## wherein R, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and B are as defined in general formula I, and L is chloro, bromo, iodo, methanesulphonyloxy, p-toluenesulphonyloxy or trifluoromethanesulphonyloxy; or
(b) treating a substituted diamino compound of general formula IV ##STR6## wherein A.sup.1, A.sup.2, R, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and B are as defined in general formula I, with a carboxylic acid of general formula V
(c) optionally after step (a) or step (b) converting, in one or a plurality of steps, a compound of general formula I into another compound of general formula I.
The reaction of step (a) can for preference be conducted in an aprotic solvent (e.g. tetrahydrofuran, N,N-dimethylformamide or acetonitrile) to yield compounds of general formula I. In the case where an unsymmetrically substituted imidazole derivative is used the reaction can yield an isomeric mixture, which is separated by chromatography to yield compounds of general formula I.
In step (b), derivatives of carboxylic acids of general formula V, which are suitable substrates for the reaction include acid halides of general formula VI
By means of step (c) compounds of general formula I wherein B is a --CONR.sup.11 R.sup.12 group wherein R.sup.11 and R.sup.12 are as defined for general formula I, may be prepared by the following methods;
i) by treatment of a compound of general formula I wherein B is a --CO.sub.2 R.sup.10 group wherein R.sup.10 is a benzyl group with hydrogen in the presence of a noble metal catalyst (e.g. 10% palladium on charcoal) to give a carboxylic acid which is then treated with an amine of general formula HNR.sup.11 R.sup.12 in the presence of a coupling reagent (e.g. 1,3-dicyclohexylcarbodiimide);
ii) by treatment of a compound of general formula I wherein B is a --CO.sub.2 R.sup.10 group wherein R.sup.10 is lower alkyl with a dimethylaluminium amide of general formula X
Also by means of step (c) certain compounds of general formula I wherein B is a --CO.sub.2 R.sup.10 group wherein R.sup.10 is as defined in general formula I, may be prepared by base catalysed hydrolysis to give a compound of general formula I wherein B is a --CO.sub.2 H group which is subsequently esterified with an alcohol of general formula HOR.sup.10 in the presence of a coupling reagent (e.g. 1,3-dicyclohexylcarbodiimide).
Also by means of step (c) certain compounds of general formula I wherein B is a --CO.sub.2 R.sup.10 group wherein R.sup.10 is as defined in general formula I or a CONR.sup.11 R.sup.10 group wherein R.sup.11 and R.sup.12 are as defined in general formula I but are not hydrogen atoms, may be prepared by treatment of a compound of general formula I wherein R.sup.5 is hydrogen with base followed by an electrophile of general formula XI
Also by means of step (c) certain compounds of general formula I wherein R.sup.5 is as defined in general formula I but is not a hydrogen atom, B is a --CO.sub.2 R.sup.10 group wherein R.sup.10 is as defined in general formula I or a --CONR.sup.11 R.sup.12 group wherein R.sup.11 and R.sup.12 are as defined in general formula I but are not hydrogen atoms, can be prepared by treatment of a compound of general formula I wherein R.sup.4 is a hydrogen atom with a suitable base (e.g. sodium bis(trimethylsilyl)amide) in an aprotic solvent (e.g. tetrahydrofuran) followed by an electrophile of the general formula LR.sup.4 wherein R.sup.4 is --C.sub.1 -C.sub.6 alkyl, --C.sub.3 -C.sub.6 alkenyl, --C.sub.3 -C.sub.6 alkynyl, --CO.sub.2 C.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkoxy or --(C.sub.1 -C.sub.6 alkyl)phenyl and L is chloro, bromo, iodo, methanesulphonyloxy, p-toluenesulphonyloxy or trifluoromethanesulphonyloxy or by a C.sub.1 -C.sub.6 alkyl disulphide or phenyl disulphide electrophile. Electrophiles of the general formula LR.sup.4 and disulphide electrophiles are available in the art or can be prepared by methods analogous to those known in the art.
Imidazole derivatives of general formula II may be prepared by a number of methods. The first method involves treatment of a 1,2-diamine of general formula XII ##STR9## wherein A.sup.1, A.sup.2, R.sup.1 and R.sup.2 are as defined in general formula I, with a carboxylic acid of general formula V, an acid halide of general formula VI, an acid anhydride of general formula VII, a trialkylorthoester of general formula VIII or an imino ether salt of general formula IX.
1,2-Diamines of general formula XII are available in the art or may be prepared by the reduction of a 1,2-nitroamine of general formula XIII ##STR10## wherein A.sup.1, A.sup.2, R.sup.1 and R.sup.2 are as in general formula I, for example in the presence of hydrogen and a catalyst such as palladium or platinum.
1,2-Nitroamines of general formula XIII are available in the art or can be prepared by methods analogous to those known in the art.
In a second method imidazole derivatives of general formula II may be prepared by the treatment of an 1,2-nitroamide of general formula XIV ##STR11## wherein A.sup.1, A.sup.2, R.sup.1, R.sup.2 and R.sup.3 are as defined in general formula I, with a suitable reducing agent (e.g. tin in acetic acid).
1,2-Nitroamides of general formula XIV may be prepared by the treatment of a 1,2-nitroamine of general formula XIII with an acid chloride of general formula VI wherein R.sup.3 is as defined in general formula I, in an aprotic solvent and in the presence of a suitable base such as, for example, triethylamine. Alternatively, the reaction may be conducted utilising an acid anhydride of general formula VII wherein R.sup.3 is as defined in general formula I.
Another procedure for preparing 1,2-nitroamides of general formula XIV involves reaction of a 1,2-nitroamine of general formula XIII with a carboxylic acid of general formula V, wherein R.sup.3 is as defined in general formula I, in the presence of a coupling reagent (e.g. 1,3-dicyclohexylcarbodiimide).
Compounds of general formula III may be prepared by treatment of an amine of general formula XV ##STR12## wherein R.sup.5, R.sup.6, R.sup.7 and B are as defined in general formula I, with a sulphonyl halide of general formula XVI ##STR13## wherein R and R.sup.4 is as defined in general formula I, L is chloro, bromo, iodo, methanesulphonyloxy, p-toluenesulphonyloxy or trifluoromethanesulphonyloxy and Hal is a halide (e.g. fluoro, chloro or bromo), in the presence of a suitable base (e.g. triethylamine). Amines of general formula XV and sulphonyl halides of general formula XVI are known in the art or may be prepared by methods known in the art.
Substituted 1,2-diamines of general formula IV may be prepared by the reduction of a substituted 1,2-nitroamine of general formula XVII ##STR14## wherein A.sup.1, A.sup.2, R, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and B are as defined in general formula I, for example in the presence of hydrogen and a catalyst such as palladium or platinum.
Substituted 1,2-nitroamines of general formula XVII may be prepared by a number of methods. The first of these methods involves the treatment of a nitro compound of general formula XVIII ##STR15## wherein A.sup.1, A.sup.2, R.sup.1, R.sup.2 are as defined in general formula I and G is halo or --OC.sub.1 -C.sub.6 alkyl, is treated with an amino compound of general formula XIX ##STR16## wherein R, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and B are as defined in general formula I. Nitro compounds of general formula XVIII are available in the art or can be prepared by methods analogous to those known in the art. Amino compounds of general formula XIX can be prepared by treatment of a compound of general formula III with hexamethylenetetramine followed by treatment with ethanolic hydrochloric acid or by sequential treatment of a compound of general formula III with sodium azide followed by either triphenylphosphine or hydrogenation over a suitable catalyst.
A second procedure for the preparation of substituted 1,2-nitroamines of general formula XVII involves the reduction of an imino nitro compound of general formula XX ##STR17## wherein A.sup.1, A.sup.2, R, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and B are as defined in general formula I, for example by the action of sodium cyanoborohydride.
The imino nitro compounds of general formula XX may be prepared by treating a 1,2-nitroamine of general formula XIII with a substituted carbonyl derivative of general formula XXI ##STR18## wherein R, R.sup.5, R.sup.6, R.sup.7 and B are as defined in general formula I and R.sup.4 is as defined in general formula I but is not a C.sub.1 -C.sub.6 alkylthio group. Substituted carbonyl derivatives of general formula XXI may be prepared by treatment of a compound of general formula III with an oxidising agent (e.g. dimethyl sulphoxide).
Alternatively substituted 1,2-nitroamines of general formula XVII in which R.sup.4 is hydrogen may be prepared by the reduction of a 1,2-nitroamide of general formula XXII ##STR19## wherein A.sup.1, A.sup.2, R, R.sup.1, R.sup.2, R.sup.5, R.sup.6, R.sup.7 and B are as defined in general formula I, with a suitable metal hydride reducing agent such as for example lithium aluminium hydride.
The 1,2-nitroamides of general formula XXII may be prepared by the coupling of a 1,2-nitroamine of general formula XIII with an acid chloride of general formula XXIII ##STR20## wherein R, R.sup.5, R.sup.6, R.sup.7 and B are as defined in general formula I, in an aprotic solvent and in the presence of a suitable base such as, for example, triethylamine. Alternatively, the reaction may be conducted utilising an acid anhydride of general formula XXIV ##STR21## wherein R, R.sup.5, R.sup.6, R.sup.7 and B are as defined in general formula I. Another procedure for preparing 1,2-nitroamides of general formula XXII involves reaction of a 1,2-nitroamine of general formula XIII with a carboxylic acid of general formula XXV ##STR22## wherein R, R.sup.5, R.sup.6, R.sup.7 and B are as defined in general formula I, in the presence of a coupling reagent (e.g. 1,3-dicyclohexylcarbodiimide). Acid chlorides of general formula XXIII, acid anhydrides of general formula XXIV and carboxylic acids of general formula XXV may be prepared from carbonyl derivatives of general formula XXI wherein R.sup.4 is hydrogen by procedures known to those skilled in the art.
The appropriate solvents employed in the above reactions are solvents wherein the reactants are soluble but do not react with the reactants. The preferred solvents vary from reaction to reaction and are readily ascertained by one of ordinary skill in the art.
Compounds of general formulae II, III and IV, XVII are valuable intermediates in the preparation of compounds of general formula I, as are other novel compounds specifically or generically disclosed herein. According to a third aspect of the invention, there is therefore provided a compound of general formula II. According to a fourth aspect of the invention, there is provided a compound of general formula III. According to a fifth aspect of the invention, there is provided a compound of general formula IV. According to a sixth aspect of the invention, there is provided a compound of general formula XVII.
This invention also relates to a method of treatment for patients (or animals including mammalian animals raised in the dairy, meat, or fur trade or as pets) suffering from disorders or diseases which can be attributed to PAF as previously described, and more specifically, a method of treatment involving the administration of PAF antagonists of general formula I as the active ingredient. In addition to the treatment of warm blooded animals such as mice, rats, horses, cattle, pigs, sheep, dogs, cats, etc., the compounds of the invention are effective in the treatment of humans.
According to a seventh aspect of the invention there is provided a compound of general formula I for use in human or veterinary medicine particularly in the management of diseases mediated by PAF; compounds of general formula I can be used among other things to reduce inflammation and pain, to correct respiratory, cardiovascular, and intravascular alterations or disorders, and to regulate the activation or coagulation of platelets, to correct hypotension during shock, the pathogenesis of immune complex deposition and smooth muscle contractions.
According to an eighth aspect of the invention there is provided the use of a compound of general formula I in the preparation of an agent for the treatment of PAF-mediated diseases, and/or the treatment 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 and any other condition in which PAF is implicated.
Compounds of general formula (I) may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used-herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
According to a ninth aspect of the invention there is provided a pharmaceutical or veterinary formulation comprising a compound of general formula I and a pharmaceutically and/or veterinarily acceptable carrier. One or more compounds of general formula I may be present in association with one or more non-toxic pharmaceutically and/or veterinarily acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin, capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic monoor diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical application to the skin compounds of general formula I may be made up into a cream, ointment, jelly, solution or suspension etc. Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics such as the British Pharmacopoeia.
For topical applications to the eye, compounds of general formula I may be made up into a solution or suspension in a suitable sterile aqueous or non-aqueous vehicle. Additives, for instance buffers, preservatives including bactericidal and fungicidal agents, such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorohexidine, and thickening agents such as hypromellose may also be included.
Compounds of general formula I may be administered parenterally in a sterile medium. The drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
Compounds of general formula I may be used for the treatment of the respiratory tract by nasal or bucal administration of, for example, aerosols or sprays which can disperse the pharmacological active ingredient in the form of a powder or in the form of drops of a solution or suspension. Pharmaceutical compositions with powder-dispersing properties usually contain, in addition to the active ingredient, a liquid propellant with a boiling point below room temperature and, if desired, adjuncts, such as liquid or solid non-ionic or anionic surfactants and/or diluents.
Pharmaceutical compositions in which the pharmacological active ingredient is in solution contain, in addition to this, a suitable propellant, and furthermore, if necessary, an additional solvent and/or a stabiliser. Instead of the propellant, compressed air can also be used, it being possible for this to be produced as required by means of a suitable compression and expansion device.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 1.0 mg to about 3.5 g per patient per day) The dosage employed for the topical administration will, of course, depend on the size of the area being treated. For the eyes each dose will be typically in the range from 10 to 100 mg of the drug.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
It has been found that the compounds of general formula I exhibit in vitro antagonistic activities with respect to PAF. Compounds of general formula I 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 I 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 I to reverse the hypotension caused by an infusion of PAF in rats was measured according to Pharmacology Example 2.
The following examples illustrate the invention, but are not intended to limit the scope in any way.
The following abbreviations have been used in the Examples:
DCM - Dichloromethane
DIPE - Diisopropylether
DMF - N,N-Dimethylformamide
NBS - N-Bromosuccinimide
THF - Tetrahydrofuran
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745471 |
Aug 1991 |
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Patent Grant
5274094
