USO0RE42890E
(19) United States (12) Reissued Patent Eberle et a].
(10) Patent Number: US RE42,890 E (45) Date of Reissued Patent: Nov. 1, 2011
(54) FURAZANOBENZIMIDAZOLES
Database Chemcats Online, Chemical Abstracts Service, Columbus,
Ohio, US, XP002257451, Apr. 29, 2003.
(75) Inventors: Martin Eberle, Bottmingen (CH); Felix Bachmann, Basel (CH); Alessandro Strebel, Vedano al Lambro (IT); Subho
Organic Chemistry, Consultants Bureau, US, vol. 38, No. 6, 2002, pp.
Roy, West Bengal (IN); Sudhir Srivastava, West Bengal (IN); Goutam Saha, West Bengal (IN)
872-874.
(73) Assignee: Basilea Pharmaceutica AG, Basel (CH)
(21) Appl. No.:
12/796,135
(22) PCT Filed:
May 19, 2004
(86)
PCT No.:
PCT/IB2004/001723
§ 371 (0X1)’ (2), (4) Date:
Nov. 21, 2005
(87)
Sergievskii A V et a1: “4-AminofuraZan-3 -Carvoxylic Acid Iminoester in Reactions with N,O-Nucelphiles” Russian Journal of
Sergievskii A V et a1: “Reactions of Methyl 4-AminofuraZan-3
Carboximidate With Nitrogen-Containing Nucleophiles”, Russian Journal of Organic Chemistry, Consultants Bureau, US, vol. 37, No. 5, 2001, pp. 717-720. The European Search Report issued on Oct. 13, 2003 in related
European Application No. 034053652.
PCT Pub. No.: WO2004/103994
The International Search Report and Written Opinion issued on Sep. 20, 2004 in related PCT Application No. PCT/IB2004/00l723. The Communication from the Examining Division issued on Aug. 24, 2006 in related European Application No. 047338744. The Communication from the Examining Division issued on Oct. 1, 2007 in related European Application No. 047338744. European Search Report dated Oct. 13, 2003. International Search Report dated Sep. 20, 2004. DE 31 00 771 A (USV Pharma Corp) Aug. 26, 1982.
PCT Pub. Date: Dec. 2, 2004
* cited by examiner
Related US. Patent Documents
Reissue of:
(64) Patent No.:
7,385,061
Issued:
Jun. 10, 2008
Appl. No.:
10/557,539
Filed:
Nov. 21, 2005
Primary Examiner * Laura L. Stockton
(57)
ABSTRACT
The invention relates to compounds of formula (I) Wherein R represents aryl or heteroaryl, X is oxygen, a carbonyl group, an oxime derivative of a carbonyl group or an (X, [3-unsaturated
(30)
Foreign Application Priority Data
May 23, 2003
(EP) ................................... .. 03405365
carbonyl group, and the sub stituents Rl to R6 have the mean ings given in the speci?cation, for use as medicaments, to novel compounds of formula (I), to methods of synthesis of
such compounds, to pharmaceutical compositions containing (51)
(52) (58)
compounds of formula (I), to the use of a compounds of
Int. Cl. A61K 31/4245 C07D 413/04
(2006.01) (2006.01)
US. Cl. ...................................... .. 548/125; 514/364 Field of Classi?cation Search ................. .. 548/125
See application ?le for complete search history. (56)
formula (I) for the preparation of a pharmaceutical composi tion for the treatment of neoplastic and autoimmune diseases, and to methods of treatment of neoplastic and autoimmune diseases using such compounds of formula (I) or of pharma ceutical compositions containing same
References Cited R1
U.S. PATENT DOCUMENTS 2004/0034037 Al*
2004/0214817 Al
2/2004
R3
3100771 03066629 WO03/066629 A
R\N
Harbeson et al. ...... .. 5l4/255.05
l0/2004 Pierce et al.
R4
N
R5
N
\
FOREIGN PATENT DOCUMENTS DE WO WO
2
8/1982 8/2003 8/2003
OTHER PUBLICATIONS Database Chemcats Online Chemical Abstracts Service, Columbus,
R6
/
\
\T0
N/
> x
\ R
Ohio, US, XP002257449, Apr. 30, 2003. Database Chemcats Online, Chemical Abstracts Service, Columbus,
Ohio, US, XP002257450, May 19, 2003.
39 Claims, No Drawings
1
()
US RE42,890 E 1
2
FURAZANOBENZIMIDAZOLES
may lose the normal regulatory control of cell division, and may also fail to undergo appropriate cell death. As apoptosis is inhibited or delayed in most types of pro liferative, neoplastic diseases, induction of apoptosis is an option for treatment of cancer, especially in cancer types which show resistance to classic chemotherapy, radiation and
Matter enclosed in heavy brackets [ ] appears in the original patent but forms no part of this reissue speci?ca tion; matter printed in italics indicates the additions made by reissue.
immunotherapy (Apoptosis and Cancer Chemotherapy, Hickman and Dive, eds., Blackwell Publishing, 1999). Also in autoimmune and transplantation related diseases and
This application is a Reissue Application ofU.S. Pat. No. 7,385,061, issued on Jun. 10, 2008?’om US. application Ser. No. 10/557,539, ?led on Nov. 2], 2005, which is a National
pathologies compounds inducing apoptosis may be used to restore normal cell death processes and therefore can eradi
cate the symptoms and might cure the diseases. Further appli
Stage Application under 35 U.S.C. 37] ofPCTApplication
cations of compounds inducing apoptosis may be in resteno
No. PCT/IB2004/00] 723, ?led on May 19, 2004.
sis, i.e. accumulation of vascular smooth muscle cells in the walls of arteries, and in persistent infections caused by a
The invention relates to novel substituted furaZanobenZ
imidaZoles, processes for the preparation thereof, pharma
failure to eradicate bacteria- and virus-infected cells. Further more, apoptosis can be induced or re-established in epithelial
ceutical compositions containing same, the use thereof optionally in combination with one or more other pharma
cells, in endothelial cells, in muscle cells, and in others which
ceutically active compounds for the therapy of neoplastic diseases and autoimmune diseases, and a method for the
20
treatment of such a diseases.
develop into pathologies like neoplasias, endometriosis and the like. Recently, a patent application was published disclosing a
BACKGROUND OF THE INVENTION Cancer is one of the leading causes of death in humans.
have lost contact with extracellular matrix. These cells are potentially able to colonize other organs and therefore can
25
number of structurally related compounds (WO 03/066629). These compounds are described as being inhibitors of GSK-3 and LCK kinase, but have no relevance in apoptosis and medical conditions connected therewith.
Although a variety of drugs against neoplastic diseases have been developed and techniques are available such as surgery and radiation therapy, there is still a need for alternative and
improved methods of treatment of neoplastic diseases. Autoimmune diseases are associated with abnormal lym phoproliferation as a result of defects in the termination of
SUMMARY OF THE INVENTION
30
FuraZanobenZimidaZoles of formula (I) are selectively
lymphocyte activation and growth. Often, such diseases are
eases is focused on anti-in?ammatory and immunosuppres
inducing apoptosis in cancer cells, and can be used for the treatment of neoplastic and autoimmune diseases. The inven tion relates to compounds of formula (I), in particular to such compounds for use as medicaments, to methods of synthesis
sive drugs which in numerous cases show severe side effects. Hence, there is a need for alternative drugs with a new mode
ing compounds of formula (I), to the use of a compounds of
associated with in?ammation like rheumatoid arthritis, insu
lin dependent diabetes mellitus, multiple sclerosis, systemic lupus erythematosus and the like. The treatment of such dis
35
of such compounds, to pharmaceutical compositions contain formula (I) for the preparation of a pharmaceutical composi
of action showing less side effects.
tion for the treatment of neoplastic and autoimmune diseases, and to methods of treatment of neoplastic and autoimmune diseases using such compounds of formula (I) or of pharma ceutical compositions containing same.
Apoptosis is a term used to describe a series of cellular
events which occur to bring about programmed cell death. There are various apoptotic pathways, some of which have been characterized, whereas others remain to be elucidated. If
the balance between cell division and apoptosis is disturbed, life-threatening diseases including cancer, autoimmune dis orders, neurodegenerative and cardiovascular diseases may
45
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to compounds of formula (I)
occur.
In recent years it has become evident that programmed cell death (apoptosis) is as important to the health of a multicel
lular organism as cell division. By repeated cell division and differentiation throughout development or tissue repair, sur
2
R\N
plus or even harmful cells are generated. In order to maintain tissue homeostasis these cells have to be removed or killed.
/
R1
(1)
The delicate interplay between cell growth and apoptosis in an organism is mirrored in the complex molecular balance that determines whether an individual cell undergoes divi sion, arrests in the cell cycle or commits to programmed cell death.
Dysregulation of cell proliferation, or lack of appropriate cell death, has wide ranging clinical implications. A number of diseases associated with such dysregulation involve hyper
55
N/
60
proliferation, in?ammation, tissue remodeling and repair.
wherein
Familiar indications in this category include cancers, resteno
R represents aryl or heteroaryl optionally substituted by up to four substituents independently selected from
sis, neointimal hyperplasia, angiogenesis, endometriosis, lymphoproliferative disorders, transplantation related pathologies (graft rejection), polyposis, loss of neural func tion in the case of tissue remodeling and the like. Such cells
65
alkyl, cycloalkyl, cycloalkyl-lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, halo-lower alkoxy-lower
US RE42,890 E 4 3 loWer alkyl, loWer alkoxy-loWer alkoxy-loWer alkyl, halo alkyl, acyloxy-loWer alkyl, heterocyclyl, heterocyclyl-loWer alkyl, optionally substituted phenyl, optionally substituted phenyl-loWer alkyl, optionally substituted heteroaryl, option ally substituted heteroaryl-loWer alkyl, optionally substituted alkenyl, optionally substituted alkinyl, hydroxy, loWer alkoxy, optionally substituted alkenyloxy,
loWer alkoxy-loWer alkyl, heterocyclyl, heterocyclyl-loWer alkyl, optionally substituted phenyl, optionally substituted phenyl-loWer alkyl, optionally substituted heteroaryl, option ally substituted heteroaryl-loWer alkyl, optionally substituted alkenyl, optionally substituted alkinyl, hydroxy, loWer alkoxy, halo-loWer alkoxy, cycloalkoxy, cycloalkyl-loWer alkoxy, hydroxy-loWer alkoxy, loWer
optionally substituted alkinyloxy, cycloalkoxy, halo-loWer
alkoxy, cycloalkyl-loWer alkoxy, hydroxy-loWer alkoxy, loWer alkoxy-loWer alkoxy, heterocyclyloxy, heterocyclyl
alkoxy-loWer alkoxy, heterocyclyloxy, heterocyclyl-loWer
loWer alkoxy, optionally substituted phenyloxy, optionally substituted phenyl-loWer alkoxy, optionally substituted het eroaryloxy, optionally substituted heteroaryl-lower alkoxy, sulfamoyloxy, carbamoyloxy, loWer alkylcarbonyloxy,
alkoxy, optionally substituted phenyloxy, optionally substi tuted phenyl-loWer alkoxy, optionally substituted heteroary loxy, optionally substituted heteroaryl-lower alkoxy, amino, carbamoyl, sulfamoyl, amino-loWer alkyl or amino
amino, monoalkylamino, dialkylamino, aminocarbony lamino Wherein each of the tWo amino groups is optionally
loWer alkylamino, Wherein in each case the nitrogen atom is
substituted by alkyl, alkenyl, alkinyl or alkoxy-loWer alkyl,
unsubstituted or substituted by one or tWo substitutents
selected from loWer alkyl, cycloalkyl, cycloalkyl-loWer alkyl,
heterocyclylcarbonylamino Wherein heterocyclyl is bound
hydroxy-loWer alkyl, loWer alkoxy-loWer alkyl, optionally substituted phenyl, optionally substituted phenyl-loWer alkyl,
Via a nitrogen atom, aminosulfonylamino Wherein each of the
tWo amino groups is optionally substituted by alkyl, alkenyl,
alkinyl or alkoxy-loWer alkyl, heterocyclylsulfonylamino
20
optionally substituted heteroaryl, optionally substituted het
alkoxycarbonylamino, loWer alkylcarbonylamino Wherein
eroaryl-loWer alkyl and loWer alkylcarbonyl, or Wherein the tWo substituents on nitrogen form together With the nitrogen
alkyl is optionally substituted by one or tWo substituents
heterocyclyl,
Wherein heterocyclyl is bound Via a nitrogen atom, loWer
selected from optionally substituted phenyl, guanidyl, halo gen, cyano, alkoxy, optionally substituted phenoxy, alkylm ercapto and optionally substituted amino; loWer alkenylcar bonylamino Wherein alkenyl is optionally substituted by one
25
bonyl, heterocyclylcarbonyl, carboxy, loWer alkoxycarbonyl, hydroxy-loWer alkoxycarbo
or tWo substituents selected from loWer alkyl, halo-loWer
nyl, loWer alkoxy-loWer alkoxycarbonyl, optionally substi
alkyl, optionally substituted phenyl, halogen, cyano, alkoxy and optionally substituted amino; amino-loWer alkyl or amino-loWer alkylamino, Wherein the nitrogen atom is
30
unsubstituted or substituted by one or tWo substitutents
selected from loWer alkyl, cycloalkyl, cycloalkyl-loWer alkyl,
hydroxy-loWer alkyl, loWer alkoxy-loWer alkyl, optionally substituted phenyl, optionally substituted phenyl-loWer alkyl,
35
eroaryl-loWer alkyl and loWer alkylcarbonyl, or Wherein the tWo substituents on nitrogen form together With the nitrogen
and salts thereof. 40
nyl, optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, and nitro; 50
atoms of aryl or heteroaryl may form a 5 or 6 membered
carbocyclic or heterocyclic ring; X represents oxygen; a group C:Y, WhereinY stands for oxygen or nitrogen substituted by hydroxy or alkoxy; or a group 4CO4CH:CHi Wherein the C:C bond is con
sulfonyl, halogen, or nitro, or R3 and R4, R4 and R5 , or R5 and R6 together With the atoms of the phenyl ring form a 5 or 6 membered carbocyclic or
heterocyclic ring;
tuted phenyl-loWer alkoxycarbonyl, cyano, loWer alkylmer capto, optionally substituted phenylmercapto, loWer alkylsul?nyl, halo-loWer alkylsul?nyl, optionally substituted phenylsul?nyl, loWer alkylsulfonyl, halo-loWer alkylsulfo and Wherein tWo adjacent substituents together With the
tuted phenyl-loWer alkoxycarbonyl, cyano, loWer alkylmercapto, optionally substituted phenylmercapto, loWer alkylsul?nyl, halo-loWer alkylsul?nyl, optionally sub stituted phenylsul?nyl, loWer alkylsulfonyl, halo-loWer
alkylsulfonyl, optionally substituted phenylsulfonyl, aralkyl
optionally substituted heteroaryl, optionally substituted het
heterocyclyl, loWer alkylcarbonyl, formyl, cycloalkylcarbo nyl, optionally substituted phenylcarbonyl, optionally substi tuted heteroarylcarbonyl, heterocyclylcarbonyl, carboxy, loWer alkoxycarbonyl, hydroxy-loWer alkoxycarbo nyl, loWer alkoxy-loWer alkoxycarbonyl, optionally substi
loWer alkylcarbonyl, cycloalkylcarbonyl, optionally substi tuted phenylcarbonyl, optionally substituted heteroarylcar
The general terms used hereinbefore and hereinafter pref erably have Within the context of this disclosure the folloWing meanings, unless otherWise indicated: The pre?x “loWer” denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being either linear or branched With single or multiple branching. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like. Double bonds in principle can have E- or Z-con?guration. The compounds of this invention may therefore exist as iso meric mixtures or single isomers. If not speci?ed both iso meric forms are intended.
55
nected to R; R1 and R2, independently of each other, represent
Any asymmetric carbon atoms may be present in the (R)-, (S)- or (R,S)-con?guration, preferably in the (R)- or (S) con?guration. The compounds may thus be present as mix
hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, optionally sub
tures of isomers or as pure isomers, preferably as enantiomer
stituted arylalkyl, optionally substituted heteroarylalkyl,
pure diastereomers. The invention relates also to possible tautomers of the
hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxy alkoxyalkyl, cyanoalkyl, optionally substituted alkenyl,
60
optionally substituted alkinyl, or loWer alkylcarbonyl
compounds of formula (I).
Wherein loWer alkyl is optionally substituted by one or tWo
Alkyl has from 1 to 12, preferably from 1 to 7 carbon atoms, and is linear or branched. Alkyl is preferably loWer
substitutents selected from aryl, optionally substituted
alkyl.
amino, alkoxy and aryloxy, R3, R4, R5 and R6, independently of each other, represent hydrogen, loWer alkyl, halo-loWer alkyl, cycloalkyl, cycloalkyl-loWer alkyl, hydroxy-loWer alkyl, loWer alkoxy
LoWer alkyl has 1 to 4 carbon atoms and is butyl, such as 65
n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-pro pyl or isopropyl, ethyl or methyl. Preferably loWer alkyl is methyl or ethyl.
US RE42,890 E 6
5 Cycloalkyl has preferably 3 to 7 ring carbon atoms, and
Arylalkyl includes aryl and alkyl as de?ned hereinbefore,
may be unsubstituted or substituted, eg by lower alkyl or
and is e. g. benZyl, l-phenethyl or 2-phenethyl.
lower alkoxy. Cycloalkyl is, for example, cyclohexyl, cyclo
Heteroarylalkyl includes heteroaryl and alkyl as de?ned
pentyl, or methylcyclopentyl.
hereinbefore, and is eg 2-, 3- or 4-pyridylmethyl, l- or
Aryl stands for a mono- or bicyclic fused ring aromatic group With 5 to 10 carbon atoms, such as phenyl, l-naphthyl or 2-naphthyl, or also a partially saturated bicyclic fused ring comprising a phenyl group, such as indanyl, dihydro- or
2-pyrrolylmethyl, l-pyraZolylmethyl, l-imidaZolylmethyl, 2-(l-imidaZolyl)ethyl or 3-(1 -imidaZolyl)propyl. TWo adjacent substituents Which together With the atoms of aryl or heteroaryl may form a 5 or 6 membered carbocyclic or
tetrahydronaphthyl.
heterocyclic ring are, for example, propylene, l- or 2-oxopro pylene, l- or 2-oxapropylene, l-oxapropylidene, methylene
In optionally substituted phenyl, substituents are prefer
ably loWer alkyl, loWer alkoxy, loWer alkoxy-loWer alkoxy, methylenedioxy, halo-loWer alkyl, loWer alkoxy-loWer alkyl,
dioxy, di?uoromethylenedioxy, l- or 2-aZapropylene, l- or
2-aZapropylidene, 1,2- or 1,3-diazapropylidene, l,3-diaZa-2 oxopropylene, butylene, l- or 2-oxabutylene, ethylenedioxy,
halo, or nitro.
Heteroaryl represents an aromatic group containing at least one heteroatom selected from nitrogen, oxygen and sulfur, and is mono- or bicyclic. Monocyclic heteroaryl includes 5 or 6 membered heteroaryl groups containing 1, 2, 3 or 4 heteroa toms selected from nitrogen, sulfur and oxygen. Bicyclic heteroaryl includes 9 or 10 membered fused-ring heteroaryl
groups. Examples of heteroaryl include pyrrolyl, thienyl,
l- or 2-aZabutylene, or 1- or 2-aZabutadienylidene, or such
groups carrying further substituents as de?ned hereinbefore. In substituted amino, the substituents are preferably those mentioned as substituents R1 and R2. Inparticular, substituted
amino is alkylamino, dialkylamino, optionally substituted 20
furyl, pyraZolyl, imidaZolyl, triaZolyl, oxaZolyl, isoxaZolyl, oxadiaZolyl, thiaZolyl, isothiaZolyl, thiadiaZolyl, pyridyl,
arylalkylamino, or loWer alkylcarbonylamino, and also loWer alkoxycarbonylamino or optionally substituted aminocarbo
nylamino.
pyridaZinyl, pyrimidinyl, pyraZinyl, benZo fused derivatives
When X represents a group C:Y, Wherein Y stands for
of such monocyclic heteroaryl groups, such as indolyl, ben
nitrogen substituted by hydroxy, this corresponds to an oxime function. Oximes and the corresponding oxime alkyl ethers (nitrogen substituted by alkoxy) may be present in E or Z
ZimidaZolyl or benZofuryl, quinolinyl, isoquinolinyl,
25
quinaZolinyl, or purinyl. In optionally substituted heteroaryl, substituents are pref
form, or as mixture of isomers. When X represents a group 4CO4CH:CHi Wherein
erably loWer alkyl, loWer alkoxy, loWer alkoxy-loWer alkoxy, amino, optionally substituted by one or tWo substituents
selected from loWer alkyl, loWer alkenyl and alkylcarbonyl, halo-loWer alkyl, loWer alkoxy-loWer alkyl, halo, or nitro.
30
Salts are especially the pharmaceutically acceptable salts of compounds of formula (I).
Alkenyl contains one or more, e.g. tWo or three, double
bonds, and is preferably loWer alkenyl, such as l- or 2-bute
nyl, l-propenyl, allyl or Vinyl. Alkinyl is preferably loWer alkinyl, such as propargyl or
Such salts are formed, for example, as acid addition salts, 35
acetylenyl.
of formula (I) With a basic nitrogen atom, especially the
preferably loWer alkyl, loWer alkoxy, halo or di(loWer alkyl) 40
alkenyl.
sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic
acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, aZelaic acid, malic acid, tartaric acid, citric acid, amino
Heterocyclyl designates preferably a saturated, partially saturated or unsaturated, mono- or bicyclic ring containing 4-10 atoms comprising one, tWo or three heteroatoms
selected from nitrogen, oxygen and sulfur, Which may, unless otherWise speci?ed, be carbon or nitrogen linked, Wherein a ring nitrogen atom may optionally be substituted by a group
preferably With organic or inorganic acids, from compounds
pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid,
In optionally substituted alkenyl or alkinyl, substituents are amino, and are connected With a saturated carbon atom of alkenyl or alkinyl or With an unsaturated carbon atom of
the C:C bond is connected to R, R is connected to the terminal carbon atom of the C:C bond. The C:C bond may be present in E or Z form, preferably in E form.
45
acids, such as glutamic acid or aspartic acid, maleic acid,
hydroxymaleic acid, methylmaleic acid, cyclohexanecar boxylic acid, adamantane-carboxylic acid, benZoic acid, sali
selected from loWer alkyl, amino-loWer alkyl, aryl, aryl-loWer
cylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic
alkyl and acyl, and a ring carbon atom may be substituted by
acid, mandelic acid, cinnamic acid, methane- or ethane-sul
loWer alkyl, amino-loWer alkyl, aryl, aryl-loWer alkyl, het
50
eroaryl, loWer alkoxy, hydroxy or oxo. Examples of hetero
cyclyl are pyrrolidinyl, oxaZolidinyl, thiaZolidinyl, piperidi nyl, morpholinyl, piperaZinyl, dioxolanyl and tetrahydropyranyl. Acyl designates, for example, alkylcarbonyl, cyclohexyl
l,5-naphthalene-disulfonic acid, 2-, 3- or 4-methylbenZene
sulfonic acid, methylsulfuric acid, ethylsulfuric acid, dode
cylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, 55
carbonyl, arylcarbonyl, aryl-loWer alkylcarbonyl, or het eroarylcarbonyl. LoWer acyl is preferably loWer alkylcarbo nyl, in particular propionyl or acetyl.
use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharma 60
ethyl. Haloalkyl is preferably ?uoroalkyl, especially tri?uorom ethyl, 3,3,3-tri?uoroethyl or penta?uoroethyl. Halogen is ?uorine, chlorine, bromine, or iodine.
LoWer alkoxy is especially methoxy, ethoxy, isopropyloxy, or ter‘t-butyloxy.
N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid. For isolation or puri?cation purposes it is also possible to
Hydroxyalkyl is especially hydroxy-loWer alkyl, prefer ably hydroxymethyl, 2-hydroxyethyl or 2-hydroxy-2-propyl. Cyanoalkyl designates preferably cyanomethyl and cyano
fonic acid, 2-hydroxyethanesulfonic acid, ethane-l,2-disul fonic acid, benZenesulfonic acid, 2-naphthalenesulfonic acid,
ceutically acceptable salts or free compounds are employed (Where applicable in the form of pharmaceutical prepara tions), and these are therefore preferred. In VieW of the close relationship betWeen the novel com
pounds in free form and those in the form of their salts, 65
including those salts that can be used as intermediates, for example in the puri?cation or identi?cation of the novel com
pounds, any reference to the free compounds hereinbefore
US RE42,890 E 7
8
and hereinafter is to be understood as referring also to the
tion about nuclear morphology and DNA fragmentation Which are hallmarks of apoptosis. B) MTS proliferation assay measuring the metabolic activity of cells. Viable cells are metabolically active Whereas cells With compromised respi
corresponding salts, as appropriate and expedient. The compound of the formula (I) may be administered in the form of a pro-drug Which is broken doWn in the human or
animal body to give a compound of the formula (I). Examples of pro-drugs include in vivo hydrolysable esters and amides of a compound of the formula (I). Particular pro-drugs con sidered are ester and amides of naturally occurring amino acids and ester or amides of small peptides, in particular small peptides consisting of up to ?ve, preferably tWo or three
ratory chain shoW a reduced activity in this test. C) AnnexinV binding assay Which re?ects the phosphatidylserine content of the outer lipid bilayer of the plasma membrane. This event
amino acids as Well as esters and amides of pegylated
cycle arresting points can be determined. E) Proliferation assay monitoring DNA synthesis by incorporating bromode oxyuridine (BrdU). Inhibitory effects on groWth/proliferation can be directly determined. F) Cystein proteinase depen dency, respectively caspase dependency are determined by using speci?c inhibitors. This provides information about possible involvement of speci?c proteases in the mecha
is considered an early hallmark of apoptosis. D) PI staining for cell cycle distribution Which shoWs any alterations in the distribution among the different phases of the cell cycle. Cell
hydroxy acids, preferably hydroxy acetic acid and lactic acid. Pro-drug esters are formed from the acid function of the amino acid or the C terminal of the peptide and suitable
hydroxy group(s) in the compound of formula (I). Pro-drug amides are formed from the amino function of the amino acid
or the N terminal of the peptide and suitable carboxy group(s) in the compound of formula (I), or from the acid function of the amino acid or the C terminal of the peptide and suitable
amino group(s) in the compound of formula (I). The compounds of formula (I) have valuable pharmaco logical properties. The invention also relates to compounds of
20
nisms. On the basis of these studies, a compound of formula (I)
according to the invention shoWs therapeutic ef?cacy espe cially against neoplastic diseases and autoimmune diseases.
formula (I) as de?ned hereinbefore for use as medicaments.
In particular, the compounds of the invention are active
The e?icacy of the compounds of the invention in inducing
against malignancies, e.g. epithelial neoplasms, squamous
apoptosis in tumor cells can be demonstrated as folloWs: Relative ?uorescent activities of suitable tumor cell lines transfected With green ?uorescent protein (GFP) are mea
25
cell neoplasms, basal cell neoplasms, transitional cell papil lomas and carcinomas, adenomas und adenocarcinomas, adn exal and skin appendage neoplasms, mucoepidermoid neo plasms, cystic neoplasms, mucinous and serous neoplasms, ductal-, lobular and medullary neoplasms, acinar cell neo
30
plasms, complex epithelial neoplasms, specialiZed gonadal
sured in the presence of compounds of the invention and of standard tumor drugs, using the method described in WO 99/35493. Suitable tumor cell lines are A20.2J, a BALB/c B
cell lymphoma, PB-3c, an IL-3 dependent, non tumorigenic
neoplasms, paragangliomas and glomus tumors, naevi and
mastocyte line isolated from the bone marroW of a DBA/2 mouse, Jurkat, a human acute T cell leukemia cell line, K562, a human chronic myelogenous leukemia cell line, HL60, a
melanomas, soft tissue tumors and sarcomas, ?bromatous
human acute promyelocytic leukemia cell line, Ramos and
neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, complex mixed and stromal neo 35
mesothelial neoplasms, germ cell neoplasms, trophoblastic neoplasms, mesonephromas, blood vessel tumors, lymphatic
Raji, human B-cell lymphoma cell lines, H9 and Hut78, human T-cell lymphoma cell lines, HeLa and KB, human squamous cell carcinoma cell lines, MCF7, SK-BR-3, PC3, HBL-lOO, SW480, H460 and H1792, human adenocarci noma cell lines and HT-l080, a human ?brosarcoma cell line.
vessel tumors, osseous and chondromatous neoplasms, giant cell tumors, miscellaneous bone tumors, odontogenic tumors, 40
Preferred standard drugs as compounds for comparisons are: a) antimetabolites such as 5-?uorouracil (ICN), gemcit abine HCl (GemZarTM, Eli Lilly), b) alkylating agents such as
gliomas, neuroepitheliomatous neoplasms, meningiomas, nerve sheath tumors, granular cell tumors and alveolar soft
part sarcomas, Hodgkin’s and non Hodgkin’s lymphomas, other lymphoreticular neoplasms, plasma cell tumors, mast cell tumors, immunoproliferative diseases, leukemias, mis
oxaliplatin (EloxantinTM, Sano?-Synthélabo), dacarbaZin
(DetimedacTM, Medac), cyclophosphamide (EndoxanTM, Asta) and carboplatin (ParaplatinTM, Bristol-Meyers Squibb),
plasms, ?broepithelial neoplasms, synovial like neoplasms,
45
cellaneous myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.
c) cell-cycle inhibitor such as vinorelbine (NavelbineTM,
In particular, a compound of formula (I) according to the
Robapharm), vinblastine (VelbeTM, Eli Lilly), docetaxel (TaxotereTM, Aventis), d) DNA breaker (topo-isomerase
invention shoWs therapeutic ef?cacy especially against solid neoplastic diseases, eg epithelial neoplasms, squamous cell neoplasms, basal cell neoplasms, transitional cell papillomas
inhibitor, intercalator, strand breaker) such as doxorubicin
50
HCl (AdriblastinTM, Pharmacia-Upjohn), bleomycin (Asta Medica), irinotecan (CamptoTM, Aventis), etoposide phos phate (EtopophosTM, Bristol-Meyers Squibb), topotecan HCl, (HycamtinTM, Glaxo SmithKline), e) mixtures thereof, f) compounds interfering With the signal transduction pathWay,
and carcinomas, adenomas und adenocarcinomas, adnexal
and skin appendage neoplasms, mucoepidermoid neoplasms, cystic neoplasms, mucinous and serous neoplasms, ductal-, lobular and medullary neoplasms, acinar cell neoplasms, 55
dexamethasone, phorbol myristate acetate, cyclosporin A, quercetin, tamoxifen (Alexis Corporation, SWitZerland).
complex epithelial neoplasms, specialiZed gonadal neo plasms, paragangliomas and glomus tumors, naevi and mela
such as caspase activity modi?ers, agonists and antagonists of cell death receptors, modi?ers of nucleases, phosphatases and kinases such as imatinib mesylate (GleevecTM, Novartis),
nomas, soft tissue tumors and sarcomas, ?bromatous neo
plasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, complex mixed and stromal neo 60
plasms, ?broepithelial neoplasms, synovial like neoplasms,
Apoptosis is determined in a primary screen using a ?uo rescence plate reader and then in a secondary screen using
mesothelial neoplasms, germ cell neoplasms, trophoblastic neoplasms, mesonephromas, blood vessel tumors, lymphatic
FACS (?uorescence activated cell scanning). Compounds causing apoptosis Without substantial cytotoxic side effects
vessel tumors, osseous and chondromatous neoplasms, giant cell tumors, miscellaneous bone tumors, odontogenic tumors,
are chosen for further testing and characterization by using a combination of the folloWing Well established assays: A) Nuclear staining With Hoechst 33342 dye providing informa
65
gliomas, neuroepitheliomatous neoplasms, meningiomas, nerve sheath tumors, granular cell tumors and alveolar soft part sarcomas.
US RE42,890 E 9
10
The compounds of the invention are likewise active against autoimmune diseases, eg against systemic, discoid or sub
above. Other possible treatments are therapy to maintain the patient’s status after tumor regression, or even chemopreven
acute cutaneous lupus erythematosus, rheumatoid arthritis,
tive therapy, for example in patients at risk. Particularly pre
antiphospholipid syndrome, CREST, progressive systemic
ferred is the use of compounds of formula (I) in combination
sclerosis, mixed connective tissue disease (Sharp syndrome),
With radiotherapy. Therapeutic agents for possible combination are especially
Reiter’s syndrome, juvenile arthritis, cold agglutinin disease, essential mixed cryoglobulinemia, rheumatic fever, ankylos ing spondylitis, chronic polyar‘thritis, myasthenia gravis, multiple sclerosis, chronic in?ammatory demyelinating poly neuropathy, Guillan-Barre syndrome, dermatomyositis/poly myositis, autoimmune hemolytic anemia, thrompocytopenic purpura, neutropenia, typeI diabetes mellitus, thyroiditis (in
one or more cytostatic or cytotoxic compounds, for example a chemotherapeutic agent or several selected from the group
comprising indarubicin, cytarabine, interferon, hydroxyurea, bisulfan, or an inhibitor of polyamine biosynthesis, an inhibi
tor of protein kinase, especially of serine/threonine protein kinase, such as protein kinase C, or of tyrosine protein kinase, such as epidermal groWth factor receptor tyrosine kinase, a cytokine, a negative groWth regulator, such as TGF-[3 or IFN
cluding Hashimoto’ s and Grave’ disease), Addison’ s disease,
polyglandular syndrome, pemphigus (vulgaris, foliaceus, sebaceous and vegetans), bullous and cicatricial pemphigoid, ear IgA disease, lichen sclerosus et atrophicus, morbus
[3, an aromatase inhibitor, a classical cytostatic, an inhibitor of the interaction of an SH2 domain With a phosphorylated protein, an inhibitor of Bcl-2 and modulators of the Bcl-2
Duhring, psoriasis vulgaris, guttate, generaliZed pustular and localiZed pustular psoriasis, vitiligo, alopecia greata, primary
only proteins.
pemphigoid gestationis, epidermolysis bullosa acquisita, lin
biliary cirrhosis, autoimmune hepatitis, all forms of glom
family members such as Bax, Bid, Bad, Bim, Nip3 and BH3 20
A compound according to the invention is not only for the
erulo-nephritis, pulmonal hemorrhage (goodpasture syn
(prophylactic and preferably therapeutic) management of
drome), IgA nephropathy, pernicious anemia and autoim
humans, but also for the treatment of other Warm-blooded
mune gastritis, in?ammatory boWel diseases (including colitis ulcerosa and morbus Crohn), Behcet’s disease, Celic
animals, for example of commercially useful animals, for
Sprue disease, autoimmune uveitis, autoimmune myocardi tis, granulomatous orchitis, aspermatogenesis Without orchi tis, idiopatic and secondary pulmonary ?brosis,
example rodents, such as mice, rabbits or rats, or guinea-pigs. 25
other compounds. With the groups of preferred compounds of formula (I)
in?ammatory diseases With a possibility of autoimmune pathogensesis, such as pyoderma gangrensosum, lichen
ruber, sarcoidosis (including Lofgren and cutaneous/subcu taneous type), granuloma anulare, allergic type I and type IV
mentioned hereinafter, de?nitions of substituents from the 30
immunolgical reaction, asthma bronchiale, pollinosis, atopic, contact and airborne dermatitis, large vessel vasculitis (giant cell and Takayasu’s arteritis), medium siZed vessel vasculitis (polyarteritis nodosa, Kawasaki disease), small vessel vascu
35
litis (Wegener’s granulomatosis, Churg Strauss syndrome, microscopic polangiitis, Henoch-Schoenlein purpura, essen tial cryoglobulinemic vasculitis, cutaneous leukoklastic
angiitis), hypersensitivity syndromes, toxic epidermal necrolysis (Stevens-Johnson syndrome, erythema multi
40
(Coombs classi?cation) immunologic forms of reaction, 45
organs (skin, heart, kidney, bone marroW, eye, liver, spleen, lung, muscle, central and peripheral nerve system, connective tissue, bone, blood and lymphatic vessel, genito-urinary sys tem, ear, cartillage, primary and secondary lymphatic system
including bone marroW, lymph node, thymus, gastrointestinal tract, including oro-pharynx, esophageus, stomach, small intestine, colon, and rectum, including parts of above men tioned organs doWn to single cell level and substructures, e.g. stem cells). A compound of formula (I) can be administered alone or in
general de?nitions mentioned hereinbefore may reasonably be used, for example, to replace more general de?nitions With more speci?c de?nitions or especially With de?nitions char acteriZed as being preferred. In particular, the invention relates to compounds of for mula (I) Wherein R represents aryl or heteroaryl optionally substituted by up to four substituents independently selected from
alkyl, cycloalkyl, cycloalkyl-loWer alkyl, halo-loWer alkyl, hydroxy-loWer alkyl, loWer alkoxy-loWer alkyl, loWer alkoxy-loWer alkoxy-loWer alkyl, halo-loWer alkoxy-loWer
alkyl, acyloxy-loWer alkyl, heterocyclyl, heterocyclyl-lower
forme), diseases due to drug side effects, all forms of cutane ous, organ-speci?c and systemic effects due to type I-VI transplantation related pathologies, such as acute and chronic graft versus host and host versus graft disease, involving all
Such a compound may also be used as a reference standard in
the test systems described above to permit a comparison With
50
55
alkyl, optionally substituted phenyl, optionally substituted phenyl-loWer alkyl, optionally substituted heteroaryl, option ally substituted heteroaryl-loWer alkyl, optionally substituted alkenyl, optionally substituted alkinyl, hydroxy, loWer alkoxy, optionally substituted alkenyloxy, optionally substi tuted alkinyloxy, cycloalkoxy, halo-loWer alkoxy, cycloalkyl loWer alkoxy, hydroxy-loWer alkoxy, loWer alkoxy-loWer alkoxy, heterocyclyloxy, heterocyclyl-lower alkoxy, option ally substituted phenyloxy, optionally substituted phenyl loWer alkoxy, optionally substituted heteroaryloxy, option ally substituted heteroaryl-loWer alkoxy, sulfamoyloxy, carbamoyloxy, loWer alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminocarbony lamino Wherein each of the tWo amino groups is optionally
combination With one or more other therapeutic agents, pos
substituted by alkyl, alkenyl, alkinyl or alkoxy-loWer alkyl,
sible combination therapy taking the form of ?xed combina
heterocyclylcarbonylamino Wherein heterocyclyl is bound
tions, or the administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another, or the combined admin
tWo amino groups is optionally substituted by alkyl, alkenyl,
via a nitrogen atom, amino sulfonylamino Wherein each of the 60
alkinyl or alkoxy-loWer alkyl, heterocyclylsulfonylamino
istration of ?xed combinations and one or more other thera
Wherein heterocyclyl is bound via a nitrogen atom, loWer
peutic agents. A compound of formula (I) can, besides or in addition, be administered especially for tumor therapy in
alkyl is optionally substituted by one or tWo substituents
alkoxycarbonylamino, loWer alkylcarbonylamino Wherein
combination With chemotherapy, radiotherapy, immuno therapy, surgical intervention, or a combination of these.
Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described
65
selected from optionally substituted phenyl, guanidyl, halo gen, cyano, alkoxy, optionally substituted phenoxy, alkylm ercapto and optionally substituted amino; loWer alkenylcar bonylamino Wherein alkenyl is optionally substituted by one
US RE42,890 E 11
12
or tWo substituents selected from lower alkyl, halo-loWer
stituted phenylsul?nyl, loWer alkylsulfonyl, halo-loWer
alkyl, optionally substituted phenyl, halogen, cyano, alkoxy
alkylsulfonyl, optionally substituted phenylsulfonyl, aralkyl
and optionally substituted amino; amino-loWer alkyl or amino-loWer alkylamino, Wherein the nitrogen atom is
sulfonyl, halogen, or nitro,
unsubstituted or substituted by one or tWo substitutents
or R3 and R4, R4 and R5 , or R5 and R6 together With the atoms of the phenyl ring form a 5 or 6 membered carbocyclic or
selected from loWer alkyl, cycloalkyl, cycloalkyl-loWer alkyl,
heterocyclic ring;
hydroXy-loWer alkyl, loWer alkoXy-loWer alkyl, optionally substituted phenyl, optionally substituted phenyl-loWer alkyl,
and salts thereof.
More particularly the invention relates to compounds of formula (I) Wherein
optionally substituted heteroaryl, optionally substituted het eroaryl-loWer alkyl and loWer alkylcarbonyl, or Wherein the tWo substituents on nitrogen form together With the nitrogen
R represents phenyl, naphthyl, thienyl, furyl, thiaZolyl, oxa
diaZolyl, thiadiaZolyl, imidaZolyl, pyraZolyl, pyridinyl, pyri midinyl, benZothienyl, benZofuryl, indolyl, benZoisoXaZolyl,
heterocyclyl, loWer alkylcarbonyl, cycloalkylcarbonyl, optionally substituted phenylcarbonyl, optionally substituted
optionally substituted by up to four substituents indepen
heteroarylcarbonyl, heterocyclylcarbonyl, carboxy, loWer alkoxycarbonyl, hydroXy-loWer alkoxycarbo nyl, loWer alkoXy-loWer alkoxycarbonyl, optionally substi tuted phenyl-loWer alkoxycarbonyl, cyano, loWer alkylmercapto, optionally substituted phenylmercapto, loWer alkylsul?nyl, halo-loWer alkylsul?nyl, optionally sub stituted phenylsul?nyl, loWer alkylsulfonyl, halo-loWer
20
alkylsulfonyl, optionally substituted phenylsulfonyl, aralkyl sulfonyl, halogen, and nitro; and Wherein tWo adjacent sub stituents together With the atoms of aryl or heteroaryl may form a 5 or 6 membered carbocyclic or heterocyclic ring; X represents oxygen; or a group C:Y, WhereinY stands for
25
oxygen, nitrogen substituted by hydroxy or alkoxy;
R1 and R2, independently of each other, represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted ary lalkyl, optionally substituted heteroarylalkyl, hydroxyalkyl,
alkoxyalkyl,
hydroxyalkoxyalkyl,
alkoxyalkoxyalkyl,
30
dently selected from alkyl, cycloalkyl, cycloalkyl-loWer alkyl, halo-loWer alkyl, hydroXy-loWer alkyl, loWer alkoxy loWer alkyl, loWer alkoXy-loWer alkoxy-loWer alkyl, halo loWer alkoxy-loWer alkyl, acyloXy-loWer alkyl, heterocyclyl, heterocyclyl-loWer alkyl, optionally substituted phenyl, optionally substituted phenyl-loWer alkyl, optionally substi tuted heteroaryl, optionally substituted heteroaryl-loWer alkyl, optionally substituted alkenyl, optionally substituted alkinyl, hydroxy, loWer alkoxy, optionally substituted alkeny loxy, optionally substituted alkinyloxy, cycloalkoxy, halo loWer alkoxy, cycloalkyl-loWer alkoxy, hydroXy-loWer alkoxy, loWer alkoxy-loWer alkoxy, heterocyclyloxy, hetero cyclyl-loWer alkoxy, optionally substituted phenyloxy, optionally substituted phenyl-loWer alkoxy, optionally sub stituted heteroaryloxy, optionally substituted heteroaryl loWer alkoxy, sulfamoyloxy, carbamoyloxy, loWer alkylcar
tuted alkinyl, or loWer alkylcarbonyl Wherein loWer alkyl is
bonyloxy, amino, monoalkylamino, dialkylamino, aminocarbony
optionally substituted by one or tWo substitutents selected
lamino Wherein each of the tWo amino groups is optionally
cyanoalkyl, optionally substituted alkenyl, optionally substi from aryl, optionally substituted amino, alkoxy and aryloxy, R3, R4, R5 and R6, independently of each other, represent hydrogen, loWer alkyl, halo-loWer alkyl, cycloalkyl,
substituted by alkyl, alkenyl, alkinyl or alkoxy-loWer alkyl, 35
heterocyclylcarbonylamino Wherein heterocyclyl is bound Via a nitrogen atom, amino sulfonylamino Wherein each of the
cycloalkyl-loWer alkyl, hydroXy-loWer alkyl, loWer alkoxy
tWo amino groups is optionally substituted by alkyl, alkenyl,
loWer alkyl, loWer alkoxy-loWer alkoxy-loWer alkyl, halo
alkinyl or alkoxy-loWer alkyl, heterocyclylsulfonylamino
loWer alkoXy-loWer alkyl, heterocyclyl, heterocyclyl-loWer alkyl, optionally substituted phenyl, optionally substituted phenyl-loWer alkyl, optionally substituted heteroaryl, option ally substituted heteroaryl-loWer alkyl, optionally substituted alkenyl, optionally substituted alkinyl, hydroxy, loWer alkoxy, halo-loWer alkoxy, cycloalkoxy, cycloalkyl-loWer alkoxy, hydroXy-loWer alkoxy, loWer alkoxy-loWer alkoxy, heterocyclyloxy, heterocyclyl-loWer alkoxy, optionally substituted phenyloxy, optionally substi tuted phenyl-loWer alkoxy, optionally substituted heteroary loxy, optionally substituted heteroaryl-loWer alkoxy,
Wherein heterocyclyl is bound Via a nitrogen atom, loWer
amino, carbamoyl, sulfamoyl, amino-loWer alkyl or amino
40
alkoxycarbonylamino, loWer alkylcarbonylamino Wherein alkyl is optionally substituted by one or tWo substituents
selected from optionally substituted phenyl, guanidyl, halo gen, cyano, alkoxy, optionally substituted phenoxy, alkylm ercapto and optionally substituted amino; loWer alkenylcar bonylamino Wherein alkenyl is optionally substituted by one or tWo substituents selected from loWer alkyl, halo-loWer
alkyl, optionally substituted phenyl, halogen, cyano, alkoxy and optionally substituted amino; amino-loWer alkyl or amino-loWer alkylamino, Wherein the nitrogen atom is 50
unsubstituted or substituted by one or tWo substitutents
loWer alkylamino, Wherein in each case the nitrogen atom is
selected from loWer alkyl, cycloalkyl, cycloalkyl-loWer alkyl,
unsubstituted or substituted by one or tWo substitutents
hydroXy-loWer alkyl, loWer alkoxy-loWer alkyl, optionally substituted phenyl, optionally substituted phenyl-loWer alkyl,
selected from loWer alkyl, cycloalkyl, cycloalkyl-loWer alkyl,
hydroXy-loWer alkyl, loWer alkoXy-loWer alkyl, optionally substituted phenyl, optionally substituted phenyl-loWer alkyl,
optionally substituted heteroaryl, optionally substituted het
optionally substituted heteroaryl, optionally substituted het
eroaryl-loWer alkyl and loWer alkylcarbonyl, or Wherein the tWo substituents on nitrogen form together With the nitrogen
eroaryl-loWer alkyl and loWer alkylcarbonyl, or Wherein the tWo substituents on nitrogen form together With the nitrogen
heterocyclyl, loWer alkylcarbonyl, cycloalkylcarbonyl, optionally substituted phenylcarbonyl, optionally substituted
55
heterocyclyl, loWer alkylcarbonyl, cycloalkylcarbonyl, optionally substi tuted phenylcarbonyl, optionally substituted heteroarylcar
60
heteroarylcarbonyl, heterocyclylcarbonyl, carboxy, loWer alkoxycarbonyl, hydroXy-loWer alkoxycarbo
65
tuted phenyl-loWer alkoxycarbonyl, cyano, loWer alkylmercapto, optionally substituted phenylmercapto, loWer alkylsul?nyl, halo-loWer alkylsul?nyl, optionally sub stituted phenylsul?nyl, loWer alkylsulfonyl, halo-loWer
nyl, loWer alkoxy-loWer alkoxycarbonyl, optionally substi
bonyl, heterocyclylcarbonyl, carboxy, loWer alkoxycarbonyl, hydroXy-loWer alkoxycarbo nyl, loWer alkoXy-loWer alkoxycarbonyl, optionally substi tuted phenyl-loWer alkoxycarbonyl, cyano, loWer alkylmercapto, optionally substituted phenylmercapto, loWer alkylsul?nyl, halo-loWer alkylsul?nyl, optionally sub
alkylsulfonyl, optionally substituted phenylsulfonyl, aralkyl sulfonyl, halogen, and nitro;
US RE42,890 E 13
14
and wherein tWo adjacent substituents together With the
alkyl, optionally substituted phenyl, halogen, cyano, alkoxy
atoms of aryl or heteroaryl may form a 5 or 6 membered
carbocyclic or heterocyclic ring;
and optionally substituted amino; amino-loWer alkyl or amino-loWer alkylamino, Wherein the nitrogen atom is
X represents oxygen; or a group C:Y, WhereinY stands for
unsubstituted or substituted by one or tWo substitutents
oxygen or nitrogen substituted by hydroxy or alkoxy;
selected from loWer alkyl, cycloalkyl, cycloalkyl-loWer alkyl,
R1 and R2, independently of each other, represent hydrogen, loWer alkylcarbonyl or optionally substituted phenylcarbo
hydroxy-loWer alkyl, loWer alkoxy-loWer alkyl, optionally substituted phenyl, optionally substituted phenyl-loWer alkyl,
nyl;
optionally substituted heteroaryl, optionally substituted het
R3, R4, R5 and R6, independently of each other, represent hydrogen, loWer alkyl, halo-loWer alkyl, alkoxy, hydroxy loWer alkoxy, loWer alkoxy-loWer alkoxy, amino, carbamoyl,
eroaryl-loWer alkyl and loWer alkylcarbonyl, or Wherein the tWo substituents on nitrogen form together With the nitrogen
sulfamoyl, amino-loWer alkyl or amino-loWer alkylamino,
heterocyclyl, loWer alkylcarbonyl, cycloalkylcarbonyl, optionally substituted phenylcarbonyl, optionally substituted
Wherein in each case the nitrogen atom is unsubstituted or substituted by one or tWo substitutents selected from loWer
heteroarylcarbonyl, heterocyclylcarbonyl, carboxy, loWer alkoxycarbonyl, hydroxy-loWer alkoxycarbo
alkyl, cycloalkyl, cycloalkyl-loWer alkyl, hydroxy-loWer
nyl, loWer alkoxy-loWer alkoxycarbonyl, optionally substi
alkyl, loWer alkoxy-loWer alkyl, optionally substituted phe nyl, optionally substituted phenyl-loWer alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl
tuted phenyl-loWer alkoxycarbonyl, cyano, loWer alkylmercapto, optionally substituted phenylmercapto, loWer alkylsul?nyl, halo-loWer alkylsul?nyl, optionally sub stituted phenylsul?nyl, loWer alkylsulfonyl, halo-loWer
loWer alkyl and loWer alkylaminocarbonyl, or Wherein the tWo substituents on nitrogen form together With the nitrogen
20
heterocyclyl, carboxy, loWer alkoxycarbonyl, hydroxy-loWer alkoxycarbonyl, loWer alkoxy-loWer alkoxycarbonyl, option ally substituted phenyl-loWer alkoxycarbonyl, cyano, loWer alkylmercapto, optionally substituted phenylmercapto, loWer alkylsul?nyl, halo-loWer alkylsul?nyl, optionally sub stituted phenylsul?nyl, loWer alkylsulfonyl, halo-loWer
and Wherein tWo adjacent sub stituents together With the atoms of aryl or heteroaryl may form a 5 or 6 membered
carbocyclic or heterocyclic ring; 25
alkylsulfonyl, optionally substituted phenylsulfonyl, aralkyl sulfonyl, halogen, or nitro, or R3 and R4, R4 and R5, or R5 and R6 together represent
methylenedioxy;
30
and salts thereof.
Preferred are compounds of formula (I) Wherein
nitrogen substituted by hydroxy or alkoxy; R1 and R2, independently of each other, represent hydrogen or loWer alkylcarbonyl; R3 , R4, R5 and R6, independently of each other, represent hydrogen, loWer alkyl, halo-loWer alkyl, hydroxy, loWer alkoxy, carboxy, loWer alkoxycarbonyl, cyano, halogen or and salts thereof. Most preferably, the invention relates to the compounds of
35
optionally substituted by up to four substituents indepen
dently selected from alkyl, halo-loWer alkyl, hydroxy-loWer alkyl, loWer alkoxy-loWer alkyl, loWer alkoxy-loWer alkoxy loWer alkyl, halo-loWer alkoxy-loWer alkyl, acyloxy-loWer
alkyl, heterocyclyl, heterocylyl-loWer alkyl, optionally sub stituted phenyl, optionally substituted phenyl-loWer alkyl,
X represents a group C:Y, WhereinY stands for oxygen or
nitro;
R represents phenyl, naphthyl, thienyl, furyl, thiaZolyl, oxa
diaZolyl, thiadiaZolyl, imidaZolyl, pyraZolyl, pyridinyl, pyri midinyl, benZothienyl, benZofuryl, indolyl, benZoisoxaZolyl,
alkylsulfonyl, optionally substituted phenylsulfonyl, aralkyl sulfonyl, halogen, and nitro;
40
the Examples and pharmaceutically acceptable salts, espe cially to the compounds
4-(1 -Phenacyl- l H-benZimidaZol-2-yl)-furaZan-3 -ylamine; 4-(1 -Phenacyl- l H-benZimidaZol-2-yl)-furaZan-3 -ylamine oxime; 4-(1 -Phenacyl- l H-benZimidaZol-2-yl)-furaZan-3 -ylamine oxime methyl ether;
optionally substituted heteroaryl, optionally substituted het
4-[ l -(4 -Bromophenacyl)- l H-benZimidaZol-2 -yl] -furaZan-3 -
eroaryl-loWer alkyl, optionally substituted alkenyl, option ally substituted alkinyl, hydroxy, loWer alkoxy, optionally substituted alkenyloxy,
4-[ l -(4 -Bromophenacyl)- l H-benZimidaZol-2 -yl] -furaZan-3 -
ylamine; 45
ylamine oxime;
optionally substituted alkinyloxy, cycloalkoxy, halo-loWer
4-[ l -(4 -Bromophenacyl)- l H-benZimidaZol-2 -yl] -furaZan-3 -
alkoxy, cycloalkyl-loWer alkoxy, hydroxy-loWer alkoxy, loWer alkoxy-loWer alkoxy, heterocyclyloxy, heterocyclyl
4-[ l -(4 -Chlorophenacyl)- l H-benZimidaZol-2 -yl] -furaZan-3 -
loWer alkoxy, optionally substituted phenyloxy, optionally substituted phenyl-loWer alkoxy, optionally substituted het eroaryloxy, optionally substituted heteroaryl-loWer alkoxy, sulfamoyloxy, carbamoyloxy, loWer alkylcarbonyloxy,
ylamine oxime methyl ether;
ylamine; 50
ylamine oxime; 4-[ l -(4 -Chlorophenacyl)- l H-benZimidaZol-2 -yl] -furaZan-3 -
amino, monoalkylamino, dialkylamino, aminocarbony
ylamine oxime methyl ether; 4-[ l -(4 -Methoxyphenacyl)- l H-benZimidaZol-2 -yl] -furaZan
lamino Wherein each of the tWo amino groups is optionally
substituted by alkyl, alkenyl, alkinyl or alkoxy-loWer alkyl,
55
heterocyclylcarbonylamino Wherein heterocyclyl is bound
3-ylamine oxime;
Via a nitrogen atom, aminosulfonylamino Wherein each of the
4-[1-(3 -Methoxyphenacyl)- l H-benZimidaZol-2 -yl] -furaZan
3-ylamine;
alkinyl or alkoxy-loWer alkyl, heterocyclylsulfonylamino 60
4-[1-(3 -Methoxyphenacyl)- l H-benZimidaZol-2 -yl] -furaZan
alkyl is optionally substituted by one or tWo substituents
or tWo substituents selected from loWer alkyl, halo-loWer
4-[1-(3 -Methoxyphenacyl)- l H-benZimidaZol-2 -yl] -furaZan
3-ylamine oxime;
alkoxycarbonylamino, loWer alkylcarbonylamino Wherein selected from optionally substituted phenyl, guanidyl, halo gen, cyano, alkoxy, optionally substituted phenoxy, alkylm ercapto and optionally substituted amino; loWer alkenylcar bonylamino Wherein alkenyl is optionally substituted by one
3-ylamine; 4-[ l -(4 -Methoxyphenacyl)- l H-benZimidaZol-2 -yl] -furaZan
tWo amino groups is optionally substituted by alkyl, alkenyl, Wherein heterocyclyl is bound Via a nitrogen atom, loWer
4-[ l -(4 -Chlorophenacyl)- l H-benZimidaZol-2 -yl] -furaZan-3 -
3-ylamine oxime methyl ether; 4-[ l -(4 -Phenylphenacyl)- l H-benZimidaZol-2 -yl] -furaZan-3 65
ylamine; 4-[ l -(4 -Phenylphenacyl)- l H-benZimidaZol-2 -yl] -furaZan-3 -
ylamine oxime;
US RE42,890 E 15
16
4-[1-(4-Phenylphenacyl)-1H-benZimidaZol-Z-yl]-furaZan-3 -
X represents a group C:Y, WhereinY stands for oxygen or
ylamine oxime methyl ether; and 4-[1-(2,4-Dichlorophenacyl)-1H-benZimidaZol-2-yl]
nitrogen substituted by hydroxy or alkoxy;
Rl represents cyanoalkyl; R2 represents hydrogen; R3, R4, R5 and R6, independently of each other, represent hydrogen, loWer alkyl, halo-loWer alkyl, hydroxy, loWer
furaZan-3-ylamine; and to pharmaceutically acceptable salts thereof. In another embodiment, the invention relates to com
pounds of formula (I) Wherein R represents phenyl, naphthyl, thienyl, furyl, thiaZolyl, oxa
alkoxy, carboxy, loWer alkoxycarbonyl, cyano, halogen or
nitro;
diaZolyl, thiadiaZolyl, imidaZolyl, pyraZolyl, pyridinyl, pyri midinyl, benZothienyl, benZofuryl, indolyl, benZoisoxaZolyl,
and salts thereof.
optionally substituted by up to four substituents indepen
mula (I) Wherein R, X and R2 to R6 are as de?ned in the
dently selected from alkyl, halo-loWer alkyl, hydroxy-loWer alkyl, loWer alkoxy-loWer alkyl, loWer alkoxy-loWer alkoxy loWer alkyl, halo-loWer alkoxy-loWer alkyl, acyloxy-loWer
preceding paragraphs and R1 represents hydroxyalkyl, and
alkyl, heterocyclyl, heterocyclyl-loWer alkyl, optionally sub stituted phenyl, optionally substituted phenyl-loWer alkyl,
pounds of formula (I) Wherein R represents phenyl, thienyl, pyridinyl or pyridaZinyl, option
optionally substituted heteroaryl, optionally substituted het
ally substituted by one or tWo substituents independently selected from
eroaryl-loWer alkyl, optionally substituted alkenyl, option ally substituted alkinyl, hydroxy, loWer alkoxy, optionally substituted alkenyloxy,
Alternatively, the invention relates to compounds of for
salts thereof. In yet another embodiment, the invention relates to com
20
optionally substituted alkinyloxy, cycloalkoxy, halo-loWer
alkoxy, cycloalkyl-loWer alkoxy, hydroxy-loWer alkoxy, loWer alkoxy-loWer alkoxy, heterocyclyloxy, heterocyclyl loWer alkoxy, optionally substituted phenyloxy, optionally substituted phenyl-loWer alkoxy, optionally substituted het eroaryloxy, optionally substituted heteroaryl-lower alkoxy, sulfamoyloxy, carbamoyloxy, loWer alkylcarbonyloxy,
25
the nitrogen heterocyclyl, loWer alkylcarbonyl, formyl, 30
substituted by alkyl, alkenyl, alkinyl or alkoxy-loWer alkyl, heterocyclylcarbonylamino Wherein heterocyclyl is bound
carboxy, loWer alkoxycarbonyl, cyano, halogen, and nitro; and Wherein tWo adjacent substituents are methylenedioxy; X represents oxygen; a group C:Y, WhereinY stands for oxygen or nitrogen substituted by hydroxy or alkoxy; or a
via a nitrogen atom, aminosulfonylamino Wherein each of the
tWo amino groups is optionally substituted by alkyl, alkenyl,
alkinyl or alkoxy-loWer alkyl, heterocyclylsulfonylamino
nylamino, loWer alkylcarbonylamino, substituted amino Wherein the tWo substituents on nitrogen form together With
amino, monoalkylamino, dialkylamino, aminocarbony lamino Wherein each of the tWo amino groups is optionally
alkyl, halo-loWer alkyl, hydroxy-loWer alkyl, loWer alkoxy loWer alkyl, acyloxy-loWer alkyl, phenyl, hydroxy, loWer alkoxy, hydroxy-loWer alkoxy, loWer alkoxy loWer alkoxy, phenyl-loWer alkoxy, loWer alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, loWer alkoxycarbo
group iCO4CH:CHi Wherein the C:C bond is con 35
nected to R;
R1 represents hydrogen, loWer alkylcarbonyl, hydroxy-loWer
Wherein heterocyclyl is bound via a nitrogen atom, loWer
alkoxycarbonylamino, loWer alkylcarbonylamino Wherein
alkyl or cyano-loWer alkyl;
alkyl is optionally substituted by one or tWo substituents
R2, R3 and R6 represent hydrogen;
selected from optionally substituted phenyl, guanidyl, halo gen, cyano, alkoxy, optionally substituted phenoxy, alkylm ercapto and optionally substituted amino; loWer alkenylcar bonylamino Wherein alkenyl is optionally substituted by one
40
and salts thereof. Preferred are compounds of formula (I) Wherein
or tWo substituents selected from loWer alkyl, halo-loWer
alkyl, optionally substituted phenyl, halogen, cyano, alkoxy and optionally substituted amino; amino-loWer alkyl or amino-loWer alkylamino, Wherein the nitrogen atom is
R represents phenyl, thienyl, pyridinyl or pyridaZinyl, 45
Wherein phenyl is optionally substituted by one or tWo sub
50
hydroxy-loWer alkyl, loWer alkoxy-loWer alkyl, acyloxy loWer alkyl, phenyl, hydroxy, loWer alkoxy, hydroxy-loWer alkoxy, loWer alkoxy-loWer alkoxy, phenyl-loWer alkoxy, loWer alkylcarbonyloxy, amino, monoalkylamino, dialky
stituents independently selected from alkyl, halo-loWer alkyl,
unsubstituted or substituted by one or tWo substitutents
selected from loWer alkyl, cycloalkyl, cycloalkyl-loWer alkyl,
hydroxy-loWer alkyl, loWer alkoxy-loWer alkyl, optionally substituted phenyl, optionally substituted phenyl-loWer alkyl,
R4 and R5 , independently of each other, represent hydrogen, loWer alkyl or loWer alkoxy; or R4 and R5 together represent methylenedioxy;
optionally substituted heteroaryl, optionally substituted het
lamino, loWer alkoxycarbonylamino, loWer alkylcarbony
eroaryl-loWer alkyl and loWer alkylcarbonyl, or Wherein the tWo substituents on nitrogen form together With the nitrogen
nitrogen form together With the nitrogen heterocyclyl, loWer
heterocyclyl, loWer alkylcarbonyl, cycloalkylcarbonyl, optionally substituted phenylcarbonyl, optionally substituted
lamino, substituted amino Wherein the tWo substituents on
alkylcarbonyl, formyl, carboxy, loWer alkoxycarbonyl, 55
heteroarylcarbonyl, heterocyclylcarbonyl, carboxy, loWer alkoxycarbonyl, hydroxy-loWer alkoxycarbo
cyano, halogen, and nitro; and Wherein tWo adjacent sub stitu ents are methylenedioxy;
and Wherein pyridinyl or pyridaZinyl are optionally substi
nyl, loWer alkoxy-loWer alkoxycarbonyl, optionally substi
tuted by loWer alkoxy, amino or halogen;
tuted phenyl-loWer alkoxycarbonyl, cyano, loWer alkylmercapto, optionally substituted phenylmercapto, loWer alkylsul?nyl, halo-loWer alkylsul?nyl, optionally sub stituted phenylsul?nyl, loWer alkylsulfonyl, halo-loWer
X represents a group C:Y, WhereinY stands for oxygen or 60
Rl represents hydrogen, loWer alkylcarbonyl, hydroxy-loWer alkyl or cyano-loWer alkyl; R2, R3 and R6 represent hydrogen;
alkylsulfonyl, optionally substituted phenylsulfonyl, aralkyl sulfonyl, halogen, and nitro; and Wherein tWo adjacent substituents together With the atoms of aryl or heteroaryl may form a 5 or 6 membered
carbocyclic or heterocyclic ring;
nitrogen substituted by hydroxy or loWer alkoxy;
65
R4 and R5 , independently of each other, represent hydrogen, loWer alkyl or loWer alkoxy; or R4 and R5 together represent methylenedioxy; and pharmaceutically acceptable salts thereof.
US RE42,890 E 17
18
More preferred are compounds of formula (I) Wherein R represents phenyl, thienyl or pyridinyl
X represents oxygen;
Wherein phenyl is optionally substituted by one or tWo sub
alkyl or cyano-loWer alkyl; R2, R3 and R6 represent hydrogen;
Rl represents hydrogen, loWer alkylcarbonyl, hydroxy-loWer
stituents independently selected from alkyl, halo-loWer alkyl,
R4 and R5 , independently of each other, represent hydrogen, loWer alkyl or loWer alkoxy; or R4 and R5 together represent methylenedioxy; and pharmaceutically acceptable salts thereof. Likewise preferred are compounds of formula (I) Wherein
hydroxy-loWer alkyl, loWer alkoxy-loWer alkyl, acyloxy loWer alkyl, phenyl, hydroxy, loWer alkoxy, hydroxy-loWer alkoxy, loWer alkoxy-loWer alkoxy, phenyl-loWer alkoxy, loWer alkylcarbonyloxy, amino, monoalkylamino, dialky lamino, loWer alkoxycarbonylamino, loWer alkylcarbony
R and R1 to R6 are de?ned as in the preceding paragraphs, and
lamino, substituted amino Wherein the tWo substituents on
X represents nitrogen substituted by alkoxy, and pharmaceu tically acceptable salts thereof.
nitrogen form together With the nitrogen heterocyclyl, loWer alkylcarbonyl, carboxy, loWer alkoxycarbonyl, cyano, halo
Other preferred compounds that come into consideration are compounds of formula (I)
gen, and nitro; and Wherein tWo adjacent substituents are
methylenedioxy;
Wherein
and Wherein pyridinyl is optionally substituted by loWer alkoxy, amino or halogen;
Wherein phenyl is optionally substituted by one or tWo sub
R represents phenyl or pyridinyl
stituents independently selected from alkyl, halo-loWer alkyl,
X represents a group C:Y, WhereinY stands for oxygen or
nitrogen substituted by hydroxy or loWer alkoxy;
Rl represents hydrogen, loWer alkylcarbonyl, hydroxy-loWer
20
alkyl or cyano-loWer alkyl;
lamino, loWer alkoxycarbonylamino, loWer alkylcarbony
R2, R3 and R6 represent hydrogen; R4 and R5, independently of each other, represent hydrogen,
lamino, substituted amino Wherein the tWo substituents on
nitrogen form together With the nitrogen heterocyclyl, loWer
loWer alkyl or loWer alkoxy;
or R4 and R5 together represent methylenedioxy; and pharmaceutically acceptable salts thereof. Particularly preferred are compounds of formula (I)
25
ents are methylenedioxy;
and Wherein pyridinyl is optionally substituted by loWer alkoxy, amino or halogen;
R represents phenyl, thienyl, pyridinyl or pyridaZinyl, 30
stituents independently selected from alkyl, halo-loWer alkyl,
hydroxy-loWer alkyl, loWer alkoxy-loWer alkyl, acyloxy loWer alkyl, phenyl, hydroxy, loWer alkoxy, hydroxy-loWer alkoxy, loWer alkoxy-loWer alkoxy, phenyl-loWer alkoxy, loWer alkylcarbonyloxy, amino, monoalkylamino, dialky lamino, loWer alkoxycarbonylamino, loWer alkylcarbony
X represents oxygen;
Rl represents cyano-loWer alkyl; R2, R3, R4, R5 and R6 represent hydrogen; and pharmaceutically acceptable salts thereof. More preferred are compounds of formula (I) Wherein R represents phenyl or pyridinyl
35
Wherein phenyl is optionally substituted by one or tWo sub
stituents independently selected from alkyl, loWer alkoxy
loWer alkyl, acyloxy-loWer alkyl, hydroxy, loWer alkoxy, hydroxy-loWer alkoxy, loWer alkoxy-loWer alkoxy, amino, monoalkylamino, dialkylamino, loWer alkoxycarbony
lamino, substituted amino Wherein the tWo substituents on
nitrogen form together With the nitrogen heterocyclyl, loWer
alkylcarbonyl, formyl, carboxy, loWer alkoxycarbonyl, cyano, halogen, and nitro; and Wherein tWo adjacent substitu
alkylcarbonyl, carboxy, loWer alkoxycarbonyl, formyl, cyano, halogen, and nitro; and Wherein tWo adjacent sub stitu
Wherein
Wherein phenyl is optionally substituted by one or tWo sub
hydroxy-loWer alkyl, loWer alkoxy-loWer alkyl, acyloxy loWer alkyl, phenyl, hydroxy, loWer alkoxy, hydroxy-loWer alkoxy, loWer alkoxy-loWer alkoxy, phenyl-loWer alkoxy, loWer alkylcarbonyloxy, amino, monoalkylamino, dialky
40
lamino, loWer alkylcarbonylamino, substituted amino
ents are methylenedioxy;
Wherein the tWo substituents on nitrogen form together With
and Wherein pyridinyl or pyridaZinyl are optionally substi tuted by loWer alkoxy, amino or halogen;
the nitrogen heterocyclyl, halogen, and nitro;
X represents a group C:Y, WhereinY stands for oxygen or
and Wherein pyridinyl is optionally substituted by loWer alkoxy, amino or halogen;
nitrogen substituted by hydroxy or loWer alkoxy;
and Wherein tWo adjacent substituents are methylenedioxy; 45
Rl represents cyano-loWer alkyl; R2, R3 and R6 represent hydrogen; R4 and R5 , independently of each other, represent hydrogen, loWer alkyl or loWer alkoxy; or R4 and R5 together represent methylenedioxy; and pharmaceutically acceptable salts thereof. Highly preferred are compounds of formula (I) Wherein R represents phenyl or pyridinyl
X represents oxygen;
Rl represents cyano-loWer alkyl; R2, R3, R4, R5 and R6 represent hydrogen; 50
according to claim 8 Wherein
R represents phenyl or pyridinyl Wherein phenyl is optionally substituted by one or tWo sub
stituents independently selected from alkyl, loWer alkoxy
Wherein phenyl is optionally substituted by one or tWo sub
stituents independently selected from alkyl, halo-loWer alkyl,
55
hydroxy-loWer alkyl, loWer alkoxy-loWer alkyl, acyloxy loWer alkyl, phenyl, hydroxy, loWer alkoxy, hydroxy-loWer alkoxy, loWer alkoxy-loWer alkoxy, phenyl-loWer alkoxy, loWer alkylcarbonyloxy, amino, monoalkylamino, dialky lamino, loWer alkoxycarbonylamino, loWer alkylcarbony
and pharmaceutically acceptable salts thereof. Particularly preferred are compounds of formula (1)
loWer alkyl, acyloxy-loWer alkyl, hydroxy, loWer alkoxy, hydroxy-loWer alkoxy, loWer alkoxy-loWer alkoxy, amino, monoalkylamino, dialkylamino, loWer alkoxycarbony lamino, loWer alkylcarbonylamino, substituted amino Wherein the tWo substituents on nitrogen form together With
60
the nitrogen heterocyclyl, halogen, and nitro;
lamino, substituted amino Wherein the tWo substituents on
and Wherein tWo adjacent substituents are methylenedioxy;
nitrogen form together With the nitrogen heterocyclyl, loWer
and Wherein pyridinyl is optionally substituted by loWer alkoxy, amino or halogen;
alkylcarbonyl, carboxy, loWer alkoxycarbonyl, formyl,
X represents nitrogen substituted by alkoxy;
cyano, halogen, and nitro; and Wherein tWo adjacent substitu ents are methylenedioxy;
and Wherein pyridinyl is optionally substituted by loWer alkoxy, amino or halogen;
65
Rl represents cyano-loWer alkyl; R2, R3, R4, R5 and R6 represent hydrogen; and pharmaceutically acceptable salts thereof.
US RE42,890 E 19
20
Other preferred compounds of formula (I) are those
A) a process, Wherein a compound of formula (II)
Wherein R represents phenyl optionally substituted by one or tWo
substituents independently selected from alkyl, halo-loWer
(11)
alkyl, hydroxy-loWer alkyl, loWer alkoxy-loWer alkyl, acy loxy-loWer alkyl, phenyl, hydroxy, loWer alkoxy, hydroxy loWer alkoxy, loWer alkoxy-loWer alkoxy, phenyl-loWer alkoxy, loWer alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, loWer alkoxycarbonylamino, loWer alkylcar bonylamino, substituted amino Wherein the tWo substituents
on nitrogen form together With the nitrogen heterocyclyl, loWer alkylcarbonyl, carboxy, loWer alkoxycarbonyl, cyano, halogen, and nitro; and Wherein tWo adjacent sub stituents are
Wherein R1, R2, R3 , R4, R5 and R6 are de?ned as for formula (I), or a derivative thereof With functional groups in protected form and/or a salt thereof, is alkylated With an alkylating
methylenedioxy; X represents a group 4COiCH:CHi Wherein the C:C
bond is connected to R;
agent of formula (III)
R1 represents cyano-loWer alkyl; R2, R3, R4, R5 and R6 represent hydrogen; and pharmaceutically acceptable salts thereof.
20
Most preferred are compounds selected from the group
B) a process, Wherein a compound of formula (II) Wherein R1, R2, R3, R4, R5 and R6 are de?ned as for formula (I), or a derivative thereof With functional groups in protected form
4-[ l -(4-Chlorophenacyl)- l H-benZimidaZol-2 -yl] -furaZan-3 -
yl-N-(2-cyanoethyl)-amine; 25
imidaZol-2-yl] -furaZan-3-ylamine;
ethane type compound of formula Zl-CH2-Z2 (IV), wherein
yl-N-(2-cyanoethyl)-amine;
oxygen;
4-[ l -(4 -Aminophenacyl)- l H-benZimidaZol-2 -yl] -furaZan-3 30
4-[ l -(4-Methoxyphenacyl)- l H-benZimidaZol-2 -yl] -furaZan
35
4-[ l -(4-Ethylphenacyl)- l H-benZimidaZol-2 -yl] -furaZan-3 -
yl-N-(2-cyanoethyl)-amine; 3-ylamine; 40
3-ylamine; 45
described hereinbefore for use as medicaments.
The invention also relates to the use of a compound of
formula (I), a prodrug or a pharmaceutically acceptable salt of such a compound for the preparation of a pharmaceutical composition for the treatment of a neoplastic disease, autoim
50
mune disease, transplantation related pathology and/or degenerative disease, in particular for the treatment of a solid
neoplastic disease. Furthermore, the invention provides a method for the treat
ment of a neoplastic disease, autoimmune disease, transplan tation related pathology and/ or degenerative disease, in par ticular of a solid neoplastic disease, Which comprises
55
administering a compound of formula (I), a prodrug or a
pharmaceutically acceptable salt thereof, Wherein the radi cals and symbols have the meanings as de?ned above, in a quantity effective against said disease, to a Warm-blooded animal requiring such treatment.
60
Method of Preparation A compound of the invention may be prepared by pro cesses that, though not applied hitherto for the neW com
pounds of the present invention, are knoWn per se, in particu lar
bromide or iodide, or sulfonates, e.g. aromatic sulfonic acid esters such as benZenesulfonates, p-toluenesulfonates or p-nitrobenZenesulfonates, or also methanesulfonate or trif
luormethanesulfonate. Also other customary leaving groups are considered, e. g. ammonium salts, aZides, diaZonium salts,
and pharmaceutically acceptable salts thereof. Especially, the invention relates to compounds as
converted into another compound of formula (I), a free com pound of formula (I) is converted into a salt, an obtainable salt of a compound of formula (I) is converted into the free com pound or another salt, and/or a mixture of isomeric com
pounds of formula (I) is separated into the individual isomers. Suitable nucleophilic leaving groups Z in an alkylating agent of formula (III) are for example halides, e.g. chloride,
4-[ l -(6-Chloro-3 -pyridyl)- l H-benZimidaZol-2 -yl] -furaZan 4-[ l -(6 -Amino-3 -pyridyl)- l H-benZimidaZol-2 -yl] -furaZan 3-yl-N-(2-cyanoethyl)-amine; and 4-[ l -(6 -Amino-3 -pyridyl)- l H-benZimidaZol-2 -yl] -furaZan
any protecting groups in a protected derivative of a compound of the formula (I) are removed;
and, if so desired, an obtainable compound of formula (I) is
3-yl-N-(2-cyanoethyl)-amine; 4-[ l -(3 ,4-Dimethylphenacyl)- l H-benZimidaZol-2 -yl] -fura
Zan-3-yl-N-(2-cyanoethyl)-amine;
and/or a salt thereof, is alkylated With a mixture of a dihalom
Z1 and Z2 are leaving groups, and a compound of formula RiXH (V), Wherein R is as de?ned for formula (I) and X is
4-[ l -(4-Bromophenacyl)- l H-benZimidaZol-2 -yl] -furaZan-3 -
yl-N-(2-cyanoethyl)-amine;
CH:CHi and Z is a nucleophilic leaving group; or
consisting of 4 -[ l - (3 -Methoxy-4 -methoxymethoxy-phenacyl) - l H-b enZ
RiX4CH2-Z (111) wherein R is as de?ned for formula (I), X is CO or iCOi
65
di(p-toluenesulfonyl)-amines, nitrates, oxonium salts, sulfo nium salts, or phosphonium salts. Suitable nucleophilic leav ing groups Z1 and Z2 in a dihalomethane type compound formula (IV) are those mentioned above, in particular chlo rine, bromine and iodine. Alkylation of a compound of formula (II) With an alkylat ing agent of formula (III) is performed in a manner knoWn per se, usually in the presence of a suitable polar or dipolar aprotic solvent, With cooling or heating, for example in a temperature range from approximately —30° C. to approximately +150o C., especially approximately around 0° C. to room tempera ture. Optionally a suitable base is added, in particularly a tertiary amine base such as triethylamine or diisopropylethy lamine, or an inorganic basic salt, eg potassium or sodium carbonate. Mixed alkylation of a compound of formula (II) and of a compound of formula (V) With a dihalomethane type com pound of formula (IV) is performed in the presence of a
suitable polar or dipolar aprotic solvent, With cooling or heat ing, for example in a temperature range from approximately —30° C. to approximately +150o C., especially approximately around 0° C. to room temperature. Suitable bases used in this
reaction are for example potassium and sodium carbonate.
US RE42,890 E 21
22 under conditions used for amide formation knoWn per se in
If one or more other functional groups, for example car
boxy, hydroxy or amino, are or need to be protected in a
peptide chemistry, eg with activating agents for the carboxy
compound of formula (II), (III) or (V), because they should
group, such as 1-hydroxybenZotriaZole, optionally in the presence of suitable catalysts or co-reagents.
not take part in the reaction, these are such protecting groups
Compounds of formula (I) Wherein X:NOH may be alky
as are usually applied in the synthesis of amides, in particular
peptide compounds, cephalosporins, penicillins, nucleic acid
lated alloWing access to the corresponding oxime ethers. The reaction conditions leading to this transformation include
derivatives and sugars.
combinations of Weak bases and alkylating agents. Typical
The protecting-groups may already be present in precur sors and should protect the functional groups concerned
bases include metal carbonates or bicarbonates. Reduction of a nitro group in an nitro-substituted aryl or heteroaryl group R or in one of the substituents R3 , R4, R5 or
against unWanted secondary reactions, such as alkylations,
acylations, etheri?cations, esteri?cations, oxidations, sol
R6 to give the corresponding amino group is done, e.g., With iron poWder in alcohol or With other reducing agents. A carboxy group in a carboxy-substituted aryl or het
volysis, and similar reactions. It is a characteristic of protect
ing groups that they lend themselves readily, i.e. Without
undesired secondary reactions, to removal, typically by sol volysis, reduction, photolysis or also by enZyme activity, for example under conditions analogous to physiological condi
eroaryl group R or in one of the substituents R3 , R4, R5 or R6 may be amidated under conditions used for amide formation knoWn per se in peptide chemistry, e. g. With the correspond
tions, and that they are not present in the end products. The specialist knoWs, or can easily establish, Which protecting groups are suitable With the reactions mentioned hereinabove
and hereinafter.
20
ing amine and an activating agent for the carboxy group, such as 1-hydroxybenZotriaZole, optionally in the presence of suit able catalysts or co-reagents.
The protection of such functional groups by such protect ing groups, the protecting groups themselves, and their
A bromo or iodo substitutent in an aryl or heteroaryl group R or in one of the substituents R3, R4, R5 or Re may be
removal reactions are described for example in standard ref erence books for peptide synthesis and in special books on protective groups such as J. F. W. McOmie, “Protective
Groups in Organic Chemistry”, Plenum Press, London and
replaced by phenyl or a phenyl derivative by reaction With a suitable phenylboronic acid in a Suzuki reaction, preferably in a dipolar aprotic solvent such as dimethyl for'mamide, or in a polar ether, e. g. tetrahydrofuran or dimethoxyethane, in the
NeW York 1973, in “Methoden der organischen Chemie”
presence of a soluble palladium(0) or related metal catalyst,
(Methods of organic chemistry), Houben-Weyl, 4th edition,
for example tetrakis-(triphenylphosphine)palladium.
Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, and in T. W. Greene, “Protective Groups in Organic Synthesis”, Wiley,
25
Salts of a compound of formula (I) With a salt-forming 30
group may be prepared in a manner knoWn per se. Acid
NeW York. In the additional process steps, carried out as desired, func
addition salts of compounds of formula (I) may thus be
tional groups of the starting compounds Which should not take part in the reaction may be present in unprotected form or may be protected for example by one or more of the protect ing groups mentioned hereinabove under “protecting groups”. The protecting groups are then Wholly or partly
exchange reagent.
obtained by treatment With an acid or With a suitable anion
35
metal carbonates, alkali metal hydrogencarbonates, or alkali
metal hydroxides, typically potassium carbonate or sodium
hydroxide.
removed according to one of the methods described there. In the conversion of an obtainable compound of formula (1)
into another compound of formula (I), X With the meaning
40
C:Y WhereinY is oxygen may, for example, be reacted With an optionally O-substituted hydroxylamine to give the corre sponding oxime or oxime ether of formula (I) Wherein X is
C:Y andY is nitrogen substituted by hydroxy or alkoxy. An obtainable compound of formula (I), wherein R1 and/or R2 is hydrogen, may be alkylated or acylated With a com pound of formula Rl-Z or R2-Z, respectively, Wherein Z is a nucleophilic leaving group as described above, to give a com pound of formula (I), wherein R1 and/or R2 is different from hydrogen. Preferred acylation conditions include the use of acid anhydrides and acid chlorides at elevated temperatures, typically in a range from approximately +30o C. to approxi mately +150o C. An acidic or basic catalyst may be employed if desired. A compound of formula (I) wherein R1 and/or R2 is
alkyl may be obtained by alkylation of the parent compound of formula (1). Typical reaction conditions alloWing this trans formation include the combination of a strong base, such as a metal hydride or a metal alcoholate and a compound of for mula Rl-Z or R2-Z. Further amino groups present in an aryl or heteroaryl group R or in one of the substitutents R3, R4, R5 or R6 may be
It should be emphasiZed that reactions analogous to the conversions mentioned in this chapter may also take place at the level of appropriate intermediates. All process steps described here can be carried out under
knoWn reaction conditions, preferably under those speci? cally mentioned, in the absence of or usually in the presence 45
of solvents or diluents, preferably such as are inert to the
reagents used and able to dissolve these, in the absence or
presence of catalysts, condensing agents or neutralising
agents, for example ion exchangers, typically cation exchang ers, for example in the H+ form, depending on the type of 50
reaction and/or reactants at reduced, normal, or elevated tem
perature, for example in the range from —1000 C. to about 1900 C., preferably from about —80° C. to about 1500 C., for example at —80 to +600 C., at —20 to +400 C., at room tem 55
perature, or at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, Where appropriate under pressure, and/or in an inert atmosphere, for example under argon or nitrogen.
Salts may be present in all starting compounds and tran sients, if these contain salt-forming groups. Salts may also be 60
present during the reaction of such compounds, provided the reaction is not thereby disturbed.
transformed to other nitrogen containing substituents under conditions knoWn in the art. For example, alkylation at nitro gen may be performed With an aldehyde under reducing con
ditions. For acylation the corresponding acyl chloride (ZICl)
Salts can usually be converted to free compounds, eg by treating With suitable basic agents, for example With alkali
At all reaction stages, isomeric mixtures that occur can be
separated into their individual isomers, e.g. diastereomers or enantiomers, or into any mixtures of isomers, e.g. racemates 65
or diastereomeric mixtures.
is preferred. Alternatively, an acid anhydride may be used, or
The invention relates also to those forms of the process in
acylation may be accomplished With the free acid (ZIOH)
Which one starts from a compound obtainable at any stage as
US RE42,890 E 23
24
a transient and carries out the missing steps, or breaks off the process at any stage, or forms a starting material under the reaction conditions, or uses said starting material in the form of a reactive derivative or salt, or produces a compound obtainable by means of the process according to the invention
embodiment from approximately 20% to approximately 90% active ingredient and forms that are not of single-dose type
comprising in the preferred embodiment from approximately 5% to approximately 20% active ingredient. Unit dose forms are, for example, coated and uncoated tablets, ampoules, vials, suppositories, or capsules. Further dosage forms are,
and further processes the said compound in situ. In the pre ferred embodiment, one starts from those starting materials Which lead to the compounds described hereinabove as pre
for example, ointments, creams, pastes, foams, tinctures, lip sticks, drops, sprays, dispersions, etc. Examples are capsules
ferred, particularly as especially preferred, primarily pre
containing from about 0.05 g to about 1.0 g active ingredient.
The pharmaceutical compositions of the present invention
ferred, and/ or preferred above all. In the preferred embodiment, a compound of formula (I) is prepared according to or in analogy to the processes and process steps de?ned in the Examples.
are prepared in a manner knoWn per se, for example by means
of conventional mixing, granulating, coating, dissolving or lyophiliZing processes.
The compounds of formula (I), including their salts, are
Preference is given to the use of solutions of the active
also obtainable in the form of hydrates, or their crystals can
ingredient, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions Which, for example in the case of lyophiliZed compositions
include for example the solvent used for crystallization, ie be present as solvates. NeW starting materials and/or intermediates, as Well as
processes for the preparation thereof, are likeWise the subject of this invention. In the preferred embodiment, such starting
comprising the active ingredient alone or together With a carrier, for example mannitol, can be made up before use. The 20
pharmaceutical compositions may be steriliZed and/or may
materials are used and reaction conditions so selected as to
comprise excipients, for example preservatives, stabiliZers,
enable the preferred compounds to be obtained.
Wetting agents and/ or emulsi?ers, solubiliZers, salts for regu
Starting materials of formula (II), (III), (IV) and (V) are
lating osmotic pressure and/or buffers and are prepared in a manner knoWn per se, for example by means of conventional
knoWn, commercially available, or can be synthesiZed in analogy to or according to methods that are knoWn in the art.
25
The present invention relates also to pharmaceutical com
positions that comprise a compound of formula (I) as active ingredient and that can be used especially in the treatment of the diseases mentioned at the beginning. Compositions for enteral administration, such as nasal, buccal, rectal or, espe
dissolving and lyophiliZing processes. The said solutions or
suspensions may comprise viscosity-increasing agents, typi cally sodium carboxymethylcellulose, carboxymethylcellu
Pharmaceutical Preparations, Methods, and Uses
lose, dextran, polyvinylpyrrolidone, or gelatins, or also solu biliZers, e.g. TWeen 80® (polyoxyethylene(20)sorbitan 30
mono-oleate). Suspensions in oil comprise as the oil component the veg
etable, synthetic, or semi-synthetic oils customary for injec
cially, oral administration, and for parenteral administration, such as intravenous, intramuscular or subcutaneous adminis
tion purposes. In respect of such, special mention may be
tration, to Warm-blooded animals, especially humans, are
made of liquid fatty acid esters that contain as the acid com
especially preferred. The compositions comprise the active
35
ingredient alone or, preferably, together With a pharmaceuti cally acceptable carrier. The dosage of the active ingredient
these fatty acid esters has a maximum of 6 carbon atoms and is a monovalent or polyvalent, for example a mono-, di- or
depends upon the disease to be treated and upon the species,
trivalent, alcohol, especially glycol and glycerol. As mixtures
its age, Weight, and individual condition, the individual phar macokinetic data, and the mode of administration.
40
The present invention relates especially to pharmaceutical compositions that comprise a compound of formula (I), a tautomer, a prodrug or a pharmaceutically acceptable salt, or a hydrate or solvate thereof, and at least one pharmaceutically
acceptable carrier.
45
The invention relates also to pharmaceutical compositions
of fatty acid esters, vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and groundnut oil are especially useful. The manufacture of injectable preparations is usually car ried out under sterile conditions, as is the ?lling, for example, into ampoules or vials, and the sealing of the containers. Suitable carriers are especially ?llers, such as sugars, for
example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/ or calcium phosphates, for example trical cium phosphate or calcium hydrogen phosphate, and also
for use in a method for the prophylactic or especially thera
peutic management of the human or animal body, in particu lar in a method of treating neoplastic disease, autoimmune
disease, transplantation related pathology and/or degenera
ponent a long-chained fatty acid having from 8 to 22, espe cially from 12 to 22, carbon atoms. The alcohol component of
50
binders, such as starches, for example corn, Wheat, rice or
potato starch, methylcellulose, hydroxypropyl methylcellu
tive disease, especially those mentioned hereinabove. The invention relates also to processes and to the use of
lose, sodium carboxymethylcellulose, and/or polyvinylpyr
compounds of formula (I) thereof for the preparation of phar maceutical preparations Which comprise compounds of for mula (I) as active component (active ingredient). A pharmaceutical composition for the prophylactic or especially therapeutic management of a neoplastic disease, autoimmune disease, transplantation related pathology and/
rolidone, and/or, if desired, disintegrators, such as the above
or degenerative disease, of a Warm-blooded animal, espe cially a human or a commercially useful mammal requiring
mentioned starches, also carboxymethyl starch, crosslinked 55
sodium alginate. Additional excipients are especially ?oW conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium 60
dose administration forms comprising in the preferred
stearate, and/or polyethylene glycol, or derivatives thereof. Tablet cores can be provided With suitable, optionally
enteric, coatings through the use of, inter alia, concentrated sugar solutions Which may comprise gum arabic, talc, poly vinyl-pyrrolidone, polyethylene glycol and/or titanium diox
such treatment, comprising a novel compound of formula (I) as active ingredient in a quantity that is prophylactically or
especially therapeutically active against the said diseases, is likeWise preferred. The pharmaceutical compositions comprise from approxi mately 1% to approximately 95% active ingredient, single
polyvinylpyrrolidone, alginic acid or a salt thereof, such as
65
ide, or coating solutions in suitable organic solvents or sol vent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl-methylcellulose phtha
US RE42,890 E 25
26
late. Dyes or pigments may be added to the tablets or tablet coatings, for example for identi?cation purposes or to indi
The folloWing Examples serve to illustrate the invention Without limiting the invention in its scope.
cate different doses of active ingredient. Pharmaceutical compositions for oral administration also
EXAMPLES
include hard capsules consisting of gelatin, and also soft, Abbreviations:
sealed capsules consisting of gelatin and a plasticiZer, such as glycerol or sorbitol. The hard capsules may contain the active
DMSO
ingredient in the form of granules, for example in admixture With ?llers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or
Example 1
suspended in suitable liquid excipients, such as fatty oils, paraf?n oil or liquid polyethylene glycols or fatty acid esters
4-(1-Phenacyl-1H-benZimidaZol-2-yl)-furaZan-3 -
ylamine
of ethylene or propylene glycol, to Which stabiliZers and
detergents, for example of the polyoxyethylene sorbitan fatty
Phenacylbromid (0.1 g, 0.49 mmol) is added to an e?i
acid ester type, may also be added.
ciently stirred suspension of 4-(1H-benZimidaZol-2-yl)-fura Zan-3-ylamine (0.1 g, 0.4 mmol) [A. V. Sergievskii, O. A.
Pharmaceutical compositions suitable for rectal adminis tration are, for example, suppositories that consist of a com bination of the active ingredient and a suppository base. Suit
Krasnoshek, S. F. Mel’nikova, I. V. Tselinskii, Russian Jour 20
able suppository bases are, for example, natural or synthetic
temperature. After 4 hours the reaction mixture is diluted With 25
ethyl acetate and the organic phase is Washed repeatedly With brine. Drying of the solvent, ?ltering and evaporation of the solvent under reduced pressure gives the title compound in crude form. The title compound is obtained in pure form by chromatography over silicagel, mp. 202-2040 C.
tain viscosity-increasing substances, for example sodium car
boxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers, are especially suitable. The active ingredient, optionally together With excipients, can also be in the form of
nal of Organic Chemistry, 2002, 38, 915-917] and potassium carbonate (0.172 g, 1.24 mmol) in dry DMF (5 ml) at room
triglycerides, paraf?n hydrocarbons, polyethylene glycols or higher alkanols. For parenteral administration, aqueous solutions of an active ingredient in Water-soluble form, for example of a Water-soluble salt, or aqueous injection suspensions that con
dimethyl:sulfoxide;
THF?etrahydrofuran, DMAP:N,N-dimethylaminopyri dine, DMF:N,N-dimethylformamide, DlPEA:N,N-diiso propyl-N-ethylamine.
Example 2 30
a lyophiliZate and can be made into a solution before
4- [1 -(4-Bromophenacyl)- 1 H-benZimidaZol-2-yl] -
parenteral administration by the addition of suitable solvents.
furaZan-3 -ylamine oxime
Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.
Preferred preservatives are, for example, antioxidants,
A mixture of 4-[1-(4-bromophenacyl)-1H-benZimidaZol 35
such as ascorbic acid, or microbicides, such as sorbic acid or
according to Example 1), sodium bicarbonate (0.021 g, 0.25 mmol) and hydroxylamine hydrochloride (0.014 g, 0.21 mmol) in ethanol (5 ml) is re?uxed for 20 hours. Partitioning
benZoic acid. The present invention relates furthermore to a method for the treatment of a neoplastic disease, autoimmune disease,
transplantation related pathology and/ or degenerative dis ease, Which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, Wherein the
of the reaction mixture betWeen ethyl acetate and Water, sepa 40
Methyl-{4- [1 -(4-chlorophenacyl)- 1 H-benZimidaZol 2-yl] -furaZan-3 -yl} -amine 50
individual having a bodyWeight of about 70 kg the daily dose administered is from approximately 0.05 g to approximately 5 g, preferably from approximately 0.25 g to approximately 1.5 g, of a compound of the present invention. The present invention relates especially also to the use of a
Example 3
45
cially in the form of pharmaceutical compositions, prophy lactically or therapeutically, preferably in an amount effective against the said diseases, to a Warm-blooded animal, for example a human, requiring such treatment. In the case of an
ration of the organic phase folloWed by drying and evapora tion of the solvent gives the crude product. Puri?cation by chromatography on silicagel yields the title compound as an E/Z-mixture, mp. 198-2010 C.
radicals and symbols have the meanings as de?ned above for formula (I), in a quantity effective against said disease, to a Warm-blooded animal requiring such treatment. The com pounds of formula (I) can be administered as such or espe
2-yl]-furaZan-3-ylamine (0.083 g, 0.21 mmol, prepared
A suspension of 4-[1-(4-chlorophenacyl)-1H-benZimida Zol-2-yl] -furaZan-3 -ylamine (0.10 g, 0.282 mmol, prepared according to Example 1), potassium carbonate (0.233 g, 1.69 mmol) and dimethylsulfate (0.142 g, 1.12 mmol) in acetone
55
(5 ml) is stirred at room temperature for 1 6 hours. Filtration of the solids, concentration of the ?ltrate under reduced pres sure
compound of formula (I), or a pharmaceutically acceptable salt thereof, especially a compound of formula (1) Which is
ethyl acetate as eluent gives the title compound as a colorless
said to be preferred, or a pharmaceutically acceptable salt
solid, mp. 210-2140 C.
and chromatography of the residue on silicagel using hexane
thereof, as such or in the form of a pharmaceutical formula
tion With at least one pharmaceutically acceptable carrier for the therapeutic and also prophylactic management of one or more of the diseases mentioned hereinabove, in particular a
60
Example 4
Dimethyl-{4-[1-(4-chlorophenacyl)-1H-benZimida Zol-2 -yl] -furaZan-3 -yl} -amine
neoplastic disease, autoimmune disease, transplantation related pathology and/ or degenerative disease.
The preferred dose quantity, composition, and preparation of pharmaceutical formulations (medicines) Which are to be
A suspension of 4-[1-4-chlorophenacyl)-lH-benzimida Zol-2-yl]-furaZan-3-ylamine (0.10 g, 0.282 mmol), potas
used in each case are described above.
sium carbonate (0.60 g, 4.22 mmol) and dimethylsulfate
65
US RE42,890 E 27
28
(0.50 g, 2.82 mmol) in DMF (5 ml) is stirred at 60° C. for 6 hours. The reaction mixture is diluted With ethyl acetate,
resulting residue betWeen Water and ethyl acetate folloWed by drying of the organic solution over sodium sulphate and chro matography of the residue gives the title compound as a
Washed With Water and dried over sodium sulphate. Filtration
of the sodium sulphate, concentration of the ?ltrate under reduced pressure and chromatography of the residue on sili cagel using hexane-ethyl acetate as eluent gives the title com pound as a yelloWish solid, mp. 120-123° C.
colorless solid, mp. 171 -173° C. 5
Example 8 4- [1 -(4-Fluorophenoxymethyl)- 1 H-benZimidaZol-2
yl] -furaZan-3 -ylamine
Example 5
N-{4-[1-(4-Chlorophenacyl)-1H-benZimidaZol-2-yl]
To a solution of 4-(1H-benZimidaZol-2-yl)-furaZan-3
furaZan-3 -yl } -acetamide
ylamine (0.10 g, 0.497 mmol) is added potassium carbonate (0.172 g, 1.24 mmol) folloWed by 4-?uorophenol (0.0557 g, 0.497 mmol) and diiodomethane (0.133 g, 0.497 mmol). The
A solution of 4-[1-(4-chlorophenacyl)-1H-benZimidaZol
2-yl]-furaZan-3-ylamine (0.05 g, 0.143 mmol), pyridine (0.022 g, 0.282 mmol), acetyl chloride (0.013 g, 0.169 mmol) and a catalytic amount of DMAP in DMF (5 ml) is stirred at 80° C. for 16 hours. The reaction mixture is diluted With ethyl acetate, Washed With Water and dried over sodium sulphate. Filtration of the sodium sulphate, concentration of the ?ltrate under reduced pressure and chromatography of the residue on
mixture is stirred over night. Evaporation of the solvent under reduced pressure and partitioning of the resulting residue betWeen Water and ethyl acetate folloWed by drying of the
organic solution over sodium sulphate and chromatography of the residue gives the title compound as a colorless solid, 20
m.p.155-158° C.
Example 9
silicagel using hexane-ethyl acetate as eluent gives the title compound as a yelloWish solid, mp. 202-205° C.
4- [1 -(4-Chlorophenacyl)- 1 H-benZimidaZol-2-yl] -
Example 6
25
A suspension of 4-(1H-benZimidaZol-2-yl)-?.1raZan-3-yl N-(2-methoxycarbonylethyl)-amine (0.052 g, 0.181 mmol),
4- [1 -(4 -Chlorophenacyl)- 1 H-benZimidaZol-2-yl] -
furaZan-3 -yl-N- (2 -cyanoethyl)-amine A suspension of 4-(1H-benZimidaZol-2-yl)-?.1raZan-3-yl N-(2-cyanoethyl)-amine (0.10 g, 0.39 mmol), potassium car bonate (0.08 g, 0.58 mmol) and 4-chlorophenacyl bromide (0.11 g, 0.47 mmol) in DMF (5 ml) is stirred at room tem perature for 16 hours. The reaction mixture is diluted With ethyl acetate, Washed With Water and dried over sodium sul
furaZan-3 -yl-N- (2 -methoxycarbonylethyl) -amine
30
potassium carbonate (0.062 g, 0.452 mmol) and 4-chlo rophenacyl bromide (0.047 g, 0.199 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mix
ture is diluted With ethyl acetate, Washed With Water and dried over sodium sulphate. Filtration of the sodium sulphate, con centration of the ?ltrate under reduced pressure and chroma 35
phate. Filtration of the sodium sulphate, concentration of the ?ltrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives
tography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as hygroscopic
the title compound as a yelloWish solid, mp. 191-192° C. 40
Example 6a
solid of unde?ned melting point. 1H-NMR (400 MHZ, d°-DMSO): 8.14 (d, 2H); 7.87 (m, 2H); 7.41 (m, 2H); 7.32 (d, 2H); 7.29 (t, 1H); 6.37 (s, 2H); 3.63 (m, 2H); 3.61 (s, 3H); 2.76 (t, 2H). Example 9a
4-(1H-BenZimidaZol-2-yl)-furaZan-3-yl-N-(2-cyano ethyl) -amine
4- [1 -( 1 H-BenZimidaZol-2 -yl] -furaZan-3 -yl-N-(2 45
methoxycarbonylethyl)-amine
To a solution of 4-(1H-benZimidaZol-2-yl)-?1raZan-3
ylamine (0.10 g, 0.497 mmol) in pyridine (5 ml) sodium in
A solution of 4-(1H-benZimidaZol-2-yl)-furaZan-3-yl-N
methanol (0.02 g, 0.86 mmol in 1 ml) and acrylonitrile (0.03
(2-cyanoethyl)-amine (0.05 g, Example 6a) in methanol satu
g, 0.39 mmol) are added sequentially at 0° C. The mixture is stirred over night. Evaporation of the solvent under reduced
50
pressure and partitioning of the resulting residue betWeen Water and ethyl acetate folloWed by drying of the organic solution over sodium sulphate gives the title compound in
pure form. 1H-NMR (400 MHZ, d°-DMSO): 13.7 (s, 1H); 7.82 (d, 1H); 7.60 (d, 1H); 7.36 (m, 2H); 7.20 (t, 1H); 3.67 (q, 2H); 2.94 (t, 2H).
The combined organic extracts are dried and evaporated to dryness under reduced pres sure. Trituration With hexane and 55
?ltering yields the title compound in pure form. 1H-NMR
(400 MHZ, d6-DMSO): 13.8 (s, 1H); 7.80 (m, 1H); 7.59 (m, 1H); 7.32 (m, 2H); 703 (m, 1H); 3.63 (m, 2H); 3.61 (s, 3H); 2.76 (t, 2H).
Example 7
4-(1-Phenoxymethyl-1H-benZimidaZol-2-yl)-?1ra
rated With hydrochloric acid (5 ml) is heated at re?ux for 40 minutes. After addition of a drop of Water re?uxing is contin ued for 2 hours. The mixture is neutraliZed using sodium bicarbonate and then extracted repeatedly using ethyl acetate.
60
Example 10
Zan-3 -ylamine
4-[1 -(3,4-Dimethylphenoxymethyl)-1H-benZimida Zol-2 -yl] -furaZan-3 -yl-N-(2 -cyanoethyl)-amine
To a solution of 4-(1H-benZimidaZol-2-yl)-?1raZan-3
ylamine (0.10 g, 0.497 mmol) is added potassium carbonate (0.172 g, 1.24 mmol) and iodomethoxy benZene (0.128 g, 0.546 mmol). The mixture is stirred over night. Evaporation
A suspension of 4-(1H-benZimidaZol-2-yl)-?.1raZan-3-yl N-(2-cyanoethyl)-amine (0.15 g, 0.59 mmol, Example 6a),
of the solvent under reduced pres sure and partitioning of the
potassium carbonate (0.325 g, 2.36 mmol), diiodomethane
65
US RE42,890 E 29
30
(0.16 g, 0.59 mmol) and 3,4-dimethylphenol (0.072 g, 0.59
for 20 hours. Evaporation to dryness yields a mixture con
mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted With ethyl acetate,
taining the title compound that is used in the subsequent step
Without puri?cation.
Washed With Water and dried over sodium sulphate. Filtration
of the sodium sulphate, concentration of the ?ltrate under reduced pressure and chromatography of the residue on sili cagel using hexane-ethyl acetate as eluent gives the title com pound as a yelloWish solid, mp. 132-1350 C.
Example 12b
5
1 -Chloro-3-(triphenylphosohanylidene)-propane-2 one
Example 11
A mixture of triphenylphosphine (10.0 g, 38.1 mmol) and 1,3-dichloroacetone (4.84 g, 38.1 mmol) in THF (20 ml) is
4- [1 -(4 -Chlorophenacyl)- 1 H-benZimidaZol-2-yl] -
heated at re?ux for 4 hours. On cooling the resulting precipi tate is ?ltered, Washed With THF and dried. To the ef?ciently stirred precipitate in methanol (20 ml) a 20% aqueous solu tion of sodium carbonate (2.02 g, 19 mmol) is added folloWed by additional Water. The resulting product is ?ltered and dried
furaZan-3 -yl-N- (3 -hydroxypropyl) -amine A suspension of 4-(1H-benZimidaZol-2-yl)-furaZan-3-yl
N-(3 -hydroxypropyl)-amine (0.70 g, 0.27 mmol), potassium
to yield the pure product. 1H-NMR (400 MHZ, d6-DMSO): 7.61 (m, 15H); 4.07 (2s, 0.5H each); 3.98 (s, 2H).
carbonate (0.472 g, 3.42 mmol) and 4-chlorophenacyl bro mide (0.069 g, 0.29 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted With
20
Example 13
ethyl acetate, Washed With Water and dried over sodium sul
phate. Filtration of the sodium sulphate, concentration of the ?ltrate under reduced pres sure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as a yelloWish solid, mp. 166-1690 C.
4- [1 -(4-Aminophenacyl)- 1 H-benZimidaZol-2-yl] -
furaZan-3-yl-N- (2-carboxyethyl)-amine 25
A solution of 4-[1-(4-acetaminophenacyl)-1H-benZimida
Example 1 1a
Zol-2-yl]-furaZan-3-yl-N-(2-cyanoethyl)-amine (0.061 g) in
4-(1H-BenZimidaZol-2-yl)-furaZan-3 -yl-N- (3 -hy
re?ux for tWo hours. The mixture is diluted With Water and
aqueous hydrochloric acid (5 ml, HCl conc.) is heated at
droxypropyl) -amine
30
With ethyl acetate, drying over sodium sulphate, ?ltering and evaporation of the resulting ?ltrate to dryness gives the title compound in pure form, mp. 174-1770 C. 1H-NMR (400
A solution of 4-(1H-benZimidaZol-2-yl)-?.1raZan-3 -yl-N (2-cyanoethyl)-amine (0.272 g, 0.947 mmol, Example 6a) in THF (5 ml) is added dropWise at 00 C. to an ef?ciently stirred
suspension of LiAlH4 (0.054 g, 1.42 mmol) in THF (5 ml).
35
After stirring for 16 hours at room temperature the mixture is
MHZ, d6-DMSO): 12.40 (s, 1H); 7.84 (m, 4H); 7.38 (m, 3H); 6.65 (m, 2H); 6.28 (S, 2H); 6.17 (s, 2H); 3.57 (m, 2H); 2.66 (t,
2H).
quenched by careful addition of aqueous saturated solution of sodium sulphate. The suspension is ?ltered and the ?ltrate
evaporated to dryness. Crystallization by addition of hexane yields the title compound in pure form. 1H-NMR (400 MHZ,
neutraliZed by addition of sodium bicarbonate. Extraction
Example 14 40
4- [1 -(3 -Amino -4 -chlorophenacyl)- 1 H-benZimidaZol
2-yl] -furaZan-3 -ylamine
d6-DMSO): 13.6 (s, 1H); 7.66 (m, 2H); 7.31 (m, 2H); 6.92 (t, 1H); 4.61 (m, 1H); 3.51 (m, 2H); 3.39 (m, 2H); 1.81 (m, 2H).
To a stirred solution of 4-[1-(4-chloro-3-nitrophenacyl)
Example 12
45
E-1-[2-(4-AminofuraZan-3-yl)-benZimidaZol-1-yl]-4 phenyl-but-3-en-2-one
1H-benZimidaZol-2-yl]-furaZan-3-ylamine (0.07 g, 0.175 mmol) in ethanol (6 ml) and Water (1 ml) is added tWo drops of concentrated hydrochloric acid and iron poWder (0.1 g, 17.5 mmol). The reaction mixture is heated at 800 C. for 8
hours. Filtration and evaporation at reduced pressure gives
A suspension of 4-(1H-benZimidaZol-2-yl)-furaZan-3 ylamine (0.275 g, 1.37 mmol), potassium carbonate (0.472 g, 3.42 mmol) and 1-chloro-4-phenyl-but-3-en-2-one (0.297 g,
50
acetate and chromatography on silicagel yields the title com pound as colorless solid, mp 228-2300 C.
1.64 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted With ethyl acetate, Washed With Water and dried over sodium sulphate. Filtration
the crude product. Puri?cation by extraction With ethyl
Example 14a 55
4-[1-(4-Chloro-3-nitrophenacyl)-1H-benZimidaZol
of the sodium sulphate, concentration of the ?ltrate under reduced pressure and chromatography of the residue on sili cagel using hexane-ethyl acetate as eluent gives the title com pound as a yelloWish solid, mp. 176-1800 C.
2-yl] -furaZan-3 -ylamine
Example 12a
A suspension of 4-(1H-benZimidaZol-2-yl)-furaZan-3 ylamine (0.228 g, 1.14 mmol), potassium carbonate (0.40 g, 2.85 mmol) and 4-chloro-3-nitrophenacyl bromide (0.35 g,
1-Chloro-4-phenyl-but-3 -en-2 -one
1.25 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted With ethyl acetate,
60
Washed With Water and dried over sodium sulphate. Filtration A mixture of 1 -chloro-3 -(triphenylpho sphanylidene) -pro -
pane-2-one (2.8 g, 7.9 mmol) and freshly distilled benZalde hyde (0.7 g, 6.6 mmol) in toluene (10 ml) is heated at re?ux
65
of the sodium sulphate, concentration of the ?ltrate under reduced pressure and chromatography of the residue on sili cagel using hexane-ethyl acetate as eluent gives the title com
US RE42,890 E 31
32
pound as a solid, mp. 198-2000 C. (This compound is also listed as Example 66 in Table 1.)
Example 15a
Example 15
4-[1-(3 -Methoxy-4-hydroxyphenacyl)-1H-benZimi daZol-2-yl]-?1raZan-3-yl-amine
4- [1 -(3 -Methoxy-4-methoxymethoxy -phenacyl)- 1 H
benZimidaZol-2-yl]-?.1raZan-3 -ylamine A mixture of 4-[1-(3-methoxy-4-hydroxyphenacyl)-1H
benZimidaZol-2-yl]-furaZan-3-ylamine (0.10 g, 0.27 mmol), DIPEA and methoxymethyl chloride in dry DMF is stirred at room temperature for 14 hours. The reaction mixture is diluted With ethyl acetate, Washed With Water and dried over
sodium sulphate. Filtration of the sodium sulphate and con centration of the ?ltrate under reduced pressure gives the title compound as colorless, pure solid, mp. 190° C.
To a solution of 4-[1-(3-methoxy-4-benZyloxyphenacyl)
1H-benZimidaZol-2-yl]-furaZan-3-ylamine (1.00 g) in THF (20 ml) is added palladium on carbon (10%, 0.2 g). The mixture is stirred under a hydrogen atmosphere for 1 hour. The catalyst is ?ltered and the ?ltrate is evaporated to dryness to give the title compound in pure form, mp. 2650 C. (This compound is also listed as Example 74 in Table 1.)
The folloWing compounds are prepared in analogy to Examples 1-15: TABLE 1
R1
/ HN N
\ N
\
\TO
N/
Y R Ex R
Y
R1
Salt
O
H
i
17 U
NOH
H
i
E/Z
2100 C.
18 U
NOMe H
i
E/Z
l56—l58° C.
19
O
O
H
i
U
NOH
H
i
E/Z
176-1780 C.
U
NOH
H
i
E/Z
204—206° C.
/©/
NOMe H
i
E/Z
206—208° C.
16
/©/
Comment
mp.
198-200° C.
Cl
160-1620 C.
MeO
20 MeO
21 Cl
22 Cl
US RE42,890 E 35
36 TABLE I-continued
R1
/ HN N
\ N
\T N/
O
Y R EX R
Y
R1
Salt
Comment
{n.p.
34
NOMe
H
i
E/Z
138-140” C.
O
H
i
NOH
H
i
E/Z
188—190° C.
NOMe
H
i
E/Z
125-1270 C.
NOMe
H
i
E/Z
110-1130 C.
0
H
i
2020 C
40 U
0
Ac
i
226° C
41
O
H
i
2260 C.
42
O
H
i
180-183° C.
43
O
H
i
215-2180 C.
: Cl 35
36
37
Cl\ : / Cl\ : / CL : /
38
192-1940 C.
MeO : 39
U BEN
F3C :
