Note: Descriptions are shown in the official language in which they were submitted.
2~8~
- 1 - T1096Y
IND~ZOLE-8UB8TITUTED FIVE-MEMBERED
ETERO~ROMATIC CO~POUND8
The present invention relates to a class of
indazole~substituted five-membered heteroaromatic
compounds which act on 5-hydroxytryptamine (5-HT)
receptors, being specific agonists of so-called "5-HTl-
like" receptors. They are therefore ussful in the
treatment of clinical conditions for which a selective
agonist of these receptors is indicated.
5 HTl-like receptor agonists which exhibit
selective vasoconstrictor activity have recently been
described as being of use in the treatment of migraine
(see, for example, A. Doenicke et al., The Lancet, 1988,
Vol. 1, 1309-11). The compounds of the present
invention, being specific 5-HTl-like receptor agonists,
are accordingly of particular use in the treatment of
migraine and associated conditions, e.g. cluster
headache, chronic paroxysmal hemicrania and headache
20 associated with vascular disorders.
EP-A-0313397 describes a class of tryptamine
derivatives substituted by a five-membered
heteroaliphatic ring, which are stated to act as specific
agonists of a particular type of "5-HTl-like" receptor
25 and thus to be effective therapeutic agents for the
treatment of clinical conditions,-particularly migraine,
requiring this activity. However, EP-A-0313397 neither
discloses nor suggests the heteroaromatic compo~mds
provided by the present invention.
EP-A-0328200 describes a class of 5-membered
heterocyclic compounds having at least one heteroakom,
substituted on the heterocyclic ring by an azacyclic or
azabicyclic ring system or an amino substituent. Thes~
compounds are stated to be useful in the treatment of
, , . ."~ :
.
.
5~' l3 ~
- 2 - T1096Y
psychotic disorders (e.g. schizophrenia and mania);
anxiety; alcohol or drug withdrawal; pain; gastric
stasis; gastric dysfunction; migraine, nausea and
vomiting: and presenile and senile dementia. However,
they have no action on the 5-HTl-like receptors of which
the heteroaromatic compounds of the present invention are
specific agonists, and therefore elicit their effect by a
different mechanism.
The present invention provides a compound of
formula I, or a salt or prodrug thereof:
~,W~ E - F
~ ,`l
A~Y--z
( I )
wherein the broken circle represents two non-adjacent
double bonds in any position in the five-membered ring;
W, X, Y and Z independently represent oxygen,
sulphur, nitrogen or carhon, provided that one of W, X, Y
and Z represents oxygen or sulphur and at least one of W,
X, Y and Z represents carbon;
A represents hydrogen, hydrocarbon, halogen,
cyano, trifluoromethyl, nitro, -ORX, -OCORX, -ONRXRY,
-SRX, -NRXRY, -NRXORY, -NRZNRXRY, -NRXCORY, -NRXC02RY,
-NRXSO2RY~ -NRZCVNRXRY~ -CORX, ~C02RX or -CONRXRY;
E represents a bond or a straight or branched
alkylene chain containing from 1 to 4 carbon atoms;
F represents a group of formula
2 ~ rl
-- 3 -- T1096Y
R 1
R3
Rl represents -CH2.CHR4.NRXRY or a group of
formula
R5
in which the broken line represents an optional chemical
bond;
R3, R4 and R5 independently represent hydrogen,
C1_6 alkyl, C2_6 alkenyl or C~-6 alkynyl;
Rx and RY independently represent hydrogen or
hydrocarbon, or Rx and RY together represent a C2_6
alkylene group;
RZ represents hydrogen or hydrocarbon;
V represents oxygen, sulphur or a group of
formula =N.G; and
G represents hydrocarbon or an electron-
withdrawing group.
For use in medicine, the salts of the
compounds of formula I will be non-toxic pharmaceutically
acceptable salts. Other sal~s may, however, be useful in
the preparation of the compounds according to the
~: '
20~8~r'j
- 4 - T1096Y
invention or of their non-toxic pharmaceutically
acceptable salts. Suitable pharmaceutically acceptable
salts of the compounds of this invention include acid
addition salts which may, for example, be formed by
mixing a solution of the compound according to the
invention with a solution of a pharmaceutically
acceptable non-toxic acid such as hydrochloric acid,
fumaric acid, maleic acid, succinic acid, acetic acid,
citric acid, tartaric acid, carbonic acid or phosphoric
acid. Furthermore, where the compounds of the invention
carry an acidic moiety, suitable pharmaceutically
acceptable salts thereof may include alkali metal salts,
e.g. sodium or potassium salts; alkaline earth metal
salts, e.g. calcium or magnesium salts; and salts formed
with suitable organic ligands, e~g. quaternary ammonium
salts.
The term "hydrocarbon" as used herein includes
straight-chained, branched and cyclic groups, including
heterocyclic groups, containing up to 18 carbon atoms,
suitably up to 15 carbon atoms, and conveniently up to 12
carbon atoms. Suitable hydrocarbon groups include Cl_6
alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C3_7
cycloalkyl(C1_6)alkyl, aryl, aryl(C1_6~alkyl, C3_7
heterocycloalkyl, C3_7 heterocycloalkyl(C1_6)alkyl,
hetexoaryl and heteroaryl(C1_6)alkyl.
Suitable alkyl groups include straight-
chained and branched alkyl groups containing from 1 to 6
carbon atoms. Typical examples include methyl and ethyl
groups, and straight-chained or branched propyl and butyl
groups. Particular alkyl groups are methyl, ethyl and
t-butyl.
Suitable alkenyl groups include straight-
chained and branched alkenyl groups containing from 2 to
- 5 - T1096Y
6 carbon atoms. Typical examples include vinyl and allyl
groups.
Suitable alkynyl groups include straight-
chained and branched ~lkynyl groups containing from 2 to
6 carbon atoms Typical examples include ethynyl and
propargyl groups.
Suitable cycloalkyl groups include groups
containing from 3 to 7 carbon atoms. Particular
cycloalkyl groups are cyclopropyl and cyclohexyl.
Suitable aryl groups include phenyl and
naphthyl groups.
Particular aryl(Cl_6)alkyl groups include
benzyl, phenethyl and phenylpropyl.
Suitable heterocycloalkyl groups include
azetidinyl, pyrrolidyl, piperidyl, piperazinyl and
morpholinyl groups.
Suitable heteroaryl groups include pyridyl,
quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl,
pyrazinyl, pyranyl, furyl, benzofuryl, dibenzofuryl,
thienyl, benzthienyl, imidazolyl, oxadiazolyl and
thiadiazolyl groups.
A particular heteroaryl(Cl_6)alkyl group is
pyridylmethyl.
The hydrocarbon group may in turn be optionally
substituted by one or more groups selected from Cl_6
alkyl, adamantyl, phenyll halogen, C1_6 haloalkyl, Cl_6
aminoalkyl, trifluoromethyl, hydroxy, Cl_6 alkoxy,
aryloxy, keto, Cl_3 alkylenedioxy, nitro, cyano, carboxy,
C2_6 alkoxycarbonyl, C2_6 alkoxycarbonyl(Cl~6)alkyl, C2_6
alkylcarbonyloxy, arylcarbonyloxy, C2_6 alkylcarbonyl,
arylcarbonyl, Cl_6 alkylthio, Cl_6 alkylsulphinyl, Cl_6
alkylsulphonyl, arylsulphonyl, -NR~R~, -NRVCORw,
-NRYC02RW, -NRVS02RW, -CH2NRVS02RW, -NHCONRVRw, -CONRVR~,
-S02NRVRw and -CH2S02NRVRw, in which Rv and Rw
~8~3
- 6 - T1096Y
independently represent hydrogen, Cl_6 alkyl, aryl or
aryl(Cl_6)alkyl, or Rv and Rw together represent a C2_6
alkylene group.
When Rx and RY, or Rv and RW, together
represent a C2_6 alkylene group, this group may be an
ethylene, propylene, butylene, pentamethylene or
hexamethylene group, preferably butylene or penta-
methylene.
When the group G represents an electron-
withdrawing group, this group is suitably cyano, nitro,-CORX, -CO2RX or -SO2RX, in which Rx is as defined above.
The term "halogen" as used herein includes
fluorine, chlorine, bromine and iodine, especially
fluorine.
The present invention includes within its scope
prodrugs of the compounds of formula I above. In
general, such prodrugs will be functional derivatives of
the compounds of formula I which are readily convertible
in vivo into the required compound of formula I.
Conventional procedures for the selection and preparation
of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard,
Elsevier, 1985.
Where the compounds according to the invention
have at least one asymmetric centre, they may accordingly
exist as enantiomers. Where the Gompounds accor~ing to
the invention possess two or more asymmetric centres,
they may additionally exist as diastereoisomers. It is
to be understood that all such isomers and mixtures
thereof are encompassed within the scope of the present
nvent ion .
The five-membered heteroaromatic ring in
formula I containing the substituents W to Z may be, for
example, a furan, thiophene, oxazole, thiazole,
.
:
.. ' : '
2~8~
- 7 - T1096Y
isoxazole, isothiazole, oxadiazole or thiadiazole ring,
in particular a 1,2,4-oxadiazole, 1,3,4-oxadiazole,
1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,3-oxazole or 1,3-
thiazole ring. Preferably the ring is a 1,2,4-
oxadiazole, 1,2,4-thiadiazole, 1,3-oxazole or 1,3-
thiazole ring.
The alkylene chain E may be, for example,
methylene, ethylene, l-methylethylene, propylene or
2-methylpropylene. Alternatively, the group E may
represent a single bond such that the indazole moiety F
in form~la I is attached directly to the five-membered
heteroaromatic ring.
Suitable values for the group A include C1_6
alkyl, C3_7 cycloalkyl, aryl, aryl(Cl_6)alkyl, C3_7
heterocycloalkyl or heteroaryl(Cl_6)alkyl, any of which
groups may be optionally substituted; and hydrogen,
halogen, cyano, trifluoromethyl, nitro, Cl_6 alkoxy, C1_6
alkylthio, -NRXRY or -CONRXRY, in which Rx and RY are as
defined above. Examples of optional substituents on the
group A suitably include phenyl, trifluoromethyl, C1_6
alkoxy, C2_6 alkoxycarbonyl, C2_6 alkylcarbonyl, Cl_6
alkylsulphonyl, arylsulphonyl, amino, mono- or
di(Cl_6)alkylamino, C2_6 alkylcarbonylamino,
arylcarbonylamino, C2_6 alkoxycarbonylamino, C1_6
alkylsulphonylamino, arylsulphonylamino, C1_6
alkylsulphonylaminomethyl, aminocarbonylamino, mono- or
di(Cl_6)alkylaminocarbonylamino, mono- or
diarylaminocarbonylamino, pyrrolidylcarbonylamino,
aminocarbonyl, mono- or di(C1_5)alkylaminocarbonyl, Cl_6
alkylaminosulphonyl, aminosulphonylmethyl, and mono- or
di(Cl_6)alkylaminosulphonylmethyl.
Particular values of A include methyl,
methoxymethyl, aminomethyl, dimethylaminomethyl,
acetylaminomethyl, b~nzoylaminomethyl, t-butoxy-
.
-
2~5~0~
- 8 - T1096Y
carbonylaminomethyl, methylsulphonylaminomethyl,
phenylsulphonylaminomethyl/ aminocarbonylmethyl, ethyl,
aminoethyl, acetylaminoethyl, benzoylaminoethyl,
methoxycarbonylaminoethyl, ethoxycarbonylaminoethyl,
t-butoxycarbonylaminoethyl, methylsulphonylaminoethyl/
aminocarbonylaminoethyl/ methylaminocarbonylaminoethyl,
t-butylaminocarbonylaminoethyl, phenylaminocarbonyl-
aminoethyl, pyrrolidylcarbonylaminoethyl, cyclopropyl,
phenyl, methylsulphonylaminophenyl, aminocarbonylphenyl,
methylaminocarbonylphenyl, methylsulphonylaminomethyl-
phenyl, aminosulphonylmethylphenyl/ methylaminosulphonyl-
methylphenyl/ dimethylaminosulphonylmethylphenyl,
naphthyl/ benzyl, diphenylmethyl, trifluoromethylbenzyl,
methoxybenzyl, acetylaminobenzyl/ methylsulphonylamino-
benzyl, aminocarbonylaminobenzyl, aminocarbonylbenzyl
methylaminocarbonylbenzyl, methylsulphonylbenzyl,
methylaminosulphonylbenzyl, phenethyl, phenylpropyl,
acetylpiperazinyl, methoxycarbonylpiperazinyl,
t-butoxycarbonylpiperazinyl, methylaminocarbonyl-
piperazinyl, methylsulphonylpiperazinyl, phenylsulphonyl-
piperazinyl, pyridylmethyl, methoxypyridylmethyl, amino,
methylamino, benzylamino, dimethylamino, t-butoxy-
carbonylaminoethylamino, methylsulphonylaminoethylamino,
aminocarbonyl, methylaminocarbonyl, azetidinylcarbonyl
and pyrrolidylcarbonyl.
Representative values of R1 include aminoethyl,
N-methylaminoethyl, N,N-dim~thylaminoethyl and l-methyl-
4-piperidyl. Preferably, R1 represents aminoethyl or
N,N-dimethylaminoethyl.
Suitably, the groups R3 to R5 independently
represent hydrogen or C1_6 alkyl, in particular hydrogen
or methyl.
: , ' -:
2 0
- g - T1096Y
A particular sub-class of compounds according
to the invention iæ represented by the compounds of
formula IIA, and salts and prodrugs thereof:
A1Y ~(~ H2)n~ ~ XRY
R13
(IIA)
wherein
zl represents oxygen or sulphur;
lS n is zero, 1, 2 or 3;
Al represents C1_6 alkyl, C2_6 alkenyl, C2_6
alkynyl, C3_7 cycloalkyl, aryl, aryl(C1_6~alkyl, C3_7
hetarocycloalkyl, heteroaryl or heteroaryl(C1_6)alkyl,
any of which grGups may be optionally substitu~ed; or
hydrogen, halogen, cyano, trifluoromethyl, nitro, C1~6
alkoxy, Cl_6 alkylthio, -NRXRY or -CONRXRY;
R13 and R14 independently represent hydrogen,
C1_6 alkyl, C2_6 alkenyl or C2~6 alkynyl; and
R~ and RY independently represent hydrogen or
hydrocarbon, or Rx and RY together represent a C2_6
alkylene group.
Examples of optional substituents on the group
Al suitably include phenyl, trifluoromethyl, Cl_6 alkoxy,
C2_6 alkoxycarbonyl, C2~6 alkylcarbonyl, C1_6
alkylsulphonyl, arylsulphonylt amino, mono- or
di(Cl_6)alkylamino, C2 6 alkylcarbonylamino,
arylcarbonylamino, C2_6 alkoxycarbonylamino, C1_6
alkylsulphonylamino, arylsulphonylamino, C1_6
alkylsulphonylaminomethyl, aminocarbonylamino, mono- or
2 ~ ;.3
- 10 ~ T1096Y
di(Cl_6)alkylaminocarbonylamino, mono- or
diarylaminocarbonylamino, pyrrolidylcarbonylamino,
aminocarbonyl, mono- or di(C1_6)alkylaminocarbonyl, Cl_6
alXylaminosulphonyl, aminosulphonylmethyl, and mono- or
di(Cl_6)alkylaminosulphonylmethyl.
Particular values of Al with respect to formula
IIA include methyl, methoxymethyl, aminomethyl, dimethyl-
aminomethyl, acetylaminomethyl, benzoylaminomethyl,
t-butoxycarbonylaminomethyl, methylsulphonylaminomethyl,
phenylsulphonylaminomethyl, aminocarbonylmethyl, ethyl,
aminoethyl, acetylaminoethyl, benzoylaminoethyl,
methoxycarbonylaminoethyl, ethoxycarbonylaminoethyl,
t-butoxycarbonylaminoethyl, methylsulphonylaminoethyl,
aminocarbonylaminoethyl, methylaminocarbonylaminoethyl,
t-butylaminocarbonylaminoethyl, phenylaminocarbonyl-
aminoethyl, pyrrolidylcarbonylaminoethyl, cyclopropyl,
phenyl, methylsulphonylaminophenyl, aminocarbonyl~henyl,
methylaminocarbonylphenyl, methylsulphonylaminomethyl-
phenyl, aminosulphonylmethylphenyl, methylaminosulphonyl-
methylphenyl, dimethylaminosulphonylmethylphenyl,
naphthyl, benzyl, diphenylmethyl, tri~luoromethylbenzyl,
methoxybenzyl, acetylaminobenzyl, methylsulphonylamino-
benzyl, aminocarbonylaminobenzyl, aminocarbonylbenzyl,
methylaminocarbonylbenzyl, methylsulphonylb~nzyl,
methylaminosulphonylbenzyl, phenethyl, phenylpropyl,
acetylpiperazinyl, methoxycarbonylpiperazinyl,
t-butoxycarbonylpiperazinyl, methylaminocarbonyl-
piperazinyl, methylsulphonylpiperazinyl, phenylsulphonyl-
piperazinyl, pyridylmethyl, methoxypyridylmethyl, amino,
methylamino, benzylamino, dimethylamino, t-butoxy- -
carbonylaminoethylamino, methylsulphonylaminoethylamino, :
aminocarbonyl, methylaminocarbonyl, azetidinylcarbonyl
and pyrrolidylcarbonyl. In a preferred embodiment,
represents amino.
- 11 - T1096Y
Preferably, R13 and R14 each represents
hydrogen. Preferred values of Rx and RY with respect to
formula IIA include hydrogen and methyl.
Another sub-class of compounds according to the
invention is represented by the compounds of formula IIB,
and salts and prodrugs thereof:
A1 ~ ~ ~ ~CH2)n ~ XR~
R23
(I 1~)
wherein
yl represents oxygen or sulphur;
n is zero, 1, 2 or 3;
Al is as defined with reference to formula IIA
above;
R23 and R24 independently represent hydrogen,
Cl_6 alkyl, C2_6 alkenyl or C2_6 alkynyl; and
Rx and RY independently represent hydrogen or
hydrocarbon, or Rx and RY together represent a C2_6
alkylene group.
Particular values of Al with respect to formula
IIB include methyl and benzyl. Preferably, R23 and R24
each represents hydrogen. Preferred values of Rx and RY
with respect to formula IIB include hydrogen and methyl.
A further sub-class of compounds according to
the invention is represented by the compounds of formula
IIC, and salts and prodrugs thereof:~
~88~ 3
- 12 - T1096Y
N ~ xRr
l~3
( I lC~
wherein
wl represents oxygen or sulphur;
n is zero, 1, 2 or 3;
Al is as defined with reference to formula IIA
above;
R33 and R34 independently represent hydrogen,
C1_6 alkyl, C2_6 alkenyl or C2_6 alkynyl; and
Rx and RY independently represent hydrogen or
hydrocarbon, or Rx and RY together represent a C2_6
alkylene group.
A particular value of A1 with respect to
formula IIC is methyl. Preferably, R33 and R34 each
represents hydrogen. Preferred values of Rx and RY with
respect to formula IIC include hydrogen and methyl.
A still further sub-class of compounds
according to the invention is represented by the
compounds of formula IID, and salts and prodrugs thereof:
R45
~"~`N~
A ~ N\~ ( C H z ) n ~J
I 43
~ i I 1) )
- 13 - T1096Y
wherein
z represents oxygen or sulphur;
n is zero, 1, 2 or 3;
Al is as defined with reference to formula IIA
above;
R43 and R45 independently represent hydrogen,
C1_6 alkyl, C2_6 alkenyl or C2_6 alkynyl; and
Rx and RY independently represent hydrogen or
hydrocarbon, or Rx and RY together repre~ent a C2_6
alkylene group.
Particular values of A1 with respect to formula
IID include amino, and optionally substituted benzyl or
pyridylmethyl, especially methylsulphonylaminobenzyl.
Preferably, R43 represents hydrogen.
Preferably, R45 represents hydrogen or Cl_6 alkyl,
especially methyl.
Specific compounds within the scope of the
present invention include:
2-[5-(3-methyl-1,2,4-oxadiazol-5-yl)-lH-indazol-3-
yl]ethylamine;N,N-dimethyl-2-[5-(3-methyl-1,2,4-oxadiazol-5-yl)-lH-
indazol-3-yl]ethylamine;
N,N-dimethyl-2-[5-(3-amino-1,2,4-thiadiazol-5-yl)-l~-
indazol~3-yl]ethylamine;
and salts and prodrugs thereof.
The invention also provides pharmaceutical
compositions comprising one or more compounds o~ this
invention in association with a pharmaceutically
acceptable carrier. Preferably these composi~ions are in
unit dosage forms such as tablets, pills, capsules,
powders, granules, sterile parenteral solutions or
suspensions, or suppositories, ~or oral, parenteral or
rectal administration. For preparing solid compositions
such as tablets, the principal active ingredient is mixed
- 14 - T1096Y
with a pharmaceutical carrier, e.g. conventional
tableting ingredients such as corn starch, lactose,
sucrose, sorbitol, talc, stearic acid, magnesium
stearate, dicalcium phosphate or gums, and other
pharmaceutical diluents, e~g. water, to form a soli~
preformulation composition containing a homogeneous
mixture of a compound of the present invention, or a non~
toxic pharmaceutically acceptable salt thereof. When
referring to these preformulation compositions as
homogeneous, it is meant that the active ingredient is
dispersed evenly throughout the composition so that the
composition may be readily subdivided into equally
effective unit dosage forms such as tablets, pills and
capsules. This solid preformulation composition is then
subdivided into unit dosage forms ~f the type described
above containing from 0.1 to about 500 mg of the active
ingredient of the present invention. The tablets or
pills of the novel composition can be coated or otherwise
compounded to provide a dosage form affording the
advantage of prolonged action. For example, the tablet
or pill can comprise an inner dosage and an outer dosage
component, the latter being in the form of an envelope
over the former. The two components can be separated by
an enteric layer which serves to resist disintegration in
the stomach and permits the inner component to pass
intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers
or coatings~ such materials including a number of
pol~meric acids and mixtures of polymeric acids with such
materials as shellac, cetyl alcohol and cellulose
acetate.
The liquid forms in which the novel
compositions of the present invention may be incorporated
for administration orally or by injection include aqueous
2 ~ P3
- 15 - T1096Y
solutions, suitably flavoured syrups, aqueous or oil
suspensions, and flavoured emulsions with edible oils
such as cottonseed oil, sesame oil, coconut oil or peanut
oil, as well as elixirs and similar pharmaceutical
vehicles. Suitable dispersing or suspending agents for
aqueous suspensions include synthetic and natural gums
such as tragacanth, acacia, alginate, dextran, sodium
carboxymethylcellulose, methylcellulose, polyvinyl
pyrrolidone or gelatin.
lo In the treatment of migraine, a suitable dosage
level is about 0.01 to 250 mg/kg per day, preferably
about 0.05 to 100 mg/kg per day, and especially about
0.05 to 5 mg/kg per day. The compounds may be
administered on a regimen of 1 to 4 times per day.
The oxadiazole compounds of this invention may
be prepared by a process which comprises reacting a
reactive derivative of a carboxylic acid of formula
RC-CO2H with a compound either of formula III or of
formula IV, or a salt thereof:
.0
NOH
1~ 11
Rd~C~N~ Rd NHNH2
(lll) (IV)
wherein one of Rc and Rd is a group of formula A, and the
other is a group of formula -E-F, as defined with
reference to formula I above.
Suitable reactive derivatives of the acid
RC-CO2H include esters, for example Cl_4 alkyl esters;
thioesters, for example pyridylthioesters; acid
anhydrides, for example (RCCO)20; acid halides, for
:
2~8
- 16 - T1096Y
example acid chlorides; orthoesters; and primary,
secondary and tertiary amides.
A preferred reactive derivative of the acid
RC-co2H is the iminoether derivative of formula V:
NH . HC I
I I
~C~
RC OR
( V )
where R is C1_~ alkyl.
When the compound of formula III is employed
the product of the reaction is a 1,2,4-oxadiazole. It
will be appreciated that the compound III can also be
considered as the alternative tautomeric form IIIA:
NHOH
I
Rd~ ~NH
(I I 1~)
wherein Rd i~ as defined above.
A 3-substituted-1,2,4-oxadiazol-5-yl compound
is produced if Rc represents a group -E-F and Rd in
formula III represents a group A; whereas a 5-
substituted-1,2,4-oxadiazol-3-yl compound is produced by
the process of this invention when Rc represents a group
A and Rd represents a group -E F. A preferred reactive
derivative of the acid RC-CO2H in this case is a C1_4
alkyl ester. The reaction is conveniently carried out in
the presence of a strony base, e~g. sodium hydridel using
a suitable solvent, for example tetrahydrofuran,
dimethylformamide or a lower alkanol such as ethanol,
.
2 ~
- 17 - T1096Y
propanol or isopropanol, at about 20C to 100C for about
1 to 6 hours.
When the compound of formula IV is employed,
the product of the process of this invention is a 1,3,4-
oxadiazole. In this case, a preferred reactivederivative of the acid RC-CO2H is an orthoester of
formula RCC(ORPj3 where RP represents Cl_3 alkyl. The
process is conveniently effected by heating the hydrazide
IV with the orthoester in a solvent such as methanol at
reflux temperature for about 2 to 8 hours. An
intermediate of formula Rd.CO.NH.N=C(RC)ORP may be
isolated by evaporation of the solvent. The intermediate
is then treated with a strong base such as potassium
t-butoxide or 1,8-diazabicyclo[5.4.0]undec-7-ene, in
butanol for about 10 to 24 hours at about gOC to 150C.
The reactive derivative of a carboxylic acid of
formula RC-C02H or the compound of formula III or IV,
wherein Rc or Rd represents a group of formula -E-F, may
be prepared by the cyclisation of a compound of formula
VI:
Q-E~ ~ ~ N D
NH2
(V I )
wherein Q represents a reactive carboxylate moiety, or a
group of formula -CtNOH)NH2 or -CONHNH2 or a protected
derivative thereof or precursor thereto; E and Rl are as
defined above; and D represents a readily displaceable
.
2~58~
-- 18 -- ' Tl096Y
group; followed, where required, by N-alkylation by
standard methods to introduce the moiety R3.
The cyclisation of compound VI is conveniently
achieved in a suitable organic solvent at an elevated
temperature, for example in a mixture of m-xylene and
2,6-lutidine at a temperature in the region of 140C; or
in the melt, which requires a temperature of
approximately 170~C.
When the moiety Q in the compounds of formula
VI represents a precursor to a group of formula
-C~NOH)NH2 or -CONHNH2, this group is suitably a nitrile
group.
The readily displaceable group D in the
compounds of formula VI suitably represents a CI_4
alkanoyloxy group, preferably acetoxy, or an
arylsulphonyl group such as p-toluenesulphonyl (tosyl). ?
Where D in the desired compound of formula VI represents
acetoxy, this compound may be conveniently prepared by
treating a carbonyl compound of formula VII:
R
Q- E~J~
N H 2
( V I I )
wherein R1, E and Q are as defined above; or a protected
derivative thereof; with hydroxylamine hydrochloride,
advantageously in pyridine at the reflux temperature of
the solvent; followed by acetylation with acetic
anhydride, advantageously in the presence of 4-
2~5~
- 19 - T1096Y
dimethylaminopyridine, in dichloromethane at room
temperature.
The N-formyl protected derivative of the
intermediate of formula VII may be conveniently prepared
by ozonolysis of an indole derivative of formula VIII:
R1
Q-E ~
H
(VIII)
wherein Rl, E and Q are as defined above; followed by a
reductive work-up, advantageously using dimethylsulphide.
The indole derivatives of formula VIII may be
prepared by methods analogous to those described in the
accompanying Examples, or by procedures well known from
the art.
The 1,2,4-thiadiazoles of formula I may be
prepared by a process which comprises the cyclisation of
a compound of formula IX:
R~ ~ N(R )2
N ~
Rd
( lX~
wherein Rc and Rd are as defined above, and Re is
hydrogen or an alkyl group.
Cyclisation of compound IX can be achieved
using an aminating agent such as hydroxylamine-O-
''
.
3.~
- 20 ~ T1096Y
sulphonic acid in a lower alkanol such as methanol,
ethanol or propanol, in the presence of pyridine, at
between -20C and 50C for about 1-6 hours.
Cyclisation of compounds of formula IX in which
Re is hydrogen may also be achieved by use of an
oxidising agent such as bromine, iodine, hydrogen
peroxide or nitric acid.
The compounds of formula IX above may be
prepared by the processes described in Comprehensive
Heterocyclic Chemistry, ed. A.~. Katritzky and C.W. Rees,
Pergamon Press, 1984, Vol. 6, p. 496, or by methods
analogous thereto.
The 1,2,4-thiadiazoles may also be prepared by
cycloaddition of a nitrile sulphide RC-C--N+-S with a
nitrile of formula Rd-CN where Rc and Rd are as defined
above.
1,3,4-Thiadiazoles of this invention may be
prepared by dehydration of a thiosemicarbazide of formula
RCCSNHNHCONRsRt, where Rc is as defined above and Rs and
Rt are hydrogen or an alXyl group, with a dehydrating
agent such as sulphuric acid, polyphosphoric acid or
methanesulphonic acid; followed by attachment of the Rd
group by conventional means.
1,2,5-Thiadiazoles of this invention may be
prepared by reacting a diamine of the type
RC NH2
~d NH2
where Rc and Rd are as defined above, with a sulphur
chloride such as thionyl chloride or sulphur dichloride.
.
- . . . ~:
.
2~58~3
- 21 - T1096Y
The oxazoles and thiazoles of this invention
may be prepared by reaction of an amide or thioamide
of formula X with a a-haloketone of formula XI:
Ha I
U
R a~ C~ N H ,~C~ d
(X) (X I )
wherein U is oxygen or sulphur, Hal represents halogen,
and Rc and Rd are as defined above. The conditions for
this reaction are as described in Synthesis, 1975, 389.
Furans possessing a 2,5-substitution pattern
may, for exampleJ be prepared by treating a compound of
formula XII:
~3
Rd
~XI 1)
wherein Rd is as pL-eviously defined, with a reagent
capable of generating an anion thereof by abstraction of
the proton adjacent to the oxygen atom; and subsequently
reacting the anionic species thereby obtained with an
electrophilic species capable of providing the moiety RC,
wherein Rc is as previously defined.
The reagent capable of generating an anion of
the compound of formula XII by abstraction of the proton
adjacent to the oxygen atom is suitably an alkyl lithium,
e.g. n-butyllithium.
The electrophilic species capable of providing
the moiety Rc is suitably a carbonyl-containing compound
,
- .:
2~a~ .3
~ 22 - T1096Y
or a compound of formula RC-L, in which L represents a
suitable leaving group such a~ halogen atom, e.g.
chlorine or bromine. In the former case, the compound
obtained from reaction of the carbonyl compound with the
anion derived from compound XII will contain a hydroxy
moiety as part of the resulting Rc group. This hydroxy
moiety may, if desired, be retained intact, or may be
removed by standard procsdures, for example elimination
with POC13 ~ollowed by hydrogenation.
Illustrative experimental details for
performing the above process are, for example, described
in J. Med. Chem., 1990, 33, 1128.
The intermediate of formula XII may be prepared
by conventional methods, for example:
L I -C--C--C2 E t = D I b~ I--H /~
Rd_CHO Rd o Rd ~o;
(X I I )
wherein Rd is as defined above.
In an alternative process, the compounds
according to the invention may he prepared by a method
which comprises reacting a compound of formula XIII:
,",.W~,
X,' `~
H ~ I y--~--R d
(Xl I 1)
.. . ~
~ ~ 3
- 23 - T1096Y
with a reagent which ~rovides an anion RC, where W, X,
y~ z, Rc and Rd are as previously defined and Hal
represents halogen.
Compound XIII may be prepared by conventional
procedures known from the art. For example, if compound
XIII is a 1,2,4-thiadiazole, this compound may be
prepared by the general method described in Chem. Ber.,
1957, 90, 182.
Reagents which may provide the anion Rc
include Grignard reagents RCMgHal (where Hal = halogen~;
organocuprate reagents such as LiRC2Cu; organolithium
reagents RCLi; or compounds which stabilise the anion by
means of an adjacent activating group such as an ester or
enolisable ketone function. In this case, the adjacent
ester or ketone function may be retained after the
process is complete, or may be removed. For example, an
ester moiety may be hydrolysed and decarboxylated.
In a further process, the compounds according
to the invention may be prepared by a method which
comprises cyclising a compound of formula XIV:
R 1
(X lV)
wherein W, X, Y, Z, A, E, R1 and D are as defined above;
followed, where required, by N-alkylation by standard
methods to introduce the moiety R30
As with the cyclisation of compound VI, that of
compound XIV is conveniently achieved in a suitable
8 ~ .~
- 24 - T1096Y
organic solvent at an elevated temperature, for example
in a mixture of m-xylene and 2,6-lutidine at a
temperature in the region of 140C; or in the melt.
The compounds ~f formula XIV may, for example,
be prepared from the corresponding compound of fo~mula
XV:
\~N 11
( X V ~ '
wherein W, X, Y, Z, A, E and Rl are as defined above; or
a protected derivative thereof; which in turn may be
prepared from the corresponding ~ompound of formula XVI:
E ~ R~
(XYI) H
wherein W, X, Y, Z, A, E and R1 are as defined above;
using methods analogous to those described above with
reference to the compounds of formulae VII and VIII.
Thusl for example, when Q in the compounds of formula
VIII represents a group of formula -C(NOH)NH2 or
-CONHNH2, the compounds of formula XVI may be prepared
therefrom by reaction with a reactive derivative of a
20~8~ ~
- 25 - T1096Y
carboxylic acid of formula A-CO~H, where A is as defined
previous~y. Alternatively, when Q in the compounds of
formula VIII represents a reactive carboxylate moiety,
the compounds of formula XVI may be prepared therefrom by
reaction with a compound of formula A-C(NOH)NH2 or
A-CONHNH~.
The compounds of formula Q-E-F, wherein Q, E
and F are as defined above, and salts and prodrugs
thereof, are novel compounds in their own right, and
accordingly represent a further feature of the present
invention. A particular subgroup of such compounds is
represented by the compounds of formula Q1-E-F, wherein E
and F ars as defined above and Q1 repxesents a Cl_4 alkyl
ester group; and salts and prodrugs thereof.
Particularly preferred compounds in this context are
2-(5-ethoxycarbonyl-lH-indazol-3-yl)ethylamine;
2-(5-ethoxycarbonylmethyl-lH-indazol-3-yl~ethylamine;
N,N-dimethyl-2-(5-methoxycarbonylmethyl-lH-indazol-3-
yl)ethylamine;
and salts and prodrugs thereof.
It will be appreciated that any compound of
formula I initially obtained from any of the above
processes may, where appropriate, subsequently be
elaborated into a fur*her compound of formula I by
techniques known from the art. In particular, a compound
o~ formula I wherein R3 is hydrogen initially obtained
may be converted into a compound of formula I wherain R3
represents Cl_6 alkyl, C2_6 alkenyl or C2_6 alkynyl by
standard techniques such as alkylation, for example by
treatment with an alkyl iodide, e.g~ methyl iodide,
typically under basic conditions, e.g. sodium hydride in
dimethylformamida. Similarly, a compound of formula I
wherein Rl represents a group of formula -CH2oCHR4~NH2
initially obtained may be converted into a compound of
, . .
2~58~
- 26 - T1096Y
formula I wherein Rl represents a group of formula
-CH2.CHR4.NRXRY in which Rx and RY are as defined above
with the exception of hydrogen, for example by
conventional N-alkylation or N-arylation techniques, e.g.
by treatment with the appropriate aldehyde in the
presence of a reducing agent such as sodium
cyanoborohydride.
Where the above-described processes for the
preparation of the compounds according to the invention
give rise to mixtures of stereoisomers, these isomers may
be separated by conventional techniques such as
preparative chromatography.
The novel compounds may be prepared in racemic
form, or individual enantiomers may be prepared either by
enantiospecific synthesis or by resolution. The novel
compounds may, for example, be resolved into their
component enantiomers by standard techniqu~s, such as the
formation of diastereomeric pairs by salt formation with
an optically active acid, such as (-)-di-p-toluoyl-d-
tartaric acid and/or (~-di-p-toluoyl-l-~artaric acid
followed by fractional crystallization and regeneration
of the free base. The novel compounds may also be
resolved by formation of diastereomeric esters or amides,
followed by chromatographic separation and removal of the
chiral auxiliary.
During any of the above synthetic sequences it
may be necessary and/or desirable to protect sensitive or
reactive groups on any of the molecules concerned. This
- may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in
Orqanic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973;
and T.W. Greene, Protective Groups in Orqanic Synthesis,
John Wiley & Sons, 1981. The protecting groups may be
2 ~
- 27 - T1096Y
removed at a convenient subsequent stage using methods
known from the art.
- The following Examples illustrate the
preparation of compounds according to the invention.
The ability of test compounds to bind to
5-HTl-like receptors was measured in membranes prepared
from pig caudate using the procedure described in
J. Neurosci., 1987, 7, 894. Binding was determined using
2 nM 5-hydroxytryptamine creatinine sulphate,
5-[1,2-3H(N)) as a radioligand. Cyanopindolol (100 nM~
and mesulergine (100 nM) were included in the assay to
block out 5-HT1A and 5-HTlC binding sites respectively.
The concentration of the compounds of the accompanying
Examples required to displace 50% of the specific binding
(IC50) is below 1 ~M in each case.
The activity of test compounds as agonists of
the 5-HTl-like receptor was measured in te~ms of their
ability to mediate contraction of the saphenous vein of
New Zealand White rabbits, using the procedure described
in Arch. Pharm., 1990, 342, 111. Agonist potencies were
- calculated as -loglOEC50 (pEC50) values, from plots of
percentaye 5-HT (1 ~m) response against the concentration
of the agonist. The compound of accompanying Example 2
was tested and was found to possess a pEC50 value in this
assay of not less than 5Ø
:
- ~ 2~30~j
- 28 - T1096
EXAMPLE 1
2-(5-Carboethoxy-1H-indazol-3-yl)eth~lami~e h~,Tdro~en
oxalate
1. 2-(5-Carboethox~T-1E-indol-3-yl)ethylamine
';
a. Ethyl-p-hsrdrazinobenzoate hydrochloride
lo A solution of soclium nitrite (17.0g, 0.24mol) in water
(9Oml) was added to a cooled solution of ethyl-p-amino benzoate
(40g, 0.24mol) in concentrated hydrochloric acid (225ml) at such
a rate that the temperature did not exceed 0C. The mi~ture
was stirred at 0C for 10 minutes before adding a stirred
solution of tin (II) chloride dihydrate (202g, 0.89m~1) in
concentrated hydrochloric acid (135ml) at such a rate that the
temperature did not exceed -5C. The resulting suspension was
allowed to warm to room temperature over a 1 hour period,
filtered and washed with ether. m.p. 215-217C. NMR ~
(360MHz, D20) 1.38 (3H, t, J = 7Hz), 4.37 (2H, q, J - 7~z), 7.06
(2E, d, J = 9Hz), 8.03 (2H? d, J = 9Hz).
b. 2-(5-Carboetho~ H-indol-3-yl)eth~lamine
A solution of ethyl-p-hydrazinobenzoate hydrochloride
(lOg, 46mmol) and 4-chlorobutanal dimethyl acetal (7.8g,
;~ 46mmol) in ethanol/water (5:1, 5Qûml) was heated at re~ for 2
.
- ~ :
,
2 ~ 3 8 ~ ~ ~f3
- 29 - T1096
hours. The solvent was removed under vacuum and the residue
chromatographed through silica gel eluting with
dichloromethane/ethanol/ammonia (40:8:1) to give the title
indole (3.69g) as an oil. NMR o (360MHz, CDC13) 1.42 (3E, t, J
= 7Hz), 2.94 (2H, t, J = 7Hz), 3.06 (2H, t, J = 7Hz), 4.40 (2H, q, J
- 7Ez), 7.10 (lH, br s), 7.35 (lH, d, J = 9Hz), 7.91 (lH, dd, J = 9
and 2Hz), 8.30 (lH, br s), 8.38 (lH, s).
2. N-(tert-But~lo~carbonyl)-2-(5-carboethoxy-lH-indol-3-
lo yl)ethylamine
To a stirred solution of 2-(5-carboethoxy-lH-indol-3-
yl)ethylamine hydrochloride (2.0g, 7.4mmol) and di-tert-
butyldicarbonate (2.06g, 9.4mmol) in dichlorc~methane (52ml) at
0C, was added triethylamine (1.3ml, 9.4mmol). The solution
was stirred overnight at room temperature, then partitioned
with water (50ml). The organic layer was separated, dried
(MgSO4) and e~Taporated in vacuo. The crude residue was
chromatographed using 95:5 dichloromethane:methanol, to give
N-(tert-butylo~ycarbonyl)-2-(5-carboethoxy-lH-indol-3-
yl)ethylamine (1.58g, 64%) as an oil. NMR ~ (2~0MHz, CDC13)
1.44 (12H, m), 2.88 (2H, t, J = 7Hz), 3.49 (2H, m), 4.41 (2H, q, J
= 7Hz~, 4.61 (lH, br s), 7.09 (lH, d, J = 2Hz), 7.37 (lH, d, J -
9Hz), 7.92 (lH, dd, J = 9 and 2Hz), 8.35 ~2H, m).
2~
2 ~
- 30 - T1096
3. Ethyl-4-formylamino-3-[3'-(N-tert-
butyloxycarbonylamino)propionyl]benzoate
Ozone was bubbled through a solution of N-(tert-
butyloxycarbonyl)-2(5-carboethoxy-lH-indol-3-yl)ethylamine
(6.06g, 18mmol) in dichloromethane (300ml) at -78C for 2
hours. Dimethyl sulphide (8ml, llOmmol) was then added
dropwise at -78C, and the solution allowed to attain room
temperature. After stirring at room temperature overnight the
solvents were evaporated in vacuo. :3ther (lOOml) was added
and the desired product (4.5g, 92%) was collected by filtration.
m.p. 135-137C. NMR ~ (250MHz, CDCl3) 1.43 (12H, m) 3.32
(2H, t, J - 6Hz), 3.66 (2H, m), 4.42 (2H, q, J = 7Hz), 5.05 (lH, br
s), 8.27 (lH, dd, J = 9 and 2Hz), 8.~6 (l~I~ br s), 8.60 (lH, d, J =
2Hz), 8.84 (lH, br s), 11.66 (lH, br s).
4. Ethyl-4-amino-3-[3'-(N-tffrt-butyloxycarbonrlamino
- hydroxyiminopropyl]benzoate
A solution of ethyl-4-formylamino-3-[3'-(N-tert-
butyloxycarbonylamino)propionyl]ben~oate (7.04g, 20mmol) and
hydroxylamine hydrochloride (7.65g, llOmmol) in pyridine
(200ml), was heated at reflux for 15 hours. After this time the
solution was cooled to ambient temperature and the solvent
evaporated in vacuo. The residue was chromatographed (eluent
1:1 petrol:ethyl acetate) to give the title oxime (5.0g, 71%) as a
2 0 ~
- 31 - T1096
solid. m.p. 138-140C. NMR ~ (250MHz, CDCl3) 1.40 (12H, m),
3,13 (2HJ t, J = 7Hz), 3.40 (2H, m), 4.31 (2H, q, J = 7Hz), 5.19
(1H,brS),6.11(~2H,brS),6.66(1H,d,J=9HZ),7.73(1H,dd,J-
9 and 2HZ), 8,10 (1~I, br s), 10.46 (1H, br s).
5. Eth~1-4-amino-3-~3'-(N-tert-hutyloxyc~rbonylamino)-1'-
acetoxs7iminopropyl]benzoate
To a stirred solution of ethyl-4-amino-3 ~3'-(N-tert-
butyloxycarbonylamino)-1~-h~dro~{yiminopropyl]benzoate (4.8g,
14mmol) and dimethylamino pyridine (1.67g, 14mmol) in
dichloromethane (200ml) was added acetic anhydride (1.3ml,
14mmol), under an atmosphere of nitrogen. A~ter 2 hours the
solution was poured into water (200ml) and partitioned. The
i5 organic layer was separated, washed once more with water
(200ml), then the combined organic phases dried (MgSO4). The
solvent was removed in vacuo, to af~ord an oily solid. Ether
(200ml) was added, and the mixture evaporated in ~racuo once
more to give ~ white solid. The solid was taken up in more ether
(100ml) and filtered off, to afford the title compound (4.4g, 82%)
as a white solid. m.p. 130-13~C. NMR ~ (250MHz, CD(~i3)
1.40 (12H, m), 2.27 (3H, s), 3.18 (2H, t, J = 7~Iz), 3.43 (2H, m),
4.33 (2H, q, J = 7Hz), 4.70 (1H, br s), 6.69 (lH, d, J = 9Hz~, 7.82
(1H, dd, J = 9 and 2Hz), 8.17 (lH, br s).
2~8~
- 32 - T1096
6. N-(tert-Butylo~carbonyl)-2-(~-carboethoxY-lH-indazol-
3 -yl)ethylamine
A solution of ethyl-4-amino-3-[3'-(N-tert-
5 butyloxycarbonylamino)-l/-acetoxyiminopropyl]benzoate (2.8g,
7.1mmol) and 2,6-lutidine (0.83ml, 7.1mmol) in m-xylene
(200ml), was heated at reflux in Dean-Stark apparatus for 5
hours. The solution was then cooled to ambient temperature
and the solvent evaporated in vacuo. The crude residue was
lo purified by flash chromatography (eluent 1:1 petrol:ethyl
acetate) to give the inda~ole (0.95g, 67%) as a colourless oil.
NMR (250MHz, CDC13) o 1.42 (12H, m), 3.20 (2H, t, J = 7Hz),
3.65 (2H, m), 4.41 (2H, q, J = 7Hz), 5.09 (lH, br t), 7.44 (lH, d, J
= 9Hz), 8.05 (lH, dd, J = 9 and 2Hz), 8.45 (lH, br s), 10.~0 (lH,
br s).
7. 2-(5-Carboethoxv-lH-indazol-3-yl)ethylamine hydro~en
oxalate
~ solution of N-(tert-butyloxycarbcnyl) 2-(5-carboethoxy-
lH-inda~ol-3-yl)ethylamine (461mg, 1.4mmol) and
trifluoroacetic acid (1.5ml) in dichloromethane (20ml), under an
atmosphere of nitrogen, was stirred ~or 4 hours. The mixture
was then evaporated and the crude residue chromatographed
using a gradient elution (1:1 petrol:ethyl acetate then 30:8:1
dichloromethane:ethanol:ammonia). This afforded 2-(5-
carboethox~r-lH-indazol-3-yl)ethylamine (218mg, 67%) as a pale
2 ~ 3 ~
33 T1096
yellow solid. The oxalate salt was prepared: M.p. 212-214C.
NMR (360MHz, D20-D6-DM~0) ~ 1.41 (3H, t, J = 7Hz), 3.39
(2H, m), 3.~0 (2H, m), 4.40 (2H, q, J = 7Hz), 7.61 (lH, d, J =
9Hz), 8.02 (lE, dd, J = 9 and 2Hz), 8.50 (lH, br s). m/æ (CI,
NH3),234 (M+1),204, 186,151,131, 91.
EXAMPLE 2
2-[5-(3-Methyl-1 ~2.4-oxadiazol-5-yl)-1H-indazol-3-
10 ~l])et~Ylamine hydroFen oxalate
To a stirred solution of ethanol (lOml), under an
atmosphere of nitrogen, was added sodium (64mg, 2.8mmol)
cautiously. After dissolution methyl acetamide oxime (228mg,
5 3.1mmol) was added portionwise and the mixture stirred at
room temperature for 30 minutes. After this time a solution of
2-(5-carboe~hoxy-1H-indazol-3-yl)ethylamine (218mg,0.93mmol)
in ethanol (5ml) was added, and the reaction heated at reflux for
10 hours. The solution was then cooled to ambient temperature
20 and the solvent evaporated in vacuo. The crude residue was
chromatographed, using dichloromethane:ethanol:ammonia
(35:8:1) as the eluent, to give a mixture of the desired product
and starting material in an 80:20 ratio. Therefore, both
compounds were combined and the reaction repeated using a
25 further 52mg of the oxime and 15mg of sodium in ethanol
(15ml). After heating the mixture at reflux for a ~urther 9
. .
~ 0 3 ~3 8 ~3 3
- 34 - T1096
hours, the m~xture was cooled to room temperature, evaporated
in vacuo, and chromatographed (eluent
_
dichloromethane:ethanol:a~nonia 35:8:1). 2-[~-(3-Methyl-1,2,4-
oxadiazol-5-yl)-lH-indazol-3-yl]ethylamine (63mg, 28%) was
isolated as a colourless oil. The oxalate salt was prepared: M.p.
230-233C. NMR (360MHz, D20-D6-DMSO) ~ 2.40 (3H, s), 3.38
(2H, t, J = 7Hz), 3.46 (2H, t, J = 7Hz), 7.66 (lH, d, J = 9Hz), 7.93
(lH, d, J = 9Hz), 8.39 (lH, s). m/z (CI, NH3), 244 (M+1), 212,
166, 151, 130.
EXAMPLE 3
N,N-Dimethy1-2-[5-(3-methyl-1 2t4-oxadiazol-5-yl)-lE-
indazol-3-yl]ethylamine hYdro~en oxalate
A solution of formaldehyde (0.75ml of a 37% (w/v) solution
in water, 9.3mmol) in methanol (5ml) was added dropwise,
under a nitrogen atmosphere, to a stirred solution of 2-(5-
carboethoxy-lH-indazol-3-yl)ethylamine (641mg, 2.32mmol),
sodium cyanoborohydride (0.29g, 4.64mmol) and acetic acid
(0.42ml, 7.0mmol) in methanol (11ml). A~ter 3 hours the
methanol was evaporated in vacuo and the residue dilutea wi~h
dichloromethane (30ml). The solution was washed with
saturated potassium carbonate solution (30ml), and the organic
2~ phase separated. The aqueous layer was extracted with more
dichloromethane (2 x ~Oml), then the organic phases combined,
dried (MgSO4) and evaporated in vacuo. The crude residue was
chromatographed, using dichloromethane:ethanol:ammonia
ri
- 35 - T1096
80:8:1 as the eluent. Two inseparable products (Rf 0.4) were
collected, one of which was the desired N,N-dimethy1-2-(5-
carboethoxy-1H-indazol-3-yl)ethylan~ine. This was not purifiecl
further.
To a stirred solution of ethanol (5ml), under an
atmosphere of nitrogen, was added sodium (63mg, 2.75mmol)
cautiously. After dissolution, methyl acetamide oxime (204mg,
2.75mmol) was added portionwise and the mixture stirred at
lo room temperature for 30 minutes. A~ter this time a solution of
the above mixture (120mg) (Rf 0.4; in
dichloromethane:ethanol:ammonia 80:8:1) in ethanol (5ml) was
added, and the solution heated at rellux for 20 hours. The
mixture was then cooled to ambient temperature and the solvent
removed in vacuo. Dichloromethane (20ml) was added and the
solu~ion partitioned with water (20ml). The organic layer was
separated and the aqueous phase extracted with more
dichloromethane (2 x 20ml). The organic layers were combined,
dried (MgSO4) and e~aporated in vacuo. The crude residue was
chromatographed (eluent dichloromethane:ethanol:ammonia
50:8:1) to afford N,N-dimethyl-2-~5-(3-methyl-1,2,4-oxadiazol-5-
yl)-lH-indazol-3-yl]ethylamine (66mgs) as a colourless oil. The
oxalate salt was prepared: m.p. 207-210C. NMR ~360MHz,
D2O) ~ 2.34 ~3E, s), 3.00 (6H, s), 3.42 (2H, t, J = 7Hz), 3.64 (2H,
t, J = 7Hz), 7.55 (lH, d, J = 9Hz), 7.76 (1:EI, dd, J = 9 ancl 1Hz),
8.14 (lH, s). m/z (CI, NH3), 272 (M+1), 186.
!
`: : ,
~ ~ 'P3 8 ~ 3
36- T1096
EXAMPLE 4
N.N-Dimeth~1-2-(5-carbomethoxymeth~ lH-indazol-3-
yl)ethylamir~e
1. 4-(CarboethoxymethYl)PhenYlhYdrazine. Hydrochloride
The title compound was prepared from ethyl 4
aminophenylacetate by a similar method to that described for
lo Example 1 (Step la); mp 171-174C (absolute ethanol); ~H
(360MHz, DMSO-d6) 10.02 (br s -N~H3), 8.14 (br s, -NH-), 7.16
(2H, d, J = 8.5Hz, Ar-H), 6.92 (2H, d, J = 8.5Hz, Ar-H), 4.06 (2H,
q, J = 7.1Hz, -OCH2-), 3.56 (2H, s, Ar-CH2-), 1.17 (3H, t, J =
7.1Hz, -CH3); m/z (EI) 194 (M~).
1~
2. 2-(5-Carboethoxymethyl-lH-indol-3-yl)ethylamine.
Hydrochloride
The title compound was prepared from 4-
(carboetho~y~ethyl)phenylhydrazine hydrochloride and 4-
chlorobutanal dimethylacetal by a similar method to that
described for Example 1 (Step lb); mp 204-206C (ethanol-
diethyl ether); ~H (360MHz, DMSO-d6) 10.7Q (lH, br s, indole
N-H), 8.09 (3H, br s, -N+H3), 7.43 (lH, s, ~r-~3:), 7.31 (lH, d, J -
8.3Hz, Ar-H), 7.23 (lH, d, J = 2.3Hz, Ar-H), 6.99 (lH, dd, J = 8.3
and 1.6Hz, Ar-H), 4.07 (2H, q, J = 7.1Hz, -OCH2-), 3.68 (2H, s,
Ar-C~I2CO-), 3.02 (4H, m, -CH2CH2 ), 1.18 (3H, t, J = 7.1Hz,
37- T1096
-CH3); m/z (CI) 247 (M~+1).
3._(tert-Butyloxycarbon:gl)-2-(5-carboetho~rmethyl-1H-
indol-3-yl)ethylamine
The title compo~nd was prepared in 98% yield from 2-(5-
car~oethoxymethyl-1H-indol-3-yl)ethylamine hydrochloride hy a
sil:nilar method to that described for E~ample 1 (Step 2);
colourless thick oil; ~H (360MHz, CDCl3), 8.06 (lH, br s, i:ndole
lo N-H), 7.48 (lH, s, Ar-H), 7.30 (1H, d, J = 8.3Hz, Ar-H), 7.13 (lH,
d, J = 8.3Hz, Ar-H), 6.99 (lH, s, Ar-H), 4.58 (lH, br s, -NH~),
4.15 (2H, q, J = 7.1Hz,-OCH2-), 3.70 (2H, s, Ar-CH2-CO-), 3.45
(2H, m, -CH2N-), 2.92 (2H, t, J = 6.8Hz, -CH2-), 1.43 (9H, s, t-
Bu), 1.25 (3H, t, J - 7.1Hz, -CH3); m/z (EI) 346 (M~
4. }3thyl 4-formylamino-3-[3'-(N-tert-
but;~,Tloxycarbo~ylamino)propionyl~phenylacet~t~
The title comPound was prepared in 64% isolated yield
from N-(tert-butyloxycarbonyl)-2-(5-carboetho2~:y:l:nQthyl-lH-
indol-3-yl)ethylamine by a similar method to that dascribed for
Example 1 (Step 3); pale yellow oil; ~H (360MHz, CDCl3) 11.49
(l~I, br s), 8.75 ~lH, d, J = 7.5Hz), 8.49 (lH, s3, 7.63 (lH, s), 7.49
(lE, d, J = 7.5Hz), 5.02 (1H, br s), 4.17 (2H, q, J = 7.1Hz), 3.62
-; 25 (2~, s), 3.53 (2H, br q, J = 6Hz), 3.28 (2H, br t, J = 6:Hz), 1.43
(9EI, s), 1.27 (3II, t, J = 7.1Hz); rn/z (CI) 378 (M+).
..
2 ~
- 38 - T1096
5. Ethyl 4-amino~$-[3'-(N-t_-but:ylo~Ycarbonylam~no~ 1'
hydroxyiminopropyl]phenylacetate
The title compou~d was prepared in 43% yield from the
product of Step 4 using a similar method to that described for
.,
Example 1 (Step 4); off white solid; ~H (360MHz, CDCl3) 7.28
(lH, br s), 7.04 (lH, dd, J = 8.2 and 1.8Hz), 6.68 (lH, d, J =
8.2Hz), 4.93 (lH, br s), 4.14 (2H, q, J = 7.1Hz), 3.50 (2H, s), 3.40
(2H, m), 3.07 (2H, t, J = 6.9~Iz), 1.42 (9E, s), 1.25 (3H, t, J =
lo 7.1Hz); m/z (EI) 365 (M+).
6. Ethyl 4-amino-3-[3'-(N-tert-butyloxycarbonYlam~no)-1'-
acetoxyiminopropyl]phenYlacetate
The title compound was prepared in 67% yield fi om ethyl
4-amino-3-[3'-(N-tert-butyloxycarbonylamino)-1'-
hydroxyiminopropyl]phenylacetate by a similar method tv that
described for Example 1 (Step 5); pale yellow oil; ~H (3~0MHz,
CDCl3) 7.3~ (lH, br s), 7.10 (1~, dd, J = 8.3 and 1.9Hz), 6.69
(lH, d, J = 8.3Hz), 4.77 (lH, br s), 4.13 (2H, q, J = 7.1Hz), 3.51
(2H, s), 3.39 (2H, br q, 6.7Hz), 3.11 (2E, t, J = 6.7Hz), 2.24 (3H5
s), 1.42 (9H, s), 1.24 (3H, t, J = 7.1Hz); m/z (FAB) 408 (M+~1).
7. N-(tert-Butyloxycarbonyl)-2-(5-carboethox~methYI-1H-
26 indazol-3-yl)eth~lamine
The title compound was prepared in 61~ yield from ethyl
., - -. ~ . .
2 ~ 3 g ~) ~ r3
39 T1096
4-amino-3-[3'-(N-tert-butyloxycarbonylamino)-1'-
acetoxy~minopropyl]phenylacetate as described for Example 1
(Step 6); ~H (360MHz, CD(~13) 7.57 (lH, s), 7.39 (lH, d, J =
8.4Hz), 7.32 (lHg dd, J = 8.4 and 1.~Hz), 5.06 (lH, br s), 4.16
(2H, q, J - 7.1Hz), 3.72 (2H, s), 3.61 (2H5 br q, J ~ 6.5Hz), 3.14
(2H, t, J = 6.5Hz), 1.43 (9H, s), 1.26 (3H, t, J = 7.1Hz); m/z (CI)
348 (M++1).
8. 2-(5-Carboethoxymeth~l-1H-indazol-3-s~l)ethylamine
The title compound was prepared in 80% yield from N-
(tert-butyloxycarbonyl)-2-(5-carboethoxymethyl-1H-indazol-3-
yl)ethylamine by a similar method to that described for Example
1 (Step 7~; pale yellow solid; H (360MHz, CDCl3) 7.54 (lH, s),
736 (1H, d, J = 8.5Hz), 7.28 (lH, d, J = 8.5Hz), 4.16 (2H, q, J =
7.1Hz), 3.70 (2H, s), 3.24-3.02 (4H, m), 1.26 (3H, t, J = 7.1Hz);
m/z (CI) 248 (M+~1).
9. NlN-Dimethyl-2-(5-carbon~ethox,~nmethyl-lH-indazol-3-
yl)ethylamine
To a cooled (0C) and stirred solution of 2-(5-
carboethoxymethyl-1H-indazol-3-yl)ethylamine (0.4~g, 1.7mmol)
in absolute methanol (30ml) and glacial acetic acid (0.48ml,
8.5mmol) was added sodium cyanoborohydride (0.21g, 3.4mmol)
followed by dropwise addition of a solution of formaldehyde (38%
w/v aqueous solution; 0.35ml) in methanol (6ml) over 8 m~nutes.
The resulting solution was stirred at 0C for 20 minutes and at
'
: '. ., .,,: - ' .
2 ~ :~ 3 & ~ ~
- 40 - T1096
room temperature for 1.5 hour~ before saturated aqueous
potassium carbonate (20ml) was added and the methanol was
removed under vacuum. The remaining aqueous solution was
extracted with ethyl acetate (2 x ~Oml) and the combined
organic phases were washed with brine (2 x 60ml), dried
(MgS04) and concentrated. Flash chromatography (silica gel,
dichloromethane-methanol-ammonia 50:8:1) of the crude residue
afforded 0.29g ~69~o) of the title compouIId as a low-melting
solid; H (250M~Iz, CDCl3) 7.47 (lH, s), 7.16-7.07 (2H, m), 3.63
(2H, s), 3.62 (3H, s), 3.09 (2H, t, J = 7.1Hz), 2.74 (2H, t, J =
7.1Hz), 2.29 (6H, s); m/z (CI) 262 (M~
E~AMPLE 5
i
1~ N~N-Dimethyl-2~ (3-amino-1,2,4-thiadiazol-5-yl)methyl-
lH-indazol-3-yllethylamine. Oxalate
1 . N, N - D_i m e t h Y l - 2 - [ 5 - ( 4 -_
methoxybenz~l)o2{vcarbonylmethxl-lH-indazol-3-yl]ethyla~ e
To a cooled (-78C) and stirred solution of 4-
methoxybenzyl alcohol (2g, 14.~mmol) in anhydrous
tetrahydrofuran (30ml) was added dropwise, lmder nitrogen, n-
butyllithium (1.6M in hexane, 7.8ml) over 10 minutes. After
26 further 10 minutes at -78C, a solution of N,N-dimethyl-2-(5-
carbometho~ymethyl-lH-indazol-3-yl)ethylamine ~780mg,
3~nmol) in anhydrous tetrahydrofuran (20ml) was added and the
'' ' '
,
- 41 - T1096
resulting solution was stirred at -78C ~or 1 hour and at room
temperature for 2 hours. Solvents were removed under vacuum
and the residue was azeotroped with toluene (2 x 30ml). The
remaining residue was diluted with water (50ml) and extracted
with diethyl ether (1 x 30ml) and ethyl acetate (2 x 10ml). The
combined organic solutions were dried (MgSO4) and
concentrated. Flash chromatography of the remaining oil (silica
gel, dichloromethane-methanol-ammonia 90:10:1) gave 958mg
(87~o) of the title compound as an oil; H (360MHz, CDCl3) 7.57
lo (lH, s), 7.36 (lH, d, J = 8.5Hz), 7.27 (3H, m), 6.86 (2H, m), 5.08
(2EI, s),3.80 (3H, s),3.16 (2H, s), 3.16 (2H, m),2.82 (2H, m),2.36
(6H, s); m/z (CI) 368 (M++1).
2 . N N - D i m e t h y l - 2 - [ 5 ~ ( 4 -
methoxYbenzvl)oxYcarbonvlmeth~l-1-tert-butyloxycarbonYl-
indazol-3-yl]ethylamine
To a stirred solution of the preceding ester (279mg,
0.76mmol) in anhydrous acetonitrile (5ml) was added a solution
of di-tert-butyl dicarbonate (200mg, 0.92mmol) in anhydrous
acetonitrile (2ml) followed by a solution of 4-
dimethylaminopyridine (20mg, 0.1~mmol) in anhydrous
acetonitrile (1ml). A~ter being stirred at room temperature for
17 hours, under nitrogen, the solvent was removed under
25 vacuum annd the remaining residue was purified by flash
chromatography (silica gel, dichloromethane-methanol-ammonia
95:5:0.5) to give 295mg (83%) of the title compound as an oil; H
,. . - ~ .
.
g 8 ~
42 T1096
(250MHz, CDCl3) 8.V0 (lH, d, J = 8.5Hz), 7.57 (lE, s), 7.42 (lH,
m), 7.26 (2H, m), 6.86 (2H, m), 5.08 (2H, s), 3.79 (3H, s), 3.15
(2H, 8~, 2.80 (2H, m), 2.35 (6H, s), 1.72 (9H, s); m/z (CI~ 468
(M~+1). (Found: C, 66.70; H, 7.17; N, 8.86. C26H33N3O5
6 requires: C, 66.79; H, 7.11; N, 8.99%~.
3. N,N-Dimethyl-2-[5-(4-methoxybeIlzyl)oxycarbo~r1(3-
amino-1,2 4-thiadiazol-~-yl)methyl-1-t_-butYlox~carbonyl-
indazol-3-yl]ethylamine
To a cooled (VC) and stirred solution of the preceding
ester (286mg, 0.61mmol) in anhydrous dimethylformamide (5ml)
was added sodium hydride (60% dispersion in oil, 80mg) and the
mixture was stiITed for 5 minutes before a solution of 3-amino-5-
1~ chloro-1,2,4-thiadiazole (120mg, O.B9mmol) in anhydrous
dimethylformamide (2.5ml) was added. After further 15
minutes, the reaction was quenched with aqueous phosphate
buffer (pH 7; 15ml) and products were extracted with ethyl
acetate (3 x 20ml). The combined organic solutions were dried
(MgSO4) and concentrated. Flash chromatography of th~
residue (silica gel, dichloromethane-methanol 95:5 to 80:20)
a~forded 107mg (31%) of the title compound; ~H (250MHz,
CDC13) 8.02 (1H, d, J = 8.5Hz), 7.68 (LEI9 S), 7.47 (1H, m), 7.18
(2H, m), 6.81 (2H, m), 5.38 (lH, s), 5.16 (2H, m), 4.93 (2H, br s),
3.78 (3H, s), 3.13 (2H, m), 2.79 (2H~ m~, 2.35 (6H, s)~ 1.70 (9H, s).
2 ~ ~ 8 ~
- 43 - T1096
4. N,N-Dimeth~ 2-[5-(3-amino-1~2 4-thiadiazol-5-
yl)methyl-1H-indazol-3-vl]ethylamine. Oxalate
A solution of the preceding product (1321ng, û.23mmol) in
6 a mixture of dichloromethane (5ml), water (0.2ml) and
trifluoroacetic acid ~1ml) was stirred at room temperature for 30
minutes. Solvents were removed under vacuum and the
remaining re~idue was azeotroped with a mixture of toluene and
methanol (4:1; 2 x 20ml). The resiaue was then dissolved in
10 D~etha~ol, refluxed for 2 minut~s and the m~thanol was r~moved
under vacuum. The resulting oil was chromatographed over
neutral alumina (grade 2.5) (ethyl acetate-methanol 9r):~ to
85:15) to give the title compound and N,N-dimethyl-2-[~-(3-
amino-1,2,4-thiadiazol-5-yl)methyl-1-tert-butylo:Rycarbonyl-
15 indaæol-3-yl]ethylamine. The later product was treated under
the same conditions as above to produce more of the title
compound as a white solid (combined yield: 39mg, 55%~. The
hydrogen oxalate salt was prepared and recrystallised from
ethanol-di~thyl ether; mp 217-218C; ~H (360MHz, DMSO-d6)
~o 7.75 (lEI, s), 7.47 (lH, d, J = 8.5Hz), 7.32 (lH, d, J = 8.5E[z), 6.~8
(2H, br s), 4.38 (2H, s), 3.16 (2H, m), 3.13 (2H, m~, 2.~7 (6~, s~;
m/z (FAB) 303 (M~+1). (Found: C, 48.99; H, ~.08; N, 21.83.
C14H18N6S 1.0 ~2H2V4 re~uires: C, 48.97; H, 5.14; N,
21.40~o).
.
:~'
:`
`~ `
:`
'
.. ~. ~..... . . .
~ ~ 5~
- 44 - T1096
EXAMPLE 6
Tablet Preparation
Tablets containing 1.0, 2.0, 25.0, 26~0, 50.0
and 100.0 mg respectively of the Eollowing compounds are
prepared as illustrated below:
2-[5-(3-methyl-1,2,4-oxadiazol-5-yl)-lH-indazol-3-
yl~ethylamine hydrogen oxalate;
N,N-dimethyl-2-[5-(3-methyl-1,2,4-oxadiazol-5-yl)-1~-
indazol-3-yl]ethylamine hydrogen oxalate.
:
;
2 ~ 5 3 ~ O ~
- 45 - T1096
TABLE FOR DOSES CONTAINING FROM
1-25 MG OF THE ACTIVE COMPOUND
Amount-mg
Active Compound l.O 2.3 25.0
Microcrystalline cellulose 49.25 48.75 37.25
Modified food corn starch 49.25 4~.75 37.25
Magnesium stearate 0.50 0.50 0.50
TABLE FOR DOSES CONTAINING FROM
26-100 MG OF THE ACTIVE COMPOUND
- Amount-mg ,
Active Compound 26.0 50.0 100.0
Microcrystalline cellulose 52.0 100.0 200.0
20 Modified food corn starch 2.21 4.25 8.5
Magnesium stearate 0.3g 0.75 1.5
All of the active compound, cellulose, and a portion of
the corn starch are mixed and granulated to 10% corn
starch paste. The resulting granulation is sieved, dried
and blended with the remainder of the corn starch and the
magnesium stearate. The resulting granulation is then
compressed into tablets.
~ 30
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~ '
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:
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