| Full Text |
The invention is concerned with novel heteroary] fused cyclic amines of formula (I),
wherein
A is a heteroary! ring which is a monocyclic or bicyclic aromatic ring of 5 Lo 12 ring atoms, containing one, two, or three ring heteroatoms selected from N, O, and S, the remaining ring atoms being C, one or two carbon atoms of said ring being optionally replaced with a carbonyl group;
R' and R-
are independently hydrogen, C]^ alkyl, C1-6, alkoxy, fluoro Ci-s alkoxy, hydroxy Ci.fialkoxy, C^^salkoxy C]_6alkoxy, mono or di Ci-salkyl substituted amino Ci-ii alkoxy, halogen, cyano, nitro, -N(R')-CO-{Ci-fi alkyl optionally substituted by one or more fluorine atoms), in which R is hydrogen. Ci^, alkyl or fluoro Ci-p alkyi, -N(R')-CO-0-(C,_fi alkyl optionally substituted by one or more fluorine atoms), in which R' is hydrogen, Ci^^ alkyl or fluoro Ci_6 alkyl. -N(R')-CO-N(R") (R'"), in which R\ R" and R"' are independently hydrogen. Cue alkyl or fluoro Cy-t, alkyl or -N(R')-S02-(Ci-6 alkyl optionally substituted by one or more fluorine atoms), in which R" is hydrogen. Ci_6 alkyl or fluoro Ci^i alkyl or
R' and R'
are independently -SOrN(R')(R"), -CfO)-N(R'KR") or -N{R")(R"). in which R'
and R" are independently hydrogen, C^ alky] or fluoro C|.6 alkyl or R' and R', together with the nitrogen atom to which they are attached, form helerocycyi;
X' is -qOHCfl-6 aIkylene)-NR^-(Q,.fi alkylene)-, -(Co^ alkylene)-C(0)-NR'-(Co-f, alkylene)-, -
(G,_6 alkylene)- or -^(O) ^^ .
X^ is arylene, heleroarylene or heterocyclylene, said arylene, heteroarylene and heterocyclylen being optionally substituted by one or more substiluents independently selected from the group consislingofC|.ft alkyl, Ci^alkoxy, halogen, cyano, nitro, amino, -N(R')-CO-(Ci-fi alkyl opfionally substituted by one or more fluorine atoms), in which R' is hydrogen. Ci-^ alkyl or fluoro C].6 alkyl, -N(R')-CO-0-(Cj^i alkyl optionally substituted by one or more fluorine atoms), in which R' is hydrogen, C,^ alky! or fluoro Ci-f, alkyl, -N(R")-CO-N(R") (R'"), in which R', R'" and R'" are independently hydrogen. C,.,, alkyl or fluoroCi.6 alkyl, -C{0)-N(R')(R"), in which R" and R" are independently hydrogen, C]^ alkyl or fluoro Ci^^ alkyl, or R' and R", together with the nitrogen atom to which they are attached, form heterocycyl, -NR'R", in which R' and R" are independently hydrogen, C] j; alkyl or fluoro Ci-6 alkyl, or R' and R", together with the nitrogen atom to which they are attached, form
heterocycyl, wherein R' and R" are independently Ci-6 alkyl or
fluoro Ci-ft alkyl, or R' and R'\ together with the nitrogen atom to which thev
•^^■»
are attached, form heterocyclyl, ° wherein R and R ' are
independently Ci-*, alkyl or fluoro Ci-e alkyl, or R' and R", together with the
11
nitrogen atom to which they are attached, form heterocyclyl.
in which R1 is fluoro CM alkyl and ^ , in which R" is fluoro C,.^
alkyi,
and one or two carbon atoms of said aryiene, heteroarylene or heterocyclylene being optionally replaced with a carbonyl group;
X' is hydrogen, aryl, heteroaryl or heterocyclyl, said aryl, heteroaryi and heterocyclyl being optionally substituted by one or more substituents independently selected from the group consisting of Ci^ alkyi, Cw. alkoxy, halogen, cyano, nitro, amino, mono-C,-f, aikyl substituted amino, di-Ci^ alkyl substituted amino, mono-C]^ aikyl substituted amino-Ci_fi alkyl, di-Ci.ft alkyl substituted amino-C,-6 alkyl, -S02-C,-6 alkyl, -SO2-NH2, -SO2-NH-C1.6 alkyl and -S03-N(C,^, alkyl)2,
and one or two carbon atoms of said aryl, heteroaryl and heterocyclyl being optionally replaced with a carbonyl group;
R" is hydTOgen or C1-6alkyl;
Y' is --C(0)-NR-'H:C(M> alkyleneK -(Q^ alkylene)-NR'-C(O)-{Co-E, alkylene)- or Qp^ alkylene;
Y^ is aryiene, heteroarylene or heterocyclylene, said aryiene, heteroarylene and heterocyclylene being oplionaily substituted by one or more substituents independently selected from the group consisting of Ci-s alkyl. Ci-6 alkoxy, halogen, cyano, nitro, amino, -■N(R')-CO-(C|^ alkyl optionally substituted by one or more fluorine atoms), in which R' is hydrogen, Cj^alkyl or fluoro Cij^ alkyl, -N(R')-CO-0-(Ci^ alkyl optionally substituted by one or more fluorine atoms), in which R' is hydrogen, Ci^alkyl orfluoroCi.fi alky], -N(R')-CO-N(R") (R'")' in which R', R" and R'" are independently hydrogen, Cusalkyl or fluoro C,.6 alkyl, -C(0>N(R')CR"), in which R' and R" are independently hydrogen, Ci-f, alkyl or halo Ci.f, alkyl, or R' and R"\ together with the nitrogen atom to which they are attached, form heteiocycyl, -NR'R", in which R' and R" are independently hydrogen, C1.6 aikyl or halo C)-fi alkyl, or R' and
and one OT two carbon atoms of said arylene, heleioarylene or heierocyclylene being optionally yeplaced with a carbonyl group;
Y is hydrogen, aryl, heteroaryl or heterocyclyl, said aryl, heteroaryl and helerocyclyl being optionally substiiuted by one or more substiluents independently selecled from the group consisting of d-,; alkyl, Ci ^ alkoxy, halogen, cyano, nitro, amino, mDno-Ci.rt aikyl substituted amino, di-C|^ alkyl substituted amino, mono-Cj^; alkyl substituted amino-C|^, alkyl, di-Cj-c alkyl substituted amino-Ci-c alkyl, -SO2-C1.6 alkyl, .S03-NH:, -SO:-NH-Ci.r, alkyl and -S02-N(Ci-fi alkyl)2, and one or two carbon atoms of said aryl, heteroaryl and heterocyclyl being optionally replaced with a carbonyl group;
Z is attached to the same carbon atom as -Y'-Y^-Y"\ and hydrogen or C]^, alkyl;
n is 0, 1 or 2;
m is 0, 1 or 2;
m+n is 2 or 3;
0 is an integer from 1 to 5;
and prodrugs and phannaceutically acceptable salts thereof.
Further, the invention is concerned with a process and an intermediaie for the manufacture of the above compounds, pharmaceutical preparations which contain such compounds, the use of these compounds for the production of pharmaceutical preparations as well as a process for the manufacture of the intermediate.
The compounds of formula (I) are active compounds and inhibit the coagulation factor Xa. These compounds consequently influence blood coagulation. They therefore inhibit the formation of thrombin and can be used for the treatment and/or prevention of thrombotic disorders, such as amongst others, arterial and venous thrombosis, deep vein thrombosis, peripheral arterial occlusive disease (PAOD), unstable angina pectoris, myocardial infarction, coronary artery disease, pulmonary embolism, stroke (cerebral thrombosis) due to atrial fibrillation, inflammation and arteriosclerosis. They have potentially benefit in the treatment of acute vessel closure associated with thTomboiylic therapy and restenosis, e.g. after transluminal coronary angioplasty (PTCA) or bypass grafting of the coronary or peripheral arteries and in the maintenance of vascular access patency in long term hemodialysis patients. F.Xa inhibitors of this invention may form pari of a combination therapy with an anticoagulant with a different mode of action or with a platelet aggregation inhibitor or with a thrombolytic agent. Furthermore, these compounds have an effect on tumour cells and prevent metastases. They can therefore also be used as antitumour agents.
Other inhibitors of factor Xa had previously been suggested for the inhibition of the formation of thrombin and for the treatment of related diseases. However, there is still a need for novel factor Xa inhibitors which exhibit improved pharmacological properties, e.g. an improved selectivity towards thrombin.
The present invention provides novel compounds of formula (1) which are factor Xa inhibitors. The compounds of the present invention unexpectedly inhibit coagulation factor Xa and also exhibit improved pharmacological properties compared to other compounds already known in the art.
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term "haiogen" or "halo" means fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred, and fluorine and chlorine being more preferred.
The term "'C1-6 alkyl", alone or in combination with other groups, means a branched or straight-chain monovalent alkyl radical, having one to six carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-buEyl, s-butyl, l-butyl. C1-4 alkyl is more preferred.
The terra "Qi-h alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms or a bond when C is 0, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene.
The term "C]-fi alkoxy", alone or in combination with other groups, means the group R"-0-, wherein R' is a Ci^ alkyl.
The term "hydroxy C1-6 alkoxy" means Ci-s alkoxy substituted by one or more hydroxy group.
The term "fluoro C].ft alkyl'" or "fluoro Ci-s alkoxy" means C]^, alkyl or C,_f, alkoxy substituted by one or more fluorine atoms, preferably one to three fluorine atoms.
The term "aryl" means phenyl or naphtltyl. Phenyl is preferred.
The term "aryjene" , alone or in combination with other groups, means a divalent aryl group as defined above. 1,4-phenylene is preferred.
The term "helerocyciyl", alone or combination with other groups, means non-aromatic mono- or bi-cyclic radicals of three to eight ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0)jj (where n is an integer from 0 to 2), the remaining ring atoms being C. Monocyclic radicals are preferred.
The term "heterocyclylene", alone or combination with other groups, means a divalent heterocyclyl group as defined above.
The term "heteroaryl", alone or combination with other groups, means a monocyclic or bicycUc aromatic radical of 5 to 12 ring atoms, containing one, two, or three ring
heteroatoms selected from N, O, and S, the remaining ring atoms being C, one or two carbon atoms of said ring being optionally replaced with a carhonyl group, with the understanding that the attachment point of the heteroaryl radical will be on an aiomalic ring. Monocyclic radicals are preferred.
The term "heteroarylene", alone or combination with other groups, means a divalent heteroaryl group as defined above.
The term "bicyclic aromatic ring" or "bicyclic arotnatic radical" contains both an aromatic monocyclic ring fused by another aromatic monocyclic ring and an aromatic monocyclic ring fused by a non-aromatic monocyclic ring. When the term "bicyclic aromatic ring" or "bicyclic aormatic radical' is used in the context of the definition of "heteroaryl" or "heteroaryl ring", at least one heteroalom must exist in the aromatic ring as a ring member. When the heteroaryl ring as A ring in formula I is a bicyclic aromatic ring, and this bicyclic aromatic ring is an aromatic monocyclic ring fused by a non-aromatic monocyclic ring, then the aromatic ring is directly fused to the nitrogen containing ring to which -Y'-Y^-Y\ -X'-X^-X-"* and Z are attached.
Preferred radicals for the chemical groups whose definitions are given above are those specifically exemplified in Examples.
Compounds of formula (I) can form pharmaceutically acceptable acid addition salts. Examples of such pharmaceutically acceptable salts are salts of compounds of formula (I) with physiologically compatible mineral acids, such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The term "pharmaceutically acceptable salts" refers to such salts. Compounds of formula (I) in which a COOH group is present can further form salts with bases. Examples of such salts are alkaline, earth-alkaline and ammonium salts such as e.g. Na-, K-, Ca- and trimelhyiammoniumsalt. The term "pharmaceutically acceptable salts" also refers to such salts. Acid addition salts as described above are preferred.
"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it Hne*; nnt for example, "aryl group
optionally substituted with an alky] group" means thai the alky] may but need not be present, and the description includes situations where the aryj group is subslituied with an alkyi group and situations where the aryl group is not substituted with the alkyl group.
"Phaimaceutically acceptable excipient" means an excipienl that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient.
Compounds that have the same molecular Formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are lermed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimf>osable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enanliomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "raceraic mixture".
The compounds of formula (I) can possess one or more asymmetric centers. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are we[l-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 1992).
While the broadest definition of this invention is described before, certain compounds of formula (I) are preferred.
i) A preferred compound of the invention is a compound of formula (I) wherein A is a heleroaryl ring which is a monocyclic aromatic ring of 5 or 6 ring atoms, containing one or two, preferably two ring nitrogen atoms.
ii) Another preferred compound of the invention is a compound of formula (I) which is
wherein X', X^ X^ Y' , Y\ Y\ R' and R^ are as defined before. -Y'-Y'-Y'^ is preferably located at 4 position of the pyrrolopyrazole ring.
iv) Another preferred compound of the invention is a compound of formula (1) wherein X^ is arylene or heteroarylene, said arylene and heteroarylene being optionally substituted by one or more substituents independently selected from the group consisting of C]^ alkoxy and halogen, and X^ is hydrogen. Preferably -X--X"' forms phenyl or pyridyl, said phenyl and pyridyl being optionally substituted by one or more same or different halogen atoms. More preferably -X^-X^ forms 4-chlorQphenyl or 5-chloropyridyn-2-yI.
v) Another preferred compound of the invention is a compound of formula (I) wherein Y' is -(C,,^ alkyIene)-C(0>-NR-VCo* alkylene)-, preferably -C(0)-NR-^- in which R"' is as defined before, more preferably -C(0)-NH-.
vi) Another preferred compound of the invention is a compound of formula (I) wherein Y' is 1,4-phenylene optionally substituted by one or more same or different halogen atoms, preferably 1,4-phenylene optionally substituted by one or more fluorine aloms, more preferably 2-fluoro-l,4 phenylene,
vii) Another preferred compound of the invention is a compound of formula (I) wherein Y is heteroaryl optionally substituted by one or more subsfituents independently selected from the group consisting of Ci-6 alkyi, C}^ alkoxy, halogen, cyano, nitro, amino, mono-Ci^ alkyi substituted amino, di-Ci^ alkyl substituted amino, mono-C]_(, alkyl substituted amino-Ci^ alkyl, di-Cj-^ alkyl substituted amino-Ci-ft alkyi, -SO^-Ci* alkyl, -SO2-NH2, -S02-NH-C|^ alkyl and -S02-N(CM alkyl)2, and one or two carbon atoms of said heteroaryl being optionally replaced with a carbonyl group. Preferably Y"' is unsubstituted heteroaryl which is a monocyclic aromatic ring of 5 or 6 ring atoms, containing one or two, preferably one ring nitrogen atom, and one carbon atom of said heteroaryl being optionally replaced with a carbonyl group. Preferably the ring nitrogen atom of the heteroaryl is directly attached to Y^, and one of the ring carbon atoms next to said ring nitrogen atom is replaced with a carbonyl group. Y"* is especially 2-oxo-2H-pyridyn-l-yl.
viii) Another preferred compound of the invention is a compound of formula (I) wherein R' and R^ is hydrogen, and the other is Ci ^ alkyl.
ix) Another preferred compound of the invention is a compound of formula (i) wherein Z is hydrogen.
x) Another preferred compound of the invention is a compound of formula (I) which is
xi) Particularly prefened compounds of the present invenlion are:
(R)-l-Methyl-4,6-dihydrQ-!H-pyrrolof3,4-c]pyrazole-4,5-dicarboxy!icacid 5-[(4-cliloro-phenyi)-amide]4-{[2-fluorQ-4-(2-oxo-2H-pyridin-l-y!)-phenyl]-a.mide),
(R)-l-Methyl-4,6-diliydro-lH-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylicacid 5-[(4-cliloro-phenyl)-amidel 4-{[4-(2-oxo-2H-pyrazin-l-yl)-phenyl]-amide},
(R)-l-Methyl-4-,6-dihydio-lH-pyiTo!o[3,4-c]pyrazoIe-4,5-dicaTboxy!icacid5-{{4-chloro-phenyl)-aniide] 4-{[2-fluoro-4-(2-oxo-2H-pyrazin-l-yl)-pheTiyI]-aniide},
(R)-l-Methyl-4,6-dihydro-lH-pyiTolo[3,4-c]pyrazole-4,5-dicarboxyIicacid5-[(4-chloro-phenyl)-amide] 4-{[4-(2-oxo-2H-pyridin-l-yl)-pheiiyI]-amide},
(R)-l-Methyl-4,6-difiydro-lH-pyrrolo[3,4-c]pyra2oJe-4,5-dicarbo>:ylicacid 5-[(4-chloro-phenyl)-amide] 4-{[2,6-difluoro-4-(2-oxo-2H-pyridiii-l-yl)-phenyl]-amide}.
The compounds of the present invention can be prepared, for example, by the general synthetic procedures described below.
General Synthetic Procedures
Abbreviations
AcOEf. Ethyl acetate
Boc^O : Di-terE-buty]-dicarbonate
BOP: Benzotriazolyi-N-oxy-tris{dimetfiylamino)-phosphonium hexafluorophosphaie
BOPCl: Bis-(2-oxo-3-oxazoIidinyl)-phosphinic acid chloride
tBuOMe: l-Butyldimethylether
DIPEA: Diisopropyl ethyl amine
DMA: N,N-Diinethylacetamide
DMAP-. 4-DimethykniinQpyridine
DME; 1,2-Dimethoxyethan e
DMF: N,N-Dimethylformamide
DMSO: Dimethylsulfoxide
EDCI: N-(3-DimetylamitiQprQpy!)-N'-ethyl-carbodiimide hydrochloride
HATU; l-[Bis(dimethy]ainino)methyiene]-lH-l,2,3-triazolo[4,5-b]pyridiiiium 3-oxide, hexa-fluorophosphate
HOBT: l-Hydroxybenzotriazole
MeOH; Methanol
TEA: Triethylamine
TFA: Trifluoroacetic acid
THF: Tetrahydfofuran
General procedures
Amidation: The intermediate carboxylic acid is reacted with an amine HjNY'Y-^ in a suitable solvent such as CH2CI2, DMF, acetonitrile, THF. Activation is effected by an amide coupling reagent such as BOP, BOP-Cl, HATU/HOBT, EDCI/DMAP in the presence of a base like TEA, DIPEA, N-methylmorpholine etc. at 0 "C lo 50 "C. Reaction times ranged from 1 hr - 72 hrs. Preferred conditions are DMF, BOPCl and DIPEA.
Deprotection :The intermediate is treated with a mineral acid such as HCl, HBr, H2SO4 or H_iP04 or a carbonic acid, in a solvent such as CHjCb, dioxane or HOAc at 0 to 60 °C. Preferred conditions are 4N HCI in dioxane.
Acylation : The intermediate is reacted with a substituted phenyl isocyanate in a suitable solvent such as DMF, DMSO, THF at 0 to 120 °C. Preferred conditions are OMF at 80
As described above, fhe compounds of formula (I) are active compounds and inhibit the coagulation factor Xa. These compounds consequently influence both platelet activation which is induced by this factor and plasmatic blood coagulation. They therefore inhibit the fonnation of thrombi and can be used for the treatment and/or prevention of thrombotic disorders, such as, amongst others, arterial and venous thrombosis, deep vein thrombosis, peripheral arterial occlusive disease (PAOD), unstable angina pectoris, myocardial infarction, coronary artery disease, pulmonary embolism, stroke (cerebral thrombosis) due to atrial fibrillation, inflammation and arteriosclerosis. The compounds
of Ihe present invention can also be used in the treatment of acute vessel closure associated with thrombolytic therapy and restenosis, e.g. after transluminal coronary angioplasty (PTCA) or bypass grafting of the coronary or peripheral arteries and in the maintenance of vascular access patency in long term hemodialysis patients. F.Xa inhibitors of this invention may form part of a combination therapy with an anticoagulant with a different mode of action or with a platelet aggregation inhibitor or with a thrombolytic agent. Furthermore, these compounds have an effect on tumour cells and prevent metastases. They can therefore also be used as antitumour agents.
Prevention and/or treatment of thrombotic disorders, particularly arterial or deep vein thrombosis, is the preferred indication.
The invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable excipient.
The invention likewise embraces compounds as described above for use as therapeutically active substances, especially as therapeutically active substances for the treatment and/or prophylaxis of diseases which are associated with the coagulation factor Xa, particularly as therapeutically active substances for the treatment and/or prophylaxis of thrombotic disorders, arterial thrombosis, venous thrombosis, deep vein thrombosis, peripheral arterial occlusive disease, unstable angina pectoris, myocardial infarction, coronary artery disease, pulmonary embolism, stroke due to atrial fibrillation, inflammation, arteriosclerosis, acute vessel closure associated with thrombolytic therapy or restenosis, and/or tumour.
In another preferred embodiment, Ihe invention relates to a method for the therapeutic and/or prophylactic treatment of diseases which are associated with the coagulation factor Xa, particularly for the therapeutic and/or prophylactic treatment of thrombotic disorders, arterial thrombosis, venous thrombosis, deep vein thrombosis, peripheral arterial occlusive disease, unstable angina pectoris, myocardial infarction, coronary artery disease, pulmonary embolism, stroke due to atrial fibrillation, inflammation, arteriosclerosis, acute vessel closure associated with thrombolytic therapy or restenosis, and/or tumour, which method comprises administering a compound as defined above to a human being or animal.
The invention also embraces the use of compounds as defined above for the therapeutic and/or prophylactic treatment of diseases which are associated with the coagulation factor Xa, particularly for the therapeutic and/or prophylactic treatment of thrombotic disorders, arterial thrombosis, venous thrombosis, deep vein thrombosis, peripheral arterial occlusive disease, unstable angina pectoris, myocardial infarction, coronary artery disease, pulmonary embolism, stroke due to atrial fibrillation, inflammation, arteriosclerosis, acute vessel closure associated with thrombolytic therapy or restenosis, and/or tumour.
The irivention also relates to the use of compounds as described above for the preparation of medicaments for the therapeutic and/or prophylactic treatment of diseases which are asscnciated with the coagulation factor Xa, particularly for the therapeutic and/or prophylactic treatment of thrombotic disorders, arterial thrombosis, venous thrombosis, deep vein thrombosis, peripheral arterial occlusive disease, unstable angina pectoris, myocardial infarction, coronary artery disease, pulmonary embolism, stroke due to atrial fibrillation, inflammation, arteriosclerosis, acute vessel closure associated with thrombolytic therapy or restenosis, and/or tumour. Such medicaments comprise a compound as described above.
The invention also relates to the process and the intermediates for manufacturing the compounds of formula (I) as well as the process for manufacturing the intermediates.
The inhibition of the coagulation factor Xa by the compounds of the present invention can be demonstrated with the aid of a chroraogenic peptide substrate assay as described hereinafter.
Factor Xa activity was measured spectrophotometrically in microliter plates in a final volume of 150 |il using the following conditions: Inhibition of human factor Xa (Enzyme Research Laboratories) was tested at an enzyme concentration of 3 nM using Ihe chromogenic substrate S-2222 (Chromogenix AB, Molndal, Sweden) at 200 nM. The reaction kinetics of the enzyme and the substrate were linear with both time and the enzyme concentration. The inhibitors were dissolved in DMSO and tested al various concentrations up to 100 |iM. The inhibitors were diluted using HNPT buffer consisting of HEPES lOOmM, NaCl 140mM, PEG 6000 0.1% and Tween 80 0.02%, pH 7.8. The cleavage of S-2222 by human factor Xa was followed at 405 nm for 5 minutes at room
temperature. The velocity of the reaction was determined by the autoreader from the slope of the linear regression fit to 7 time points (1 minule). The initial velocily for each inhibitor concentration was determined by the slope of at least 4 time points in the linear phase by a linear regression fit (mOD/min"). Apparent dissociation constants Ki were calculated according lo Cheng and Prusoff [Cheng, Y. C; Prusoff, W. H. Relationship between the inhibition constant (Kj) and the concentration of the inhibitor that causes 50 percent inhibition (IC50) of an enzyme reaction. Biochem. Pharmacol. 1973, 22, 3099-3108.] based on the IC50 and the respective Km, determined previously (Ki = ICso/ (1 +S/K,n)). The Kn, for the substrate used was determined under the conditions of the lest with at least 5 substrate concentrations ranging from 0.5 to 15 times K^. [Lotlenberg R, Hall JA, Blinder M, Binder EP, Jackson CM., The action of thrombin on peptide p-nitroanilide substrates. Substrate selectivity and examination of hydrolysis under different reaction conditions. Biochim Biophys Acta. 1983 Feb 15; 742(3):539-57]. According to Eadie [Eadie G.S. The inhibition of chohnesterase by physostigmine and prostigmine. J. Biol. Chem. 1942, 146, 85-93.], the K„ for S-2222 amounted to 613 \iU.
The activity of the low molecular weight substances can, moreover, be characterized in the "prothrombin time" (PT) clotting test. The substances are prepared as a 10 mM solution in DMSO and thereafter made up to the desired dilution in the same solvent. Thereafter, 0.25 ml of human plasma (obtained from whole blood anticoagulaied with 1/10 volume of 108 mM Na citrate) was placed in the instrument-specific sample container. In each case 5 )il of each dilution of the substance-dilution series was then mixed with the plasma provided. This plasma/inhibitor mixture was incubated at 37 "C for 2 minutes. Thereafter, there were pipetted to the semi-automatic device (ACL, Automated Coagulation Laboratory (Instrument Laboratory)) 50 fxl of plasma/ inhibitor mixture in the measurement container. The clotting reaction was initiated by the addition of 0.1 ml of Dade® Innovin® (recombinant human tissue factor combined with calcium buffer and synthetic phospholipids, Dade Behring, Inc., Cat. B4212-50). The time up to the fibrin cross-linking was determined photooptically from the ACL. The inhibitor concentration, which brought about a doubling of the PT clotting time, was determined by fitting the data to an exponential regression (XLfit).
The compounds of the present invention can furthermore be characterised by the Activated Partial Thromboplastin time (aPTT). This coagulation test can e.g. be run on
the ACL 300 Coagulation System (Instrumentation Laboratory) automatic analyzer. The substances are prepared as a 10 mM solution in DMSO and thereafter made up to the desired dilution in the same solvent. The test is performed with the Dade® Actin® FS Activated PTT reagent {purified soy phosphatides in 1.0X10"'M ellagic acid, stabilizers and preservative, Dade Behring, Inc., Cat. B4218-100). Thereafter, 0.25 mi aliquots of human plasma (obtained from whole blood anticoaguiated with 1/10 volume of 108 mM Na citrate) are spiked with 5 |il of lesl compound in at least 6 concentrations. 50 \x\ plasma al 4 "C containing 1/50 vol. inhibitor in solvent are incubated with 50 |il Dade® Actin® FS Activated FIT reagent in water at 37 °C for 3 min., then 50 \il CaCl2.2H20 25 mM in water al 37 "C are added. The time up to the fibrin cross-linking was determined photooptically from the ACL. The inhibitor concentration, which brought about a doubling of the APTT clotting time, was determined by fitting the data to an exponential regression (XLfit).
The Ki values of the active compounds of the present invention preferably amount to about 0.001 to 50 ^JM, especially about 0.001 to 1 [JM. The PT values preferably amount to about 0.5 to 100 ^M, especially to about 0.5 to 10 fiM. The aPTT values preferably amount to about 0.5 to 100 fxM, especially to about 0.5 to 10 |iM.
The compounds of formula (I) and/or their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of
injection solutions or suspensions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils. Oral administration is preferred.
The production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula 1 and/or their pharmaceulicaily acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, com starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no caniers might, however, be required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar. Suitable earner materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
Usual stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
The dosage of the compounds of formula (I) can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitied to the individual requireinenis in each particular case. For adult patients a daily dosage of about 1 to 1000 mg, especially about 1 to 300 mg, comes into consideration. Depending on severity of the disease and
the precise pharmacokinetic profile the compound could be administered with one or several daily dosage units, e.g. in 1 to 3 dosage units.
The pharmaceutical preparations conveniently contain about 1-500 mg, preferably 1-100 mg, of a compound of formula (I).
The following Examples serve to illustrate the present invention in more detail. They are, however, not intended to limit its scope in any manner.
Examples
Example 1
(R)-1 -Methy 1-4,6-dihydro-1 H-pyrroIo[3,4-c)pyra2ole-4,5-dicarboxylic aci d 5 - [(4-ch loro-phenyl)-amidej-4-{[2-nuoro-4-(2-oxo-2H-pyridin-l-yl)-phenyl]-amide}
A (R)-4-[2-Fluoro-4-(2^oxo-2H-pyridin-l-yl)-phenyicarbamoyI]-l-methy]-4,6-dihydro-lH-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester
To a solution of (R)-l-methy]-4,6-dihyclro-lH-pyiTolo[3,4-c]pyra2ole-4,5-dicarboxylic acid 5-tert-butyI ester (478 mg, described in US2002/0193399), l-(4-amino-3-fluoro-phenyI)-lH-pyridin-2-one (365 mg; CAS 536747-52-1) and DIPEA {0.46 ml) in 20 mi acetonitrile and 2 ml DMF was added BOPCl (1.366 g). The reaction mixture was stirred for 24h at rt, diluted with AcOEt and washed with IM HCI, IM NaOH and brine. The organic layers were dried over magnesium sulfate, evaporated and purified by chromatography (silica gel; AcOEt) to deliver the title compound as a yellow oil (510 mg). MS: 454.5 (M+H)*
B (R)-l-Methyl-l,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazoIe-4-carboxylic acid [2-fluoro-4-(2-Qxo-2H-pyridin-1 -yl)-phenyl] -amide
A solution of (R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-phenylcarbamoyl]-l-methyl-4,6-dihydro-lH-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (258 mg) in 1 mi 4M HCI/dioxane was stirred 18 h at rt. The reaction mixture was portionned between AcOEt and IM NaOH / ice. The organic layers were washed with brine, dried over magnesium sulfate and evaporated to deliver a white residue (115 mg) of the title compound. MS: 354.3 (M+H)*
C (R)-l-Methyl-4,6-dihydro-lH-pyrrolo[3,4-c]pyrazole-4,5-dicarboxyIic acid 5-[(4-chloro-pheryl)-aniide] 4-{[2-fluoro-4-(2-oxo-2H-pyndiii-l-yl)-phei)yl]-amide}
To a solution of (R)-l-methyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazo]e-4-carboxylie acid [2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-phenyI]-amide (83 rag) in 2 ml dichloromethane at CC, 4-chlorophenyl-isocyanate (72 mg) was added. The reaction mixture was kept for 2 hrs under ice cooling, then heptane was added and the precipitate filtrated. (R)-l-Me(I[yJ-4,6-dihydro-IH-pyrroJo[3,4-cJpyra2ote-4,5-dicarbox-y]ic acid 5-l(4-chloro-phenyl)-amide] 4-{[2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-phenyl]-atnide} was tjbtained as a white solid (119 mg). MS: 507.2 (M+H)^
Example 2
(R)-l-Methyl-4,6-dihydro-lH-pyrrolo[3,4-c]pyrazole-4,5-dicarboxyIic acid 4-{[2-f]uoro-4-(2-oxo-2H-pyridin-l-yl)-phenyI]-amide} 5-[(4-methoxy-phenyl)-amide7
Using the same procedure described in example 1 and 4-methoxyphenyi-isocyanate as reagent in (he last step, the title compound was delivered as a white solid (29 mg). MS: 503.1 (M+H)*
Example 3
(R)-l-Methyl-4,6-dihydro-lH-pyrTolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(5-chloro-pyridin-2-yl)-amide] 4-{[2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-pheny]]-amide}
A solution of (R)-l-Methyl-l,4,5,6-tetrahydro-pyiTolo[3,4-c]pyrazole-4-caTboxylic acid [2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-pheny]]-amide (example IB), 36 mg), (5-chloro-pyridin-2-yl)-carbamic acid 4-nitro-phenyl ester (44 mg; CAS 536746-34-6) and DIPEA (0.042 ml) in 2 ml DMF was heated for 4hrs at 90°C. The reaction mixture was cooled, diluted with AcOEt, washed twofold with IM NaOH, IM HCI and brine. The aqueous layers were extracted with AcOEt, dried over magnesium sulfate, evaporated and purified by chromaiography (silica geJ, AcOEt) to yield the title compound as a white solid (8 mg). MS: 508.3 (M+H)*
Example 4
(R)-5-(lH-lndole-6-carbonyl)-l-methyl-l,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole-4-carboxylic acid [2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-phenyl]-amide
A solution of (R)-l-methyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyra2oIe-4-carboxylie acid [2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-phenyl]-amide (example IB), 38 mg), 6-indolecarboxylic acid (22 mg), 0.03 ml (DIPEA) and BOPCl (51 mg) in 2 ml acetonitrile was stirred for 2hrs at 0°C. A consecutive basic and acidic work up delivered a yellow oil which was purified by chromatography (silica gel, AcOEt). (R)-5-(lH-Indole-6-carbonyl)-l-methyl-l,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole-4-carboxylic acid [2-fluoro-4-(2-Dxo-2H-pyridin-l-yI)-pbeny]]-amide was obtained as a white solid (13 mg). MS: 497.0 (M+H)^
Using the same procedure described in example 1, but starting from (S)-l-methyl-4,6-dihydro-lH-pyrrolo[3,4-c]pyrazoIe-4,5-dicarboxylic acid 5-tert-bulyl ester, the title compound was obtained as a white solid (14 mg). MS: 507.2 (M+H)""
Using the same procedure described in example 1 (with l-(4-amino-phenyl)-lH-pyTazin-2-one, CAS 4444002-64-6) the title compound was obtained as a white solid (35 mg). MS: 490.8 (M+H)*
Example 7
1-Methyl-4,6-dihydro-lH-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(4-chloTO-phenyl)-amide] 4-{[2-f]uoro-4-(2-oxo-2H-pyrazin-l-yI)-phenyl]-amide}
Using the same procedure described in example 1 using l-(4-amino-3-nuoro-phenyl)-lH-pyTazin-2-one (prepared from 2-fluoro-4-iodoaniline by reaction with lH-pyrazin-2-one, Cu(I)I, N,N'-dimethylethylenediamine and cesium carbonate in dioxane ^t 120 °C), the title compound was obtained as a white solid (15 rag). MS: 508.0 (M+H)"^
Example 8
(R)-l-Methyl-4,6-dihydro-lH-pyrrolo[3,4-c]pyTazole-4,5-dicarboxylic acid 5-t(4-ch]oro-phenyl)-amide] 4-{[2-fluoro-4-(3-oxo-morpho]in-4-yI)-phenyl]-amide}
Using the same procedure described in example 1 (with 4-(4-amino-3-flLioro-phenyI)-morpholin-3-one, CAS 742073-22-9) the title compound was obtained as a white solid (88 mg). MS: 513.3 (M+H)^
Example 9
(R)-l-MethyI-4,6-dihydro-lH-pyrToIo[3,4-c]pyra2ole-4,5-dicarboxyfic acid 5-[(4-chloro-phenyl)-amide] 4-{[4-(2-oxo-2H-pyridin-l-yl)-phenyl]-amide}
Using the same procedure described in example 1 (with l-(4-amino-phenyl)-lH-pyridin-2-one, CAS 13143-47-0) the title compound was obtained as a while solid (25 mg). MS: 489.1 (M-HH)^
Example 10
{R)-l-Methyl-4,6-dihydro-lH-pyiTolo[3,4-c]pyrazole-4,5-dicarboxyIic acid 5-[(3-fluoro-4-methoxy-phenyl)-amide] 4-{[2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-phenyl]-aniide}
Using the same procedure described in example 3 and {3-fluoro-4-methoxy-phenyl)-carbamic acid 4-nitTo-phenyl ester (prepared from 3-fluoro-4-methoxy-aniline by reaction with p-nilropJienyJ chloroioimai and pyridine in dichJoromelhane) the title compound was obtained as a white solid (26 mg). MS: 521.2 (M+H)*
Example 11
(R)-l-Methyl-4,6-dihydro-lH-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(4-chloTo-phenyl)-amide] 5-{[2,6-difluoro-4-(2-oxo-2H-pyridin-l-yI)-phenyl]-amide}
Using the same procedure described in example 1 (with l-(4-amino-3,5-difluoro-
phenyl)-
lH-pyridin-2-one prepared from 4-bromo-2.6-difluoroaniline by reaction with
2-hydroxypyridine, Cu(I)I, potassium carbonate, 8-hydroxyquinoline in DMSO at
150°C) the title compound was obtained as a white solid (110 mg). MS: 525.3 (M+Hf
Example 12
(R)-l-Methyl-4,6-dihydro-lH-pyrTolo[3,4-c]pyrazo]e-4,5-dicarboxylic acid 5-[(5-chioro-pyridin-2-yl)-amide] 4-{[2-fluoro-4-(2-oxo-2H-pyrazin-l-yl)-pheiiyl]-amide}
Using the same procedure described in example 1 (with l-(4-amino-3-fluoro-phenyl)-lH-pyrazin-2-one) and for the last step following the method described in example 3, the title compound was obtained as a white solid (70 mg). MS: 509.5 (M+H)*
Example 13
(R)-l-Methyl-4,6-dihydro-lH-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylie acid 4-{[2-nuoro-4-{3-oxo-morpholin-4-y!)-phenyl]-aniide} 5-[(4-methoxy-phenyl)-amide]
Using the same procedure described in example 1 (with 4-(4-amino-3-fluoro-phenyl)-morpholin-3-one, CAS 742073-22-9) and using 4-methoxyphenyl-isocyanate in the last step, the title compound was obtained as a white solid (33 mg). MS: 507.4 (M-H)"
Example 14
(R)-l-Methyl-4,6-dihydro-lH-pyrrolo(3,4-c]pyrazole-4,5-dicarboxylie acid 5-[(5-chloTO-pyridin-2-yl)-amide] 4-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-amide}
Using the same procedure described in example 1 (with 4"(4-amino-3'fluoTO-phenyl)-morphoIin-3-one, CAS 742073-22-9) and in the last step the procedure described in example 3, the title compound was obtained as a white solid (27 mg). MS: 514.2 (M+H)^
Example 15
(R}-I-Methyi-4,6-dihydro-lH-pyrroio[3,4-c]pyrazoIe-4,5-dicarboxyiic acid 5-[(3-fluoro-4-methoxy-phenyl)-amide] 4-{[2-fluoro-4-(3-oxo-morphoiin-4-yl)-phenyl]-ainide}
Using the same procedure described in example 1 (with 4-(4-ainino-3-fluoro-phenyl)-
morphoiin-3-one, CAS 742073-22-9) and in the oast step the procedure described in
example 3 using
(3-fluoro-4-methoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (prepared from 3-fluoTo-4-methoxy-aniline by reaction with p-nilrophenyl chloroformal and pyridine in dichloromethane) the title compound was obtained as a white solid (26 mg). MS: 523.1 (M+Hf
Example 16
2,3-Dihydro-pyrrolo[2,3-b]pyridine-L,2-dicarboxyHc acid l-[(4-chloro-phenyl)-amide] 2-{[2-fl uoro-4-(2-oxo-2H-py ridin-1 -y l)-phenyl]-amide }
A 2,3-Dihydro-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester
A solution of pyrro]o[2,3-b]pyridine-],2-dicarboxyIic acid 1 -tert-butyJ ester 2-elhy! esier (9.53 g; CAS 577711-88-7) in 240 ml ethanol was treated with 5% Pd/C 2h at 40 "C
under a hydrogene atmosphere. The reaction mixture was filtered and the title compound obtained as a yellow oil (9.3 g).
B 2,3-Dihydro-pyiTolo[2,3-b]pyridine-l,2-dicarboxylic acid 1-tert-buty! ester
A suspension of 2,3-dihydro-pyrrolo{2,3-b]pyridine-l,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (1 g) and lithium hydroxide (0.25 g) in 6 ml THF, 3 ml MeOH and 3 ml water was stirred 0.5h at rl. The reaction mixture was poured onto IM HCl/ice and washed three times with dichloromethane. The aqueous layer was neutralized with IM NaOH, evaporated to dryness and purified by chromatography (silica gel, dichloromethane/methanol, 4/1) to yield 2,3-dihydrD-pyrrolo[2,3-l>]pyri dine-1,2-dicarboxyiic acid 1-tert-butyl ester as a white solid (400 mg). MS: 263.4 (M- H)"
C 2,3-Dihydro-pyrrolo[2,3-b]pyridine-l,2-dicarboxylic acid l-[(4-chloro-pheny])-amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-phenyl]-amide}
Starting from 2,3-dihydro-pyrroIo[2,3-b]pyridine-I,2-dicarboxyIic acid 1-tert-butyI ester and using the procedure described in example 1, 2,3-dihydro-pyrrolo[2,3-b] pyridine-1,2-dicarboxyJic acid l-[(4-ch]oro-pheny!)-amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-l-y!)-phenyl]-amide}was obtained as a white solid (63 mg). MS: 504.3 (M+ H)"^
Example 17
2,3-Dihydro-pyrrolo[2,3-b]pyridine-l,2-dicarboxylic acid l-[(5-chloro-pyridin-2-yl)-amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-phenyl]-araide}
Starting from 2,3-dihydro-pyrrolo[2,3-b]pyridine-l,2-dicarboxylic acid l-terl-butyl ester and using the procedure described in example 3, the title compound was obtained as a white solid (20 mg). MS: 505.2 (M+ H)^
Example 18
5,8-Dihydro-6H-[l,7]naphthyridine-6,7-dicarboxylic acid 7-[(4-chloro-phenyl)-amide] 6-{[2-fluoro-4-(2-oxo-2H-pyTidin-l-yl)-phenyl]-amide}
A 5,8-DihydTo-6H-[l,7]naphthyridine-6,7-dicarboxylic acid 7-terl-biJtyl esler and 7,8-Dihydro-5H-[l,6]naphthyridine-6,7-dicarboxy]ic acid 6-tert-butyl ester
To a solution of 5,6,V,8-tetrahydro-[l,7]naphthyridine-6-carboxylic acid methyl ester hydrochloride and 5,6,7,8-ielrahydro-[l,6]naphthyridine-7-carboxylic acid methyl ester hydrochloride (500 mg) ) in 12 ml acetonilrile and 1 ml water under ice cooling, were added successively BociO (478 mg), triethylamine (1.11 ml) and DMAP (12 mg). The reaction mixture was stirred 2h at rt, evaporated and purified by chromatography (silica geJ, dichlorometJiane/methanoI, 4/1) to yield a mixture of the two compounds as a yellow residue (313 mg). MS: 277.4 (M- H)"
B 7-[2-Ruoro-4-(2-oxo-2H-pyridin-l-y])-pheny]carbamoy]]-7,8-dihydrD-5H-[l,6]naphthy-ridine-6-carboxylic acid tert-butyl ester and 6-[2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-phenylcarbamoyl]-5,8-dihydro-6H-[l,7]naphthyridine-7-carboxyIic acid tert-buty] ester
To a solution of the above mixture (707 mg) in 20 m! THF was added lithium hydroxide
(58 mg) and vigourously stirred for 15 min. TTien, molecular sieves was added, followed
by
N-methylmorpholine (0.84 ml). The reaction mixture was cooled, treated with isobulyl
chloroformate (0.49 ml) and stirred for 30 min. After addition of l-(4-amino-3-fluoro-
phenyl)-lH-pyridin-2-one (622 mg; CAS 536747-52-1), the suspension was kept for Ih
at CC and for IShrs at rt. The reaction mixture was evaporated and filtrated. The residue
was diluted with dicJiloromethane and washed wilh water and hrine. The organic layers were dried over magnesium sulfate, evaporated and purified by chromatography (silica gel, AcOEl/MeOH, 50:1) to deliver the two isomers. 6-[2-FIuoro-4-(2-oxo-2H-pyridin-l-yl)-phenylcarbamoyl]-5,S-dihydro-6H-[l,7]naphthyridine-7-carboxylic acid tert-butyl ester was obtained as a white solid (205 mg; Rf=0.5, AcOEt/MeOH 19:1) and 7-[2-fluoro-4-(2-oxo-2H-pyridiTi-l-yl)-phenylcarbamoyl]-7,8-dihydro-5H-[l,6]naph-thyndine-6-carboxyIic acid teit-bufyl ester as a light yellow solid (351 mg; Rf=0.4, AcOEt/MeOH19:l). MS: 465.5 (M+H)^
C 5,6,7,8-Tetrahydro-[l,7]naphthyridine-6-carboxytic acid [2-fluoro-4-(2-oxo-2H-pyridin -1 -yl)-phenyl] -amide
A solution of 7-[2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-phenylcarbamoyl]-7,8-dihydro-5H-[l,6]naphthyridine-6-carboxylic acid tert-butyl ester (310 mg) in 8 ml dichloromethane and 1.53 ml TFA was stirred for 4hrs at rt. The reaction mixture was poured onto IM NaOH/ice and extracted twice with dichloromethane. The organic layers were dried over magnesium sulfate, evaporated and purified by chromatography (silica gel, AcOEt/methanol 9:1) to deliver the title compound as a light yellow solid (151 mg). MS: 365.5 (M+H)^
D 5,8-Dihydro-6H-[l,7]naphthyridine-6,7-dicarboxylic acid 7-[(4-chloro-phenyl)-amide] 6-{[2-fluoro-4-(2-oxo-2H-pyridin-l-y))-phenyI]-amide}
To a solution of 5,6,7,8-tetrahydro-Il,7]naphthyridine-6-carboxylic acid [2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-phenyI]-amide (40 mg) in 4 ml THF at -78'C, was added a solution of 4-chlorophenylisocyannate in 2 ml THF. After 30 mn, the reaction mixture was kept at rt for Ih, diluted with heptane and the white precipitate of the title compound was filtered (38 mg). MS: 518.5 (M+H)*
Example 19
7,8-Dihydro-5H-[l,6]naphthyridine-6,7-dicarboxylic acid 6-[(4-chloro-phenyl)-amide] 7-{[2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-phenyl]-amide}
A 5,6,7,8-Tetrahydfo-[l,6]naphthyridine-7-carboxylic acid [2-fluoro-4-(2-oxo-2H-pyridJn-1 -y])-phenyl}-amide
A solution of 6-[2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-phenylcarbamoyl]-5,8-dihydTo-6H-[l,7]naphthyridiiie-7-carboxylic acid terl-butyl ester (170 mg; example 16B) in 5 ml dichloromethane and 0.84 ml TFA was stined for 4hrs at rt. The reaction mixture was poured onto IM NaOH/ice and extracted twice with dichloromethane. The organic layers were dried over magnesium sulfate and evaporated to deliver the title compound as a white foam (123 mg). MS: 365.5 (M+ Hf
B 7,8-Dihydro-5H-[l,6]naphthyridine-6,7-dicarboxylic acid 6-[(4-chloro-phenyl)-amide] 7-{[2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-phenyl]-amide}
This compound prepared from 5,6,7,8-tetrahydro-[l,6]naphthyridine-7-carboxylic acid [2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-phenyl]-amide with the procedure described in example 16D) was obtained as a white solid (50 mg). MS: 518.5 (M+ H)*
Example A
Film coated tablets containing the following ingredients can be manufactured in a conventional manner:
Ingredients Per tablet
Kernel:
Compound of formula (I) 10.0 mg 200.0 mg
Microcrystalline cellulose 23.5 rag 43.5 mg
Lactose hydrous 60.0 mg 70.0 mg
Povidone K30 12.5 mg 15.0 mg
Sodium starch glycolale 12.5 mg 17.0 mg
Magnesium stearate 1.5 mg 4.5 mg
(Kernel Weight) 120.0 mg 350.0 mg
Film Coat:
Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg
Polyethylene glycol 6000 0.8 mg 1.6 mg
Talc 1.3 mg 2.6 mg
Irof? oxyde (yellow) O.S mg 1.6 mg
Titan dioxide 0.8 mg 1.6 mg
The active ingredient is sieved and mixed with microcristalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidon in water. The granulate is mixed with sodium starch glycolate and magesiumstearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aqueous solution / suspension of the above mentioned film coat.
Example B
Capsules containing the following ingredients [:an be manufactured in a conventional manner:
Ingredients Per capsule
Compound of formula (I) 25.0 mg
Lactose 150.0 mg
Maize starch 20.0 mg
Talc 5.0 mg
The components are sieved and mixed and filled into capsules of size 2. Example C
Injection solutions can have the following composition:
Compound of formula (1) 3.0 mg
Polyethylene Glycol 400 150.0 mg
Acetic Acid q.s. ad pH 5.0
Water for injection solutions ad 1.0 ml
The active ingredient is dissolved in a mixture of Polyethylene Glycol 400 and water for
injection (part). The pH is adjusted to 5.0 by Acetic Acid. The volume is adjusted to 1,0
ml by addition of the residual amount of water. The solution is filtered, filled into vials
using an appropriate overage and sterilized.
Example D
Soft gelatin capsules containing the following ingredients can be manufactured in a convenlional manner;
Capsule contenis
Comp>ound of formula (!) 5.0 mg
Yellow wax S.O rag
Hydrogenated Soya bean oil 8.0 mg
Partially hydrogenated plant oils 34.0 mg
Soyabean oil 110.0 mg
Weight of capsule contents 165.0 rag
Gelatin capsule
Gelatin 75.0 mg
Glycerol 85 % 32.0 mg
Karion 8S S.O mg (dry matter)
Titan dioxide 0.4 mg
Iron Qxidt. yellow 1.2 mg
The active ingredient is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures.
Example E
Sachets containing the following ingredients can be manufactured in a conventional manner:
Compound of formula (1) 50.0 mg
Lactose, fine powder 1015.0 mg
Microcristalline cellulose (AVICEL PH 102) 1400.0 mg
Sodium carboxymethyl cellulose 14.0 mg
Polyvinylpyrrolidon K 30 10.0 mg
Magnesiumstearate 10.0 mg
Flavoring additives I.O mg
The active ingredient is mixed with lactose, microcristaJIine cellulose md sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidon in water. The granulate is mixed with magnesiumstearate and the flavouring additives and filled into sachets.
Claims
wherein
A is a heteroaryl ring which is a monocyclic or bicyclic aromatic ring of 5 to 12 ring atoms, containing one, two, or three ring heteroatoms selected from N, O, and S, the remaining ring atoms being C, one or two carbon atoms of said ring being optionally replaced with a carbonyl group;
R' and R^
are independently hydrogen, CM alkyl, C,^ alkoxy, fluoro Ci-^^alkoxy,
hydroxy Ci-fialkoxy, Ci-salkoxy Cj-^alkoxy, mono or di Cj-^alkyl substituted amino Cm alkoxy, halogen, cyano, nitro, -N(R')-CO-(Ci^ alkyl optionally substituted by one or more fluorine atoms), in which R' is hydrogen, Cijs alkyl or fluoro d^ alkyl, -N(R')-C0-0-(Ci.6 alkyl optionally substituted by one or more fluorine atoms), in which R' is hydrogen, Ci-6alkyl or fluoro Ci^s alkyl, -N(R')-CO-N(R") (R'"), in which R', R" and R'" are independently hydrogen, Ci-6 alkyl or fluoro Cjs alkyl or -N(R'>S02-{C]-fi alkyl optionally substituted by one or more fluorine atoms), in which R' is hydrogen, Ci^ alkyl or fluoro Ci-6 alkyl or
R' and R-
are independently -SOrN(R')(R"). -C(0)-N(R')(R") or -N(R')(R'"), in which R'
and R" are independently hydrogen, C,^ alky! or fluoro Ci-6 aikyi or R' and R", together with the nitrogen atom to which they are attached, form heterocycyl;
X is arylene, heteroarylene or heterocyclylene, said arylene, heteroarylene and heterocyclylen being optionally substituted by one or more substituents independently selected from the group consisting of Ci-6 alkyl, C]-6 alkoxy, halogen, cyano, nitro, amino, -N(R')-CO-(Ci-(, alkyl optionally substituted by one or more fluorine atoms), in which R' is hydrogen, Cjjs alkyl or fluoro Ci.6 alkyl, -N(R')-CO-0-(Ci^ alkyl optionally substituted by one or more fluorine atoms), in which R' is hydrogen, C; ^ alkyl or fluoro Cj.(. alkyl, -N(R')-CO-N(R") (R'"), in which R', R" and R'" are independently hydrogen, C,_f,alky! or fluoroCi-fi atkyl, -C{0)-N(R')(R"), in which R' and R" are independently hydrogen, Ci-6alkyl or fluoro Ci-6 alkyl, or R' and R", together with the nitrogen atom to which they are attached, form heterocycyl, -NR'R", in which R' and R" are independently hydrogen, C;^ alkyl or fluoTo C]-f, alkyi, or R' and R", together with the nitrogen atom to which they are attached, form
and one or two carbon atoms of said aryl, heteroaryl and heterocyclyl being optionally replaced with a carbonyl group;
R^ is hydrogen or d-f, alkyl;
Y' is -(Co-fi alkylene)-C(0)-NR^Co-6 alkylene)-, -(Qw alkylene)-NR^-C(O)-(Co-fi alkylene}- or Co.6 alkylene;
Y^ is arylene, heteroarylene or heterocyclylene, said arylene, heteroarylene and heterocyclylene being optionally substituted by one or more substituents independently selected from the group consisting of Ci-*^ aikyl, Ci-6 alkoxy, halogen, cyano, nitro, amino, -N(R')-CO-(Ci* alkyl optionally substituted by one or more fluorine atoms), in which R' is hydrogen, Ci-6 alkyl or fluoroCi-(, alkyl, -N(R')-CO-0-(Ci^ alkyl optionally substituted by one or more fluorine atoms), in which R' is hydrogen, Ci_6alfcyl orfluoroCi^ alkyl, -N(R')-CO-N(R") (R'"), in which R', R" and R'" are independently hydrogen, Cn,alky] or fluaroC,.6 alkyl, -C(0)-N(R')(R"), in which R' and R" are independently hydrogen, C|j^ alkyl or halo C]^ alkyl, or R' and R", together with the nitrogen atom to which they are attached, form heterocycyl, -NR'R", in which R' and R" are independently hydrogen, C^^ alkyl or halo C|.6 alkyl, or R' and
Y"' is hydrogen, aryf, heteroaryl or heterocyclyl, said aryl, heleroaryi and heterocyclyl being optionally substituted by one or more substituents independently selected from the group consisting of C|-6 alkyl, Ci_f, ^ikoxy, halogen, cyano, nitro, amino, mono-Ci-e alkyl substituted amino, di-Ci_f, alkyl substituted amino, mono-C]^ affeyf substituted amino-Ci-6 a!kyi, di-Ci^a(fcyi substituted amino-Ci-6 alkyl, -SOj-Ci-fi alkyl, -SO2-NH2, -S02-NH-C:,.f, alkyl and -S02-N(Ci^ alkyl)2, and one or two carbon atoms of said aryl, heteroaryl and heterocyclyl being optionally replaced with a carbonyl group;
Z is attached to the same carbon atom as -Y'-Y^-Y"*, and hydrogen or C,^ alkyl;
n is 0, 1 or 2;
m is 0, 1 or 2;
m+n is 2 or 3;
o is an integer from 1 to 5;
and prodrugs and pharmaceutically acceptable salts Ihereof;
wherein,
unless otherwise indicated,
the term "ar;'l" means phenyl or naphthyl;
the term "heteroaryl" means a monocyclic or bicyclic aromatic radical of 5 to 12 ring atoms, conlaining one, two, OT V^iree ring VieteToaloms selected irom N, O, and S, iVie remaining ring atoms being C, one or two carbon atoms of said ring being optionally replaced with a carbonyl group, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring;
the term "helerocyclyr means non-aromatic mono- or bi-cyclic radicals of three to eight ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0)n
(where n is an integer from 0 to 2), the remaining ring atoms being C.
5. The compounds according to any one of claims 1 to 4, wherein X' is -C(0)-NH-.
6. The compounds according to any one of claims 1 to 5, wherein X^ is arj'lene or heteroarylene, said arylene and heteroarylene being optionally substituted by one or more substituents independently selected from the group consisting of C]^ alkoxy and halogen, and X^ is hydrogen.
7. The compounds according to any one of claims 1 to 6, wherein -X'-X"* forms phenyl or pyridyl, said phenyl and pyridyl being optionally substituted by one or more same or different halogen atoms,
8. The compounds according to any one of claims 1 to 7, wherein -X'-X" forms 4-chlorophenyl or 5-chloropyridyn-2-yl.
9. The compounds according to any one of claims 1 to 8, wherein Y' is -C(0)-
NH-.
10. The compounds according to any one of claims 1 to 9, wherein Y" is 1,4-phenylene optionally substituted by one or more same or different halogen atoms.
11. The compounds according to any one of claims 1 to 10, wherein Y" is 2-fluoro-1,4 phenylene.
12. The compounds according to any one of claims 1 to 11, wherein Y' is heteroaryl optionally substituted by one or more substituents independently selected from the group consisting of Ci-6alkyl, Ci-6alkoxy, halogen, cyano, nitro, amino, mono-Ci-i^ alkyl substituted amino, di-Ci-s alkyl substituted amino, mono-Ci.6 alkyl substituted amino-Cm alkyl, di-Q^ alkyl substituted amino-Ci-6 alkyl, -SOi-Ci-f, alkyl, -SO;-NH:, -SO2-NH-C1.6 alkyl and -S02-N(Ci^ alkyl):, and one or two carbon atoms of said heteroaryl being optionally replaced with a carbonyl group.
13. The compounds according to any one of claims 1 to 12, wherein Y' is 2-oxo-2H-pyridyn-l-yl.
14. The compounds according to any one of claims 1 lo 13, wherein one of R'
and R^ is hydrogen, and the other is C^^ alkyl.
15. The compounds according to any one of claims 2 to 14, wherein one of R' and R^ is C|-6 alkyl and at 1 position of the pyrrolopyrazole ring, and the other is hydrogen.
16. The compounds according to any one of claims 2 to 15, wherein one of R' and R- is methyl and at 1 position of the pyrrolopyrazole ring, and the other is hydrogen.
17. The compounds according to claim 1, which is
(R)-l-Methyl-4,6-dihydro-lH-pyrrolo[3,4-c]pyrazole-4,5-dicarboxy]ic acid 5-((4-chloro-phenyl)-amide] 4-{[2-fluoro-4-(2-oxo-2H-pyridin-l-yl)-phenyl]-amide},
(R)-l-Methyl-4,6-dihydro-lH-pyTroIo[3,4-cjpyra2ole-4,5-dicarboxylic acid 5-[(4-chloro-phenyl)-amide] 4-{[4-(2-oxo-2H-pyrazin-l-yl)-phenyI]-amide},
(R)-l-Methyl-4,6-dihydro-lH-pyrrolof3,4-c]pyra2ole-4,5-dicarboxylic acid 5-[(4-chloro-phenyl)-amide]4-{[2-fluoro-4-(2-oxo-2H-pyTazin-l-yl)-phenyi]-amide},
(R)-l-Methyl-4,6-dihydro-lH-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylie acid 5-[(4-ch]oro-phenyl)-amide] 4-{[4-(2-oxo-2H-pyridin-l-yl)-phenyl]-amide} or
(R)-l-Methyl-4,6-dihydro-lH-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylie acid 5-[(4-chloro-phenyl)-amide] 4-{[2,6-difluoro-4-(2-oxo-2H-pyridin-l-yl)-phenyl]-amide}.
18. A process forpreparaing compounds of Formula (V),
comprising a step of acylating compounds of Formula (II)
wherein x\ X^ Y^, Y^ R' and R' are as defined in claim 1.
19. Pharmaceutical compositions comprising a compound according to any of
claims 1 to 17 and a pharmaceuticaliy acceptable excipient.
20. The compounds according to any one of claims 1 to 17 for use as therapeutic active substances.
21. The compounds according to any one of claims 1 to 17 for use as therapeutic active substances for the treatment and/or prophylaxis of diseases which are associated with the coagulation factor Xa.
22. Use of compounds according to any of claims 1 to 17 for the preparation of
medicaments for the therapeutic and/or prophylactic treatment of diseases which are
associated with the coagulation factor Xa.
23. The use according to claim 21, wherein the disease is thrombotic disorders, arierial thrombosis, venous thrombosis, deep vein thnambosis, peripheral arterial occlusive disease, unstable angina pectoris, myocardial infarction, coronary artery disease, pulmonary embolism, stroke due to atrial fibrillation, inflammation, arteriosclerosis, acute vessel closure associated with thrombolytic therapy or restenosis, and/or tumour.
24. The invention as hereinbefore defined, particularly with reference to the new compounds, intermediates, medicaments, uses and processes.
|