U.S. patent application number 12/542135 was filed with the patent office on 2009-12-10 for trisubstituted thiophenes as progesterone receptor modulators.
Invention is credited to James J. Fiordeliso, Weiqin Jiang, Zhihua Sui.
Application Number | 20090306118 12/542135 |
Document ID | / |
Family ID | 35840022 |
Filed Date | 2009-12-10 |
United States Patent
Application |
20090306118 |
Kind Code |
A1 |
Jiang; Weiqin ; et
al. |
December 10, 2009 |
Trisubstituted Thiophenes as Progesterone Receptor Modulators
Abstract
The present invention is directed to novel trisubstituted
thiophene derivatives, pharmaceutical compositions containing them
and their use in the treatment or prevention of disorders and
diseases mediated by agonists and antagonists of the progesterone
receptor. The clinical usage of these compounds are related to
hormonal contraception, the treatment and/or prevention of
secondary dysmenorrhea, amenorrhea, dysfunctional uterine bleeding,
uterine leiomyomata, endometriosis; polycystic ovary syndrome,
carcinomas and adenocarcinomas of the endometrium, ovary, breast,
colon or prostate. Additional uses of the invention include
stimulation of food intake.
Inventors: |
Jiang; Weiqin; (Raritan,
NJ) ; Fiordeliso; James J.; (Raritan, NJ) ;
Sui; Zhihua; (Raritan, NJ) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
35840022 |
Appl. No.: |
12/542135 |
Filed: |
August 17, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11255445 |
Oct 21, 2005 |
|
|
|
12542135 |
|
|
|
|
60622581 |
Oct 27, 2004 |
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Current U.S.
Class: |
514/278 ;
514/318; 514/336 |
Current CPC
Class: |
A61P 15/00 20180101;
C07D 491/10 20130101; C07D 409/04 20130101; A61P 15/18 20180101;
C07D 409/14 20130101; A61P 35/00 20180101; A61P 1/14 20180101 |
Class at
Publication: |
514/278 ;
514/336; 514/318 |
International
Class: |
A61K 31/4436 20060101
A61K031/4436; A61K 31/438 20060101 A61K031/438; A61K 31/4545
20060101 A61K031/4545; A61P 15/00 20060101 A61P015/00; A61P 35/00
20060101 A61P035/00 |
Claims
1. A method of treating or preventing a disorder mediated by a
progesterone receptor, wherein the disorder is selected from the
group consisting of: secondary amenorrhea, dysfunctional bleeding,
uterine leiomyomata, endometriosis; polycystic ovary syndrome,
carcinomas and adenocarcinomas of the endometrium, ovary, breast,
colon or prostate, in a subject in need thereof comprising
administering to the subject a therapeutically effective amount of
a compound of formula (I): ##STR00031## wherein R.sub.1 and R.sub.2
are connected together with the carbon atom to which they are bound
via a --O(CH.sub.2).sub.2O-- linker to form a ring, or R.sub.1 and
R.sub.2 are connected together with the carbon atom to which they
are bound to form C(O), R.sub.3 is aryl or pyridinyl, optionally
substituted by up to three of R.sup.5; R.sub.4 is selected from the
group consisting of: CH.sub.3CH.sub.2--, CH.sub.3CH(CH.sub.3),
CH.sub.3CH.sub.2CH.sub.2--, aryl and pyridinyl, wherein the aryl
and pyridinyl are optionally substituted with up to three R.sub.5;
R.sub.5 is selected from the group consisting of: halogen,
CF.sub.3, MeO, NO.sub.2 and CN; or a pharmaceutically acceptable
salt thereof.
2. The method of claim 1 wherein said compound is selected from the
group consisting of:
[5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-(3--
methoxy-phenyl)-methanone;
(3-Bromo-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-t-
hiophen-2-yl]-methanone;
1-[5-(4-Fluoro-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one;
1-[5-(3,5-Bis-trifluoromethyl-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-pipe-
ridin-4-one; and
1-[5-(3,5-Bis-trifluoromethyl-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-pipe-
ridin-4-one.
3. The method of claim 1 wherein said therapeutically effective
amount of said compound is from about 0.1 to about 500 mg/day.
4. The method of claim 2 wherein said therapeutically effective
amount of said compound is from about 0.1 to about 500 mg/day.
Description
RELATED APPLICATION
[0001] This application is a Divisional of U.S. application Ser.
No. 11/255,445 filed Oct. 21, 2005, which claims the benefit of
U.S. Provisional Application No. 60/622,581, filed Oct. 27, 2004,
which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to novel trisubstituted
thiophene derivatives, pharmaceutical compositions containing them
and their use in the treatment or prevention of disorders and
diseases mediated by agonists and antagonists of the progesterone
receptors. The clinical usage of these compounds are related to
hormonal contraception, the treatment and/or prevention of
secondary dysmenorrhea, amenorrhea, dysfunctional uterine bleeding,
uterine leiomyomata, endometriosis; polycystic ovary syndrome,
carcinomas and adenocarcinomas of the endometrium, ovary, breast,
colon, prostate. Additional uses of the invention include
stimulation of food intake.
BACKGROUND OF THE INVENTION
[0003] Intracellular receptors are a class of structurally related
proteins involved in the regulation of gene proteins. Steroid
receptors are a subset of these receptors, including the
progesterone receptors (PR), androgen receptors (AR), estrogen
receptors (ER), glucocorticoid receptors (GR) and mineralocorticoid
receptors (MR). Regulation of a gene by such factors requires the
intracellular receptor and a corresponding ligand which has the
ability to selectively bind to the receptor in a way that affects
gene transcription.
[0004] Progesterone receptor modulators (progestagens) are known to
play an important role in mammalian development and homeostasis.
Progesterone is known to be required for mammary gland development,
ovulation and the maintenance of pregnancy. Currently, steroidal
progestin agonists and antagonists are clinically approved for
contraception, hormone replacement therapy (HRT) and therapeutic
abortion. Moreover, there is good preclinical and clinical evidence
for the value of progestin antagonists in treating endometriosis,
uterine leiomyomata (fibroids), dysfunctional uterine bleeding and
breast cancer.
[0005] The current steroidal progestagens have been proven to be
quite safe and are well tolerated. Sometimes, however, side effects
(e.g. breast tenderness, headaches, depression and weight gain)
have been reported that are attributed to these steroidal
progestagens, either alone or in combination with estrogenic
compounds.
[0006] Steroidal ligands for one receptor often show
cross-reactivity with other steroidal receptors. As an example,
many progestagens also bind to glucocorticoid receptor.
Non-steroidal progestagens have no molecular similarity with
steroids and therefore one might also expect differences in
physicochemical properties, pharmacokinetic (PK) parameters, tissue
distribution (e.g. CNS versus peripheral) and, more importantly,
non-steroidal progestagens may show no/less cross-reactivity to
other steroid receptors. Therefore, non-steroidal progestagens will
likely emerge as major players in reproductive pharmacology in the
foreseeable future.
[0007] It was known that progesterone receptor existed as two
isoforms, full-length progesterone receptor isoform (PR-B) and its
shorter counterpart (PR-A). Recently, extensive studies have been
implemented on the progesterone receptor knockout mouse (PRKO,
lacking both the A- and B-forms of the receptors), the mouse
knockoutting specifically for the PR-A isoform (PRAKO) and the PR-B
isoform (PRBKO). Different phenotypes were discovered for PRKO,
PRAKO and PRBKO in physiology studies in terms of fertility,
ovulation uterine receptivity, uterine proliferation, proliferation
of mammary gland, sexual receptivity in female mice, sexual
activity in male mice and infanticide tendencies in male mice.
These findings provided insights for synthetic chemists to
construct not only selective progesterone receptor modulator
(SPRM), but also PR-A or PR-B selective progesterone receptor
modulator.
SUMMARY OF THE INVENTION
[0008] The present invention provides novel trisubstituted
thiophenes of formula (I):
##STR00001##
[0009] wherein
[0010] R.sub.1 and R.sub.2 are independently selected from the
group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, aryl,
aralkyl, heteroaryl and heteroaryl-alkyl; wherein the cycloalkyl,
aryl, aralkyl, heteroaryl or heteroaryl-alkyl group is optionally
substituted with one or more substituents independently selected
from the group consisting of halogen, hydroxy, alkyl, alkoxy,
--S(alkyl), --SO.sub.2R.sup.C, NO.sub.2, CN, CO.sub.2H, R.sup.C,
--OR.sup.C, --SO.sub.2--NR.sup.DR.sup.E, --NR.sup.DR.sup.E,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4--C(O)--ORF and
CF.sub.3;
[0011] wherein R.sup.C is selected from the group consisting of
alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl,
heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl;
[0012] wherein Q is selected from the group consisting of O, S, NH,
N(alkyl) and --CH.dbd.CH--;
[0013] wherein R.sup.D and R.sup.E are each independently selected
from the group consisting of hydrogen and alkyl; alternatively
R.sup.D and R.sup.E are taken together with the nitrogen atom to
which they are bound to form a 4 to 8 membered ring selected from
the group consisting of heteroaryl or heterocycloalkyl; wherein the
heteroaryl or heterocycloalkyl group is optionally substituted with
one or more substituents independently selected from halogen,
hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino,
nitro, CF.sub.3 or cyano;
[0014] wherein R.sup.F is selected from the group consisting of
hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl,
heteroaryl, heteroaryl-alkyl, heterocycloalkyl and
heterocycloalkyl-alkyl; wherein the cycloalkyl, aryl, heteroaryl,
heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group
is optionally substituted with one or more substituents
independently selected from halogen, hydroxy, alkyl, alkoxy,
carboxy, amino, alkylamino, dialkylamino, CF.sub.3 nitro or
cyano;
[0015] alternatively, R.sub.1 and R.sub.2 are taken together with
the carbon atom to which they are bound to form C(O), or to form a
cycloalkyl or hetero-cycloalkyl.
[0016] R.sub.3 is aryl or heteroaryl, optionally substituted by up
to three of R.sup.5; wherein
[0017] R.sub.5 is independently selected from the group consisting
of halogen, hydroxy, R.sup.C, amino, alkylamino, dialkylamino,
nitro, cyano, CF.sub.3, SO.sub.2(alkyl), --C(O)R.sup.G,
--C(O)OR.sup.G, --OC(O)R.sup.G, --OC(O)OR.sup.G,
--OC(O)N(R.sup.G).sub.2, --N(R.sup.G)C(O)R.sup.G
OSi(R.sup.G).sub.3--OR.sup.G, --SO.sub.2N(R.sup.G).sub.2,
--O-(alkyl).sub.1-4-C(O)R.sup.G and
--O-(alkyl).sub.1-4-C(O)OR.sup.G;
[0018] wherein each R.sup.G is independently selected from
hydrogen, alkyl, aryl, aralkyl; wherein the alkyl, aryl or aralkyl
group is optionally substituted with one or more substituents
independently selected from alkyl, halogenated alkyl, alkoxy,
halogen, hydroxy, nitro, cyano, --OC(O)-alkyl or --C(O)O-alkyl;
[0019] alternatively two R.sup.G groups are taken together with the
nitrogen atom to which they are bound to form a heterocycloalkyl
group; wherein the heterocycloalkyl group is optionally substituted
with one or more substituents independently selected from halogen,
hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino,
nitro or cyano;
[0020] R.sub.4 is alkyl, aryl or heteroaryl, wherein the aryl or
heteroaryl are optionally substituted with up to three R.sub.5;
[0021] or a pharmaceutically acceptable salt thereof.
[0022] Illustrative of the invention is pharmaceutical composition
comprising a pharmaceutically acceptable carrier and any of the
compounds described above. An illustration of the invention is a
pharmaceutical composition made by mixing any of the compounds
described above and a pharmaceutically acceptable carrier.
Illustrating the invention is process for making a pharmaceutical
composition comprising mixing any of the compounds described above
and a pharmaceutically acceptable carrier.
[0023] Exemplifying the invention are methods of treating a
disorder mediated by one or more progesterone receptors in a
subject in need thereof comprising administering to the subject a
therapeutically effective amount of any of the compounds or
pharmaceutical compositions described above.
[0024] Illustrating the invention is a method of contraception
comprising administering to a subject in need thereof co-therapy
with a therapeutically effective amount of a compound of formula
(I) with an estrogenic compound.
[0025] Another example of the invention is the use of any of the
compounds described herein in the preparation of a medicament for
treating: (a) dysfunctional bleeding, (b) endometriosis, (c)
uterine leiomyomata, (d) secondary amenorrhea, (e) polycystic ovary
syndrome, (f) carcinomas and adenocarcinomas of the endometrium,
ovary, breast, colon, prostate, (g) stimulation of food intake in a
subject in need thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0026] The present invention is directed to a compound of formula
(I):
##STR00002##
[0027] wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as herein
defined, useful for the treatment of disorders mediated by
progesterone receptors. More particularly, the compounds of the
present invention are useful for the treatment and prevention of
disorders mediated by the progesterone-A and progesterone-B
receptors. More preferably, the compounds of the present invention
are tissue selective progesterone receptor modulators.
[0028] The progesterone receptor antagonists of this invention,
used alone or in combination with an estrogenic compound, can be
utilized in methods of contraception and the treatment and/or
prevention of benign and malignant neoplastic disease. Specific
uses of the compounds and pharmaceutical compositions of invention
include the treatment and/or prevention of uterine myometrial
fibroids, endometriosis, benign prostatic hypertrophy; carcinomas
and adenocarcinomas of the endometrium, ovary, breast, colon,
prostate, pituitary, meningioma and other hormone-dependent tumors.
Additional uses of the present progesterone receptor antagonists
include the synchronization of the estrus in livestock.
[0029] The progesterone receptor agonists of this invention, used
alone or in combination, can be utilized in methods of
contraception and the treatment and/or prevention of dysfunctional
bleeding, uterine leiomyomata, endometriosis; polycystic ovary
syndrome, carcinomas and adenocarcinomas of the endometrium, ovary,
breast, colon, prostate. Additional uses of the invention include
stimulation of food intake.
[0030] In an embodiment of the invention, R.sub.1 and R.sub.2 are
taken together with the carbon atom to which they are bound to form
C(O), or to form a cycloalkyl or hetero-cycloalkyl.
[0031] In another embodiment, R.sub.3 is selected from the group
consisting of aryl, thienyl and pyridinyl
[0032] In another embodiment, R.sub.4 is substituted aryl.
[0033] In yet another embodiment of the present invention, R.sub.4
is C.sub.1-8 alkyl.
[0034] In an embodiment of the present invention are compounds of
formula (I) wherein R.sub.3 is 4-pyridinyl and R.sub.4 is aryl,
heteroaryl, substituted aryl, substituted heteroaryl or C.sub.1-4
alkyl.
[0035] For use in medicine, the salts of the compounds of this
invention refer to non-toxic "pharmaceutically acceptable salts."
Other salts may, however, be useful in the preparation of compounds
according to this invention or of their pharmaceutically acceptable
salts. Suitable pharmaceutically acceptable salts of the compounds
include acid addition salts which may, for example, be formed by
mixing a solution of the compound with a solution of a
pharmaceutically acceptable acid such as hydrochloric acid,
sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic
acid, benzoic 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. Thus, representative pharmaceutically
acceptable salts include the following:
[0036] acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,
bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,
chloride, clavulanate, citrate, dihydrochloride, acetate, fumarate,
gluceptate, gluconate, glutamate, glycollylarsanilate,
hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
hydroxynaphthoate, iodide, isothionate, lactate, lactobionate,
laurate, malate, maleate, mandelate, mesylate, methylbromide,
methylnitrate, methylsulfate, mucate, napsylate, nitrate,
N-methylglucamine ammonium salt, oleate, pamoate (embonate),
palmitate, pantothenate, phosphate/diphosphate, polygalacturonate,
salicylate, stearate, sulfate, subacetate, succinate, tannate,
tartrate, teoclate, tosylate, triethiodide and valerate.
[0037] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds which are readily
convertible in vivo into the required compound. Thus, in the
methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
disorders described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
the patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,
1985.
[0038] As used herein, the term "progestogen antagonist" shall
include mifepristone, J-867 (Jenapharm/TAP Pharmaceuticals), J-956
(Jenapharm/TAP Pharmaceuticals), ORG-31710 (Organon), ORG-33628
(Organon), ORG-31806 (Organon), onapristone and PRA248 (Wyeth).
[0039] As used herein, unless otherwise noted, "halogen" shall mean
chlorine, bromine, fluorine and iodine.
[0040] As used herein, unless otherwise noted, the term "alkyl"
whether used alone or as part of a substituent group, includes
straight and branched chain compositions of one to eight carbon
atoms. For example, alkyl radicals include methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the
like. Unless otherwise noted, "lower" when used with alkyl means a
carbon chain composition of 1-4 carbon atoms. Similarly, the group
"-(alkyl).sub.0-4-", whether alone or as part of a large
substituent group, shall mean the absence of an alkyl group or the
presence of an alkyl group comprising one to four carbon atoms.
Suitable examples include, but are not limited to --CH.sub.2--,
--CH.sub.2CH.sub.2--, CH.sub.2--CH(CH.sub.3)--,
CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH(CH.sub.3)CH.sub.2--,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and the like.
[0041] As used herein, unless otherwise noted, "alkoxy" shall
denote an oxygen ether radical of the above described straight or
branched chain alkyl groups. For example, methoxy, ethoxy,
n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
[0042] As used herein, unless otherwise noted, "aryl" shall refer
to unsubstituted carbocyclic aromatic groups such as phenyl,
naphthyl, and the like.
[0043] As used herein, unless otherwise noted, "aralkyl" shall mean
any lower alkyl group substituted with an aryl group such as
phenyl, naphthyl and the like. Suitable examples include benzyl,
phenylethyl, phenylpropyl, naphthylmethyl, and the like.
[0044] As used herein, unless otherwise noted, the term
"cycloalkyl" shall mean any stable 3-8 membered monocyclic,
saturated ring system, for example cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[0045] As used herein, unless otherwise noted, the term
"cycloalkyl-alkyl" shall mean any lower alkyl group substituted
with a cycloalkyl group. Suitable examples include, but are not
limited to cyclohexyl-methyl, cyclopentyl-methyl, cyclohexyl-ethyl,
and the like.
[0046] As used herein, unless otherwise noted, the terms "acyloxy"
shall mean a radical group of the formula --O--C(O)--R where R is
alkyl, aryl or aralkyl, wherein the alkyl, aryl or aralkyl is
optionally substituted. As used herein, the term "carboxylate"
shall mean a radical group of the formula --C(O)O--R where R is
alkyl, aryl or aralkyl, wherein the alkyl, aryl or aralkyl is
optionally substituted.
[0047] As used herein, unless otherwise noted, "heteroaryl" shall
denote any five or six membered monocyclic aromatic ring structure
containing at least one heteroatom selected from the group
consisting of O, N and S, optionally containing one to three
additional heteroatoms independently selected from the group
consisting of O, N and S; or a nine or ten membered bicyclic
aromatic ring structure containing at least one heteroatom selected
from the group consisting of O, N and S, optionally containing one
to four additional heteroatoms independently selected from the
group consisting of O, N and S. The heteroaryl group may be
attached at any heteroatom or carbon atom of the ring such that the
result is a stable structure.
[0048] As used herein, unless otherwise noted, the term
"heteroaryl-alkyl" shall mean any lower alkyl group substituted
with a heteroaryl group. Suitable examples include, but are not
limited to pyridyl-methyl, isoquinolinyl-methyl, thiazolyl-ethyl,
furyl-ethyl, and the like.
[0049] As used herein, the term "heterocycloalkyl" shall denote any
five to seven membered monocyclic, saturated or partially
unsaturated ring structure containing at least one heteroatom
selected from the group consisting of O, N and S, optionally
containing one to three additional heteroatoms independently
selected from the group consisting of O, N and S; or a nine to ten
membered saturated, partially unsaturated or partially aromatic
bicyclic ring system containing at least one heteroatom selected
from the group consisting of O, N and S, optionally containing one
to four additional heteroatoms independently selected from the
group consisting of O, N and S. The heterocycloalkyl group may be
attached at any heteroatom or carbon atom of the ring such that the
result is a stable structure.
[0050] Examples of suitable heteroaryl groups include, but are not
limited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl,
imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl,
morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,
indolinyl, chromenyl, 3,4-methylenedioxyphenyl,
2,3-dihydrobenzofuryl, and the like.
[0051] As used herein, unless otherwise noted, the term
"heterocycloalkyl-alkyl" shall mean any lower alkyl group
substituted with a heterocycloalkyl group. Suitable examples
include, but are not limited to piperidinyl-methyl,
piperazinyl-methyl, piperazinyl-ethyl, morpholinyl-methyl, and the
like.
[0052] When a particular group is "substituted" (e.g., cycloalkyl,
aryl, heteroaryl, heterocycloalkyl), that group may have one or
more substituents, preferably from one to five substituents, more
preferably from one to three substituents, most preferably from one
to two substituents, independently selected from the list of
substituents. Additionally when aralkyl, heteroaryl-alkyl,
heterocycloalkyl-alkyl or cycloalkyl-alkyl group is substituted,
the substituent(s) may be on any portion of the group (i.e. the
substituent(s) may be on the aryl, heteroaryl, heterocycloalkyl,
cycloalkyl or the alkyl portion of the group.)
[0053] With reference to substituents, the term "independently"
means that when more than one of such substituents is possible,
such substituents may be the same or different from each other.
[0054] Under standard nomenclature used throughout this disclosure,
the terminal portion of the designated side chain is described
first, followed by the adjacent functionality toward the point of
attachment. Thus, for example, a
"phenylC.sub.1-C.sub.6alkylaminocarbonylC.sub.1-C.sub.6alkyl"
substituent refers to a group of the formula
##STR00003##
[0055] Abbreviations used in the specification, particularly the
Schemes and Examples, are as follows
Ac=Acetyl group (--C(O)--CH.sub.3)
DCM=Dichloromethane
DIPEA or DIEA=Diisopropylethylamine
DMAP=N,N-Dimethylaminopyridine
[0056] DMF=Dimethyl formamide ERT=Estrogen replacement therapy
Et=ethyl (i.e. --CH.sub.2CH.sub.3) EtOAc=Ethyl acetate FBS=Fetal
bovine serum HPLC=High pressure liquid chromatography HRT=Hormone
replacement therapy LHMDS or LiHMDS or=Lithium
Hexamethyldisilazinamide (TMS).sub.2NLi or LiN(TMS).sub.2
MeOH=Methanol
Ph=Phenyl
[0057] PPTS=Pyridinium p-toluenesulfonate
TBAF=Tetra(n-butyl)ammonium fluoride
TBDMS=Tert-butyldimethylsilane
TBS=Tert-butyl-dimethyl-silyl
[0058] TBSCI=Tert-butyl-dimethyl-silyl chloride
TEA or Et.sub.3N=Triethylamine
[0059] TFA=Trifluoroacetic acid
THF=Tetrahydrofuran
TMS=Trimethylsilyl
[0060] TsOH=Tosic acid
[0061] The term "subject" as used herein, refers to an animal,
preferably a mammal, most preferably a human, who has been the
object of treatment, observation or experiment.
[0062] The term "therapeutically effective amount" as used herein,
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes alleviation of
the symptoms of the disease or disorder being treated. Wherein the
present invention directed to co-therapy comprising administration
of one or more compound(s) of formula I and a progestogen or
progestogen antagonist, "therapeutically effective amount" shall
mean that amount of the combination of agents taken together so
that the combined effect elicits the desired biological or
medicinal response. For example, the therapeutically effective
amount of co-therapy comprising administration of a compound of
formula I and progestogen would be the amount of the compound of
formula I and the amount of the progestogen that when taken
together or sequentially have a combined effect that is
therapeutically effective. Further, it will be recognized by one
skilled in the art that in the case of co-therapy with a
therapeutically effective amount, as in the example above, the
amount of the compound of formula I and/or the amount of the
progestogen or progestogen antagonist individually may or may not
be therapeutically effective.
[0063] As used herein, the term "co-therapy" shall mean treatment
of a subject in need thereof by administering one or more compounds
of formula I with a progestogen or progestogen antagonist, wherein
the compound(s) of formula I and progestogen or progestogen
antagonist are administered by any suitable means, simultaneously,
sequentially, separately or in a single pharmaceutical formulation.
Where the compound(s) of formula I and the progestogen or
progestogen antagonist are administered in separate dosage forms,
the number of dosages administered per day for each compound may be
the same or different. The compound(s) of formula I and the
progestogen or progestogen antagonist may be administered via the
same or different routes of administration. Examples of suitable
methods of administration include, but are not limited to, oral,
intravenous (iv), intramuscular (im), subcutaneous (sc),
transdermal, and rectal. Compounds may also be administered
directly to the nervous system including, but not limited to,
intracerebral, intraventricular, intracerebroventricular,
intrathecal, intracisternal, intraspinal and/or peri-spinal routes
of administration by delivery via intracranial or intravertebral
needles and/or catheters with or without pump devices. The
compound(s) of formula I and the progestogen or progestogen
antagonist may be administered according to simultaneous or
alternating regimens, at the same or different times during the
course of the therapy, concurrently in divided or single forms.
[0064] 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 indirectly, from combinations of the specified ingredients in
the specified amounts.
[0065] Compounds of formula (I) wherein R3 is 4-pyridyl, R4 is aryl
and R1 and R2 is O may be prepared according to the processes
outlined in Scheme 1.
[0066] More particularly, a suitably substituted compound of
formula (II), where X and Y are O or S, a known compound or
compound prepared by known methods, is reacted with a compound of
formula (III), a known compound, in the presence of an organic acid
such as acetic acid, p-TSA, oxalic acid and the like, in an organic
solvent such as THF, 1,4-dioxlane, ethyl ether, and the like, at a
temperature in the range of 0 to 25.degree. C., to yield the
corresponding
##STR00004##
compound of formula (IV). The condensation of compound II and III
with sulfur to yield compound IV can be effected by various
coupling reactions including Willgerodt-Kindler Reaction.
[0067] The compound of formula (IV) is reacted with a suitably
substituted compound of formula (V), a known cyclic or normal
secondary amine, in the presence of HC(OEt).sub.3 or HC(OMe).sub.3
at a temperature in the range of 0 to 250.degree. C., to yield the
corresponding compound of formula (VI).
[0068] Accordingly, the compound of formula (VI) is reacted with a
suitably substituted bromoketone, in the presence of an organic
base, such as triethyl amine, diisopropyl ethyl amine, pyridine and
the like; or inorganic base, such as K.sub.2CO.sub.3,
Na.sub.2CO.sub.3 and the like, in an organic solvent such as MeOH,
toluene, benzene, THF, methylene chloride, at an elevated
temperature in the range of 25 to 150.degree. C., to yield the
corresponding compound of formula (VII).
[0069] The compound of formula (VII) is deprotected to yield
compound of formula (VIII) in the presence of organic protic acid,
such as acetic acid, camphor sulfonic acid, p-TSA, oxalic acid and
the like in an organic solvent, such as acetone, THF, 1,4-dioxane
and the like.
[0070] One skilled in the art will recognize that it may be
necessary and/or desirable to protect one or more of the R.sup.1,
R.sup.2 and/or R.sup.3, R.sup.4 groups at any of the steps within
the process described above. This may be accomplished using known
protecting groups and know protection and de-protection reagents
and conditions, for example such as those described in Protective
Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press,
1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in
Organic Synthesis, John Wiley & Sons, 1991.
TABLE-US-00001 TABLE 1 ##STR00005## I ##STR00006## II Structure
Example # or II R MF 1 I 3,4-di-Cl-phenyl
C.sub.23H.sub.20Cl.sub.2N.sub.2O.sub.3S 2 I 4-F-phenyl
C.sub.23H.sub.21FN.sub.2O.sub.3S 3 I 4-Cl-phenyl
C.sub.23H.sub.21ClN.sub.2O.sub.3S 4 I 4-NO.sub.2-phenyl
C.sub.23H.sub.21N.sub.3O.sub.5S 5 I Et
C.sub.19H.sub.22N.sub.2O.sub.3S 6 I Phenyl
C.sub.23H.sub.22N.sub.2O.sub.3S 7 I 3-MeO-phenyl
C.sub.24H.sub.24N.sub.2O.sub.4S 8 I 3,5-di-CF.sub.3-phenyl
C.sub.25H.sub.20F.sub.6N.sub.2O.sub.3S 9 I 2-MeO-phenyl
C.sub.24H.sub.24N.sub.2O.sub.4S 10 I 3-Br-phenyl
C.sub.23H.sub.21BrN.sub.2O.sub.3S 11 II Phenyl
C.sub.21H.sub.18N.sub.2O.sub.2S 12 II 3-MeO-phenyl
C.sub.22H.sub.20N.sub.2O.sub.3S 13 II 4-F-phenyl
C.sub.21H.sub.17FN.sub.2O.sub.2S 14 II 3,5-di-CF.sub.3-phenyl
C.sub.23H.sub.16F.sub.6N.sub.2O.sub.2S 15 II 2-MeO-phenyl
C.sub.22H.sub.20N.sub.2O.sub.3S 16 II 4-Cl-phenyl
C.sub.21H.sub.17ClN.sub.2O.sub.2S 17 II 4-NO.sub.2-phenyl
C.sub.21H.sub.17N.sub.3O.sub.4S 18 II Et
C.sub.17H.sub.18N.sub.2O.sub.2S 19 II 3-NO.sub.2-phenyl
C.sub.21H.sub.17N.sub.3O.sub.4S 20 II 3-Br-phenyl
C.sub.21H.sub.17BrN.sub.2O.sub.2S
[0071] It is intended that the definition of any substituent or
variable at a particular location in a molecule be independent of
its definitions elsewhere in that molecule. It is understood that
substituents and substitution patterns on the compounds of this
invention can be selected by one of ordinary skill in the art to
provide compounds that are chemically stable and that can be
readily synthesized by techniques known in the art as well as those
methods set forth herein.
[0072] The compounds of the present invention can be used in the
form of salts derived from pharmaceutically or physiologically
acceptable acids or bases. These salts include, but are not limited
to, the following salts with inorganic acids such as hydrochloric
acid, sulfuric acid, nitric acid, phosphoric acid and as the case
may be, such organic acids as acetic acid, oxalic acid, succinic
acid, and maleic acid. Other salts include salts with alkali metals
or alkaline earth metals, such as sodium, potassium, calcium or
magnesium in the form of esters, carbamates and other conventional
"pro-drug" forms, which, when administered in such form, convert to
the active moiety in vivo.
[0073] This invention includes pharmaceutical compositions
comprising one or more compounds of this invention, preferably in
combination with one or more pharmaceutically acceptable carriers
and/or excipients. The invention also includes methods of
contraception and methods of treating or preventing maladies
associated with the progesterone receptor, the methods comprising
administering to a mammal in need thereof a pharmaceutically
effective amount of one or more compounds as described above
wherein R4 is alkyl, aryl, heteroaryl or alkylaryl group.
[0074] The progesterone receptor antagonists of this invention,
used alone or in combination with estrogen or partial estrogen
antagonist, can be utilized in methods of contraception and the
treatment and/or prevention of benign and malignant neoplastic
disease. Specific uses of the compounds and pharmaceutical
compositions of invention include the treatment and/or prevention
of uterine myometrial fibroids, endometriosis, benign prostatic
hypertrophy; carcinomas and adenocarcinomas of the endometrium,
ovary, breast, colon, prostate, pituitary, meningioma and other
hormone-depent tumors. Additional uses of the present progesterone
receptor antagonists include the synchronization of the estrus in
livestock.
[0075] When used in contraception the progesterone receptor
antagonists of the current invention may be used either alone in a
continuous administration of between 0.1 and 500 mg per day, or
alternatively used in a different regimen which would entail 2-4
days of treatment with the progesterone receptor antagonist after
21 days of a progestin. In this regimen between 0.1 and 500 mg
daily doses of the progestin (e.g. levonorgestrel, trimegestone,
gestodene, norethindrone acetate, norgestimate or cyproterone
acetate) would be followed by between 0.1 and 500 mg daily doses of
the progesterone receptor antagonists of the current invention.
[0076] The progesterone receptor agonists of this invention, used
alone or in combination, can also be utilized in methods of
contraception and the treatment and/or prevention of dysfunctional
bleeding, uterine leiomyomata, endometriosis; polycystic ovary
syndrome, carcinomas and adenocarcimomas of the endometrium, ovary,
breast, colon, prostate. Additional uses of the invention include
stimulation of food intake.
[0077] When used in contraception the progesterone receptor
agonists of the current invention are preferably used in
combination or sequentially with an estrogen agonist (e.g. ethinyl
estradiao). The preferred dose of the progesterone receptor agonist
is 0.01 mg and 500 mg per day.
[0078] This invention also includes pharmaceutical compositions
comprising one or more compounds described herein, preferably in
combination with one or more pharmaceutically acceptable carriers
or excipients. When the compounds are employed for the above
utilities, they may be combined with one or more pharmaceutically
acceptable carriers, or excipients, for example, solvents, diluents
and the like and may be administered orally in such forms as
tablets, capsules, dispersible powders, granules, or suspensions
containing, for example, from about 0.05 to 5% of suspending agent,
syrups containing, for example, from about 10 to 50% of sugar, and
elixirs containing, for example, from 20 to 50% ethanol, and the
like, or in the form of sterile injectable solutions or suspensions
containing from about 0.05 to 5% suspending agent in an isotonic
medium. Such pharmaceutical preparations may contain, for example,
from about 25 to about 90% of the active ingredient in combination
with the carrier, more usually between about 5% and 60% by
weight.
[0079] The effective dosage of active ingredient employed may vary
depending on the particular compound employed, the mode of
administration and the severity of the condition being treated.
However, in general, satisfactory results are obtained when the
compounds of the invention are administered at a daily dosage of
from about 0.01 to about 500 mg/kg of animal body weight,
preferably given in dual doses two to four times a day, or in a
sustained release form. For most large mammals, the total daily
dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg.
Dosage forms suitable for internal use comprise from about 0.5 to
500 mg of the active compound in intimate admixture with a solid or
liquid pharmaceutically acceptable carrier. This dosage regimen may
be adjusted to provide the optimal therapeutic response. For
example, several divided doses may be administered daily or the
dose may be proportionally reduced as indicated by the exigencies
of the therapeutic situation.
[0080] These active compounds may be administered orally as well as
by intravenous, intramuscular, or subcutaneous routes. Solid
carriers include starch, lactose, dicalcium phosphate,
microcrystalline cellulose, sucrose and kaolin, while liquid
carriers include sterile water, polyethylene glycols, non-ionic
surfactants and edible oils such as corn, peanut and sesame oil, as
are appropriate to the nature of the active ingredient and the
particular form of administration desired. Adjuvants customarily
employed in the preparation of pharmaceutical compositions may be
advantageously included, such as flavoring agents, coloring agents,
preserving agents, and antioxidants, for example, vitamin E,
ascorbic acid, BHT and BHA.
[0081] The preferred pharmaceutical compositions from the
standpoint of ease of preparation and administration are solid
compositions, particularly tablets and hard-filled or liquid-filled
capsules. Oral administration of the compounds is preferred.
[0082] These active compounds may also be administered parenterally
or intraperitoneally. Solutions or suspensions of these active
compounds as a free base or pharmacologically acceptable salt can
be prepared in water suitably mixed with a surfactant such as
hydroxylpropylcellulose. Dispersions can also be prepared in
glycerol, liquid, polyethylene glycols and mixtures thereof in
oils. Under ordinary conditions of storage and use, these
preparations contain a preservative to prevent the growth of
microorganisms.
[0083] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions of
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringe ability exits. It must be
stable under conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such
as bacterial and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol (e.g., glycerol,
propylene glycol and liquid polyethylene glycol), suitable mixtures
thereof, and vegetable oil.
[0084] The following non-limiting examples illustrate preparation
and use of the compounds of the invention.
Example 1
A.
1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-pyridin-4-yl-ethanethione
##STR00007##
[0086] 1-Pyridin-4-yl-ethanone (12.1 g, 0.1 mole), sulfur (3.36 g,
0.105 mol) and 1,4-dioxa-8-aza-spiro[4.5]decane were mixed with
p-toluene sulfonic acid (0.50 g, 2.8 mmole) and heated to
120.degree. C. for 3 hours. The slurry was poured into MeOH (50
mL). A bright yellow solid precipitated out. This was filtered and
washed with another 20 mL of MeOH. The solid was dried to provide
the product (24 g, 86.3%). .sup.1H NMR (CD.sub.3OD) .delta. 8.41
(m, 2H), 7.42 (m, 2H), 4.35 (m, 4H), 3.91 (m, 4H), 3.78 (m, 2H),
1.80 (m, 2H), 1.48 (m, 2H). MS (m/z): 279 (MH.sup.+).
B.
1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridin-4-yl--
propenethione
##STR00008##
[0088]
1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-pyridin-4-yl-ethanethione
(20 g, 72 mmol), HC(OEt).sub.3 (21.3 g, 144 mol), morpholine (48 g,
55 mmol) was stirred at 125.degree. C. for 4 hours. The solvent and
excess reagent were distilled out at 100.degree. C. under house
vacuum. A yellow precipitate came out. After 30 min at 0.degree.
C., the precipitate was collected and washed with water (10 mL) and
dried overnight under air suction to provide the product (20 g,
54%). .sup.1H NMR (CDCl.sub.3) .delta. 8.32 (m, 2H), 7.02 (m, 2H),
6.40 (s, 1H), 4.61 (m, 1H), 4.30 (m, 1H), 3.98 (m, 4H), 3.70 (m,
6H), 3.5 (s, 4H), 3.20 (m, 2H), 2.10 (m, 1H), 1.80 (m, 2H). MS
(m/z): 376 (MH.sup.+).
C.
(3,4-Dichloro-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-Pyridin-
-4-yl-thiophen-2-yl]-methanon
##STR00009##
[0090]
1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridin-4-
-yl-propenethione (75 mg, 0.020 mmol),
2-bromo-1-(3,4-dichloro-phenyl)-ethanone (67 mg, 0.020 mmol) was
stirred in MeOH (1 mL) with Et.sub.3N (21 mg, 0.02 ml) for 4 hours
at 65.degree. C. This was diluted with EtOAc (20 mL) and washed
with brine three times. The residue was purified by a preparative
silica gel plate (5% MeOH/CH.sub.2Cl.sub.2) to provide product as a
yellow solid (33 mg, 35%). .sup.1H NMR (CDCl.sub.3) .delta. 8.6 (m,
2H), 7.81 (s, 1H), 7.61-7.47 (m, 5H), 3.72 (m, 3.56 (m, 3H), 3.52
(s, 4H), 3.41 (m, 1H), 3.23 (m, 4H), 1.82 (m, 4H). MS (m/z): 475
(MH.sup.+).
Example 2
[5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-(4-f-
luoro-phenyl)-methanone
##STR00010##
[0092] The title product was prepared in 33% yield according to the
procedure described in Example 1c using
1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridin-4-yl-pr-
openethione and 2-bromo-1-(4-fluoro-phenyl)-ethanone as starting
material. .sup.1H NMR (CDCl.sub.3) .delta. 8.61 (dd, J=1.5 and 4.6
Hz, 2H), 7.86-7.83 (m, 2H), 7.53-7.50 (m, 3H), 7.20-7.15 (m, 2H),
3.98 (s, 4H), 3.23 (t, J=5.7 Hz, 4H), 1.83 (t, J=5.7 Hz, 4H); MS
(m/z): 425 (MH.sup.+).
Example 3
(4-Chloro-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-t-
hiophen-2-yl]-methanone
##STR00011##
[0094] The title product was prepared in 29% yield according to the
procedure described in Example 1c using
1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridin-4-yl-pr-
openethione (374.5 mg, 1 mmol),
2-bromo-1-(4-chloro-phenyl)-ethanone (233 mg, 1 mmol) as starting
material. .sup.1H NMR (CDCl.sub.3) .delta. 8.62-8.58 (m, 2H),
7.78-7.74 (m, 2H), 7.52-7.45 (m, 5H), 3.98 (s, 1H), 3.24 (t, J=5.7
Hz, 4H), 1.83 (t, J=5.8 Hz, 4H); MS (m/z): 441 (MH.sup.+); HRMS:
calc'd MH.sup.+ for C.sub.23H.sub.21ClN.sub.2O.sub.3S 441.1039;
found 441.1025.
Example 4
[5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-(4-n-
itro-phenyl)-methanone
##STR00012##
[0096] The title product was prepared in 18% yield according to the
procedure described in Example 1c using
1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridin-4-yl-pr-
openethione (374.5 mg, 1 mmol), 2-bromo-1-(4-nitro-phenyl)-ethanone
(244 mg, 1 mmol) as starting material. .sup.1H NMR (CDCl.sub.3)
.delta. 8.61 (dd, J=1.6 and 4.5 Hz, 2H), 8.36-8.33 (m, 2H),
7.95-7.92 (m, 2H), 7.47-7.46 (m, 3H), 3.99 (s, 4H), 3.27 (t, J=5.7
Hz, 4H), 1.83 (t, J=5.7 Hz, 4H); MZ (m/e): 452 (MH.sup.+). HRMS:
calc'd MH.sup.+ for C.sub.23H.sub.21N.sub.3O.sub.5S 452.1280; found
452.1286
Example 5
1-[5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-1--
one
##STR00013##
[0098] The title product was prepared in 22% yield as a white solid
according to the procedure described in Example 1c using
1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridin-4-yl-pr-
openethione (374.5 mg, 1 mmol), 1-bromo-butan-2-one (90%, 0.11 mL,
1 mmol) as starting material. .sup.1H NMR (CDCl.sub.3) .delta. 8.62
(dd, J=1.5 and 4.6 Hz, 2H), 7.65 (s, 1H), 7.55 (dd, J=1.5 and 4.6
Hz, 2H), 3.97 (s, 4H), 3.17 (t, J=5.7 Hz, 4H), 2.85 (q, J=7.4 Hz,
2H), 1.82 (t, J=5.7 Hz, 4H), 1.23 (t, J=7.4 Hz, 3H). MS (m/z): 359
(MH.sup.+); HRMS: calc'd MH.sup.+ for
C.sub.19H.sub.22N.sub.2O.sub.3S 359.1429; found 359.1420
Example 6
[5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-phen-
yl-methanone
##STR00014##
[0100] The title product was prepared in 28% yield as a yellow
solid according to the procedure described in Example 1c using
2-bromo-1-phenyl-ethanone as starting material. .sup.1H NMR
(CDCl.sub.3) .delta. 8.56 (m, 2H), 7.75 (m, 2H), 7.5 (m, 6H), 4.01
(s, 4H), 3.23 (m, 4H), 1.88 (m, 4H); MS (m/z): 407 (MH.sup.+);
HRMS: calc'd MH.sup.+ for C.sub.23H.sub.22N.sub.2O.sub.3S 407.1429;
found 407.1436.
Example 7
[5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-(3-m-
ethoxy-phenyl)-methanone
##STR00015##
[0102] The title product was prepared in 24% yield as a yellow
solid according to the procedure described in Example 1c using
2-bromo-1-(3-methoxy-phenyl)-ethanone as starting material. .sup.1H
NMR (CDCl.sub.3) .delta. 8.65 (m, 2H), 7.59-7.10 (m, 7H), 3.95 (s,
4H), 3.25 (m, 4H), 1.82 (m, 4H); MS (m/z): 437 (MH.sup.+); HRMS:
calc'd MH.sup.+ for C.sub.24H.sub.24N.sub.2O.sub.4S 437.1535; found
437.1534.
Example 8
(3,5-Bis-trifluoromethyl-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-
-pyridin-4-yl-thiophen-2-yl]-methanone
##STR00016##
[0104] The title product was prepared in 18% yield according to the
procedure described in Example 1c using
1-(3,5-bis-trifluoromethyl-phenyl)-2-bromo-ethanone as starting
material. .sup.1H NMR (CDCl.sub.3) .delta. 8.60-7.39 (m, 7H), 3.95
(s, 4H), 3.28 (m, 4H), 1.82 (m, 4H); MS (m/z): 543 (MH.sup.+);
HRMS: calc'd MH.sup.+ for C.sub.25H.sub.20F.sub.6N.sub.2O.sub.3S
543.1177; found 543.1157.
Example 9
[5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-(2-m-
ethoxy-phenyl)-methanone
##STR00017##
[0106] The title product was prepared in 23% yield according to the
procedure described in Example 1c using
1-(2-methoxy-phenyl)-2-bromo-ethanone as starting material. .sup.1H
NMR (CDCl.sub.3) .delta. 8.55 (m, 2H), 7.45-7.30 (m, 7H), 6.95 (m,
2H), 3.95 (s, 4H), 3.21 (m, 4H), 1.81 (m, 4H); MS (m/z): 437
(MH.sup.+); HRMS: calc'd MH.sup.+ for
C.sub.24H.sub.24N.sub.2O.sub.4S 437.1535; found 437.1541.
Example 10
(3-Bromo-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-th-
iophen-2-yl]-methanone
##STR00018##
[0108] The title product was prepared in 25% yield according to the
procedure described in Example 1c using
1-(3,5-bis-trifluoromethyl-phenyl)-2-bromo-ethanone as starting
material. .sup.1H NMR (CDCl.sub.3) .delta. 8.61 (m, 2H), 7.91-7.31
(m, 7H), 3.94 (s, 4H), 3.23 (m, 4H), 1.81 (m, 4H); MS (m/z): 485,
487 (MH.sup.+); HRMS: calc'd MH.sup.+ for
C.sub.23H.sub.21BrN.sub.2O.sub.3S 485.0534; found 485.0514.
Example 11
1-(5-Benzoyl-3-pyridin-4-yl-thiophen-2-yl)-piperidin-4-one
##STR00019##
[0110] A solution of
[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-phe-
nyl-methanone (39.5 mg, 0.097 mmole), p-toluenesulfonic acid
monohydrate (37 mg, 0.194 mmole, 2 eq.), acetone (2 mL), and water
(1 mL) was heated to reflux overnight. The solution was diluted
with water and made basic to pH 14 with 4N sodium hydroxide or 1M
sodium carbonate solution. The solution was extracted twice with
ethyl acetate. The organic extracts were dried over magnesium
sulfate, filtered, and purified by column chromatography to provide
the product as yellow solid (22 mg, 63%). .sup.1H NMR (CDCl.sub.3)
.delta. 8.61 (m, 2H), 7.81-7.45 (m, 8H), 3.46 (m, 4H), 2.52 (m,
4H). MS (m/z): 363 (MH.sup.+), 385 (MNa.sup.+).
Example 12
1-[5-(3-Methoxy-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one
##STR00020##
[0112] The title product was prepared in 73% yield according to the
procedure described in Example 11 using
[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-(3--
methoxy-phenyl)-methanone as starting material. .sup.1H NMR
(CDCl.sub.3) .delta. 8.65 (m, 2H), 7.51-7.12 (m, 9H), 3.42 (m, 4H),
2.62 (m, 4H); Ms (m/z): 393 (MH.sup.+), 391 (MH.sup.-); HRMS:
calc'd MH.sup.+ for C.sub.22H.sub.20N.sub.2O.sub.3S 393.1273; found
393.1280.
Example 13
1-[5-(4-Fluoro-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one
##STR00021##
[0114] The title product was prepared in 69% yield according to the
procedure described in Example 11 using
[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-(4--
fluoro-phenyl)-methanone as starting material. .sup.1H NMR
(CDCl.sub.3) .delta. 8.62-7.11 (m, 9H), 3.42 (m, 4H), 2.61 (m, 4H);
MS (m/z): 413 (MNa.sup.+), 379 (MH.sup.-); HRMS: calc'd MH.sup.+
for C.sub.21H.sub.17FN.sub.2O.sub.2S 381.1073; found 381.1080.
Example 14
1-[5-(3,5-Bis-trifluoromethyl-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piper-
idin-4-one
##STR00022##
[0116] The title product was prepared in 33% yield as a yellow
solid according to the procedure described in Example 11 using
(3,5-bis-trifluoromethyl-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)--
4-pyridin-4-yl-thiophen-2-yl]-methanone as starting material.
.sup.1H NMR (CDCl.sub.3) .delta. 8.65-7.42 (m, 8H), 3.51 (m, 4H),
2.61 (m, 4H); MS (m/z): 499 (MH.sup.+), 497 (MH.sup.-).
Example 15
1-[5-(2-Methoxy-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one
##STR00023##
[0118] The title product was prepared in 48% yield as a yellow
solid according to the procedure described in Example 11 using
(2-methoxy-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-
-thiophen-2-yl]-methanone as starting material. .sup.1H NMR
(CDCl.sub.3) .delta. 8.62-6.97 (m, 9H), 3.80 (s, 3H), 3.42 (m, 4H),
2.58 (m, 4H); MS (m/z): 393 (MH.sup.+), 391 (MH.sup.-); HRMS:
calc'd MH.sup.+ for C.sub.22H.sub.20N.sub.2O.sub.3S 393.1273; found
393.1289.
Example 16
1-[5-(4-Chloro-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one
##STR00024##
[0120] The title product was prepared in 74% yield according to the
procedure described in Example 11 using
(4-chloro-phenyl)-[5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-4-pyridin-4-yl-t-
hiophen-2-yl]-methanone as starting material. .sup.1H NMR
(CDCl.sub.3) .delta. 8.65-7.40 (m, 9H), 3.41 (m, 4H), 2.59 (m, 4H).
Ms (m/z): 397 (MH.sup.+), 395 (MH.sup.-); HRMS: calc'd MH.sup.+ for
C.sub.21H.sub.17ClN.sub.2O.sub.2S 397.0777; found 397.0767.
[0121] Anal. calc'd for C.sub.21H.sub.17ClN.sub.2O.sub.2S, C,
63.55%; H, 4.32%; N, 7.06%;
[0122] found, C, 63.29%; H, 4.20%; N, 7.06%.
Example 17
1-[5-(4-Nitro-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one
##STR00025##
[0124] The title product was prepared in 47% yield as a yellow
solid according to the procedure described in Example 11 using
(4-nitro-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-t-
hiophen-2-yl]-methanone as starting material. .sup.1H NMR
(CDCl.sub.3) .delta. 8.65-6.97 (m, 9H), 3.24 (m, 4H), 2.60 (m, 4H).
Ms (m/z): 408 (MH.sup.+), 407 (MH.sup.-); HRMS: calc'd MH.sup.+ for
C.sub.21H.sub.17N.sub.3O.sub.4S 408.1018; found 408.1024.
Example 18
1-(5-Propionyl-3-pyridin-4-yl-thiophen-2-yl)-piperidin-4-one
##STR00026##
[0126] The title product was prepared in 60% yield as a white solid
according to the procedure described in Example 11 using
1-[5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-pr-
opan-1-one as starting material. .sup.1H NMR (CDCl.sub.3) .delta.
8.68 (m, 2H), 7.55 (m, 2H), 3.41 (m, 4H), 2.91 (m, 2H), 2.56 (m,
2H), 1.24 (m, 3H). Ms (m/z): 315 (MH.sup.+), 313 (MH.sup.-); HRMS:
calc'd MH.sup.+ for C.sub.17H.sub.18N.sub.2O.sub.2S 315.1167; found
315.1171.
[0127] Anal. calc'd for C.sub.17H.sub.18N.sub.2O.sub.2S, C, 64.94%;
H, 5.77%; N, 8.91%; found, C, 64.16%; H, 5.77%; N, 8.52%.
Example 19
1-[5-(3-Bromo-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one
##STR00027##
[0129] The title product was prepared in % yield according to the
procedure described in Example 11 using
(3-bromo-phenyl)-[5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-4-pyridin-4-yl-th-
iophen-2-yl]-methanone as starting material.
[0130] HRMS: calc'd MH.sup.+ for C.sub.21H.sub.17N.sub.3O.sub.4S
408.1018; found 408.1028.
Example 20
1-[5-(3-Bromo-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one
##STR00028##
[0132] The title product was prepared in 71% yield according to the
procedure described in Example 11 using
(3-bromo-phenyl)-[5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-4-pyridin-4-yl-th-
iophen-2-yl]-methanone as starting material. .sup.1H NMR
(CDCl.sub.3) .delta. 8.68 (m, 2H), 7.92-7.35 (m, 7H), 3.43 (m, 4H),
2.61 (m, 2H). Ms (m/z): 441 (MH.sup.+), 439 (MH.sup.-); HRMS:
calc'd MH.sup.+ for C.sub.21H.sub.17BrN.sub.2O.sub.2S 441.0272;
found 441.0263.
[0133] Anal. calc'd for C.sub.21H.sub.17BrN.sub.zO.sub.2S, C,
57.15%; H, 3.88%; N, 6.35%; found, C, 57.48%; H, 3.93%; N,
5.97%.
Example 21
In Vitro Test
[0134] T47D human breast cancer cells are grown in RPMI medium
without phenol red (Invitrogen) containing 10% (v/v)
heat-inactivated fetal bovine serum (FBS; Hyclone), 1% (v/v)
penicillin-streptomycin (Invitrogen), 1% (w/v) glutamine
(Invitrogen), and 10 mg/mL insulin (Sigma). Incubation conditions
are 37.degree. C. in a humidified 5% (v/v) carbon dioxide
environment. For assay, the cells are plated in 96-well tissue
culture plates at 10,000 cells per well in assay medium [RPMI
medium without phenol red (Invitrogen) containing 5% (v/v)
charcoal-treated FBS (Hyclone) and 1% (v/v) penicillin-streptomycin
(Invitrogen)]. Two days later, the medium is decanted and the
compounds are added in a final concentration of 0.1% (v/v) dimethyl
sulfoxide in fresh assay medium. Twenty-four hours later, an
alkaline phosphatase assay is performed using a SEAP kit (BD
Biosciences Clontech, Palo Alto, Calif.). Briefly, the medium is
decanted and the cells are fixed for 30 minutes at room temperature
with 5% (v/v) formalin (Sigma). The cells are washed once with room
temperature Hank's buffered saline solution (Invitrogen). Equal
volumes (0.05 mL) of 1.times. Dilution Buffer, Assay Buffer and
1:20 substrate/enhancer mixture are added. After 1-hour incubation
at room temperature in the dark, the lysate is transferred to a
white 96-well plate (Dynex) and luminescence is read using a
LuminoSkan Ascent (Thermo Electron, Woburn, Mass.).
TABLE-US-00002 TABLE 2 ##STR00029## I ##STR00030## II Example #
Structure (I or II) R % inhibition 1 I 3,4-di-Cl-phenyl 6 2 I
4-F-phenyl 15 3 I 4-Cl-phenyl 27 4 I 4-NO.sub.2-phenyl 0 5 I Et 0 6
I Phenyl 34 7 I 3-MeO-phenyl 42 8 I 3,5-di-CF.sub.3-phenyl 0 9 I
2-MeO-phenyl 30 10 I 3-Br-phenyl 42 11 II Phenyl 35 12 II
3-MeO-phenyl 24 13 II 4-F-phenyl 46 14 II 3,5-di-CF.sub.3-phenyl 57
15 II 2-MeO-phenyl 39 16 II 4-Cl-phenyl 30 17 II 4-NO.sub.2-phenyl
30 18 II Et 26 19 II 3-NO.sub.2-phenyl 29 20 II 3-Br-phenyl 23
[0135] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
* * * * *