Note: Descriptions are shown in the official language in which they were submitted.
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TITLE O~' THE INVENTION
ANTAGONISTS OF GONADOTROPIN RELEASING HORMONE
BACKGROUND OF THE INVENTION
The gonadotropin-releasing hormone (GnRH), also referred
to as luteinizing hormone-releasing hormone (LHRH), is a decapeptide
that plays a key role in human reproduction. The hormone is released
from the hypothalamus and acts on the pituitary gland to stimulate the
biosynthesis and secretion of luteinizing hormone (LH) and follicle-
stimulating hormone (FSH). LH released from the pituitary gland is
primarily responsible for the regulation of gonadal steroid production
in both sexes, whereas FSH regulates spermatogenesis in males and
follicular development in females. GnRH agonists and antagonists have
proven effective in the treatment of certain conditions which require
inhibition of LH/FSH release. In particular, GnRH-based therapies
have proven effective in the treatment of endometriosis, uterine fibroids,
polycystic ovarian disease, precocious puberty and several gonadal
steroid-dependent neoplasia, most notably cancers of the prostate, breast
and ovary. GnRH agonists and antagonists have also been utilized in
various assisted fertilization techniques and have been investigated as a
potential contraceptive in both men and women. They have also shown
possible utility in the treatment of pituitary gonadotrophe adenomas,
sleep disorders such as sleep apnea, irritable bowel syndrome,
premenstrual syndrome, benign prostatic hyperplasia, hirsutism,
as an adjunct to growth hormone therapy in growth hormone deficient
children, and in marine models of lupus.
Current GnRH antagonists are GnRH-like decapeptides
which are generally administered intravenously or subcutaneously
presumably because of negligible oral activity. These have amino acid
substitutions usually at positions one, two, three, six and ten.
. Non-peptide GnRH antagonists offer the possible advantage
of oral adminstration. Non-peptide GnR,H antagonists have been
described in European Application 0 219 292 and in De, B. et al., J. Med.
Chem., 32, 2036-2038 (1989), in WO 95/28405, WO 95/29900 and EP 0679642
all to Takeda Chemical Industries, Ltd.
-1-
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Substituted indoles known in the art include those described
in the following patents and patent applications. US Patent No. 5,030,640
discloses alpha-heterocyclic ethanol aminoalkyl indoles which are
potent 13-agonists. US Patent No. 4,544,663 discloses indolamine
derivatives which are allegedly useful as male anti-fertility agents.
WO 90/05721 discloses alpha-amino-indole-3-acetic acids useful as
anti-diabetic, anti-obesity and anti-atherosclerotic agents. French
patent 2,181,559 discloses indole derivatives with sedative, neuroleptic,
analgesic, hypotensive, antiserotonin and adrenolytic activity. Belgian
patent 879381 discloses 3-aminoalkyl-1H-indole-5-thioamide and
carboxamide derivatives as cardiovascular agents used to treat
hypertension, Raynaud's disease and migraine. WO 97/21435,
WO 97/21703, WO 97/21707 and WO 97/21704 disclose non-peptidyl,
indole derivatives as GnRH antagonists.
SUMMARY OF THE INVENTION
The present invention relates to compounds which are
non-peptide antagonists of GnRH which can be used to treat a variety of
sex-hormone related conditions in men and women, to methods for their
preparation, and to methods and pharmaceutical compositions
containing said compounds for use in mammals.
Because of their activity as antagonists of the hormone
GnRH, the compounds of the present invention are useful to treat a
variety of sex-hormone related conditions in both men and women.
These conditions include endometriosis, uterine fibroids, polycystic
ovarian disease, hirsutism, precocious puberty, gonadal steroid-
dependent neoplasias such as cancers of the prostate, breast and
ovary, gonadotrophe pituitary adenomas, sleep apnea, irritable bowel
syndrome, premenstrual syndrome and benign prostatic hypertophy.
They are also useful as an adjunct to treatment of growth hormone
deficiency and short stature, and for the treatment of systemic lupus
erythematosis. Further, the compounds of the invention may be useful
in in vitro fertilization and as contraceptives. The compounds may also
be useful in combination with androgens, estrogens, progesterones,
antiestrogens and antiprogestogens for the treatment of endometriosis,
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fibroids and in contraception. They may also be useful in combination
with testosterone or other androgens or antiprogestogens in men as a
contraceptive. The compounds may also be used in combination with an
angiotensin-converting enzyme inhibitor such as Enalapril or Captopril,
an angiotensin II-receptor antagonist such as Losartan or a renin
inhibitor for the treatment of uterine fibroids. Additionally, the
compounds of the invention may also be used in combination with
bisphosphonates (bisphosphonic acids) and other agents, such as growth
hormone secretagogues, e.g. MK-0677, for the treatment and prevention
of disturbances of calcium, phosphate and bone metabolism, in
particular, for the prevention of bone loss during therapy with the
GnRH antagonist, and in combination with estrogens, progesterones,
antiestrogens, antiprogestins and/or androgens for the prevention or
treatment of bone loss or hypogonadal symptoms such as hot flashes
during therapy with the GnRH antagonist.
Additionally, a compound of the present invention may be
co-administered with a 5a-reductase 2 inhibitor, such as finasteride or
epristeride; a 5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza-5a-
cholestan-3-one, 3-oxo-4-aza-4,7b-dimethyl-16b-(4-chlorophenoxy)-5a-
androstane, and 3-oxo-4-aza-4,?b-dimethyl-16b-(phenoxy)-5a-androstane
as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5a-
reductase 1 and 5a-reductase 2 such as 3-oxo-4-aza-17b-(2,5-
trifluoromethylphenyl-carbamoyl)-5a-androstane as disclosed in
WO 95/07927; antiandrogens such as flutamide, casodex and cyproterone
acetate, and alpha-1 Mockers such as prazosin, terazosin, doxazosin,
tamsulosin, and alfuzosin.
Further, a compound of the present invention may be
used in combination with growth hormone, growth hormone releasing
hormone or growth hormone secretagogues, to delay puberty in growth
hormone deficient children, which will allow them to continue to gain
height before fusion of the epiphyses and cessation of growth at puberty.
Further, a compound of the present invention may be
used in combination or co-administered with a compound having
luteinizing hormone releasing activity such as a peptide or natural
hormone or analog thereof. Such peptide compounds include
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leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin,
histrelin, deslorelin, meterlin and recirelin.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of the general
formula
R2
CR R R~N ~A) ~B) R1
9 9a)m
R
R 1 Oa
i
~1
Rs Ro ~ ~~ Rs
R5 R4
wherein
A is R22-[aryl]-R22- or R22-[substituted aryl]-R22-;
B is optionally absent, -OR22-, -C(=O)R22-, -S(O)nR22-,
-NR18R22-~ -OC(=O)R22-, -C(=O)OR22, -OS(O)nR22- or
-S(O)nOR22-~
Rp is hydrogen, C1-Cg alkyl, substituted C1-C6 alkyl, wherein the
substituents are as defined below; aryl, substituted aryl,
aralkyl or substituted aralkyl, wherein the substituents are
as defined for R3, R4 and R~;
Rl is
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Z. N
Z1 ,, ~''1~, N
i R13 ~/~~ ' R13 ~~~ ~ Ris ~ ~ N
R Z /~.\ ~\ Z
R/~ 14 R15 R14 R15 R13 R/ R
14 R15 14 13
O
~~~Rls (Z. ~ZiRl4 ~Z~N ~N~
~~ \ R14 ~~~~R ~~ N ~I N \ _ ~ R11
14
R13 R13 R13 R19 R1~ R14
O
. Z, N Z~ ~ N,.
J ''~ J ~ ~ ~N~N ~ N ~N~~1-R11
N N R1s N-N N-N. N=N
R1s R1s ~ R11
R11
O
~N1R ~N R ~N~-NR i ~/R13 ~N~N_R11
13 ~ ~) 13 l/~~~J ' 3 ~ ~ N
R1s R14 R SN R14 R1s R14 RlsN R14 R1s
N
/ Nw ,.". ~ ~ N ,"" ~ N'~ N ,~" ~ I i R13
'~"'' I ~R1 ', ~ . J R13 ' ~ ~~R13 L/ ~.N
3 / v /. ~J
L , J ~~. R
R is R14
Ris R14 15 R14 R15 R14
/ Nw ~ZW R14>/\
R13 R14 ~~N R13 'N' \
R1s N R14 R13
the nitrogen atoms contained in the R1 heteroaromatic rings may exist
either as drawn or, when chemically allowed, in their
oxidized (N-~O) state;
R2 is hydrogen, C1-Cg alkyl, substituted C1-Cg alkyl, aralkyl,
substituted aralkyl, aryl, substituted aryl,; or
R2 and A can optionally be taken together to form a ring of 5-7 atoms;
Rg, R4 and R5 are independently hydrogen, C 1-C6 alkyl, substituted
C1-Cg alkyl, C2-C6 alkenyl, substituted C2-Cg alkenyl, CN,
vitro, C1-Cg perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl,
substituted aryl, aralkyl, substituted aralkyl, R110(CH2)p-,
-5-
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(CH2)pS(O)nRl7 or halogen; wherein R17 is hydrogen, C1-
C6 alkyl, C1-C3 perfluoroalkyl, aryl or substituted aryl; or
R3 and R4 taken together form a carbocyclic ring of 3-7 carbon atoms or a
heterocyclic ring containing 1-3 heteroatoms selected from
N, O and S;
Rg is hydrogen, C1-Cg alkyl, substituted C1-Cg alkyl, aryl,
substituted aryl, C 1-Cg perfluoroalkyl, CN, N02, halogen,
R160(CH2)p-;
R7 is hydrogen, C1-Cg alkyl, or substituted C1-Cg alkyl, unless X
is hydrogen or halogen, then R7 is absent;
Rg is hydrogen, C(O)ORg, C(O)NR11R12, NR11R12~ C(O)R11~
~12C(O)Rll~ NR12C(O)NR11R12~ ~125(O)2R11~
NR12S(O)2NR11R12~ OC(O)Rll, OC(O)NR11R12~ OR11
SOnRll, S(O)nNR11R12" a heterocyclic ring or bicyclic
heterocyciic ring with from 1 to 4 heteroatoms selected from
N, O or S which can be optionally substituted by R3, R4 and
R5, C1-C6 alkyl or substituted C1-C6 alkyl, unless X is
hydrogen or halogen, then Rg is absent; or
R7 and Rg taken together form a heterocyclic ring containing one or
more heteroatoms selected from N, O or S which can be
optionally substituted by R3, R4 and R5; or
O
R7 and Rg taken together form a carbocyclic ring of 3-7 atoms or II
when m~0;
Rg and Rga are independently hydrogen, C 1-Cg alkyl, substituted C 1-Cg
alkyl; aryl or substituted aryl, aralkyl or substituted aralkyl
when m$0; or
O
Rg and Rga taken together form a carbocyclic ring of 3-7 atoms or I~
when m~0;
Rlp and RlOa are independently hydrogen, C1-Cg alkyl, substituted C1-
Cg alkyl, aryl, substituted aryl, aralkyl or substituted
aralkyl; or
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R1p and RlOa taken together form a carbocyclic ring of 3-7 atoms or I)
Rg and Rlp when taken together form a carbocyclic ring of 3-7 carbon
atoms or a heterocyclic ring containing one or more
heteroatoms when m~0; or
Rg and R2 taken together form a heterocyclic ring containing 3-7 carbon
atoms and one or more heteroatoms when m~0; or
R1p and R2 taken together form a heterocyclic ring containing 3-7 carbon
atoms and one or more heteroatoms;
Rll and R12 are independently a bond, hydrogen , C1-C6 alkyl,
substituted C1-C6 alkyl, aryl, substituted aryl, aralkyl,
substituted aralkyl, a carbocyclic ring of 3-7 atoms, a
substituted carbocyclic ring containing 3-7 atoms, a
heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4
heteroatoms selected from N, O or S which can be optionally
substituted by Rg, R4 and R5, C1-C6-alkyl substituted by a
heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4
heteroatoms selected from N, O or S which can be optionally
substituted by Rg, R4 and R~;
R11 and R12 when taken together can form an optionally substituted
ring of 3-9 atoms;
R1g is hydrogen, OH, NR7Rg, NR16S02(C1-C6 alkyl),
NR16S02(substituted C1-C6 alkyl), NR16S02(aryl),
NR16S02(substituted aryl), NR16S02(C1-Cg perfluoroalkyl);
SO2NR16(C1-C6 alkyl), S02NR11(substituted C1-C6 alkyl),
SO2~11(~'Yl), S02NR16(substituted aryl), S02NR16(C1-C3
perfluoroalkyl); S02NR16(C(O)C1-C6 alkyl); S02NR16(C(O)-
substituted C1-C6 alkyl); S02NR16(C(O)-aryl);
S02NR16(C(O)-substituted aryl); S(O)n(C1-C6 alkyl);
S(O)n(substituted C1-C6 alkyl), S(O)n(aryl), S(O)n(substituted
aryl}, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, C1-C6
alkoxy, substituted C1-C6 aikoxy, COOH, halogen, N02 or
CN;
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R14 and Rl~ are independently hydrogen, C1-Cg alkyl, substituted C1-C6
alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, CN, vitro,
C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl,
substituted aryl, aralkyl, substituted aralkyl, R160(CH2}p-,
R16C(O)O(CH2)p-, R160C(O)(CH2)p-, -(CH2)pS(O)nRl7~ -
(CH2}pC(O) N(R16)2 or halogen; wherein R17 is hydrogen,
C1-Cg alkyl, C1-Cg perfluoroalkyl, aryl or substituted aryl;
R16 is hydrogen , C1-Cg alkyl, substituted C1-C6 alkyl, aryl,
substituted aryl, aralkyl, substituted aralkyl, a carbocyclic
ring of 3-7 atoms or a substituted carbocyclic ring containing
3-7 atoms;
Rlg is hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C(O)OR16,
C(O)N(R16)2, C(O)R16, S(O)nRl6~
Rlg is either the definition of Rlg or R14;
R22 is CO-C4 alkyl, substituted C1-C4 alkyl;
X is N, O, S(O)n, C(O), (CR11R12)p, a single bond to Rg, C2-C6
alkenyl, substituted C2-Cg alkenyl,C2-C6 alkynyl, or
substituted C2-Cg alkynyl; when X is O, S(O)n, C(O), or
CR11R12 only Rg is possible;
Z is O, S or NR1I;
m is 0, 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1, 2, 3 or 4; and
the alkyl, cycloalkyl, alkenyl and alkynyl substituents are
selected from C1-C6 alkyl, C3-C7 cycloalkyl, aryl, substituted
aryl, aralkyl, substituted aralkyl, hydroxy, oxo, cyano, C1-C6
alkoxy, fluoro, C(O)ORll~ aryl C1-C3 alkoxy, substituted aryl
C1-C3 alkoxy, and the aryl substituents are as defined for R3,
R4 and R5;
or a pharmaceutically acceptable addition salt and/or hydrate thereof, or
where applicable, a geometric or optical isomer or racemic mixture
thereof.
In a preferred embodiment, there are disclosed compounds
of formula I wherein
_g_
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A is R22-[phenyl]-R22- or R22-[substituted phenyl]-R22-;
B is optionally absent or -C(=O)R22 -;
Rp is hydrogen;
R1 is
~N1 R
i
1s
14
the nitrogen atoms contained in the R1 heteroaromatic rings
may exist either as drawn or, when chemically allowed, in
their oxidized (N--~O) state;
10 Rg, R4 and R~ are independently hydrogen, C 1-C6 alkyl, substituted
C 1-C6 alkyl or halogen;
Rg is C(O)NR11R12~
R11 and R12 are independently a bond, hydrogen , C1-Cg alkyl,
substituted C1-C6 alkyl, aryl, substituted aryl, aralkyl,
15 substituted aralkyl, a carbocyclic ring of 3-7 atoms, a
substituted carbocyclic ring containing 3-7 atoms, a
heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4
heteroatoms selected from N, O or S which can be optionally
substituted by R3, R4 and R~, C1-Cg-alkyl substituted by a
heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4
heteroatoms selected from N, O or S which can be optionally
substituted by R3, R4 and R5;
R11 and R12 when taken together can form an optionally substituted
ring of 3-9 atoms;
X is (CR11R12)p~
or a pharmaceutically acceptable addition salt and/or hydrate thereof, or
where applicable, a geometric or optical isomer or racemic mixture
thereof.
Preferred substituents when R11 and R12 are taken together
include 7-aza-bicyclo[2.2.1]heptane and 2-aza-bicyclo[2.2.2]
octane.
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Unless otherwise stated or indicated, the following
definitions shall apply throughout the specification and claims.
When any variable (e.g., aryl, heterocycle, R1, etc.) occurs
more than one time in any constituent or in formula I, its definition on
each occurrence is independent of its definition at every other
occurrence. Also, combinations of substituents and/or variables are
permissible only if such combinations result in stable compounds.
The term "alkyl" is intended to include both branched- and
straight-chain saturated aliphatic hydrocarbon groups having the
specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl,
butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl, and
the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), sec-butyl (s-
Bu), tert-butyl (t-Bu), isopentane, isohexane, etc.
The term "aryl" includes phenyl and naphthyl. Preferably,
aryl is phenyl.
The term "heteroaryl" is intended to include the compounds
shown below:
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N Z
N
N
~R ~ ( ~ ~ t iI ~~N
i 13 ~/v~ R 13 ~ ~~ ~ R
R Z /w.\ 1 15 ~ ~~ Z.
R 4 R15 14 R15 R14 R15 R13 R 4 R13
O
~Z ~R15 ~Z.N ~~iRi4 ~Z~ ~ _
~~~ R14 ~~J R14 ~~N ~'NN ~_~ R11
R13 R13 R13 R1s R13 R14
O
N
N ~ R ~N'N ~ ' N 1N~N-R11
R1s R1s N 1s N-N N-N-R N=N
11
R11 O
N
~ 13 w
l N1 ~ N R ~N'' N 13 l ~ R N N- R11
/~~~J R13 ~/ ~j 13 ~/~~~J R % W N'-''
R15 R14 R15N R14 R15 R14 R15N R14 R19
N~
N ,,." ~ ~ N ,.",! I N~~ N .~~,.r~~ i R 13
."....
. ~ R 13 ~/~~iJ R13 ~l ~iJ R13 L/ ~ ~. N
R15 \R14 R15 R14 R15 R14 R15 R74
N1 ~~~ R14~/'~Z
R13 R14 ~~~ N R13
R15 N R 14 R13
where Z is O, S, or NRII.
The term "halogen" or "halo" is intended to include
fluorine, chlorine, bromine and iodine.
The term "heterocycle" or "heterocyclic ring" is defined
by all non-aromatic, heterocyclic rings of 3-? atoms containing 1-3
heteroatoms selected from N, O, and S, such as oxirane, oxetane,
tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine,
tetrahydropyridine, tetrahydropyrimidine, tetrahydrothiophene,
tetrahydrothiopyran, morpholine, hydantoin, valerolactam,
pyrrolidinone, and the like.
As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly or
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indirectly, from combination of the specified ingredients in the specified
amounts.
In addition, it is well known to those skilled in the art that
many of the foregoing heterocyclic groups can exist in more than one
tautomeric form. It is intended that all such tautomers be included
within the ambit of this invention.
The optical isomeric forms, that is mixtures of
enantiomers, e.g., racemates, or diastereomers as well as individual
enantiomers or diastereomers of the instant compound are included.
These individual enantiomers are commonly designated according to
the optical rotation they effect by the symbols (+) and (-), (L) and (D), (1)
and (d) or combinations thereof. These isomers may also be designated
according to their absolute spatial configuration by (S) and (R), which
stands for sinister and rectus, respectively.
The individual optical isomers may be prepared using
conventional resolution procedures, e.g., treatment with an appropriate
optically active acid, separating the diastereomers and then recovering
the desired isomer. In addition, the individual optical isomers may be
prepared by asymmetric synthesis.
Additionally, a given chemical formula or name shall
encompass pharmaceutically acceptable addition salts thereof and
solvates thereof, such as hydrates.
The compounds of the present invention, while effective
themselves, may be formulated and administered in the form of their
pharmaceutically acceptable addition salts for purposes of stability,
convenience of crystallization, increased solubility and other desirable
properties.
The compounds of the present invention may be
administered in the form of pharmaceutically acceptable salts. The
term "pharmaceutically acceptable salt" is intended to include all
acceptable salts. Examples of acid salts are hydrochloric, nitric,
sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, malefic,
succinic, malonic, methane sulfonic and the like which can be used as a
dosage form for modifying the solubility or hydrolysis characteristics or
can be used in sustained release or prodrug formulations. Depending
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on the particular functionality of the compound of the present invention,
pharmaceutically acceptable salts of the compounds of this invention
include those formed from cations such as sodium, potassium,
aluminum, calcium, lithium, magnesium, zinc, and from bases such
as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine,
ornithine, choline, N,N'-dibenzyiethylenediamine, chloroprocaine,
diethanolamine, procaine, N-benzylphenethylamine, diethylamine,
piperazine, tris(hydroxymethyl)aminomethane, and
tetramethylammonium hydroxide. These salts may be prepared by
standard procedures, e.g. by reacting a free acid with a suitable organic
or inorganic base, or alternatively by reacting a free base with a suitable
organic or inorganic acid.
Also, in the case of an acid (-COOH) or alcohol group being
present, pharmaceutically acceptable esters can be employed, e.g.
methyl, ethyl, butyl, acetate, maleate, pivaloyloxymethyl, and the like,
and those esters known in the art for modifying solubility or hydrolysis
characteristics for use as sustained release or prodrug formulations.
The compounds of the present invention may have chiral
centers other than those centers whose stereochemistry is depicted in
formula I, and therefore may occur as racemates, racemic mixtures
and as individual enantiomers or diastereomers, with all such
isomeric forms being included in the present invention as well as
mixtures thereof. Furthermore, some of the crystalline forms for
compounds of the present invention may exist as polymorphs and as
such are intended to be included in the present invention. In
addition, some of the compounds of the instant invention may form
solvates with water or common organic solvents. Such solvates are
encompassed within the scope of this invention.
The compounds of the invention are prepared by the
following reaction schemes. All substituents are as defined above unless
indicated otherwise.
Scheme A
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Re
~X Rsa Rs
R~ ~~ NH2
s
R ~ J ~~ R~oa
\ N Rio
Ro
O O
O Rs
N-~ X Rsa Rs ~ /
O OEt RR r~ N~
s \ I I Rlo RioaO
J
THF N
2 Ro
R O
is R R
pyridine~HBr~Br2 ~X sa s N
R~ r.
THF/CHCI3 Rs- ~ N (~BRr o~R~oaO
Ro
B(OH)2
i.: ~ R3 Rs O
R5 R4 ,X Rsa Rs
r~
Na2C03, LiCI RRs ~ i I N
Pd(PPhg)4 \ N R ~ 10a0
toluenelEtOH I 1
Ro ~~~~ R3
R5 Ra
Rs
H2NNH2 iX Rsa R9
R, r\. N H2
THF/EtOH Rs-
\ I N I R1 ~ Boa
i
Ro ~ ~~~,~ Rs
R5 R4
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Reaction Scheme A
As shown in reaction Scheme A, treatment of tryptamine
(1) with N-carboxyphthalimide in an inert organic solvent such as
tetrahydrofuran at a temperature of 20-65°C, preferably 65°C,
for a
period of 12-48 hours gives the corresponding N-phthalimidotryptamine
derivative (2). The N-phthalimidotryptamine (2) could be further
modified by treatment with a brominating agent such as pyridinium
hydrobromide perbromide, pyrrolidone hydrotribromide, or the like in
an inert organic solvent such as tetrahydrofuran, methylene chloride,
chloroform, or mixtures thereof at 0-25°C for a period of 30 minutes to
4
hours to provide the 2-bromotryptamine (3). Bromide (3) may be reacted
with an arylboronic acid (prepared essentially as described in
Gronowitz, S.; Hornfeldt, A.-B.; Yang, Y.-H. Chem. Scr. 1986, 26, 311-
314.) with palladium (0) catalysis, a weak base such as aqueous sodium
carbonate or the like, and a chloride source such as lithium chloride in
an inert solvent like toluene, benzene, ethanol, propanol or mixtures
thereof at a temperature of 25°-100°C, preferably 80°C,
for a period of 1-6
hours to give the 2-aryltryptamine derivative (4). Finally, the
phthalimido group may be removed by treatment of (4) with aqueous
hydrazine in an inert solvent such as methanol or ethanol at a
temperature of 0°-25°C for a period of 4-24 hours to give
tryptamine (5).
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Scheme B
HO ~(A)-(B)- R1
O 6
R$
~X Rsa Rs EDC, HOBt
R~ r~ NHR2 NMM, CH2CI2
s
R ~ I N I R1 ~ Boa X A - or
R 1 R ( ) (B)-R1
RS R4 O 8
triethylamine
CH2CI2
R8
R ~X . Rsa Rs N2 (A)- B -R
()
R-
s ~ ~ N ~ R~ ~ loa0
Ro ~ Rs
~~~J
R5 Ra
Reaction Scheme B
As shown in reaction Scheme B, the 2-aryltryptamine
may be condensed with a carboxylic acid of type (6) using the coupling
reagent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDC), 1,3-dicyclohexylcarbodiimide (DCC) or the like with or without
I-hydroxybenzotriazole (HOBt) and a tertiary amine base such as N-
methylmorpholine (NMM), triethylamine or the like in an inert organic
solvent such as methylene chloride, chloroform, dimethylformamide, or
mixtures thereof at or near room temperature for a period of 3-24 hours
to provide the corresponding amide derivative {7). Alternatively, 2-
aryltryptamine (5) can be treated with an active ester or acid chloride of
type (8) in an inert organic solvent such as methylene chloride,
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chloroform, tetrahydrofuran, diethyl ether, or the like and a tertiary
amine base such as triethylamine, diisopropylethylamine, pyridine or
the like at a temperature of 0°-25°C for 30 minutes to 4 hours
to give (7).
Scheme C
R8
R R R2
~X 9a 9 I
R~ r~ (A)-(B)-R~ BH3, THF
R ~ ~ N ~ R~ ~ ioap LiAlH4rTHF~
7 R0 I /.~~~J R3
R~ R4
R8
' R
R9a R9
R~ r. . ~(A)- (B)- R ~
R-
R ~ \ 1 Oa
N
RO ~ ~J Ra
9
R5 R4
Reaction Scheme C
As shown in reaction Scheme C, the amide carbonyl of (7)
can be reduced by treatment with borane, lithium aluminum hydride,
or equivalent hydride sources in an inert organic solvent such as
tetrahydrofuran, diethyl ether, 1,4-dioxane or the like at 25°-
100°C,
preferably 65°C, for a period of 1-$ hours to give the corresponding
amine compound (9).
-17-
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Scheme D
Rs
R R
R7~ ~~ ~B)- R1
sa s
N _
~A)-
/v
Rs ~ ~ ~ R1 O
\
10a
Ro ~ ~ R (R2) 10a
3
23 /~\~J -~-
Rs TFA, 3 ~1
R4 sieves
NaCNBH3, MeOH
Ra
Rsa Rs or
R~ ~\
NHR2
Rs ' R~ (A) ~B) R1
~ O
l0
N ~ 10b
a
I
Ro _ TFA, 3 ~ sieves
(
/~\-J
R3
R5 NaCNBH3, MeOH
R4
Rs R2
R
R7~X/ . Rsa s N-~A)-~B)-Ri
Rs ~~
N R~ ~ 1oa
I
11 Ro I /.~\~~ R3
R5 R4
Reaction Scheme D
As shown in reaction Scheme D, the 2-aryltryptamine (23 or
5) can be modified by treatment with an aldehyde or ketone of type (l0a or
lOb) in the. presence of a weak acid such as trifluoroacetic acid (TFA),
acetic acid or the like, with or without a dessicant such as 3E~ molecular
sieves or magnesium sulfate, and a hydride source such as sodium
borohydride or sodium cyanoborohydride, in an inert organic solvent
such as methanol, ethanol, isopropanol, tetrahydrofuran, dichloro-
methane, chloroform, or mixtures thereof at a temperature of 0°-
25°C
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for a period of 1-12 hours to give the corresponding secondary or tertiary
amine derivative (11).
Scheme E
O
R3 Rsa
~FiCI R4 ~~. I ~ Rs 13 R
NHNH2 R5 Rio Rioa ~X Rsa Rs
n-butanol R~ ~~ NH2
\ \ 6 - or - R6-
R ~ ~ R1 \ 10a
N
R? X, R Rsa Rs H ~ ,~.~ Rs
s R CI 5
R r,~ ~ ~ Rs R4
I
12 4 ly R10 Rloa
R5 14
methanol/t-butanol
Reaction Scheme E
As shown in reaction Scheme E, treatment of an
arylhydrazine or arylhydrazine hydrochloride (12) with an
arylcyclopropylketone of type (13) in a polar organic solvent such as
methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol,
preferably n-butanol, at a temperature of 70°-120°C for a period
of 8-24
hours gives 2-aryltryptamine (5). Alternatively, when an arylhydrazine
or arylhydrazine hydrochloride (12) is treated with an arylbutyl ketone
of type (14) containing a leaving group (chloride, bromide, iodide,
O-methansulfonate, O-trifluoromethansulfonate, or the like) at the
4-position in a polar solvent such as methanol, ethanol, n-propanol,
isopropanol, n-butanol, t-butanol, or mixtures thereof at room
temperature for a period of 30 minutes to 2 hours followed by heating
to a temperature of 65°-100°C for 4-24 hours, 2-aryltryptamine
(5) is
produced.
-19-
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Scheme F
R3
NH2 R~ ~ ~ NH2 ~ ~~ R4
I Ra Ri i / / ~ Rs
Rs ~ ~ s Rs ~ J PdCi2, CH3CN
Pd(PPh3)4
R X, R CuBr, Et3N 16 R ,X, R
15 ~ 8 ~ 8
R8
R~
Rs ~
17 H ~ ~~ R3
/./
R5 R4
Reaction Scheme F
As shown in reaction Scheme F, iodoanilines of type (15)
may be reacted with aryl acetylenes, an appropriate palladium (0)
catalyst such as tetrakis(triphenylphosphine)palladium, a copper (I)
halide such as cuprous bromide in an inert organic solvent such as
triethylamine at a temperature of 50°-88°C for a period of 30
minutes to 5
hours to provide the diarylacetylene (16). Acetylene (16) may be further
modified by treatment with a palladium (II) catalyst such as palladium
(II) chloride or palladium (II) acetate in an inert organic solvent such as
acetonitrile at a temperature of 50°- 82°C for a period of 30
minutes to 6
hours to give 2-arylindole (17).
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Scheme G
O
CI~CI Xa O
R~ r~ ~ R7 ~\ CI
Rs- ~ ~ dichioroethane Rs-' ~ ~ . O
\ Ro ~ \ R3 Ro ~ J Rs
17 ~~i\J
R5 Ra R5 Ra
R$
R2 ~X O R2
H-~A)-(g)-R~ 19 RR ~~ N-(A)-(B)-Ry
s \ ~ ~ O
THF N \~ BH3,THF
Ro ~ . .J Rs _ or _
20 RwR LiAIH4, THF
R 5 4
R2
R R ~~ N_ (A)- (B)- R1
s i_
_Ro ~ /~R3
21
R5 R4
Reaction Scheme G
As shown in reaction Scheme G, treatment of 2-arylindole
(17) with oxalyl chloride neat or in an inert organic solvent such as
methylene chloride, chloroform, dichloroethane, tetrahydrofuran or
the like at a temperature of 25°-65°C for a period of 3-24 hours
gives the
acylchloride adduct (18). The crude product (18) may be reacted with
an amine of type (19) in an inert organic solvent such as diethylether,
tetrahydrofuran, methylene chloride, chloroform or the like and an
amine base such as triethylamine, diisopropylethylamine or pyridine
at a temperature of 0°C-25°C for a period of 30 minutes to 4
hours to
provide the amide derivative (20). Amide (20) may be further modified by
treatment with a reducing agent such as borane or lithium aluminum
-21-
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hydride in an inert organic solvent such as tetrahydrofuran at elevated
temperatures, preferably reflux, for a period of 1-5 hours to give
compound (21).
Scheme H
Re Ar
~X Rsa Rs
R R r\ N- (A)'- (B)- R 1
6 \ ~ ~ R 1 \ 10a
H ~ .J R3
22a ~~'~ H2
R5 R4 Pd(OH)~/C
or
O O~Ar
X R R
R~ ~ sa 9 N_ (A)_ (B)- Rt
Rs-
\ ~ N ( R1 ~ loa
s
%:W
22b R5 RQ
R8
X R R
R~ ~ sa 9 N_(A)-(B)-R~
s
R ~ ~ ~ R~R~oa
H ~ \1 Rs
23 R5~'Ra
Reaction Scheme H
As shown in reaction Scheme H, N-benzyl derivatives of
type (22a) or N-benzyloxycarbonyl derivatives of type (22b) may be reduced
to provide the secondary amine analogs (7) by treatment with hydrogen
(1 atm) and an appropriate catalyst such as palladium on carbon,
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palladium hydroxide on carbon, or the like in an inert organic solvent
such as tetrahydrofuran, ethyl acetate, methanol, ethanol, or mixtures
thereof to which has been added a weak acid such as 30% aqueous acetic
acid for a period of 10 minutes to 3 hours or until the aryl group has been
removed to give the secondary amine.
Scheme I
R R R2
02N\/ sa s N_~A~_~B)-R1
R f
s ~ ~ R~Rloa H2~ Raney~ Ni
\ N ethanol ~
24
R~ R4
R2
R R
H N' sa s N_(A~-(B~-R1
R6 ~ ~ R1 \ 10a
Ro ~ ~ j R3
R5 R4
Reaction Scheme I
As shown in reaction Scheme I, treatment of a nitroindole
of type (24) with hydrogen (1 atm) and an appropriate catalyst such as
Raney~ Nickel in an inert organic solvent such as ethanol, methanol,
or the like at room temperature for a period of 2-12 hours gives the
corresponding aminoindole derivative (25).
-23-
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Scheme J
R~
' R
R R
HXr\ sa s N_~A~-~B)-R1
R - r~
\ ~ ~ R1 ~ 1oa p
Ro ~ ~~J R3 R11 ~CI ~ or R11COOH,
25 ~~ ~ EDC, HOBt,
R5 R4 diisopropyl- NMM, CH2CI2
ethyl amine
CH2C12
R~
R11 ~X R2
Rsa Rs N-(A~-(g~-R1
r-
R6 ~ ~ R~Rloa
Ro ~ J R3
26
R5 R4
Reaction Scheme J
As shown in reaction Scheme J, amino- or hydroxyindole
(25) may be modified by acylation under a variety of conditions. For
example, treatment of (25) with an acid chloride, acid anhydride or
active ester and an amine base such as triethylamine, diisopropylethyl-
amine, pyridine, or the like in an inert organic solvent such as
methylene chloride, chloroform, tetrahydrofuran, or mixtures thereof
at 0°C to room temperature for a period of 1 to 12 hours gives the
corresponding amide or ester derivatives (26). Alternatively (25) may be
coupled with a carboxylic acid by one of the many dehydrating agents
commonly employed. For instance, treatment of aminoindole (25) with
an appropriate carboxylic acid and 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide
(DCC) or the like with or without 1-hydroxybenzotriazole (HOBt) and a
tertiary amine base such as N-methylmorpholine (NMM), triethylamine
or the like in an inert organic solvent such as methylene chloride,
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chloroform, dimethylformamide, or mixtures thereof at or near room
temperature for a period of 3-24 hours provides the corresponding amide
or ester derivative (26).
Scheme K
g_ O
R7HX Rsa R9 R2(A) R1 R11 ~N~CI 27a
)
Rs r~ ~ ~ R R R12 ~ R~1'N 27b
\ 1 10a ~ ; or
\1 diisopropyl- ; or diisopropyl
Ro ~ , ~J R3 ethyl amine ethyl amine
25 R5"~R4 CH2C12 CH2CI2
R> > R~
i. triphosgene R~2~ . X R9a R9 N2 A -
pYndine ( ) (g)-R1
ii. R~2R11N1"I O Rs \ ~ ~ R~R~oa
Ro ~ \j Rs
28
R5 R4
Reaction Scheme K
As shown in reaction Scheme K, urea or carbamate
derivatives of (25) can be prepared by treatment with a carbamoyl
chloride of type (27a), or alternatively with an isocyanate reagent
of type (27b), and an amine base such as pyridine, triethylamine,
diisopropylethylamine, N-methylmorpholine or the like in an inert
organic solvent such as methylene chloride, chloroform, dimethyl-
formamide, tetrahydrofuran or mixtures thereof at a temperature of
0°-65°C for a period of 1-72 hours to give (28). Compound (25)
can also
be modified by treatment with a bis(electrophilic) reagent such as
phosgene, triphosgene, 1,1'-carbonyldiimidazole, N,N'-disuccinimidyl
carbonate, or the like with or without the addition of an amine base such
as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine
-25-
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in an inert solvent such as methylene chloride, chloroform, or the like at
a temperature of -20°-0°C for a period of 20 minutes to 2 hours.
After this
time, the reaction mixture is treated with an appropriate mono- or
disubstituted amine at -20° to 25°C for a period of 1-5 hours to
give the
urea or carbamate analog (28).
Scheme L
R2
R~HN~ Rsa Rs t
N_~A)-(B)-R1
R ~~
s ~ ~ ~ R1 \ 1oa
1
Ro ~ \,J Rs
25 w
R5 R4
R7
R11 ~S~N Rsa Rs R2
~. ~O N_~A)yB)-R1
O, ,O
R 'S~C! 29 '~' N R1 ~ ioa
11 ~ Rs Ro I i R3
diisopropyl- 3~ R/~\/R
ethyl amine s a
CH2CI2
R11 R7
O,, ~O 30 ~N~ ~N Rsa Rs N2 tA)- B - R
11R12N ~S'C) R12 O S~~O / ~ ) 1
[.
R1 ~ 10a
diisopropyl- ~~ N
ethyl amine Rs Ro ~ / ~~J Rs
1 ~ CH2CI2 32 R5v R4
Reaction Scheme
As shown in reaction Scheme L, amine (25) can be modified
by treatment with an appropriate sulfonyl chloride of type (29) or
sulfamyl chloride of type (30) with an amine base such as pyridine,
-26-
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WO 98/55116 PCTNS98/11207
triethylamine, diisopropylethylamine, N-methylmorpholine in an inert
solvent such as methylene chloride, chloroform, dichloroethane or the
like at a temperature of -20°-25°C for a period of 20 minutes to
2 hours to
give the corresponding N-sulfonamide (31) or N-sulfamylamide (32)
derivatives, respectively.
Scheme M
R8
X R R R2 O
i 9a 9
R~ ~. NH ~(A)-(g)-R~
R6 ~ I I R~R~oa 34
R ~ \~ R MeOH
33 ° /.s~~J s
R5 R4
R8
R7 X R9a R9 R2 OH
w
N~(A)WB)-R~
R6 ~ I N I Rt ~ Boa
i
35 R° ~~~ J Rs
R5 Ra
Reaction Scheme M
As shown in reaction Scheme M, the 2-aryltryptamine (33)
can be modified by treatment with an epoxide such as (34) in an inert
organic solvent such as methanol, ethanol, isopropanol, butanol, tert-
butanol, or mixtures thereof at a temperature of fi5°-110°C for
a period
of 8-20 hours to give~the corresponding amino-alcohol derivative (35).
-27-
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Scheme N
O
HO- \ R R Rsa Rs R2
12 11 C) ~ N -,.(,4~- ~B)- R 1
.. ~
Rs r ~ ~ R; \Rloa
Ro ( \ R RIPyBOP
36 R5"~R4 3 CH2C12lTHF
O
R11 \N~ R R Rsa R9 R2
i p~ 12 11C)~~ N-(A)-~B)-R1
R12 R -
R1 ~ 1oa
Ro /w.~JRs
37
R5 R4
Reaction Scheme N
As shown in reaction Scheme N, amide derivatives of
an acid-containing indole derivative such as (36) can be prepared by
treatment with an appropriate amine (R12R11 NH) and a suitable
coupling agent such as benzotriazol-1-yloxy-tris(pyrrolidino)
phosphonium hexafluorophosphate (PyBOP), benzotriazol-1-yloxy-
tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1-(3-
dimethylaminopropyl}-3-ethylcarbodiimide hydrochloride (EDC), 1,3-
dicyclohexylcarbodiimide (DCC) or the like with or without 1-
1 S hydroxybenzotriazole (HOBt) and a tertiary amine base such as N-
methylmorpholine (NMM), triethylamine or the like in an inert organic
solvent such as methylene chloride, chloroform, tetrahydrofuran,
dimethylformamide, or mixtures thereof at or near room temperature
for a period of 3 hours to 7 days provides the corresponding amide
derivative (37).
-28-
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Scheme O
X8 (CR9R9a)m~ NH2
R~ ~~ Rloa 2,4-dinitrobenzene
-sulfonyl chloride
' \ --~-
R~ N - R 2 4 6-collidine
,~ > >
s Ro ~ / \ ~ s
R5 R4 CH2C12
Ra "R~o N O ,O N02
~X (CRsRsa)m < HO-{A)- (B)- R1
R7 \/ ~ ~ R~oa ~ ~ 1 ~ 39
' ~ PPh3, DEAD
R N R N02 benzene
Ro
38
R5 R4 2. n-propylamine
X (CR R RAG N (A) (B) Ri
i 9 9a)m
R7 \' ~ ~ R~oa
' \
R~ N -R
s Ro ~ / \ i s
-J
..
R~ R4
23
5
Reaction Scheme O
As shown in reaction Scheme O, the tryptamine 5
can be modified by reaction with an arylsufonyl chloride such as
2-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride or
2,4-dinitrobenzenesulfonyl chloride and a hindered amine base such
as 2,4,6-collidine, 2,6-lutidine or the like in an inert organic solvent
such as methylene chloride to provide the corresponding sulfonamide
38. Sulfonamides such as 38 can be further modified by reaction with
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an alcohol of type 39 in the presence of triphenylphosphine and an
activating agent such as diethyl azodicarboxylate (DEAD), diisopropyl
azodicaboxylate or the like in an inert organic solvent such as benzene,
toluene, tetrahydrofuran or mixtures thereof to give the dialkylsulfon-
amide adduct. Removal of the sulfonyl group is accomplished by
treatment with a nucleophilic amine such as n-propylamine or the like
in an inert organic solvent such as methylene chloride to give secondary
amines of type 23.
The compounds of the present invention are useful in the
treatment of various sex-hormone related conditions in men and
women. This utility is manifested in their ability to act as antagonists of
the neuropeptide hormone GnRH as demonstrated by activity in the
following in vitro assays.
Human GnRH receptor binding assay
Crude membranes prepared from CHO cells expressing human GnRH
receptors were the sources for GnRH receptor. [1251]Buserelin (a
peptidyl GnRH analog) was used as the radiolabelled ligand. The
binding activity was determined as an IC50 which is the antagonist
concentration required to inhibit the specific binding of [125I]buserelin
to GnRH receptors by 50%.
Rat nituitarv GnRH receptor binding assav~
Crude plasma membranes prepared from rat pituitary tissues were
incubated in a Tris.HCl buffer (50 mM, PH. 7.5) containing bovine
serum albumin (.1%), [I-125]D-t-Bu-Serb-Pro9-ethyl amide-GnRH, and
the desired concentration of a test compound. The assay mixtures were
incubated at 4°C for 90-120 minutes followed by rapid filtration and
repeated washings through a glass fiber filter. The radioactivity of
membrane bound radioligands was determined in a gamma-counter.
From this data, the ICSp of the radioligand binding to GnRH receptors in
the presence of test compound was estimated.
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Inhibition of LH release assav~
Active compounds from the GnRH receptor binding assay were further
evaluated with an in vitro LH release assay to confirm their antagonist
activity (blocking GnRH-induced LH release).
1. Sample Preparation
The compounds to be assayed were dissolved and diluted in DMSO. The
final concentration of DMSO in the incubation medium was 0.5%.
2. Assav
The Wistar male rats (150-200 grams) were obtained from Charles River
Laboratories (Wilmington, MA). Rats were maintained at a constant
temperature (25°C) on a 12-hr light, 12-hr dark cycle. Rat chow and
water were available ad libitum. The animals were sacrificed by
decapitation and pituitary glands were aseptically removed and placed
in Hank's Balanced Salt Solution (HBSS) in a 50-mL polypropylene
centrifuge tube. The collection tube was centrifuged for 5 min at 250 x g,
and HBSS was removed by aspiration. Pituitary glands were transferred
to a disposable petri plate and minced with a scalpel. The minced tissue
was then transferred to a 50-mL disposable centrifuge tube by
suspending the tissue fragments in three successive 10-mL aliquots of
HBSS containing 0.2% collagenase and 0.2% hyaluronidase. The cell
dispersion was carried out in a water bath at 37°C with gentle stirring
for 30 min. At the end of the incubation, the cells were aspirated 20 to 30
times with a pipet and the undigested pituitary fragments were allowed
to settle for 3 to 5 min. The suspended cells were removed by aspiration,
and then subjected to a 1200 x g centrifugation for 5 min. The cells were
then resuspended in Culture medium. The undigested pituitary
fragments were treated with 30 mL aliquots of the digestion enzymes
as above for a total of 3 digestions with the collagenase/hyaluronidase
mixture. The resulting cell suspensions were pooled, counted and
diluted to a concentration of 3 x 105 cells/ml, and 1.0 ml of this
suspension was placed in each well of a 24-well tray (Costar, Cambridge,
MA). Cells were maintained in a humidified 5% C02-95% air
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atmosphere at 37°C for 3 to 4 days. The culture medium consisted of
DMEM containing 0.37% NaHC03, 10% horse serum, 2.5% fetal bovine
serum, 1% non-essential amino acids, 1% glutamine, and 0.1%
gentamycin. On the day of an experiment, cells were washed three
times 1 1/2 hrs prior to and two more times immediately before the start
of the experiment with DMEM containing 0.37% NaHCOg, 10% horse
serum, 2.5% fetal bovine serum, 1% non-essential amino acids(100X),
1% glutamine(100X), 1% Penicillin/Streptomycin(10,000 Units of
Penicillin and 10,000 micrograms of Streptomycin per ml), and 25 mM
HEPES, pH 7.4. LH release was initiated by adding 1 ml of fresh
medium containing test compounds in the presence of 2 nM GnRH to
each well in duplicate. Incubation was carried out at 37°C for 3 hr.
After incubation, medium was removed and centrifuged at 2,000 x g for
min to remove any cellular material. The supernatant fluid was
15 removed and assayed for LH content with a double antibody RIA
procedure using materials obtained from Dr. A. F. Parlow (Harbor-
UCLA Medical Center, Torrance, CA).
The compounds of formula I are useful in a number of
areas affected by GnRH. They may be useful in sex-hormone related
conditions, sex-hormone dependent cancers, benign prostatic
hypertrophy or myoma of the uterus. Sex-hormone dependent cancers
which may benefit from the administration of the compounds of this
invention include prostatic cancer, uterine cancer, breast cancer and
pituitary gonadotrophe adenomas. Other sex-hormone dependent
conditions which may benefit from the administration of the compounds
of this invention include endometriosis, polycystic ovarian disease,
uterine fibroids and precocious puberty. The compounds may also be
used in combination with an angiotensin-converting enzyme inhibitor
such as Enalapril or Captopril, an angiotensin II-receptor antagonist
such as Losartan or a renin inhibitor for the treatment of uterine
fibroids.
The compounds of the invention may also be useful for
controlling pregnancy, as a contraceptive in both men and women, for
in vitro fertilization, in the treatment of premenstrual syndrome, in the
treatment of lupus erythematosis, in the treatment of hirsutism, in the
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treatment of irritable bowel syndrome and for the treatment of sleep
. disorders such as sleep apnea.
A further use of the compounds of this invention is as an
. adjunct to growth hormone therapy in growth hormone deficient
children. The compounds may be administered with growth hormone
or a compound which increases the endogenous production or release
of growth hormone. Certain compounds have been developed which
stimulate the release of endogenous growth hormone. Peptides which
are known to stimulate the release of endogenous growth hormone
include growth hormone releasing hormone, the growth hormone
releasing peptides GHRP-6 and GHRP-1 (described in U.S. Patent No.
4,411,890, PCT Patent Pub. No. WO 89/07110, and PCT Patent Pub. No.
WO 89/07111) and GHRP-2 (described in PCT Patent Pub. No.
WO 93/04081), as well as hexarelin (J. Endocrinol Invest., 15(Suppl 4),
45 (1992)). Other compounds which stimulate the release of endogenous
growth hormone are disclosed, for example, in the following: U.S.
Patent No. 3,239,345; U.S. Patent No. 4,036,979; U.S. Patent No. 4,411,890;
U.S. Patent No. 5,206,235; U.S. Patent No. 5,283,241; U.S. Patent No.
5,284,841; U.S. Patent No. 5,310,737; U.S. Patent No. 5,317,017; U.S.
Patent No. 5,374,721; U.S. Patent No. 5,430,144; U.S. Patent No. 5,434,261;
U.S. Patent No. 5,438,136; EPO Patent Pub. No. 0,144,230; EPO Patent
Pub. No. 0,513,974; PCT Patent Pub. No. WO 94/07486; PCT Patent Pub.
No. WO 94/08583; PCT Patent Pub. No. WO 94/11012; PCT Patent Pub. No.
WO 94/13696; PCT Patent Pub. No. WO 94/19367; PCT Patent Pub. No.
WO 95/03289; PCT Patent Pub. No. WO 95/03290; PCT Patent Pub. No.
WO 95/09633; PCT Patent Pub. No. WO 95/11029; PCT Patent Pub. No.
WO 95/12598; PCT Patent Pub. No. WO 95/13069; PCT Patent Pub. No.
WO 95/14666; PCT Patent Pub. No. WO 95/16675; PCT Patent Pub. No.
WO 95/16692; PCT Patent Pub. No. WO 95/17422; PCT Patent Pub. No.
WO 95/17423; Science. ~0, 1640-1643 (June 11, 1993); Ann. Rep. Med
Chem., ~, 177-186 (1993); $ioorg. Med Chem Ltrs., 4(22), 2709-2?14
(1994); and Proc Natl Acad Sci USA 92, 7001-?005 (July 1995).
Representative preferred growth hormone secretagoues
employed in the present combination include the following:
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1) N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-
piperidin]-1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methyl-
propanamide;
2) N-[1(R)-[{1,2-Dihydro-1-methanecarbonylspiro[3H-indole-3,4'-
piperidin]-1'-yl)carbonyl]-2-( 1H-indol-3-yl)ethyl]-2-amino-2-methyl-
propanamide;
3) N-[1(R)-[(1,2-Dihydro-1-benzenesulfonylspiro[3H-indole-3,4'-
piperidin]-I'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methyl-
propanamide;
4) N-[1(R)-[(3,4-Dihydro-spiro[2H-1-benzopyran-2,4'-piperidin]-1'-yl)
carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;
5) N-[I{R)-[(2-Acetyl-1,2,3,4-tetrahydrospiro[isoquinolin-4,4'-piperidin]-
1'-yl)carbonyl]-2-(indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;
6) N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-
piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-
methylpropanamide;
7) N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-
piperidin]-I'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-
methylpropanamide methanesulfonate;
8) N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-
piperidin]-1'-yI)carbonyl]-2-(2',6'-difluorophenylmethyloxy)ethyl]-2-
amino-2-methylpropanamide;
9) N-[1(R)-[(1,2-Dihydro-I-methanesulfonyl-5-fluorospiro[3H-indole-3,4'-
piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-
methylpropanamide;
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10) N-[1(S)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-
piperidin]-1'-yl) carbonyl]-2-(phenylmethylthio)ethyl]-2-amino-2-
methylpropanamide;
11) N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-
piperidin]-1'-yl)carbonyl]-3-phenylpropyl]-2-amino-2-methyl-
propanamide;
12) N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'
piperidin]-1'-yl)carbonyl]-3-cyclohexylpropyl]-2-amino-2-methyl
propanamide;
13) N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-
piperidin]-1'-yl)carbonyl]-4-phenylbutyl]-2-amino-2-methyl-
propanamide;
14) N-[1{R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-
piperidin]-1'-yl)carbonyl]-2-(5-fluoro-1H-indol-3-yl)ethyl]-2-amino-2-
methylpropanamide;
15) N-[1(R)-[(1,2-Dihydro-1-methanesulfonyl-5-fluorospiro[3H-indole-
3,4'-piperidin]-1'-yl)carbonyl]-2-(5-fluoro-1H-indol-3-yl)ethyl]-2-amino-2-
methylpropanamide;
16) N-[1(R)-[(1,2-Dihydro-1-(2-ethoxycarbonyl)methylsulfonylspiro-[3H-
indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-
methylpropanamide;
17) N-[1(R)-[(1,2-Dihydro-1,1-dioxospiro[3H-benzothiophene-3,4'-
piperidin]-1'-yl)carbonyl]-2-{phenylmethyloxy)ethyl]-2-amino-2-
methylpropanamide;
and pharmaceutically acceptable salts thereof.
The compounds of the invention may also be used in
combination with bisphosphonates (bisphosphonic acids) and other
agents, such as growth hormone secretagogues, e.g. MK-0677, for the
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treatment and the prevention of disturbances of calcium, phosphate and
bone metabolism, in particular, for the prevention of bone loss during
therapy with the GnRH antagonist, and in combination with estrogens,
progesterones and or androgens for the prevention or treatment of bone
loss or hypogonadal symptoms such as hot flashes during therapy with
the GnRH antagonist.
Bisphosphonates (bisphosphonic acids) are known to inhibit
bone resorption and are useful for the treatment of bone lithiasis as
disclosed in U.S. Patent 4,621,077 to Rosini, et al.
The literature discloses a variety of bisphosphonic acids
which are useful in the treatment and prevention of diseases involving
bone resorption. Representative examples may be found in the
following: U.S. Patent No. 3,251,907; U.S. Patent No. 3,422,137; U.S.
Patent No. 3,584,125; U.S. Patent No. 3,940,436; U.S. Patent No. 3,944,599;
U.S. Patent No. 3,962,432; U.S. Patent No. 4,054,598; U.S. Patent No.
4,267,108; U.S. Patent No. 4,327,039; U.S. Patent No. 4,407,761; U.S.
Patent No. 4,578,376; U.S. Patent No. 4,621,077; U.S. Patent No. 4,624,947;
U.S. Patent No. 4,746,654; U.S. Patent No. 4,761,406; U.S. Patent No.
4,922,007; U.S. Patent No. 4,942,157; U.S. Patent No. 5,227,506; U.S.
Patent No. 5,270,365; EPO Patent Pub. No. 0,252,504; and J. Ors. Chem.,
36, 3843 (1971).
The preparation of bisphosphonic acids and halo-
bisphosphonic acids is well known in the art. Representative examples
may be found in the above mentioned references which disclose the
compounds as being useful for the treatment of disturbances of calcium
or phosphate metabolism, in particular, as inhibitors of bone resorption.
Preferred bisphosphonates are selected from the group of
the following compounds: alendronic acid, etidrononic acid, clodronic
acid, pamidronic acid, tiludronic acid, risedronic acid, 6-amino-1-
hydroxy-hexylidene-bisphosphonic acid, and 1-hydroxy-
3(methylpentylamino)-propylidene-bisphosphonic acid;
or any pharmaceutically acceptable salt thereof. A particularly
preferred bisphosphonate is alendronic acid (alendronate), or a
pharmaceutically acceptable salt thereof. An especially preferred
bisphosphonate is alendronate sodium, including alendronate sodium
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trihydrate. Alendronate sodium has received regulatory approval for
marketing in the United States under the trademark FOSAMAX~.
Additionally, a compound of the present invention may be
co-administered with a 5a-reductase 2 inhibitor, such as finasteride or
epristeride; a 5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza-5a
cholestan-3-one, 3-oxo-4-aza-4,7b-dimethyl-16b-(4-chlorophenoxy)-5a-
androstane, and 3-oxo-4-aza-4,7b-dimethyl-16b-(phenoxy)-5a-androstane
as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5a-
reductase 1 and 5a-reductase 2 such as 3-oxo-4-aza-17b-(2,5-
trifluoromethylphenyl-carbamoyl)-5a-androstane as disclosed in
WO 95/07927; antiandrogens such as flutamide, casodex and cyproterone
acetate, and alpha-1 blockers such as prazosin, terazosin, doxazosin,
tamsulosin, and alfuzosin.
Further, a compound of the present invention may be used
in combination with growth hormone, growth hormone releasing
hormone or growth hormone secretagogues, to delay puberty in growth
hormone deficient children, which will allow them to continue to gain
height before fusion of the epiphyses and cessation of growth at puberty.
For combination treatment with more than one active
agent, where the active agents are in separate dosage formulations,
the active agents may be administered separately or in conjunction. In
addition, the administration of one element may be prior to, concurrent
to, or subsequent to the administration of the other agent.
The pharmaceutical compositions containing the active
ingredient may be in a form suitable for oral use, for example, as tablets,
troches, lozenges, aqueous or oily suspensions, dispersible powders or
granules, emulsions, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any
method known to the art for the manufacture of pharmaceutical
compositions and such compositions may contain one or more agents
selected from the group consisting of sweetening agents, flavoring
agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets contain
the active ingredient in admixture with non-toxic pharmaceutically
acceptable excipients which are suitable for the manufacture of tablets.
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These excipients may be for example; inert diluents, such as calcium
carbonate, sodium carbonate, lactose, calcium phosphate or sodium
phosphate; granulating and disintegrating agents, for example, corn
starch, or alginic acid; binding agents, for example starch, gelatin or
acacia, and lubricating agents, for example, magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be coated
by known techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action over a
longer period. For example, a time delay material such as glyceryl
monostearate or glyceryl distearate may be employed. They may also be
coated by the technique described in the U.S. Patent 4,256,108; 4,166,452;
and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an inert
solid diluent, for example, calcium carbonate, calcium phosphate or
kaolin, or as soft gelatin capsules wherein the active ingredient is mixed
with water or an oil medium, for example peanut oil, liquid paraffin, or
olive oil.
Aqueous suspensions contain the active material in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-
cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and
gum acacia; dispersing or wetting agents may be a naturally-occurring
phosphatide, for example lecithin, or condensation products of an
alkylene oxide with fatty acids, for example polyoxyethylene stearate,
or condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethylene-oxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty acids
and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived from
fatty acids and hexitol anhydrides, for example polyethylene sorbitan
monooleate. The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or
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more coloring agents, one or more flavoring agents, and one or more
sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the
active ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The
oily suspensions may contain a thickening agent, for example beeswax,
hard paraffin or cetyl alcohol. Sweetening agents such as those set forth
above, and flavoring agents may be added to provide a palatable oral
preparation. These compositions may be preserved by the addition of an
anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation
of an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent, suspending
agent and one or more preservatives. Suitable dispersing or wetting
agents and suspending agents are exemplified by those already
mentioned above. Additional excipients, for example sweetening,
flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also
be in the form of an oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a mineral oil, for
example liquid paraffin or mixtures of these. Suitable emulsifying
agents may be naturally-occurring phosphatides, for example soy beans,
lecithin, and esters or partial esters derived from fatty acids and hexitol
anhydrides, for example sorbitan monooleate, and condensation
products of the said partial esters with ethylene oxide, for example
polyoxyethylene sorbitan monooleate. The emulsions may also contain
sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening
agents, for example glycerol, propylene glycol, sorbitol or sucrose.
Such formulations may also contain a demulcent, a preservative and
flavoring and coloring agents.
The pharmaceutical compositions may be in the form of a
sterile injectable aqueous or oleagenous suspension. This suspension
may be formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents which have been
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mentioned above. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally-acceptable
diluent or solvent, for example as a solution in 1,3-butane diol. Among
the acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conventionally employed as a solvent or suspending
medium. For this purpose any bland fixed oil may be employed
including synthetic mono- or diglycerides. In addition, fatty acids such
as oleic acid find use in the preparation of injectables.
Compounds of Formula I may also be administered in the
form of a suppositories for rectal administration of the drug. These
compositions can be prepared by mixing the drug with a suitable non-
irritating excipient which is solid at ordinary temperatures but liquid at
the rectal temperature and will therefore melt in the rectum to release
the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or
suspensions, etc., containing the compound of Formula I are employed.
(For purposes of this application, topical application shall include mouth
washes and gargles.)
The compounds for the present invention can be
administered in intranasal form via topical use of suitable intranasal
vehicles, or via transdermal routes, using those forms of transdermal
skin patches well known to those of ordinary skill in the art. To be
administered in the form of a transdermal delivery system, the dosage
administration will, of course, be continuous rather than intermittent
throughout the dosage regimen. Compounds of the present invention
may also be delivered as a suppository employing bases such as cocoa
butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of
polyethylene glycols of various molecular weights and fatty acid esters of
polyethylene glycol.
The dosage regimen utilizing the compounds of the
present invention is selected in accordance with a variety of factors
including type, species, age, weight, sex and medical condition of the
patient; the severity of the condition to be treated; the route of
administration; the renal and hepatic function of the patient; and the
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particular compound thereof employed. A physician or veterinarian
of ordinary skill can readily determine and prescribe the effective
amount of the drug required to prevent, counter, arrest or reverse the
progress of the condition. Optimal precision in achieving
concentration of drug within the range that yields efficacy without
toxicity requires a regimen based on the kinetics of the drug's
availability to target sites. This involves a consideration of the
distribution, equilibrium, and elimination of a drug. Preferably,
doses of the compound of structural formula I useful in the method
of the present invention range from 0.01 to 1000 mg per adult human
per day. Most preferably, dosages range from 0.1 to 500 mg/day. For
oral administration, the compositions are preferably provided in the
form of tablets containing 0.01 to 1000 milligrams of the active
ingredient, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0,
25.0,
50.0, 100 and 500 milligrams of the active ingredient for the
symptomatic adjustment of the dosage to the patient to be treated. An
effective amount of the drug is ordinarily supplied at a dosage level of
from about 0.0002 mg/kg to about 50 mg/kg of body weight per day.
The range is more particularly from about 0.001 mg/kg to 1 mg/kg of
body weight per day.
Advantageously, the active agent of the present invention
may be administered in a single daily dose, or the total daily dosage
may be administered in dividend doses of two, three or four times
daily.
The amount of active ingredient that may be combined
with the carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration.
It will be understood, however, that the specific dose level
for any particular patient will depend upon a variety of factors including
the age, body weight, general health, sex, diet, time of administration,
route of administration, rate of excretion, drug combination and the
severity of the particular disease undergoing therapy.
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The following examples illustrate the preparation of some of
the compounds of the invention and are not to be construed as limiting
the invention disclosed herein.
EXAMPLE 1
i
N
\ I
Me
1-(7-Aza-bicvclof2 2 llheut-7-vl)-2-f3-(2-ibis (4 _pyridin 3 vl benzvl)aminol
ethvll-2-(3,5-dimethvlphenyl)-1$ indol-5-vll-2-meth ~~1-,propan 1 one
Step lA 2-f3-(2-Aminoethyl)-2-(3 5-dimeth ~~1-phenvl)-1H-indol-5-,1~2
methvlpropionic acid ethyl ester
A mixture of 10.50 g of ethyl 2-(4-hydrazinophenyl)-2-
methylpropionate , 10.55 g of 3-chloropropyl 3,5-dimethyiphenyl ketone,
and 200 mL of absolute ethanol was stirred under nitrogen and heated to
reflex. After 12 hours, the mixture was cooled and filtered. The solid on
the filter was washed with additional small volumes of ethanol. The
filtrate was treated with 4 mL of concentrated sulfuric acid and stirred
at reflex under nitrogen for 4 days. The cooled mixture was stirred in
an ice bath as a solution of sodium ethoxide (21% w/w in ethanol) was
added dropwise until the mixture was basic by pH paper. The mixture
was filtered and concentrated in vacuo at 30 °C. The residue was
partitioned between diethyl ether and water, with some saturated
aqueous sodium chloride solution added to assist in separation of the
layers. The aqueous phase was washed with an additional 100 mL of
ether. The combined organic extracts were dried over sodium sulfate,
filtered, and concentrated in vacuo. The residual gum was purified by
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flash chromatograpy on silica gel (elution with 97:3:0.3 and then 95:5:0.5
methylene chloride:methanol:ammonium hydroxide) to give the title
compound (3.9g).
Step 1B 2-f3-(2-tent-Butoxvcarbonylaminoethvl)-2-(3 5-
dimethvlnhenvl)-1H indol-5y11-2-meths ropionic acid etl~,~
ester
To a solution of 2-[3-(2-aminoethyl)-2-(3,5-dimethyl-phenyl)-
iH-indol-5-yl]-2-methylpropionic acid ethyl ester (763 mg in 7 mL
tetrahydrofuran) at 0 °C was added a solution of fi82 mg di-tert-butyl
dicarbonate in 3 mL tetrahydrofuran followed by a solution of 432 mg
poatssium carbonate in 3 mL water and the resulting suspension stirred
vigourously at 0 °C. After 10 minutes, the reaction was concentrated in
vacuo and the residue dissolved in ethyl acetate. The organic portion
was washed with brine then dried over magnesium sulfate and
concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (hexane:ethyl acetate, 90:10; then 80:20;
then ?0:30) to give the title compound (910 mg}.
Step 1C ~f3-(2-tert-Butoxvcarbon~laminoethvl)- ~-(3,5
dimethvlnhenyl)-1H-indol-5-vll-2-methyl_propionic acid
A suspension of 2-[3-(2-tert-butoxycarbonylaminoethyl)-2-(3,5-
dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid ethyl ester (910
mg in 30 mL methanol and 9.5 mL of 2N aqueous potassium hydroxide)
was heated to 95 °C on an oil bath. After 8 hours, the mixture was
cooled
to room temperature and the volatile organics removed in vacuo. The
aqueous portion was washed with ethyl acetate and the acidified to pH
4 by the addition of 1N hydrochloric acid. This was then extracted with
ethyl acetate and the organic portion dried over magnesium sulfate.
Concentration in vacuo gave the crude title compound in quantitative
yield.
Step 1D f2-f5-f2-(7-Azabicvclof2 2 llhent 7 vl ~ dimethvl 2 oxo
ethvll-2-(3 5-dimethylphenvl)-1H indol 3
vllethvl)carbamicacid tert-butv~
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To a suspension of 2-[3-(2-tert-butoxycarbonylaminoethyl)-
2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid (856 mg in
8.0 mL methylene chloride) at 0° C was added 310 mg of 1-hydroxybenzo-
triazole (HOBt)followed by 400 mg 1-(3-dimethylaminopropyl)-3-ethyl-
carbodiimide hydrochloride (EDC) and the mixture stirred at low
temperature for 90 minutes. At this time, a solution of ?-aza-
bicyclo[2.2.1]heptane hydrochloride (632 mg in a mixture of 2.0 mL
methylene chloride and 0.66 mL triethylamine) was added and the
mixture warmed to room temperature. The reaction was quenched after
24 hours by dilution with methylene chloride and washing with half
saturated brine. The combined organics were dried over magnesium
sulfate and the concentrate purified by flash chromatography on silica
gel (hexane:ethyl acetate, 70:30; then 60:40; then 50:50; then 40:60) to give
the title compound (736 mg).
Step lE 2-f3-(2-Aminoethyl)-2-(3.5-dimethYlphenvl)-1H-indol-5-~ ly ll-
(7-azabicvclof2.2 llhent-7-yl)-2-meth ~~l-propan-1-one
To a solution of (2-[5-[2-(7-azabicyclo[2.2.1]kept-7-yl)-1,1-
dimethyl-2-oxo-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl] ethyl}
carbamic acid tert-butyl ester (728 mg in 30 mL methylene chloride) at
0°C was added 1.5 mL anisole followed by 10.5 mL trifluoroacetic acid
and the mixture stirred at 0 °C. After 2 hours, the mixture was
concentrated in aacuo and the residual acid quenched by the addition
of 10% ammonium hydroxide in methanol. The concentrated was then
purified by flash chromatography on silica gel (methylene chloride:l0%
ammonium hydroxide in methanol, 95:5; then 92:8) to give the title
compound (627 mg).
Step 1F 1-(7-Aza-bicvclof2.2.llhept-7-vl)-2-f3-(2-ibis-(4-nvridin-3-yl-
benzvl)aminol-ethyl)-2-(3.5-dimeth~lphe~l)-1H-indol-5-yll-
2-methyl-proDan-1-one
To a solution of 2.5 equivalents 4-pyridin-3-yl-benzaldehyde
in a mixture of methanol and glacial acetic acid is added 2-[3-(2-
aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1-(7-azabicyclo
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[2.2.1]kept-7-yl)-2-methyl-propan-1-one followed by 3A powdered
molecular seives. To this mixture, an excess of sodium cyanoboro-
hydride is added and the pH adjusted to 5.5 by the addition of 10%
methanolic acetic acid. After completion, the reaction is quenched by
S the addition of saturated sodium bicarbonate and the mixture extracted
with ethyl acetate. The organic portion is washed successively with
saturated ammonium chloride, sodium bicarbonate and brine, then
dried over sodium sulfate. Purification of the concentrate by flash
chromatography on silica gel gives the title compound. MASS: 764
(M+H)
PREPARATION OF SYNTHETIC INTERMEDIATES
Ethyl 2-(4-hvdrazinophenvl)-2-methvlpropionate
Step A: Ethyl (+/-)-2-(4-nitrophenyl_~propionate
To a solution of 9.76 g (50 mmol) of (+/-)-2-(4-
nitrophenyl)propionic acid in 150 mL of absolute ethanol was added 3.0
mL of concentrated sulfuric acid. The resulting solution was stirred at
reflux under nitrogen. After 6 hours, the solution was cooled and
stirred vigorously as 250 mL of saturated aqueous sodium bicarbonate
solution was added gradually (Caution: foaming). The mixture was
then partitioned between 750 mL of ethyl acetate and 500 mL of water.
The organic layer was washed with 100 mL of saturated aqueous sodium
bicarbonate solution and then with 100 mL of saturated aqueous sodium
chloride solution. The organic phase was dried over magnesium
sulfate, filtered, and concentrated in vacuo to give 10.86 g (97%) of an oil;
homogeneous by TLC in 9:1 hexane-ethyl acetate. 400 MHz 1H NMR
(CDC13) was consistent with the assigned structure.
Step B: Ethyl 2-methyl-2-(4-nitrophen~pro innate
A suspension of 924 (23 mmol) of sodium hydride (60%
in oil) in 21 mL of dry N,N dimethylformamide was stirred under
nitrogen in an ice bath as a solution of 4.68 g (21 mmol) of ethyl (+/-)-2-(4-
nitrophenyl)propionate in 20.5 mL of dry N,N-dimethylformamide was
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added gradually over about 10 minutes. An intense violet color developed
during the addition. The mixture was then allowed to warm to room
temperature. After about 1 hour, the mixture was again cooled in an ice
bath as a solution of 1.44 mL (3.28 g; 23 mmol) of methyl iodide in 5 mL of
dry N,N-dimethylformamide was added dropwise by syringe over about
minutes, while maintaining the internal temperature at 10-15 °C.
The mixture was allowed to warm to room temperature, and the color
changed to brown. After 1 hour, an additional 187 mL (426 mg, 3 mmol)
of iodomethane was added. By the next day, the mixture consisted of a
10 suspension of some grayish solid in a golden liquid. It was stirred
vigorously and quenched by gradual addition of 10 mL of 5% aqueous
potassium bisulfate solution. The mixture was partitioned between 400
mL of diethyl ether and 400 mL of water. The organic layer was washed
with an additonal 3 x 400 mL of water and then with 50 mL of saturated
aqueous sodium chloride solution. The organic phase was then dried
over magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography of the residue on silica gel (elution with 19:1 hexane-
ethyl acetete) yielded 4.31 g (87%) of an oil; homogeneous by TLC in 9:1
hexane-ethyl acetete. 400 MHz 1H NMR (CDC13) was consistent with the
assigned structure.
Step C: Ethvl 2-(4-Aminophenyl)-2-methylpropionate
A mixture of 4.27 g (18 mmol) of ethyl 2-methyl-2-(4-
nitrophenyl)propionate, 200 mg of 10% palladium on carbon, and 120
mL of absolute ethanol was shaken with hydrogen (initial hydrogen
pressure 47 psig) in a pressure vessel for 2 hours. The catalyst was
removed by filtration through Celite under nitrogen, and the filter cake
was washed with additional ethanol. Concentration of the filtrate in
vacuo at up to 50 °C gave 3.74 g (100%) of an oil; homogeneous by TLC
in
4:1 hexane-EtOAc. 400 MHz 1H NMR (CDCl3) was consistent with the
assigned structure. Mass spectrum (ESI): m/e = 208 (M + H).
Step D: Ethyl 2-(4-hydrazinophenyl)-2-methylpropionate
A solution of 3.725 g (18 mmol) of ethyl 2-(4-aminophenyl)-2-
methylpropionate in 18 mL of concentrated hydrochloric acid was stirred
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at -10 to -5 °C in an ice-acetone bath as a solution of 1.29 g (18.7
mmol) of
_ sodium nitrite in 7.5 mL of water was added dropwise over about 15
minutes. Stirring was continued at this temperature for an additional
30 minutes. Next, a small amount of insoluble solid was removed by
filtration into a cold receiving flask. The filtrate was then added
dropwise over 10-15 minutes to a solution of 20.3 g (90 mmol) of stannous
chloride dehydrate in 14.5 mL of concentrated hydrochloric acid stirred
under nitrogen in an ice-acetone bath. The addition was carried out at
such a rate that the internal temperature remained at about -5 °C. A
gummy material separated during the addition. After completion of the
addition, stirring was continued at -10 to -5 °C for 1 hour. The
aqueous
phase was decanted, and the residual gum was dissolved in 250 mL of
ethyl acetate. The ethyl acetate solution was treated cautiously with 250
mL of saturated aqueous sodium bicarbonate solution and shaken in a
separatory funnel. The ethyl acetate layer was washed with 50 mL of
saturated aqueous sodium chloride solution. The entire mixture was
filtered before separation of the phases. The ethyl acetate phase was
dried over magnesium sulfate, filtered, and concentrated in vacuo at
room temperature to yield 2.59 g (65%) of an oil. 500 MHz 1H NMR
(CDC13) was consistent with the assigned structure and indicated that
only minor impurities were present.
3-Chloropropvl 3 5-dimethvl ketone
Step AA: 4-Chloro-N-methoxv N-methvlbutvramide
To a solution of 4-chlorobutyryl chloride (10.0 g in 200 mL of
dry methylene chloride) was added 10.4 g of N, O-dimethylhydroxylamine
hydrochloride. The mixture was stirred under nitrogen and maintained
below 25 °C by cooling in an ice bath as necessary while triethylamine
(29.1 mL)was added dropwise over about 20 minutes, resulting in
precipitation. After 1.5 hours at room temperature, the mixture was
concentrated in vacuo. The residue was partitioned between 100 mL of
diethyl ether and 100 mL of saturated aqueous sodium bicarbonate
solution. The organic layer was washed with an additional 100 mL of
saturated sodium bicarbonate, and the aqueous fractions were back-
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extracted with ether. The combined organic phases were dried over
sodium sulfate, filtered, and concentrated in uacuo to give 10.5 g (90%} of
an oil, which had satisfactory purity by 1H NMR (CDCl3). Mass
spectrum (PB-NH3/CI): m/e = 166 (M + H).
Step BB: 3-Chlorourot~~,5-dimethvlphenyl ketone
A solution of 10.2 mL (13.9 g; ?2 mmol) 5-bromo-m-xylene
in 200 mL of anhydrous tetrahydrofuran was stirred under nitrogen at
-78°C as 35.8 mL (84 mmol) of 2.5 M n-butyllithium in tetrahydrofuran
was added dropwise. After 15 minutes at -78 °C, a solution of 10.0 g
(60 mmol) of 4-chloro-N-methoxy-N-methylbutyramide in 30 mL of
anhydrous tetrahydrofuran was added dropwise over 25-30 minutes.
The resulting solution was maintained at -78 °C for 45 minutes and
then
warmed briefly to room temperature. The reaction was quenched by
addition of 40 mL of 2 N hydrochloric acid and then partitioned between
ethyl acetate and water. The organic phase was washed with saturated
aqueous sodium bicarbonate solution and then saturated aqueous
sodium chloride solution. The organic solution was dried over sodium
sulfate, filtered, and concentrated in vacuo. Flash chromatography of
the residue afforded 8.91 g (70%) of an oil, which had satisfactory purity
by 1H NMR (CDC13).
4_-Pvridin-3-yl-benzaldehyde
Step AAA: 4-Iodobenzoic acid methyl ester
A solution of 4-iodobenzoic acid (5.0 g in a mixture of 50 mL
methanol and 2.2 mL of conc. sulfuric acid) was heated to reflux on an
oil bath. After 15 hours, the mixture was concentrated to half volume in
vacuo then poured into saturated sodium bicarbonate. This mixture was
extracted with diethyl ether and the organic portion washed with brine
and dried over magnesium sulfate. Purification of the concentrate by
flash chromatography on silica gel (hexane:ethyl acetate, 95:5) gave the
title compound (5.12 g).
Step BBB: Pyridine-3-boronic acid
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To a solution of n-butyllithium ( 16 mL of a 2.5M solution
in hexane = 50 mL dry diethyl ether) at -78° C was added a solution of
3-bromopyridine (6 g in 15 mL diethyl ether) and the mixture stirred for
25 minutes. At this time trimethyl borate (4.3 mL) was added and the
mixture allowed to warm to room temperature. After 1 hour the
reaction was quenched by the addition of 10 mL glacial acetic acid and
60 mL water and the mixture stirred for 18 hours at room temperature.
The pH of the mixture was adjusted to pHl2 by the addition of 2M sodium
hydroxide and extracted with diethyl ether. The aqueous layer was
acidified to pH 6 by the dropwise addition of 1N hydrochloric acid and
extracted with methylene chloride. The combined organics were dried
over magnesium sulfate and concentrated in vacuo. The residue was
triturated with 20 mL acetonitrile:water (1:1) and filtered to give the title
compound (1.0 g).
Step CCC: 4-Pvridin-3-yl-benzoic acid methyl ester
To a mixture of 1.18 g 4-iodobenzoic acid methyl ester,
830 mg pyridine-3-boronic acid, and 158 mg bis(triphenylphosphine)
palladium(II) chloride was added solvent (18 mL toluene and 5 mL
methanol) followed by 4.5 mL of 2M sodium carbonate and the mixture
heated to 80 °C on an oil bath. After 16 hours the mixture was cooled
to room temperature diluted with ethyl acetate and filtered through
diatomaceous earth. The organic portion was washed sequentially with
1.25N sodium hydroxide and brine, dried over magnesium sulfate and
concentrated in vacuo. Purification by flash chromatography on silica
gel (hexane:ethyl acetate, 80:20; then 70:30; then 60:40) gave the title
compound (810 mg).
Step DDD: (4-Pvridin-3-yl-phenvl)-methanol
To a solution of 4-pyridin-3-yl-benzoic acid methyl ester (124
mg in 5.0 mL dry methylene chloride) at -78 °C was added 1.46 mL of a
1M solution of diisobutylaluminum hydride in methylene chloride and
the mixture stirred at low temperature. After 2 hours, the reaction was
quenched by the addition of acetone, warmed to room temperature and
stirred for 20 minutes with 1.5 mL of a 1M solution of tartaric acid. At
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this time the mixture was extracted with methylene chloride and the
combined organics dried over sodium sulfate. Purification of the
concentrate by flash chromatography on silica gel (ethyl acetate:hexane,
1:1; then methylene chloride:methanol, 95:5) gave the title compound
(104 mg).
Step EEE: 4-Pvridin-3-yl-benzaldehyde
To a solution of (4-pyridin-3-yl-phenyl)-methanol (20 mg
in 1.0 mL methylene chloride) was added 25 mg 4-methylmorpholine
N-oxide, 20 mg 4A molecular sieves and 4 mg tetrapropylammonium
perruthenate and the mixture stirred at room temperature. After 2
hours, the mixture was applied to a silica gel column and purified by
flash chromatography (hexane:ethyl acetate, 40:60; then 60:40) to give
the title compound (11.2 mg).
Following a procedure similar to that described above, the
following compounds were prepared:
Me Me R2
w N N'- ~A)_ ~B)- R 1
O ~~ I _ . ~ ~ _ Me
Me
Ex R2
#
. m/e
N-tA)_ ~B)-R1
lA 764 (M+H)
N~ N
~N
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764 (M+H)
N~
\ I
\I
/ \
N \I
1C O
/ I O
N / \ / \
N \ I I ,N
?91 (M+H)
N
\ I / Me N
\ I Me / \ I
N \I
EXAMPLE 2
Following a procedure similar to that described above, the
following compounds were prepared:
Me Me R2
i N- ~A}- ~B~' R~
Me
Me
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R m/e
i2
N'- ~A)_ ~B)- R~
2A O
834 (M+H)
\ / I O
N / \ / \
N \ I I ~N
EXAMPLE 3
i
N~ I
I
M~ O ~ / I \ N
Me N ~ N
Me~ Me ~ N ~ Me
3-12-f Bis-(4-nvridin-3-vl-benzyl)aminol ethyl)-2-(3,5-dimeth~phen.~
1H-indole-5-carboxylic acid diisopropylamide
Step 3A N.N Diisonropvl-4-nitrobenzamide
A solution of 3.51 mL (2.53 g, 25 mmol) of diisopropylamine
and 3.62 mL (2.63 g, 26 mmol) of triethylamine in 50 mL of anhydrous
tetrahydrofuran was stirred under nitrogen and maintained at -5 °C as
a solution of 4.11 g (22.1 mmol) in 10 mL of anhydrous tetrahydrofuran
was added dropwise over 15 minutes. The mixture was allowed to warm
gradually to room temperature. After 2 hours, the mixture was filtered,
and the filtrate was partitioned between diethyl ether and 1 N
hydrochloric acid. The organic phase was then washed with saturated
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sodium carbonate3 solution, then dried over sodium sulfate and filtered.
The filtrate was concentrated in vacuo, and the residue was flash-
chromatographed on silica gel (gradient elution with 2-5% MeOH in
CH2Cl2) to yield 4.77 g (86%) of yellowish crystals, mp 141.5-142
°C;
homogeneous by TLC 2:1 hexane-EtOAc. 500 MHz 1H NMR (CDCl3) was
consistent with the assigned structure.
Step 3B 4-Amino N,N diisop~,pylbenzamide
A mixture of 4.70 g (18.8 mmol) ofN,N diisopropyl-4-
nitrobenzamide, 200 mg of 10% palladium on carbon, and 200 mL of 2-
methoxyethanol was shaken with hydrogen at approx. 50 psig for 6.5
hours. The catalyst was removed by filtration through diatomaceous
earth under nitrogen. Concentration of the filtrate in uacuo afforded a
quantitative yield of a yellow solid, mp 169.5-170 °C; homogeneous by
TLC
in 95:5 CH2C12-MeOH. 500 MHz 1H NMR (CDC13) was consistent with
the assigned structure. Mass spectrum (PB-NH3/CI): m/e = 221 (M +
H).
Step 3C 4-Hvdrazino N.N-diiso ropylbenzamide
Treatment of 4.2 g (19 mmol) of 4-amino-N,N-
diisopropylbenzamide with 15 mL of concentrated hydrochloric acid and
10 mL of water was followed by agitation. The resulting solution was
maintained at approx. -3°C as a solution of 1.32 g (19.1 mmol) of
sodium
nitrite in 9 mL of water was added dropwise. After being stirred for an
additional 30 minutes at this temperature, this solution was added
portionwise to a vigorously stirred solution of 15.1 g (66.7 mmol) of
stannous chloride dihydrate in 15 mL of concentrated hydrochloric acid,
which was maintained at about -10 °C. After completion of the addition,
the mixture was stirred at this temperature for 5 minutes and then
allowed to warm to room temperature. At this point, it was again cooled
and basified by gradual addition of 25 mL of 50% sodium hydroxide. The
resulting precipitate was collected on a filter and partitioned between
tetrahydrofuran and 5 N sodium hydroxide in a 2:1 ratio. The aqueous
layer was extracted 3 times with tetrahydrofuran. The combined
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organic fractions were concentrated in uacuo. The residue was taken up
in CH2C12-EtOAc, dried over sodium sulfate, filtered, and
reconcentrated to give 3.55 g (80%) of semisolid; homogeneous by TLC in
95:5 CH2C12-MeOH. 500 MHz 1H NMR (CDCl3) was consistent with the
assigned structure. Mass spectrum (PB-NH3/CI): m/e = 236 (M + H).
Step 3D 3-(2-Aminoethyl)-2-(3.5-dimeth~,phenyl)-11Y-indole-5-
carboxvlic acid diisoprouylamide
A solution of 3.5I g (14.9 mmol) 4-hydrazino N,N-
diisopropylbenzamide (from Step 3) in 18 mL of 2-methoxyethanol was
stirred at 100°C under nitrogen as 3.77 g (17.8 mmol) of 3-chloropropyl
3,5-dimethylphenyl ketone in 7 mL of 2-methoxyethanol was added
dropwise over 20 minutes. The solution was stirred at this temperature
for 5 hours, then cooled and filtered to remove a solid (a tetrahydro-
pyridazine by-product). The filtrate was concentrated in vacuo, and the
residue was purified by flash chromatography on silica gel (elution with
95:5 CH2C12-MeOH followed by a gradient of 98:2:0.2 to 92:8:0.8 CH2C12-
MeOH-concd. NH40H) gave 1.78 g (31%) of a brownish, stiff foam;
satisfactory purity by TLC in 95:5:0.5 CH2Cl2-MeOH-concd. NH40H. 500
MHz 1H NMR (CDC13) was consistent with the assigned structure.
Mass spectrum (PB-NH3/CI): m/e = 392.2 (M + H).
Step 3E 3-~2-fBis-(4-nvridin-3- 1-benzyl)aminolethvll-2-(3,5-
dimethvlnhenvl)-1H indole-5-carboxylic acid
diisopropylamide
To a solution of 2.5 equivalents 4-pyridin-3-yl-benzaldehyde in a
mixture of methanol and glacial acetic acid is added 3-(2-aminoethyl)-
2-(3,5-dimethylphenyl)-1FI-indole-5-carboxylic acid diisopropylamide
followed by 3~ powdered molecular seives. To this mixture, an excess
of sodium cyanoborohydride is added and the pH adjusted to 5.5 by the
addition of 10% methanolic acetic acid. After completion, the reaction
is quenched by the addition of saturated sodium bicarbonate and the
mixture extracted with ethyl acetate. The organic portion is washed
successively with saturated ammonium chloride, sodium bicarbonate
and brine, then dried over sodium sulfate. Purification of the
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concentrate by flash chromatography on silica geI gives the title
compound.
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