Thieno [2, 3-d] pyrimidine derivatives and their use to treat arrhythmia

16 Pages·2014·1.45 MB·English

US 20140206703A1
(19) United States
(12) Patent Application Publication (10) Pub. No.: US 2014/0206703 A1
Ford et al. (43) Pub. Date: Jul. 24, 2014
(54) THIENO [2, 3-D] PYRIMIDINE DERIVATIVES (30) Foreign Application Priority Data
AND THEIR USE TO TREAT ARRHYTHMIA
Apr. 1, 2011 (GB) ................................. .. 11056595
(75) Inventors: John Ford, Hemingford Grey (GB); PublicatiOn Classi?catiOH
Derek Edward John, Sawston (GB)
(51) Int. Cl.
C07D 495/04 (2006.01)
(73) Assignee: XENTION LIMITED, Cambridge (GB) (52) US, Cl,
CPC .................................. .. C07D 495/04 (2013.01)
(21) APP1-N0-I 14/008,776 USPC ...................................... .. 514/260.1; 544/278
(22) PCT Filed: Mar. 29, 2012 (57) ABSTRACT
_ The present invention relates to thienopyrimidine compounds
(86) PCT NO" PCT/GB2012/050710 Which are potassium channel inhibitors. Pharmaceutical
§ 371 (c)(1), compositions comprising the compounds and their use in the
(2), (4) Date: Apr. 4, 2014 treatment of arrhythmia are also described.
US 2014/0206703 A1 Jul. 24, 2014
THIENO [2, 3-D] PYRIMIDINE DERIVATIVES [0005] Traditional and novel class III antiarrythmic potas
AND THEIR USE TO TREAT ARRHYTHMIA sium channel blockers have been reported to have a mecha
nism of action by directly modulating Kv1.5 or KvW). The
TECHNICAL FIELD known class III antiarrythmics ambasilide (Feng et al., 1997),
quinidine (Wang et al., 1995), clo?lium (Malayev et al., 1995)
[0001] The present invention relates to thienopyrimidine and bertosamil (Godreau et al., 2002) have all been reported
compounds which are potassium channel inhibitors. Pharma as potassium channel blockers of KvW) in human atrial myo
ceutical compositions comprising the compounds and their cytes. The novel benzopyran derivative, NIP-142, blocks
use in the treatment of arrhythmia are also provided. Kv1.5 channels, prolongs the atrial refractory period and
terminates atrial ?brillation and ?utter in in vivo canine mod
BACKGROUND ART els (Matsuda et al., 2001), and S9947 inhibited Kv1.5 stably
expressed in both Xenopus oocytes and Chinese hamster
[0002] Ion channels are proteins that span the lipid bilayer ovary (CHO) cells and KvW) in native rat and human cardiac
of the cell membrane and provide an aqueous pathway myocytes (Bachmann et al., 2001). Elsewhere, other novel
through which speci?c ions such as Na+, K”, Ca2+ and CL can potassium channel modulators which target Kv1.5 or KvW)
pass (Herbert, 1998). Potassium channels represent the larg have been described for the treatment of cardiac arrhythmias,
est and most diverse sub-group of ion channels and they play these include biphenyls (Peukert et al 2003), thiophene car
a central role in regulating the membrane potential and con boxylic acid amides (W00248131), bisaryl derivatives
trolling cellular excitability (Armstrong & Hille, 1998). (WO0244137, W00246162), carbonamide derivatives
Potassium channels have been categorized into gene families (WO0100573, W00125189) anthranillic acid amides
based on their amino acid sequence and their biophysical (W02002100825, W002088073, W002087568), dihydro
properties (for nomenclature see Gutman et al., 2003). pyrimidines (W001 4023 1 ), cycloakyl derivatives
[0003] Compounds which modulate potassium channels (WOO3063797), indane derivatives (W001461 55
have multiple therapeutic applications in several disease WO9 804 52 1 ), tetralin benzo cycloheptane derivatives
areas including cardiovascular, neuronal, auditory, renal, (WO9937607), thiazolindone and metathiazanone deriva
metabolic and cell proliferation (Shieh et al., 2000; Ford et al., tives (WO9962891), benzamide derivatives (W00025774),
isoquinoline derivatives (W00224655), pyridaZinones
2002). More speci?cally potassium channels such as Kv4.3,
derivatives (WO981 8475 WO9818476), chroman derivatives
Kir2.1, hERG, KCNQl/minK, and Kv1.5 are involved in the
repolarisation phase of the action potential in cardiac myo (WO9804542), benzopyran derivatives (WO0121610,
cytes. These potassium channels subtypes have been associ WOO3000675, W00121609, W00125224, W002064581),
ated with cardiovascular diseases and disorders including benzovaine derivatives (W00012492), and the novel com
long QT syndrome, hypertrophy, ventricular ?brillation, and poundA1998 puri?ed from Ocean material Qiu & Xu, 2000).
General voltage gated potassium channel inhibitors have
atrial ?brillation, all of which can cause cardiac failure and
fatality (Marban, 2002). been reported which could also modulate Kv1.5
(US05753676, USO5821251, EP0743936B).
[0004] The human delayed recti?er voltage gated potas
[0006] Thienopyrimidines have been reported to be useful
sium channel subunit, Kv1.5, is exclusively expressed in
as anti-in?ammatory, anti-fungal, anti-osteoporosis and anti
atrial myocytes and is believed to offer therapeutic opportu
microbial agents, and as cardiovascular agents (acting
nities for the management of atrial ?brillation for several
through modulation of the phosphodiesterase group of
different reasons (see review of Brendel and Peukert, 2002):
enzymes or through modulation of the sodium/proton
(i) There is evidence that Kv1.5 underlies the cardiac
exchange system) amongst others.
ultrarapid delayed recti?er (Kv(w)) physiological current in
humans due to similar biophysical and pharmacological [0007] Thieno[2,3-d]-pyrimidines substituted in the 4-po
properties (Wang et al., 1993; and Fedida et al., 1993). This sition with an optionally substituted benzylamine or phen
has been supported with antisense oligonucleotides to Kv1.5 ethylamine moiety and in the 5-position with a methyl group
which have been shown to reduce Kv amplitude in human may serve as anti-in?ammatory or anti-osteoporosis agents
atrial myocytes (Feng et al., 1997). (ii) electrophysiological (Katada et al., 1999). Such compounds were shown to modu
recordings have demonstrated that Kve?) is selectively late the activity of several cell types including leukocytes,
expressed in atrial myocytes, and therefore avoids inducing which originate from hematopoietic precursor cells in the
potentially fatal ventricular arrhythmia through interfering bone marrow. Increased activity in leukocytes can lead to
with ventricular repolarisation (Amos et al., 1996; Li et al., various in?ammatory diseases; therefore compounds cyto
1996; and Nattel, 2002). (iii) Inhibiting KvW) in atrial ?bril toxic to leukocytes could function as anti-in?ammatory
lation-type human atrial myocytes prolonged the action drugs. Such compounds are thought to suppress cellular
potential duration compared to normal healthy human atrial activity by binding to integrins on the surface of leukocytes
myocytes (Courtemanche et al., 1999). (iv) Prolonging the and preventing downstream cellular signalling events. Thieno
action potential duration by selectively inhibiting Kv1.5 [2,3-c]pyrimidines substituted in the 4-position with het
eroarylthiols, aryl thiols, arylmethyl thiols, heteroary
could present safer pharmacological interventions for pro
tecting against atrial re-entrant arrhythmias such as atrial lamines, benzylamine, hydroxyl and chloro groups may also
?brillation and atrial ?utter compared to traditional class III be useful anti-in?ammatory agents (Stewart et al., 2001 ). This
antiarrythmics, by prolonging the atrial refractory period series of compounds were shown to inhibit induced expres
while leaving ventricular refractoriness unaltered (Nattel et sion of cell adhesion molecules on the luminal surface of
al., 1999, Knobloch et al., 2002; and Wirth et al., 2003). Class vascular endothelial thus preventing the adhesion of leuko
III antiarrythmics have been widely reported as a preferred cytes at the site of in?ammation.
method for treating cardiac arrhythmias (Colatsky et al., [0008] Thieno[2,3-d]pyrimidines with a substituted hydra
1990). Zine in the 4-position and a phenyl group in the 5 position
US 2014/0206703 A1 Jul. 24, 2014
(HoZien et al., 1996), tetrahydrobenzo[b]thieno[2,3-c]pyrim [0012] 4-[(phenyl)amino]-thieno[2,3-c/]pyrimidines bear
idines (Ismail et al., 1995), thieno[2,3-d]pyrimidines which ing a 5-thiophenyl substituent and a 2-methyl substituent
have a hydrogen, chloro, hydrazine, heterocyclyl, amino, were found to have molluscicidal activity (Hosni et al, Acta
methyl, ethyl or phenyl group in the 2-position, an alky Poloniae Pharmaceutica, 1999, 56(1), 49-56).
lamino, alkylarylamino, amino, dialkylamino or hydraZino
[0013] Recently thienopyrimidines have also been reported
substituent in the 4-position, a hydrogen or methyl group in
as potent VEGFR inhibitors (Munchhof, 2004).
the 5 -position, a hydrogen, methyl acetamide or phenyl group
in the 6-position or a tetramethylene in the 5,6-position [0014] Several publications disclose compounds which are
(GB7549025), and the lead series of 5-phenyl- and 5,6-tet indicated as acting on potassium channels. Thus, US. Pat.
ramethylenethieno[2,3-d]pyrimidines with methyl or phenyl No. 6,531,495 discloses 2'-aminomethylbiphenyl-2-carboxa
in the 2-position and alkylamino or arylamino in the 4-posi mides, WO2002/ 100825 discloses anthranillic acid amides as
tion (Konno et al., 1989) have all been shown to have anti antiarrhythmics and WO2002/ 036556 discloses acylami
microbial activity. Tetrahydrobenzothieno[2,3-d]pyrimidine noalkylbenzenesulfonamides as cardiovascular agents.
with the 2-oxo -3 -pyrrolidinylmethylene-hydraZino moiety in
[0015] Thienopyrimidine compounds that are useful as
the 4-position showed some herbicidal activity against velvet
potassium channel inhibitors, particularly for inhibiting
leaf (Ram et al., 1981). It has also been reported that 4-chlo
potassium channels Kv1.5 or KvW), are reported in WO
rotetrahydrobenzothieno[2,3-d]pyrimidine is herbicidal, tet
2004/111057.
rahydrobenzothieno[2,3-d]pyrimidines with a thiol, hydra
Zine, 2-?uoroanilino, 3-?uoroanilino or 4-diethylanilino
substituent in the 4-position are bactericidal against Strepto DISCLOSURE OF THE INVENTION
coccus fecales and tetrahyrobenzothieno[2,3-d]pyrimidines
[0016] A ?rst aspect of the invention provides a compound
with a 2,4-dichlorobenzylamino or 2-?uoroanilino substitu
ent in the 4-position are fungicidal against Pythium (Ram, of formula (Ia)
1979). Thieno[2,3-d]pyrimidines with a hydrogen, hydroxyl,
thiol, halogen or cyano group in the 2-position, alkylamino,
arylalkylamino or hydroxyalkyl amino groups in the 4-posi (Ia)
tion, a hydrogen, alkyl or halogen in the 5- and/ or 6-position
or alkylene in the 5,6-position have been reported as tick
control agents (AU 521790).
[0009] Elsewhere, tetrahydrobenzo[b]thieno[2,3-d]pyrim
idines exhibited anti-tumour activity (Shehata et al., 1996)
and analgesic activity half that of aspirin (Moneer et al.,
1994), a series of thieno[2,3-d]pyrimidines with 4-alky
lamino or arylamino, 5-H or 5-methyl, 6-methyl or 5,6-tet
ramethylene were shown to have potential as anticytokinins
(Jordis et al., 1986), a series of 5,6-dimethyl-thieno[2,3-d]
pyrimidines and 5,6-tetramethylenethieno[2,3-d]pyrim
idines, both substituted in the 2-position with arylamines or
heterocyclic amines and in the 4-position with arylamines
displayed blood platelet aggregation inhibiting properties
(DD 226893), pyrano- and thiopyrano[3,4-b]thieno[5,4-c] or a pharmaceutically acceptable ester or salt thereof.
pyrimidines with the 4-position substituted with amino, buty [0017] In one embodiment, the compound is of formula (Ib)
lamine, aniline, cyclohexylamine, benzylamine, phenethy
lamine and 2-hydroxyethylamine have been reported to
exhibit anticonvulsive activity (Noravyan et al., 1977), and
(1b)
4-[(Benzo-2,1,3 -thiadiazo lyl-4)amino] -5 ,6,7,8-tetrahy
drobenzothieno-(2,3-d)-pyrimidine has been reported to pos
sess anthelmintic activity in larval alveolar echinococcosis
(RU 2116309).
[0010] Thieno[2,3-d]pyrimidines with a substituted amino
group at the 4-position, hydrogen, alkyl or halo substitution at
the 5 and 6-positions and an alkyl chain at the 2-position are
claimed to be inhibitors of phosphodiesterase V and useful in
the treatment of cardiovascular diseases and for disturbances
in potency (DE10104802).
[0011] Elsewhere, 5-alkyl thieno[2,3-d]pyrimidines with a
piperaZinyl substituent at the 4-position were found to be
inhibitors of the sodium/proton exchanger and useful in the
treatment of various cardiovascular disorders, including
angina pectoris and arrhythmia (WO 01/27107).
US 2014/0206703 A1 Jul. 24, 2014
[0018] In another embodiment, the compound is of formula “racemic mixture” of the compounds of formula (Ib) and
(10) formula (Ic) contains an approximately 1 :1, or 50: 50, mixture
of the compounds.
(10) Enantiomeric Excess
[0026] A compound or composition comprising an “enan
tiomeric excess” of the compound of formula (lb) or of the
compound of formula (Ic) comprises more of that enantiomer
than the other (also known as a scalemic mixture).
[0027] The enantiomeric excess is the excess of one com
pound over the other, expressed as a percentage of the Whole.
OH. For instance, a 98:2 mixture of the compound of formula (Ib)
to the compound of formula (Ic) has a 96% enantiomeric
excess of the compound of formula (Ib). Thus, the com
pounds and compositions of the invention may comprise an
H enantiomeric excess of the compound of formula (lb) of at
least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,
55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or up to
100% (i.e. enantiomerically pure, up to the detection limit of
[0019] In another embodiment, the compound of formula purity). Alternatively, the compounds and compositions of
(Ia) comprises a mixture of the compounds of formulae (Ib) the invention may comprise an enantiomeric excess of the
and (Ic). In a further embodiment, the compound of formula compound of formula (Ic) of at least 5%, 10%, 15%, 20%,
(Ia) comprises a racemic mixture of the compounds of for 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,
mulae (Ib) and (Ic). In an alternative further embodiment, the 75%, 80%, 85%, 90%, 95% or up to 100%.
compound of formula (Ia) comprises an enantiomeric excess
of the compound of formula (lb) or an enantiomeric excess of R and S Nomenclature
the compound of formula (Ic).
[0020] A second aspect of the invention provides a phar [0028] As used herein, the term “R” or “S” isomer refers to
the two possible enantiomers according to the Cahn-Ingold
maceutical composition comprising at least one of the above
Prelo g system adopted by the International Union of Pure and
compounds and, optionally, one or more pharmaceutically
acceptable excipients. Applied Chemistry (IUPAC). Thus, the compound of formula
(Ib) is the “S-isomer” and the compound of formula (Ic) is the
[0021] The compounds and compositions of the invention
“R-isomer”.
are potassium channel inhibitors that are particularly useful
[0029] Pharmaceutically acceptable ester or salt thereof.
for inhibiting potassium channels Kv1.5 or KvW) for the
The term “pharmaceutically acceptable ester” includes com
treatment of cardiac arrhythmia in the atria such as atrial
pounds of the invention in Which the hydrogen atom of the
?brillation. This invention is not limited to treating cardiac
arrhythmias, the compounds also being useful to treat dis alcohol group may be replaced to form an ester (e.g. the
hydrogen atom may be replaced by 4C(O)Cl_6alkyl).
eases Which require potassium channel inhibition (e.g. Shieh
[0030] The term “pharmaceutically acceptable salt”
et al., 2000; Ford et al., 2002).
includes a salt prepared from pharmaceutically acceptable
[0022] A third aspect of the invention therefore provides a
method of potassium channel inhibition, comprising admin non-toxic acids or bases including inorganic or organic acids
and bases.
istering to a subject an effective amount of at least one com
pound or composition of the invention. This aspect of the [0031] Pharmaceutically acceptable acid addition salts of
invention further provides a compound or composition of the the compounds of the invention include, but are not limited to,
invention for use in potassium channel inhibition. In addition, those of inorganic acids such as hydrohalic acids (e.g. hydro
chloric, hydrobromic and hydroiodic acid), sulfuric acid,
this aspect of the invention further provides the use of a
compound of the invention for the manufacture of a medica nitric acid, and phosphoric acids. In addition, pharmaceuti
ment for use in potassium channel inhibition. cally acceptable acid addition salts of the compounds of the
invention include, but are not limited to, those of organic
[0023] As used herein, a “method of potassium channel
inhibition” and “use in potassium channel inhibition” include acids such as aliphatic, aromatic, carboxylic and sulfonic
classes of organic acids, examples of Which include: aliphatic
methods and uses for treating or preventing a disorder Which
responds to the inhibition of potassium channel function. The monocarboxylic acids such as formic acid, acetic acid, pro
pionic acid or butyric acid; aliphatic hydroxy acids such as
disorder may be arrhythmia.
lactic acid, citric acid, tartaric acid or malic acid; dicarboxylic
[0024] The compounds of the invention have advantageous
acids such as maleic acid or succinic acid; aromatic carboxy
properties over those of the prior art, in particular in terms of
lic acids such as benzoic acid, p-chlorobenzoic acid, pheny
potency and/ or selectivity.
lacetic acid, diphenylacetic acid or triphenylacetic acid; aro
matic hydroxyl acids such as o-hydroxybenzoic acid,
DETAILED DESCRIPTION OF THE INVENTION
p-hydroxybenzoic acid, 1-hydroxynaphthalene-2-carboxylic
acid or 3-hydroxynaphthalene-2-carboxylic acid; and sul
Racemic Mixture
fonic acids such as methanesulfonic acid, ethanesulfonic acid
[0025] A “racemic mixture” contains approximately equal or benzenesulfonic acid. Other pharmaceutically acceptable
amounts of the compounds of formula (Ib) and formula (Ic). acid addition salts of the compounds of the invention include,
In other words, a compound or composition comprising a but are not limited to, those of glycolic acid, glucuronic acid,
US 2014/0206703 A1 Jul. 24, 2014
furoic acid, glutamic acid, anthranilic acid, salicylic acid, [0034] This includes the preparation of compounds of for
mandelic acid, embonic (pamoic) acid, pantothenic acid, mula (I) using the “linear route” analogous to the synthetic
stearic acid, sulfanilic acid, algenic acid, and galacturonic
route disclosed in W02004/111057 from compounds of for
acid.
mula (II) and aminoethanol. Typically, this reaction is carried
[0032] Pharmaceutically acceptable basic salts of the com
out using a coupling reagent such as l-ethyl-3-(3-dimethy
pounds of the invention include, but are not limited to, metal
salts such as alkali metal or alkaline earth metal salts (e.g. laminopropyl)-carbodiimide (EDC) or 2-(7-aza-lH-benZ
sodium, potassium, magnesium or calcium salts) and Zinc or triazo le-l-yl)-l,1,3,3-tetramethyluronium hexa?uorophos
aluminium salts. In addition, pharmaceutically acceptable phate (HATU) utilising standard methods familiar to those
basic salts of the compounds of the invention include, but are skilled in the art such as reaction in solvent such as tetrahy
not limited to, salts formed With ammonia or pharmaceuti
drofuran, acetonitrile or dimethylformamide at a range of
cally acceptable organic amines or heterocyclic bases such as
temperatures from ambient to re?ux temperature. Altema
ethanolamines (e.g. diethanolamine), benzylamines, N-me
thyl-glucamine, amino acids (e.g. lysine) or pyridine. tively, compounds of formula (I) may be prepared from com
pounds of formula (III) by displacement of the 2-chloro sub
Synthesis stituent With a compound of formula (IX) in the presence of a
[0033] Compounds of formula (I) may be prepared as the base such as N,N-diisopropylethylamine and a solvent such
racemate, as a scalemic mixture, or as a chirally pure enanti as N-methylpyrrolidinone With conventional heating or
omer using routes described in the scheme 1 beloW: microwave irradiation.
(VIII) (VII)
(III)
(V)
linear
“convergent
route”
route7 ’
US 2014/0206703 Al Jul. 24, 2014
(11) (V)
/ I NH
S N o
H
[0038] Compounds of formula (V) may be synthesised by
the reaction of a compound of formula (V l) with an alkali
metal cyanate, preferably potassium cyanate.
[0035] Compounds of formula (II) may be prepared from a
compound of formula (III) by displacement of the 2-chloro (VI)
substituent with commercially available nipecotic acid, in the
presence of a base such as N,N-diisopropylethylamine and a
solvent such as N-methylpyrrolidinone with conventional
heating or microwave irradiation.
(III)
S NH2
[0039] A compound of formula (V I) can be prepared by the
“Gewald reaction” in which a compound of formula (Vll) is
reacted under basic conditions and in a suitable solvent such
as ethanol, with powdered sulphur. Preferably the base is
diisopropylethylamine (Hunig’ s base) and the solvent may be
an alcohol, preferably ethanol, and the reaction is carried out
between 25 and 65° C.
(VII)
[0036] Compounds of formula (III) are readily synthesised
from compounds of formula (IV) by a nucleophilic substitu
tion reaction with 2-aminomethylpyridine, optionally in the
COZEt
presence of a solvent and a base, and optionally at elevated
temperature or with microwave irradiation. Preferably the
solvent (if present) is an alcohol, preferably ethanol and the CN
base is a hindered nitrogen base such as triethylamine. The
reaction is carried out at ambient temperatures.
[0040] Compounds of formula (Vll) can be prepared by the
Knoevenagel condensation reaction by heating compound of
(IV) formula (V III) with ethylcyanoacetate (NCCHZCOZEt) in the
presence of an acid and ammonium acetate in a suitable
solvent such as toluene, optionally with azeotropic water
removal. Preferably the acid is acetic acid. This gives the
alkylidene cyano ester as a pair of (E and Z) geometric iso
mers.
(VIII)
[0037] A compound of formula (IV) may be synthesised by
reaction of a compound of formula (V) with a chlorinating
reagent such as phenylphosphonic dichloride or phosphorous
oxychloride.
US 2014/0206703 A1 Jul. 24, 2014
-continued [0050] The compositions of the invention may be presented
deg/VOH (IX) in unit dose forms containing a predetermined amount of each
O active ingredient per dose. Such a unit may be adapted to
provide 5-100 mg/day of the compound, preferably either
5-15 mg/day, 10-30 mg/day, 25-50 mg/day 40-80 mg/day or
60-100 mg/day. For compounds of the invention, doses in the
range 100-1000 mg/day are provided, preferably either 100
400 mg/day, 300-600 mg/day or 500-1000 mg/day. Such
doses can be provided in a single dose or as a number of
[0041] Compound of formula (IX) may be prepared from
discrete doses. The ultimate dose will depend on the condi
compound of formula (X) by hydrolysis of the t-butyl car
tion being treated, the route of administration and the age,
bamate (BOC) protecting group with a strong acid in a solvent weight and condition of the patient and will be at the doctor’ s
such as dichloromethane. Typically the acid is tri?uoroacetic discretion.
acid.
[0051] The compositions of the invention may be adapted
for administration by any appropriate route, for example by
the oral (including buccal or sublingual), rectal, nasal, topical
*0 0 O (X) (including buccal, sublingual or transderrnal), vaginal or
parenteral (including subcutaneous, intramuscular, intrave
i OH
nous or intradermal) route. Such formulations may be pre
pared by any method known in the art of pharmacy, for
example by bringing into association the active ingredient
with the carrier(s) or excipient(s).
[0052] Pharmaceutical formulations adapted for oral
[0042] Compound of formula Qi) may be prepared from a administration may be presented as discrete units such as
compound of formula 0(1) and aminoethanol. Typically, this capsules or tablets; powders or granules; solutions or suspen
reaction is carried out using a coupling reagent such as sions in aqueous or non-aqueous liquids; edible foams or
l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) or whips; or oil-in-water liquid emulsions or water-in-oil liquid
2-(7-aza- l H-benZtriazole- l -yl)- l , l ,3 ,3 -tetramethyluronium emulsions.
hexa?uorophosphate (HATU) utilising standard methods [0053] Pharmaceutical formulations adapted for transder
familiar to those skilled in the art such as reaction in solvent mal administration may be presented as discrete patches
such as tetrahydrofuran, acetonitrile or dimethylformamide intended to remain in intimate contact with the epidermis of
at a range of temperatures from ambient to re?ux tempera the recipient for a prolonged period of time. For example, the
active ingredient may be delivered from the patch by ionto
ture.
phoresis as generally described in Pharmaceutical Research,
3(6), 318 (1986).
(XI) [0054] Pharmaceutical formulations adapted for topical
administration may be formulated as ointments, creams, sus
pensions, lotions, powders, solutions, pastes, gels, sprays,
aerosols or oils.
[0055] For applications to the eye or other external tissues,
for example the mouth and skin, the formulations are prefer
ably applied as a topical ointment or cream. When formulated
in an ointment, the active ingredient may be employed with
either a para?inic or a water-miscible ointment base. Alter
Pharmaceutical Compositions
natively, the active ingredient may be formulated in a cream
[0043] As discussed herein, the compounds of the inven with an oil-in-water cream base or a water-in-oil base.
tion are useful in the treatment of various conditions. Thus, [0056] Pharmaceutical formulations adapted for topical
the second aspect of the invention provides a pharmaceutical administration to the eye include eye drops wherein the active
composition or formulation comprising at least one com ingredient is dissolved or suspended in a suitable carrier,
pound of the invention and optionally one or more pharma especially an aqueous solvent.
ceutically acceptable excipients. [0057] Pharmaceutical formulations adapted for topical
[0044] Typical pharmaceutically acceptable excipients administration in the mouth include lozenges, pastilles and
include: mouth washes.
[0045] diluents, e.g. lactose, dextrose, sucrose, mannitol, [0058] Pharmaceutical formulations adapted for rectal
sorbitol, cellulose and/or glycine; administration may be presented as suppositories or enemas.
[0046] lubricants, e.g. silica, talcum, stearic acid, its [0059] Pharmaceutical formulations adapted for nasal
magnesium or calcium salt and/or polyethyleneglycol; administration wherein the carrier is a solid include a coarse
[0047] binders, e.g. magnesium aluminum silicate, powder having a particle size for example in the range 20 to
starch paste, gelatin, tragacanth, methylcellulose, 500 microns which is administered in the manner in which
sodium carboxymethylcellulose and/or polyvinylpyr snuff is taken, i.e. by rapid inhalation through the nasal pas
rolidone; sage from a container of the powder held close up to the nose.
[0048] disintegrants, e.g. starches, agar, alginic acid or Suitable formulations wherein the carrier is a liquid, for
its sodium salt, or effervescent mixtures; and/or administration as a nasal spray or as nasal drops, include
[0049] absorbants, colorants, and/or sweeteners. aqueous or oil solutions of the active ingredient.
US 2014/0206703 A1 Jul. 24, 2014
[0060] Pharmaceutical formulations adapted for adminis are reported in (sigma) units down?eld from the internal
tration by inhalation include ?ne particle dusts or mists which standard tetramethylsilane (TMS) and interproton coupling
may be generated by means of various types of metered dose constants are reported in Hertz (HZ), splitting patterns are
pressurised aerosols, nebulizers or insuf?ators. designated as follows: s, singlet; d, doublet; t, triplet; q, quar
[0061] Pharmaceutical formulations adapted for vaginal tet; m, multiplet; br, broad peak; dd, doublet of doublet; dt,
administration may be presented as pessaries, tampons, doublet of triplet; bs, broad singlet; dq, doublet of quartet.
creams, gels, pastes, foams or spray formulations. [0074] IR spectra were determined on a Perkin Elmer Spec
[0062] Pharmaceutical formulations adapted for parenteral trum One instrument.
administration include aqueous and non-aqueous sterile Mass spectra were determined on an Agilent 6310 Ion trap
injection solutions which may contain anti-oxidants, buffers, instrument.
bacteriostats and solutes which render the formulation iso
[0075] HPLC analysis (method (a)) was carried out on a
tonic with the blood of the intended recipient; and aqueous Waters 2695 system using ZORBAX SB C-18 (4.6><50 mm)
and non-aqueous sterile suspensions which may include sus column;
pending agents and thickening agents. The formulations may
[0076] Mobile phase: A: 0.05% TFA (AQ,) B: 0.05% TFA
be presented in unit-dose or multi-dose containers, for
(MeCN); T % B: 0/20, 5/90, 8/90, 8.1/20; ?ow rate 1.0
example sealed ampoules and vials, and may be stored in a
mL/min;
freeze-dried (lyophilized) condition requiring only the addi
[0077] Chiral column: Chiralpak IC (4.6><250 mm)5u,
tion of the sterile liquid carrier, for example water for inj ec
mobile phase: A: Hexane, B: EtOH (70:30); ?ow rate 0.8
tions, immediately prior to use. Extemporaneous injection
solutions and suspensions may be prepared from sterile pow ml/ min run over 40 minutes.
ders, granules and tablets. [0078] Melting points were determined on an EX-Melt
instrument (Model: MPA120).
[0063] Preferred unit dosage formulations are those con
taining a daily dose or sub-dose, as herein above recited, or an [0079] Alternatively, HPLC analysis (method (b)) was car
appropriate fraction thereof, of an active ingredient. ried outwith: Waters 616 ?uid handling system, Waters 996
[0064] It should be understood that in addition to the ingre photodiode array detector.
dients particularly mentioned above, the formulations may [0080] Chiral column: Daicel Chiralpak AD-H (Chiral
also include other agents conventional in the art having regard technologies) reporting chiral purity at 244 nm; mobile phase
to the type of formulation in question, for example those 80% Hexanes:20% EtOH; ?ow rate 0.8 ml/min; temp 40° C.
suitable for oral administration may include ?avouring Mass spectra were determined on an Agilent 1100 series
agents. instrument (Model: G1946C).
[0081] Using the information outlined herein the following
MODES FOR CARRYING OUT THE INVENTION compounds can be synthesised which are given by way of
[0065] The following protocols describe preparation of:i example only. The pharmacological pro?le of compounds of
[0066] 1. racemate made using “convergent route” (Ex the present invention can readily be assessed by those skilled
amples 1 to 6) in the art using routine experimentation, such as procedures
[0067] 2. enantiomers made using “convergent route” and techniques illustrated herein and described in detail in
(Examples 1 to 5 and 7 to 12) Ford et al., 2002.
[0068] 3. enantiomers made using “linear route” (Ex
amples 1 to 5 and 13 to 16) Example 1
Synthesis and Determination of Enantiomers (Z)-2-Cyano-3-phenyl-but-2-enoic acid ethyl ester
(V11)
[0069] The desired enantiomerically pure compound was
obtained by the careful selection of reagents and the use of [0082]
appropriate experimental conditions and sequence in particu
lar with regard to steps forming the chiral center and subse
quent reaction. It was determined during the course of syn
thesis that the “linear route” was less prone to racemisation as O /—
the ?nal amide forming bond could be carried out at lower
O
temperature as opposed to the “convergent route” which pro
vided better yields but with detectable racemisation.
[0070] For the “linear route”, pure enantiomers of the nipe :N
cotic acid were obtained by classical resolution of cheap
commercially available racemic nipecotic acid using 1-(S)
[0083] A stirred mixture of acetophenone (VIII) (180 g, 1.5
camphor sulfonic acid as the resolving agent, determining ee
mol), ethyl cyanoacetate (170 g, 1.3 mol), ammonium acetate
analysis after forming a BOC derivative of a sample.
(23.1 g), acetic acid (72 g) and toluene (300 ml) was heated
[0071] The enantiomeric purity was determined by Chiral
under re?ux for 18 hours while water was removed from the
HPLC.
reaction by azeotropic distillation. The mixture was allowed
Analytical Methods to cool to ambient temperature, toluene (100 ml) was added,
then the mixture was washed with water (3x100 ml). The
[0072] Proton magnetic resonance (1H NMR) spectra were combined aqueous washings were shaken with toluene (50
recorded on a Varian 400 MHZ ml), then the combined toluene solutions were dried over
[0073] Mercury Plus spectrometer. All spectra were deter magnesium sulphate, ?ltered and the solvent was removed in
mined in dmso-d6 unless otherwise stated and chemical shifts vacuo. The residual oil was distilled under reduced pressure
US 2014/0206703 A1 Jul. 24, 2014
to give 2-cyano-3-phenyl-but-2-enoic acid ethyl ester as an and dried in vacuo at 40° C. to give 5-Phenyl-1H-thieno[2,3
oil (309 g) which was used without further puri?cation. d]pyrimidine-2,4-dione as a white solid.Yield:(1.1 g, 56%).
Example 2
Example 4
2-Amino-4-phenyl-thiophene-3 -carboxylic acid ethyl
ester (V I) 2,4-Dichloro-5 -phenyl-thieno[2,3 -d]pyrimidine (IV)
[0084]
[0089]
O
/\
O
S NHZ
[0085] 2-Cyano-3-phenyl-but-2-enoic acid ethyl ester
(513.25 g, 2.3 mol) was added at ambient temperature to a
vigorously-stirred suspension of powdered sulfur (76 g, 2.3
[0090] A stirred mixture of 5-Phenyl-1H-thieno[2,3-d]py
mol) in ethanol (500 ml). Diethylamine (200 ml) was added in rimidine-2,4-dione (1.07 g, 4.39 mmol) and phenyl phospho
portions over 20 minutes, during which time the temperature
nic dichloride (Aldrich, 10 ml, excess) was heated at 150° C.
of the reaction rose to 62° C. The mixture was allowed to cool
for 7 h then allowed to stand at ambient temperature for 18
to 36° C., then it was heated to 50° C. and stirring at that
hrs. The resulting dark solution was poured into ice-water and
temperature was continued for 1 hr. After this time, stirring
extracted with DCM (3 X150 ml). The combined extracts were
was discontinued, the hot solution was removed by decanta
washed with saturated sodium hydrogen carbonate solution
tion from unreacted sulfur, then it was allowed to cool to
(150 ml) and dried (MgSO4). The solvent was removed in
ambient temperature. The resulting solid was collected by
vacuo and the oily residue triturated with 40-60° C. petroleum
?ltration, washed with a little cold ethanol and dried in vacuo
to give 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ether to give 2,4-Dichloro-5-phenyl-thieno[2,3-d]pyrimidine
ester as an orange solid (195 g) which was used without as a pale yellow solid. Yield:(0.82 g, 66%).
further puri?cation.
Example 5
Example 3
(2-Chloro-5 -phenyl-thieno[2,3 -d]pyrimidin-4 -yl)
5 -Phenyl-1H-thieno[2,3-d]pyrimidine-2,4-dione (V)
pyridin-2-ylmethyl-amine (Ill)
[0086]
[0091]
[0087] 2-Amino-4-phenyl-thiophene-3-carboxylic acid
ethyl ester (2.0 g, 8.1 mmol), and Potassium Cyanate (Ald
rich, 2.0 g, 24.3 mmol) were added to glacial acetic acid
(VWR, 20 ml) and stirred at ambient temperature for 18 h.
The reaction was diluted with water (50 ml) and the resultant [0092] A mixture of 2,4-Dichloro-5-phenyl-thieno[2,3-d]
precipitate ?ltered, washed with water and dried to a damp pyrimidine (1.77 g, 6.3 mmol), 2-aminomethylpyridine (Ald
cake. rich, 782 [1.1, 7.6 mmol), and triethylamine (V WR, 1.06 ml,
[0088] The solid was suspended in water (100 ml) and 7.63 mmol) were re?uxed in ethanol (30 ml) for 3 hrs. On
made alkaline to pH 12-14 by the addition of concentrated cooling, the reaction was poured into water (300 ml) and
sodium hydroxide. The resultant suspension was heated at stirred for 1 hr. The resulting precipitate was ?ltered, washed
100° C. for 2 h with stirring, then cooled to ambient tempera with water (2><30 ml) and dried under vacuum at 40° C. to give
ture and acidi?ed by the addition of glacial acetic acid. The (2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2
resulting solid was collected by ?ltration, washed with water ylmethyl-amine as a pale-yellow solid.Yield:(1.55 g, 70%).
US 2014/0206703 A1 Jul. 24, 2014
Racemate4Convergent Route and concentrated. The residue was columned on silica (20 g
isolute). Eluting: MeOH/DCM 0-5% 5 CV, MeOH/DCM
Example 6 5%-5% 10 CV, MeOH/DCM 5-10% 5 CV. TLC visualized
with KMnO4. This yielded the product as a clear oil (327 mg).
(Racemic) 1-{ 5 -Phenyl-4-[(pyridin-2-ylmethyl) [0097] Similarly was prepared:
amino] -thieno [2,3 -d]pyrimidin-2 -yl} -piperidine
3carboxylic acid (2 -hydroxy-ethyl)-amide (la) Example 8
[0093]
(R)-3 -(2-Hydroxy-ethylcarbamoyl) -piperidine-1 -
carboxylic acid tert-butyl ester
Example 9
(S)-Piperidine-3-carboxylic acid
(2-hydroxy-ethyl)-amide
[0098]
OH
HN g/\/
[0094] (2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl) [0099] The product of the above reaction was stirred in 1:1
pyridin-2-ylmethyl-amine (44 mg, 0.124 mmol), Piperidine TEA/DCM for 2 hrs then concentrated in vacuo to an oil. This
3-carboxylic acid(2-hydroxyethyl)amide (Fluorochem, 32 was dissolved in MeOH (5 ml) and loaded onto a 5 g SCX
mg, 0.188 mmol, 1.5 eq) and N,N-diisopropylethylamine cartridge. The cartridge was washed with MeOH (10 ml),
(Aldrich, 0.188 mmol) were dissolved in N-Methyl Pyrroli then the product eluted with 2M NH3/MeOH (10 ml). The
dinone (1.5 ml) in a Biotage microwave tube and heated to fraction was concentrated to give a white solid. Yield:260
200° C. and maintained at this temperature for 30 min. On mg.
cooling, the solvents were removed in vacuo. The residue was [0100] Similarly was prepared:
triturated with DCM (2><10 ml) and the extracts combined,
Example 10
concentrated and puri?ed by prep TLC (eluent 10% MeOH/
DCM) to give the product as a yellow oil, which slowly
(R)-Piperidine-3-carboxylic acid
solidi?ed on standing to a waxy solid. The waxy solid may be
(2-hydroxy-ethyl)-amide
converted to a free-?owing powder by stirring in diethyl ether
for 1-2 h (0.5 g in 10 ml). Yield:18.3 mg (30%)
Example 11
Enantiomers4Convergent Route
(S)-1 -{ 5 -Phenyl-4- [(pyridin-2-ylmethyl)-amino] -
thieno [2,3-d]pyrimidin-2-yl } -piperidine-3 -carboxy
Example 7
lic acid (2 -hydroxy-ethyl)-amide (lb)
(S)-3 -(2-Hydroxy-ethylcarbamoyl)-piperidine-1 [0101]
carboxylic acid tert-butyl ester
[0095]
MOTON
[0096] (S)-Piperidine-1,3-dicarboxylic acid 1-tert-butyl
ester (500 mg, 2.2 mmol), HATU (833 mg, 2.2 mmol) and
Di-isopropylethylamine (761 ML, 4.4 mmol) were stirred in
dry DCM (10 ml) in an ice bath for 5 min, then at room
temperature for 5 min. Ethanolamine (198 ML, 3.28 mmol)
was added and the reaction stirred at room temperature for 3 [0102] (S)-Piperidine-3-carboxylic acid (2-hydroxy
hrs. The reaction was diluted with DCM (40 ml), washed with ethyl)-amide was reacted with (2-Chloro-5-phenyl-thieno [2,
water (50 ml), the DCM layer separated and dried (MgSO4) 3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine as in