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Patent US6503939 - Combination regimens using 3,3-substituted indoline derivatives - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsThis invention relates to cyclic combination therapies and regimens utilizing substituted indoline derivative compounds that are antagonists of the progesterone receptor having the structure: wherein: R1 and R2 are (i) H, OH, OAc, alkylaryl, alkylheteroaryl, 1-propynyl, 3-propynyl, and optionally substituted...http://www.google.com/patents/US6503939?utm_source=gb-gplus-sharePatent US6503939 - Combination regimens using 3,3-substituted indoline derivativesAdvanced Patent SearchPublication numberUS6503939 B2Publication typeGrantApplication numberUS 09/977,790Publication dateJan 7, 2003Filing dateOct 15, 2001Priority dateMay 4, 1999Fee statusLapsedAlso published asCA2372591A1, CN1349417A, EP1173211A1, US6329416, US20020035099Publication number09977790, 977790, US 6503939 B2, US 6503939B2, US-B2-6503939, US6503939 B2, US6503939B2InventorsGary S. Grubb, John W. Ullrich, Andrew Fensome, Jay E. Wrobel, James P. Edwards, Todd K. Jones, Christopher M. Tegley, Lin ZhiOriginal AssigneeWyeth, Ligand Pharmaceuticals, Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (68), Non-Patent Citations (69), Referenced by (20), Classifications (18), Legal Events (11) External Links: USPTO, USPTO Assignment, EspacenetCombination regimens using 3,3-substituted indoline derivatives
a) a first phase of from 18 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 μg levonorgestrel, and ethinyl estradiol at a daily dose range of from about 10 to about 35 μg; and b) a second phase of from 1 to 7 daily dosage units of an antiprogestin at a daily dose of from about 2 to 50 mg; wherein said antiprogestin is of the formula: wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, substituted alkyl, OH, O(alkyl), O(substituted alkyl), OAc, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, alkylheteroaryl, 1-propynyl, and 3-propynyl; or R1 and R2 are joined to form a ring comprising �CH2(CH2)nCH2�; �CH2CH2CMe2CH2CH2�; �O(CH2)mCH2�; O(CH2)pO�; �CH2CH2OCH2CH2�; �CH2CH2N(alkyl)CH2CH2�; or �CH2CH2NHCH2CH2�; n is an integer from 0 to 5; m is an integer from 1 to 4; p is an integer from 1 to 4; or R1 and R2 together comprise a double bond to ═C(CH3)2, ═C(C3-C6 cycloalkyl), ═O, or ═C(cycloether), wherein said cycloether is selected from the group consisting of tetrahydrofuranyl and hexahydropyranyl; R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, alkynyl, substituted alkynyl, or CORA; RA is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl; R4 is H, halogen, CN, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl; R5 is selected from the group consisting of (i), (ii), and (iii): (i) a substituted benzene ring of the formula: X is selected from the group consisting of halogen, OH, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C 3 thioalkyl, substituted C1 to C3 thioalkyl, S(O)alkyl, S(O)2alkyl, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5 or 6 membered heteroryclic ring containing in its backbone 1 to 3 heteroatoms, CORB, OCORB, and NRCCORB; RB is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl; RC is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl: Y and Z are independently selected from the group consisting of H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, and C1 to C3 thioalkyl; (ii) a five or six membered ring having it its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6′ and containing one or two independent substituents selected from the group consisting of H, halogen, CN, NO2, C1 to C4 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, CORD, and NRECORD; RD is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl; RE is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl; R6′ is H, C1 to C3 alkyl or C1 to C4 CO2 alkyl; R6 and R7 are independently selected from the group consisting of H, methyl, ethyl, propyl, butyl, iso-propyl, isobutyl, cyclohexyl aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and (iii) an indol-4-yl, indol-7-yl, or benzo-2-thiophene moiety, the moiety being optionally substituted by from 1 to 3 substituents selected from the group consisting of halogen, lower alkyl, CN, NO2, lower alkoxy, and CF3; c) optionally, an orally and pharmaceutically acceptable placebo for each remaining day of the 28 consecutive days. 2. A method of contraception of claim 1 which comprises administering to a female of child bearing age over a period of 28 consecutive days:
Jones, et al, (U.S. Pat. No. 5,688,810) describe the PR antagonist dihydroquinoline A. Jones, et al, described the enol ether B (U.S. Pat. No. 5,693,646) as a PR ligand. Jones, et al, described compound C (U.S. Pat. No. 5,696,127) as a PR ligand. Zhi, et al, described lactones D, E and F as PR antagonists (J. Med. Chem., 41, 291, 1998). Zhi, et al, described the ether G as a PR antagonist (J. Med. Chem., 41, 291, 1998). Combs, et al, disclosed the amide H as a ligand for the PR (J. Med. Chem., 38, 4880, 1995). Perlman, et. al., described the vitamin D analog I as a PR ligand (Tet. Letters, 35, 2295, 1994). Hamann, et al, described the PR antagonist J (Ann. N.Y. Acad Sci., 761, 383, 1995). Chen, et al, described the PR antagonist K (Chen, et al, POI-37, 16th Int. Cong. Het. Chem., Montana, 1997). Kurihari, et al., described the PR ligand L (J. Antibiotics, 50, 360, 1997). Elliott (Smith Kline Beecham) claimed the generic indoline M as potential endothelin receptor antagonists (WO 94/14434). The patent does not claim indolines and lacks the appropriate 5-aryl substitution, i.e. CN and NO2. wherein: R4=H, Ar, R11, OH, 1-5 C alkoxy (opt. substd. by OH, OMe or halogen), �S(O)qR11, N(R6)2, XR11, halogen or NHCOR6; X=(CH2)n, O, NR6 or S(O)q; n=0-6; q=0-2; R6=H or 1-4 C alkyl; R11=1-8 C alkyl, 2-8 C alkenyl or 2-8 C alkynl (all optionally substituted); Ar=(i) optionally substituted phenyl or benzo-fused group of (a) or (b); or (ii) napthyl, indoyl, pyridyl, thienyl, oxazolindyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, iridazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, pyrrolyl or pyrirndyl, all optionally substituted by one or more R1 or R2 groups. U.S Pat. No. 5,521,166 (Grubb) teaches cyclophasic hormonal regimens comprising an antiprogestin and a progestin wherein the progestin is administered in the alternating presence and absence of an antiprogestin. The disclosed regimens also provide for use of an estrogen for a period of from 2 to 4 days to prevent breakthrough bleeding.
The term �aryl� is used herein to refer to an aromatic system which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. The aryl groups include but not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, and phenanthryl.
The antiprogestational 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.
Typically the antiprogestin compounds of this invention are prepared in a convergent manner as shown is Scheme 1, by a suitable coupling reaction. For example, a palladium mediated coupling of an aryl halide with an aryl boronic acid provides the desired bi-aryl substituted target. The choice of the aryl halide-aryl boronic acid combination is established experimentally. As outlined in Scheme 2, the �right side� of the antiprogestin compounds of this invention may be prepared by following the procedure described of Letcher, R. M. et. al., J. Chem. Soc. Perkin Trans., 1993, Vol. 1, pp. 939-944. As an example the right side template, 2, is prepared by condensing an appropriately substituted phenyl hydrazine and a suitable ketone to give the corresponding hydrazone. This material is cyclized to an imine in refluxing acetic acid and then reduced to the desired indoline template 2. Examples 1-7 and 10-20 were prepared by this route using the appropriate ketone.
1. hPR Binding assay�This assay is carried out in accordance with: Pathirana, C.; Stein, R. B.; Berger, T. S.; Fenical, W.; laniro, T.; Mais, D. E.; Torres, A; Glodmnan, M. E., Nonsteroidal human progesterone receptor modulators from the marine alga cymoplia barbata, J. Steroid Biocherm Mol. Biol., 1992, 41, 733-738.
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New York. vol. 9, p. 1549-1553, (1966).Referenced byCiting PatentFiling datePublication dateApplicantTitleUS6713478Mar 12, 2003Mar 30, 2004WyethCyclocarbamate derivatives as progesterone receptor modulatorsUS6841568Apr 22, 2003Jan 11, 2005WyethThio-oxindole derivativesUS6964973Nov 18, 2002Nov 15, 2005Ligand Pharmaceuticals IncorporatedBicyclic androgen and progesterone receptor modulator compounds and methodsUS6982261Jan 15, 2003Jan 3, 2006WyethCyanopyrrolesUS7071205Oct 10, 2003Jul 4, 2006Ligand Pharmaceuticals Incorporated5-cycloalkenyl 5H-chromeno[3,4-f]quinoline derivatives as selective progesterone receptor modulator compoundsUS7084151Oct 10, 2003Aug 1, 2006Ligand Pharmaceuticals Incorporated5-(1',1'-cycloalkyl/alkenyl)methylidene 1,2-dihydro-5H-chromeno[3,4-�]quinolines as selective progesterone receptor modulator compoundsUS7084168Jun 6, 2003Aug 1, 2006WyethIndoline derivativesUS7091234Oct 20, 2004Aug 15, 2006WyethThio-oxindole derivativesUS7253203Mar 17, 2006Aug 7, 2007WyethIndoline derivativesUS7488822Jan 29, 2004Feb 10, 2009WyethCyclocarbamate derivatives as progesterone receptor modulatorsUS7514466Apr 25, 2005Apr 7, 2009WyethPurification of progesterone receptor modulatorsUS7569564Feb 9, 2006Aug 4, 2009WyethCyclothiocarbamate derivatives as progesterone receptor modulatorsUS7645761Jun 22, 2007Jan 12, 2010WyethIndoline derivativesUS7846924Jul 19, 2005Dec 7, 2010Wyeth LlcCyanopyrrolesUS8309594Feb 12, 2009Nov 13, 2012Wyeth LlcPurification of progesterone receptor modulatorsUS8329690Apr 8, 2009Dec 11, 2012Wyeth LlcCyclothiocarbamate derivatives as progesterone receptor modulatorsUS8466146Nov 16, 2012Jun 18, 2013Wyeth LlcCyclothiocarbamate derivatives as progesterone receptor modulatorsUS8476262Oct 29, 2010Jul 2, 2013Wyeth LlcCyanopyrrolesUS8609712Sep 14, 2012Dec 17, 2013Wyeth LlcPurification of progesterone receptor modulatorsUS8796266May 30, 2013Aug 5, 2014Wyeth LlcCyclothiocarbamate derivatives as progesterone receptor modulatorsClassifications U.S. Classification514/415, 514/409, 514/412, 514/170International ClassificationA61P5/24, A61K45/06, A61K31/57, A61K31/404, A61P15/18, C07D209/86, C07D209/08, A61K31/565, A61K31/403, A61K31/567Cooperative ClassificationA61K31/57, A61K45/06European ClassificationA61K31/57, A61K45/06Legal EventsDateCodeEventDescriptionFeb 24, 2015FPExpired due to failure to pay maintenance feeEffective date: 20150107Jan 7, 2015LAPSLapse for failure to pay maintenance feesAug 15, 2014REMIMaintenance fee reminder mailedApr 6, 2011ASAssignmentOwner name: LIGAND PHARMACEUTICALS INCORPORATED, CALIFORNIAFree format text: CORRECTIVE ASSIGNMENT TO CORRECT THE IDENTIFICATION OF THE TRUE ASSIGNEE PREVIOUSLY RECORDED ON REEL 025952 FRAME 0559. 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